WFH GUIDELINES
for the MANAGEMENT
of HEMOPHILIA
3
rd
Edition
© 2020 World Federation of Hemophilia. Haemophilia © 2020 John Wiley & Sons Ltd
How to cite this article: Srivastava A, Santagostino E, Dougall A, et al. WFH Guidelines for the Management of Hemophilia,
3rd edition. Haemophilia. 2020: 26(Suppl 6): 1-158. https://doi.org/10.1111/hae.14046
To obtain permission to reprint, redistribute, or translate this publication, please contact the Research and Education
Department at the address below.
For questions on the treatment guidelines, please contact us at TreatmentGuidelines@w.org
Please note: is material is intended for general information only. e World Federation of Hemophilia does not
endorse particular treatment products or manufacturers; any reference to a product name is not an endorsement by
the World Federation of Hemophilia. e World Federation of Hemophilia is not a regulatory agency and cannot make
recommendations relating to safety of manufacturing of specic blood products. For recommendations of a particular
product, the regulatory authority in a particular country must make these judgments based on domestic legislation, national
health policies and clinical best-practices.
Some typographical errors in the original publication, as well as the changes listed below, have been corrected in the course of
laying out this reproduction.
• Addition of sentence on prevalence to Chapter 2.
• Correction of reference 21 in Chapter 7.
• Removal of “porcine FVIII” in Table 8-5.
World Federation of Hemophilia
1425, boul. René-Lévesque O., bureau 1200
Montréal, Québec
H3G 1T7 Canada
Tel.: (514) 875-7944
Fax: (514) 875-8916
E-mail: w@w.org
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1
DOI: 10.1111/hae.14046
SUPPLEMENT ARTICLE
WFH Guidelines for the Management of
Hemophilia, 3rd edition
Alok Srivastava
1
| Elena Santagostino
2
| Alison Dougall
3
| Steve Kitchen
4
| Megan Sutherland
5
| Steven
W. Pipe
6
| Manuel Carcao
7
| Johnny Mahlangu
8
| Margaret V. Ragni
9
| Jerzy Windyga
10
| Adolfo Llinás
11
| Nicholas J. Goddard
12
| Richa Mohan
13
| Pradeep M. Poonnoose
14
| Brian M. Feldman
15
| Sandra
Zelman Lewis
16
| H. Marijke van den Berg
17
| Glenn F. Pierce
18
| on behalf of the WFH Guidelines for
the Management of Hemophilia panelists and co-authors*
1
Department of Haematology, Christian Medical College, Vellore, India
2
A. Bianchi Bonomi Hemophilia and Thrombosis Centre, IRCCS Cà Granda Foundation, Maggiore Hospital Policlinico, Milan, Italy, and
Sobi, Basel, Switzerland
3
Special Care Dentistry Division of Child and Public Dental Health, School of Dental Science, Trinity College Dublin, Dublin Dental
University Hospital, Dublin, Ireland
4
Department of Coagulation, Sheffield Haemophilia and Thrombosis Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
5
Manchester University Hospitals NHS Foundation Trust, Manchester, UK
6
Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, Michigan, USA
7
Department of Paediatrics, University of Toronto, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada
8
Department of Molecular Medicine and Haematology, University of the Witwatersrand, National Health Laboratory Service,
Johannesburg, South Africa
9
Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
10
Department of Hemostasis Disorders and Internal Medicine, Laboratory of Hemostasis and Metabolic Diseases, Institute of Hematology
and Transfusion Medicine, Warsaw, Poland
11
Fundacion Santa Fe de Bogota, and Universidad de los Andes, Bogota, Columbia
12
Department of Trauma and Orthopaedics, Royal Free Hospital, London, UK
13
Empowering Minds Society for Research and Development, New Delhi, India
14
Department of Orthopaedics, Christian Medical College, Vellore, India
15
Division of Rheumatology, Department of Paediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada
16
EBQ Consulting, LLC, Northbrook, Illinois, USA
17
PedNet Haemophilia Research Foundation, Baarn, the Netherlands
18
World Federation of Hemophilia, Montreal, QC, Canada
Correspondence: World Federation of Hemophilia, 1425 boul. René-Lévesque Ouest, Suite 1200, Montreal, QC, H3G 1T7, Canada.
Email: T[email protected]
*Abdelaziz Al Sharif (Amman, Jordan), Manuel A. Baarslag (Bemmel, the Netherlands), Lisa Bagley (London, UK), Erik Berntorp (Malmö Centre for rombosis and Haemostasis,
Lund University, Malmö, Sweden), Greig Blamey (Adult Bleeding Disorders Clinic, Winnipeg Health Sciences Centre, Winnipeg, MB, Canada), Mark Brooker (Formerly World
Federation of Hemophilia, Montreal, QC, Canada), Francisco de Paula Careta (Department of Pharmacy and Nutrition, Federal University of Espirito Santo Alegre, ES, Brazil), Kim
Chew (Kuala Lumpur, Malaysia), Donna Con (World Federation of Hemophilia, Montreal, QC, Canada), Carlos D. De Brasi (Instituto de Investigaciones Hematológicas and
Instituto de Medicina Experimental, CONICET – Academia Nacional de Medicina, Buenos Aires, Argentina), Piet de Kleijn (Van Creveldkliniek, University Medical Center Utrecht,
Utrecht, the Netherlands), Gerard Dolan (Guy’s and St omas’ Hospitals NHS Foundation Trust, London, UK), Vincent Dumez (Centre of Excellence on Partnership with Patients and
the Public, Université de Montréal, Montreal, QC, Canada), Gaetan Duport (Lyon, France), Carmen Escuriola Ettingshausen (Haemophilia Centre Rhein Main, Frankfurt-Mörfelden,
Germany), Melanie M. Golob (EBQ Consulting, LLC, Olympia, WA, USA), Emna Gouider (University of Tunis El Manar, Aziza Othmana Hospital, Tunis, Tunisia), Lucy T. Henry
(Ottawa, ON, Canada), Debbie Hum (World Federation of Hemophilia, Montreal, QC, Canada), Mathieu Jackson (Centre of Excellence on Partnership with Patients and the Public,
Université de Montréal, Montreal, QC, Canada), Radoslaw Kaczmarek (Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA), Kate Khair (Great
Ormond Street Hospital for Children, London, UK), Barbara A. Konkle (Bloodworks Northwest and Division of Hematology, University of Washington, Seattle, WA, USA), Rolf C.
R. Ljung (Department of Clinical Sciences – Pediatrics, Lund University, Lund, Sweden), Silmara A. de Lima Montalvão (INCT do Sangue Hemocentro, University of Campinas,
Campinas, SP, Brazil), Augustas Nedzinskas (Ariogala, Lithuania), Sonia O’Hara (HCD Economics, Chester, UK), Margareth C. Ozelo (INCT do Sangue Hemocentro, University of
Campinas, Campinas, SP, Brazil), Gianluigi Pasta (Fondazione IRCCS Policlinico San Matteo di Pavia, Pavia, Italy), Enrique David Preza Hernández (Mexico City, Mexico), Bradley
Rayner (Cape Town, South Africa), Fiona Robinson (World Federation of Hemophilia, Montreal, QC, Canada), R. Sathyanarayanan (Chennai, India), omas J. Schoeld (EBQ
Consulting, LLC, Santa Monica, CA, USA), Andrew Selvaggi (Melbourne, Australia), Shrimati Shetty (ICMR–National Institute of Immunohaematology, KEM Hospital, Mumbai,
India), Maura Sostack (EBQ Consulting, LLC, Philadelphia, PA, USA), Alison Street (Monash University, Melbourne, Australia), Ekawat Suwantaroj (Bangkok, ailand), Claude
Tayou Tagny (Department of Hematology, University of Yaounde I and University Teaching Hospital of Yaoundé, Yaoundé, Cameroon), Pierre Toulon (Université Côte d’Azur and
Hôpital Pasteur – CHU Nice, Nice, France).
©2020 World Federation of Hemophilia. Haemophilia © 2020 John Wiley & Sons Ltd
WFH Guidelines for the Management of Hemophilia, 3rd edition2
SUMMARY
is new edition of the World Federation of Hemophilia
(WFH) guidelines for the management of hemophilia
comes at an exciting time in the evolution of the diagnosis
and treatment of this condition. Since the publication
of the second edition in 2012, tremendous advances
have been made in several aspects of the management
of hemophilia. ese include genetic assessment as well
as therapy with many innovative therapeutic products
including extended half-life factor VIII (FVIII) and factor
IX (FIX) products, a bi-specic antibody, and hemostasis
rebalancing drugs now in clinical development. All of
these allow for more eective hemostasis than was possible
in the past. Laboratory monitoring of therapies is better
dened and prophylaxis is accepted as the only way to
change the natural history of bleeding. ere are highly
eective therapies for patients with inhibitors. Outcome
assessment with validated clinimetric instruments is widely
advocated and practiced. All these advances are reected in
this third edition of the WFH guidelines, with new chapters
devoted to several of these topics along with a new chapter
on principles of care that aims to provide a framework for
development of a comprehensive healthcare system for
hemophilia including advocacy and empowerment for
people with hemophilia (PWH). e recommendations in
this edition were all developed through a formal evidence-
informed and consensus-based methodology involving
multidisciplinary healthcare professionals (HCPs) and
well-informed PWH. While directed primarily at HCPs,
these guidelines should also be very useful for PWH as
well as advocacy organizations.
Keywords
bleeding disorders, hemophilia, management guidelines,
novel hemostasis products, outcomes, treatment
This third edition of the WFH Guidelines for the
Management of Hemophilia has been endorsed by the
Asian-Pacic Society on rombosis and Hemostasis,
European Haemophilia Consortium, and National
Hemophilia Foundation (USA).
WFH GUIDELINES DISCLAIMER
e World Federation of Hemophilia (WFH) does not
endorse any particular treatment product or manufacturer;
any reference to a product name is not an endorsement
by the WFH. e WFH does not engage in the practice of
medicine and under no circumstances recommends particular
treatments for specic individuals. Guidelines are intended
for general information only and are based on population
level research, not for the care or treatment of any particular
individual. Guidelines do not replace professional medical
care and physician advice and/or product insert information,
but should be used to educate and inform shared decision-
making between patients, caregivers, and healthcare providers.
Furthermore, guidelines may not be complete or accurate
because new research studies may have been published or
treatments, devices, or indications approved aer the cut-o
date for inclusion in these guidelines. rough a comprehensive
and systematic literature review, WFH evidence-informed
clinical practice guidelines incorporate data from the existing
peer-reviewed literature. Although this literature met the pre-
specied inclusion criteria for the guideline, and the WFH
considered this scientic content to be the best evidence
available for general clinical information purposes at the time
the guidelines were developed, this evidence is of varying
quality and varying methodological rigor.
The WFH and its officers, committees, members,
employees, and guideline authors and reviewers (“WFH
Parties”) disclaim all liability for the accuracy or completeness
and disclaim all warranties, express or implied. e WFH
Parties further disclaim all liability for any damages whatsoever
(including, without limitation, direct, indirect, incidental,
punitive, or consequential damages) arising out of the use,
inability to use, or the results of use of a guideline, any
references used in a guideline, or the materials, information,
or procedures contained in a guideline, based on any legal
theory whatsoever and whether or not there was advice on
the possibility of such damages.
3
Introduction ........................................................ 9
Chapter 1: Principles of Care ......................... 11
1.1 Principle 1: National coordination and
delivery of hemophilia care ...............................11
Comprehensive hemophilia care ..........................12
Network of hemophilia treatment centres ............. 12
National patient registry .....................................12
National or regional procurement of hemophilia
therapies ........................................................12
1.2 Principle 2: Access to safe CFCs, other
hemostasis products, and curative therapies ......13
Safe and eective CFCs.......................................13
Emerging therapies and potential cures ................13
1.3 Principle 3: Laboratory services and genetic
diagnosis of hemophilia ....................................14
Laboratory diagnosis and testing .........................14
Genetic assessment of hemophilia .......................14
1.4 Principle 4: Education and training in
hemophilia care ................................................15
Recruitment of medical specialists .......................15
1.5 Principle 5: Clinical and epidemiological
research ...........................................................15
1.6 Principle 6: Acute and emergency care for
bleeds ..............................................................15
1.7 Principle 7: Multidisciplinary care for
hemophilia .......................................................16
Patient self-management and empowerment ........16
Transition from pediatric to adult care .................16
1.8 Principle 8: Regular replacement therapy
(prophylaxis) ....................................................17
1.9 Principle 9: Management of patients with
inhibitors .........................................................17
1.10 Principle 10: Management of musculoskeletal
complications ...................................................17
1.11 Principle 11: Management of specic
conditions and comorbidities ............................18
Carriers of hemophilia .......................................18
Surgery and other invasive procedures .................18
Management of comorbidities .............................18
Medical issues with aging ...................................18
Management of transfusion-transmitted
infections ......................................................18
1.12 Principle 12: Outcome assessment .....................19
References ...............................................................19
Chapter 2: Comprehensive Care of
Hemophilia ...................................................... 21
2.1 Introduction ....................................................21
Hemophilia A and B ..........................................21
Clinical diagnosis ..............................................22
Bleeding manifestations ......................................22
Patient/caregiver education .................................22
2.2 Comprehensive care .........................................22
Key components of comprehensive care ...............23
Comprehensive care team ...................................23
Functions of a comprehensive care program .........25
2.3 Fitness and physical activity ..............................26
2.4 Adjunctive management ...................................27
2.5 Home therapy...................................................28
Clotting factor replacement therapy ..................... 28
New coagulation therapies ..................................28
Self-management ...............................................29
Central venous access devices .............................30
2.6 Pain management .............................................31
Pain caused by venous access ..............................31
Pain caused by joint or muscle bleeding ...............31
Postoperative pain .............................................31
Pain due to chronic hemophilic arthropathy .........32
Dental pain .......................................................32
2.7 Dental care and management ............................32
Oral care ...........................................................33
Dental surgery and invasive procedures ...............33
TABLE OF CONTENTS
WFH Guidelines for the Management of Hemophilia, 3rd edition4
2.8 Transition from pediatric to adult care ..............34
References ...............................................................36
Chapter 3: Laboratory Diagnosis and
Monitoring ....................................................... 39
3.1 Introduction ....................................................39
3.2 Coagulation laboratory testing .........................39
Principles of diagnosis ........................................ 39
Technical aspects ...............................................39
Post-FVIII/FIX infusion monitoring ....................44
Trained personnel .............................................. 49
3.3 Use of correct equipment and reagents ..............49
Equipment ........................................................49
Reagents ...........................................................50
3.4 Quality assurance .............................................50
Internal quality control .......................................50
External quality assessment ................................50
References ...............................................................50
Chapter 4: Genetic Assessment ...................... 55
4.1 Introduction ....................................................55
4.2 Indications for genetic assessment .....................56
4.3 Strategy for genetic testing of probands .............58
4.4 Techniques for genetic assessment .....................59
4.5 Classication and description of variants...........60
4.6 Interpretive reports ..........................................61
4.7 Strategies if causative variant is not detected ......61
4.8 Quality assurance .............................................62
References ...............................................................63
Chapter 5: Hemostatic Agents........................ 66
5.1 Introduction ....................................................66
5.2 Product selection ..............................................67
Safety and quality ..............................................67
Ecacy .............................................................68
5.3 Clotting factor concentrates (CFCs) ..................68
FVIII CFCs .......................................................68
FIX CFCs .......................................................... 69
Extended half-life products .................................71
5.4 Bypassing agents ..............................................72
Recombinant activated factor VIIa (rFVIIa)..........72
Activated prothrombin complex concentrate
(aPCC) ..........................................................72
5.5 Other plasma products .....................................73
Fresh frozen plasma (FFP) ..................................73
Cryoprecipitate ..................................................74
5.6 Other pharmacological options .........................74
Desmopressin (DDAVP) ....................................74
Tranexamic acid ................................................76
Epsilon aminocaproic acid ..................................76
5.7 Non-factor replacement therapies .....................77
Rationale and mechanisms of action ....................77
Substitution therapy ...........................................77
Hemostatic rebalancing agents ............................77
References ...............................................................78
Chapter 6: Prophylaxis in Hemophilia ............ 81
6.1 Introduction ....................................................81
Standard half-life factor replacement therapy ........ 82
Extended half-life factor replacement therapy .......82
Non-factor replacement therapy ..........................82
Basic denitions and concepts in prophylaxis with
CFCs .............................................................82
Initiation of prophylaxis: timing and approach ......82
Intensity of prophylaxis ......................................84
6.2 Benets of prophylaxis ......................................84
Prophylaxis using clotting factor concentrates .......84
Prophylaxis using non-factor replacement
therapies ........................................................84
6.3 Standard half-life factor prophylaxis .................85
Time of day dosing for SHL CFCs .......................85
6.4 Extended half-life factor prophylaxis .................85
Half-life/clearance .............................................85
Dose .................................................................85
Frequency of dosing ...........................................86
Time of day dosing for EHL CFCs .......................86
6.5 Prophylaxis with non-factor replacement
therapy.............................................................86
6.6 Fixed/non-tailored factor prophylaxis
regimens ........................................................ 87
Table of Contents 5
“One size ts all” SHL factor prophylaxis
regimens ...................................................... 88
6.7 Tailored factor prophylaxis regimens .................89
Variables that aect bleeding phenotype ............... 89
6.8 Adherence and patient/caregiver education .......91
TABLE 6-8 Basic requirements for effective
prophylaxis ..............................................................92
6.9 Health economics of prophylaxis .......................92
6.10 Low-dose prophylaxis for patients with
limited access to CFCs ......................................93
6.11 New denitions of prophylaxis ..........................93
6.12 Future research questions to be addressed .........93
References ...............................................................93
Chapter 7: Treatment of Specific
Hemorrhages .................................................... 96
7.1 Introduction ....................................................96
Patient/caregiver education .................................97
7.2 Joint hemorrhage..............................................97
Clotting factor replacement therapy ..................... 97
Pain management ..............................................98
Adjunctive care..................................................98
Physical therapy and rehabilitation ......................99
Arthrocentesis ...................................................99
7.3 Central nervous system and intracranial
hemorrhage ....................................................100
7.4 roat and neck hemorrhage ..........................100
7.5 Gastrointestinal/abdominal hemorrhage .........101
7.6 Renal hemorrhage ..........................................102
7.7 Ophthalmic hemorrhage ................................. 102
7.8 Oral hemorrhage ............................................102
7.9 Epistaxis.........................................................103
7.10 Lacerations and abrasions ...............................104
7.11 So tissue hemorrhage....................................104
7.12 Practice patterns in CFC replacement ..............106
References .............................................................106
Chapter 8: Inhibitors to Clotting Factor .......107
8.1 Introduction ..................................................107
Patient/caregiver education ...............................107
8.2 Inhibitor screening .........................................108
8.3 Hemophilia A and FVIII inhibitors ................109
Genetic and environmental risk factors .............. 109
Inhibitor incidence .......................................... 109
Disease burden ................................................ 110
Management of bleeding ..................................110
erapeutic options for FVIII inhibitor patients ..110
Surgery and invasive procedures ........................113
Immune tolerance induction .............................114
FVIII prophylaxis aer immune tolerance
induction .....................................................115
Product switching ............................................ 115
8.4 Hemophilia B and FIX inhibitors ...................115
Genetic and environmental risk factors .............. 115
Inhibitor incidence .......................................... 115
Disease burden ................................................ 116
Management of bleeding ..................................116
Immune tolerance induction .............................117
FIX prophylaxis aer immune tolerance
induction .....................................................118
Surgery and invasive procedures ........................118
Product switching ............................................ 119
References .............................................................119
Chapter 9: Specific Management Issues ......121
9.1 Introduction ..................................................121
9.2 Carriers .........................................................121
Inheritance of hemophilia .................................121
Factor levels in carriers .....................................122
Carrier factor level testing.................................122
Bleeding symptoms .......................................... 122
Genetic counselling..........................................122
Psychosocial support ........................................123
Genetic testing ................................................123
Prenatal diagnosis ............................................ 123
Pregnancy and prenatal planning ......................123
Labour and delivery ......................................... 123
Postpartum care ..............................................124
WFH Guidelines for the Management of Hemophilia, 3rd edition6
Newborn testing .............................................. 124
Miscarriage management ..................................124
9.3 Circumcision ..................................................125
9.4 Vaccinations ...................................................126
9.5 Surgery and invasive procedures .....................126
9.6 Sexuality ........................................................128
9.7 Psychosocial issues .........................................129
9.8 Comorbidities ................................................130
Cancer/malignancy ..........................................130
Cerebrovascular accident/stroke ........................131
Atrial brillation ..............................................131
Venous thromboembolism/thrombosis .............. 132
Metabolic syndrome ........................................133
Diabetes mellitus .............................................134
Renal disease ...................................................134
Osteoporosis ...................................................134
Degenerative joint disease .................................135
9.9 Medical issues with aging ................................135
Hypertension ..................................................135
Coronary artery disease ....................................136
Psychosocial issues with aging ...........................137
References .............................................................138
Chapter 10: Musculoskeletal
Complications ................................................141
10.1 Introduction ..................................................141
Patient/caregiver education ...............................141
10.2 Synovitis ........................................................141
Treatment of chronic synovitis ..........................142
10.3 Hemophilic arthropathy .................................143
Treatment of chronic hemophilic arthropathy .....144
10.4 Muscle hemorrhage ........................................145
Clotting factor replacement therapy ...................145
Clinical monitoring and management ................146
Compartment syndrome ..................................146
Physical therapy and rehabilitation for muscle
bleeds ..........................................................147
Iliopsoas hemorrhage .......................................147
10.5 Pseudotumours ..............................................147
10.6 Fractures ........................................................148
10.7 Orthopedic surgery in hemophilia ..................149
10.8 Joint replacement ...........................................149
Hemostasis during the perioperative period .......149
Surgical considerations .....................................150
Postoperative physical therapy ..........................150
Complications and long-term considerations ......150
10.9 Psychosocial impacts of musculoskeletal
complications ................................................. 151
References .............................................................151
Chapter 11: Outcome Assessment ...............155
11.1 Introduction ..................................................155
Purposes of outcome assessment .......................155
11.2 Outcome assessment in hemophilia ................. 155
Frequency of bleeding ......................................156
Pain assessment in hemophilia ..........................156
Domains to assess the impact of bleeding on the
musculoskeletal and other systems ..................156
11.3 Body structure and function ...........................157
Recommended measures of body structure and
function in hemophilia .................................. 157
11.4 Activities and participation ............................. 159
Recommended instruments for measuring
activities and participation ............................. 159
11.5 Environmental and personal factors ................160
Environmental factors ...................................... 160
Personal factors ...............................................162
11.6 Economic factors ............................................162
Direct costs .....................................................162
Indirect costs ...................................................162
11.7 Health-related quality of life ...........................162
Instruments most used for measurement of
healthrelated quality of life ............................. 162
11.8 Patient-reported outcomes .............................. 163
11.9 Core set of measures for use in the clinic or
research setting ..............................................163
References .............................................................164
Table of Contents 7
Chapter 12: Methodology .............................167
12.1 Background ....................................................167
12.2 Methodology ..................................................167
Composition of the panels: structure and review . 168
Process for panel workow and oversight ...........168
Funding ..........................................................169
12.3 Evidence generation .......................................169
Study eligibility criteria.....................................169
Data extraction and development of evidence
tables ........................................................... 170
12.4 Formal consensus achievement through
Delphi techniques ........................................... 170
A priori rules and processes .............................. 170
Delphi surveys .................................................170
Diversions from the process .............................. 171
12.5 Finalization of the recommendations and
manuscript development ................................171
Review and nalization ....................................172
12.6 Methodology limitations.................................172
12.7 Future plans for updates .................................172
12.8 Conclusion ..................................................... 172
References .............................................................173
Acknowledgements .......................................174
Author Contributions ......................................174
Guidelines Project Team ...................................175
Guidelines Process Task Force ...........................175
Reviewers .......................................................176
WFH Executive Reviewers ................................176
External Reviewers ..........................................176
Disclosures .....................................................176
Acronyms and Abbreviations ........................177
LIST OF TABLES AND FIGURES
Table 1-1 Roles of hemophilia comprehensive care
centres and hemophilia treatment centres .................13
Table 2-1 Relationship of bleeding severity to clotting
factor level .............................................................22
Table 2-2 Sites of bleeding in hemophilia .................... 23
Table 2-3 Approximate frequency of bleeding at
dierent sites .......................................................... 23
Table 2-4 Pain management strategies for people with
hemophilia ............................................................31
Table 3-1 Interpretation of screening tests ..................42
Table 3-2 Publications with data related to the use of
dierent FVIII assays in the presence of recombinant
and modied factor VIII concentrates ......................45
Table 3-3 Publications with data related to the use of
dierent FIX assays in the presence of recombinant
and modied factor IX concentrates .........................45
Table 6-1 Conventional factor prophylaxis for
hemophilia A and B dened according to when
prophylaxis is initiated ............................................83
Table 6-2 Conventional factor prophylaxis with
standard half-life clotting factor dened according to
its intensity ............................................................83
Table 6-3 Variables that aect factor levels (applies to
both SHL and EHL clotting factors) in people with
hemophilia ............................................................86
Table 6-4 Documented benets of EHL CFCs .............87
Table 6-5 Advantages and disadvantages of xed “one
size ts all” SHL factor prophylaxis regimens ............. 88
Table 6-6 Tailoring prophylaxis to patient needs .......... 90
Table 6-7 Factors that aect bleeding phenotype and
contribute to inter-patient phenotypic variability .......91
Table 7-1 Denitions of response to treatment ............98
Table 7-2 Practice patterns: peak plasma factor levels
and duration of administration ..............................105
Table 8-1 Indications for inhibitor testing ................. 108
Table 8-2 Potential risk factors for inhibitors .............109
Table 8-3 Treatment of acute bleeds in hemophilia A
patients with inhibitors ......................................... 110
WFH Guidelines for the Management of Hemophilia, 3rd edition8
Table 8-4 Sequential bypass agent therapy alternating
rFVIIa and aPCC ..................................................112
Table 8-5 Treatment of acute bleeds in hemophilia B
patients with inhibitors ......................................... 118
Table 9-1 Denition of adequacy of hemostasis for
surgical procedures ...............................................127
Figure 11-1 International Classication of
Functioning and Health (ICF) model ......................157
Figure 11-2 Hemophilia Joint Health Score 2.1
– Summary Score Sheet. .......................................158
Table 11-1 Radiological Pettersson score ..................159
Table 11-2 IPSG MRI Scale to Assess Hemophilic
Arthropathy .........................................................160
Table 11-3 HEAD-US Scoring Method ..................... 161
Table 11-4 Haemophilia Activities List (HAL)
200515 ................................................................161
Table 11-5 Haemophilia Activities List
—Pediatric (PedHAL) v.11 ....................................161
Table 11-6 Functional Independence Score in
Hemophilia (FISH) ............................................... 162
Table 11-7 Q-5D Instrument ...................................162
Table 11-8 36-Item Short Form Survey Instrument
(SF-36) ................................................................163
9
INTRODUCTION
Alok Srivastava
1
| Alain Weill
2
| Glenn F. Pierce
2
1
Department of Haematology, Christian Medical College, Vellore, India
2
World Federation of Hemophilia, Montreal, QC, Canada
With more than one million print and online distributions in
six languages and more than 1000 citations in peer-reviewed
articles since its publication in 2012, the World Federation of
Hemophilia (WFH) clinical practice resource, Guidelines for
the Management of Hemophilia, 2nd edition, has served the
community of hemophilia care providers and people with
hemophilia extensively. Endorsed by the International Society
on rombosis and Haemostasis (ISTH), the WFH guidelines
were also the rst hemophilia management guidelines to be
accepted by the National Guideline Clearinghouse (NGC),
formerly run by the Agency for Healthcare Research and
Quality (AHRQ) of the United States Department of Health
and Human Services (https://www.ahrq.gov/gam/index.html).
Over the past ve years, unprecedented progress has been
made not only in the development of newer therapeutics for
hemophilia, but major paradigm shis have also occurred in
many of the principles governing the planning and philosophy
of hemophilia treatment. Given the progress in genetic
analysis technologies, in addition to much wider access, their
applications in hemophilia have moved from the research
arena to an increasingly greater role in the management of
patients and their families. e advent of newer clotting
factor concentrates (CFCs) with extended half-life has not
only led to decreased burden of care for patients; more
importantly, extended half-life CFCs have made it possible to
maintain signicantly higher factor trough levels on regular
replacement therapy than has been possible with standard
half-life CFCs. e bar of hemostatic safety was raised
even higher with the introduction of non-CFC hemostatic
agents such as the novel bispecic monoclonal antibody.
is agent achieves hemostasis equivalent to approximately
15% FVIII levels, with subcutaneous administration and
substantially less frequent dosing compared to CFCs. People
with hemophilia treated with these newer therapies are now
able to participate in many more activities than ever before
without fear of bleeding. In addition, structured outcome
assessment has been a relatively unevolved aspect of the
management of hemophilia. With greater emphasis over the
past few years on its signicance in routine management of
hemophilia, several clinimetric instruments are now being
used for the standardized assessment and documentation of
both hemostatic and musculoskeletal outcomes.
To acknowledge these advances and establish them
more rmly in clinical practice, several modications have
been made in the third edition of these guidelines. New
chapters have been added to provide the required detail
to the following topics: genetic assessment; prophylaxis
with hemostatic agents to prevent bleeding; management
of inhibitors; and assessment of outcomes. An additional
chapter denes the principles of management of hemophilia
to provide aspirational benchmarks during the evolution of
these services, within the local contexts of countries around
the world.
Certain semantic changes introduced in this edition
should be mentioned. e term “episodic” rather than “on
demand” has been used to describe any hemostasis therapy
aer bleeding, as this term better reects the concept of
this practice. In keeping with the denition provided by
the Scientic Standardization Committee of the ISTH, the
term “exposure day” has been replaced with “exposure” to
encompass all CFC replacement doses administered within
24 hours.
To ensure that bias was avoided as much as possible, a
rigorous consensus-based methodology was adopted for
formulating the nal recommendations in these guidelines.
An independent methods and process expert, unrelated
to the eld, was appointed alongside the content lead. All
recommendations were informed by a comprehensive
and systematic review of the relevant scientic literature
and developed through an anonymous modied Delphi
process resulting in evidence-informed consensus-based
recommendations. Importantly, in addition to the experts in
hemophilia care and related clinical disciplines, the Delphi
panels included well-informed patients who also had the
opportunity to review the manuscripts and the literature, and
vote on the recommendations. All these steps are described
in detail in the Methodology chapter.
It is also important to note that the nal chapter dras
were reviewed internally both by the full panel and within
the WFH, as well as by external subject experts prior to
WFH Guidelines for the Management of Hemophilia, 3rd edition10
submission for publication. All these reviewers have been
acknowledged at the end of the guidelines along with many
others whose contributions have been invaluable to their
development. A nal round of independent peer review was
also conducted by the journal before publication. It is also
important to note that these guidelines have been endorsed
by the Asian-Pacic Society on rombosis and Hemostasis,
European Haemophilia Consortium, and National Hemophilia
Foundation (USA).
As a result of all these modications, the guidelines have
become more comprehensive than the previous edition.
However, to preserve their easy readability, the text remains
structured using short sentences in bullet points. Detailed
mechanistic explanations or descriptions of the original data
underlying recommendations have been avoided. However,
all relevant references have been cited and are listed at the
end of each chapter.
It is hoped that the clinical care community, for whom
these guidelines are primarily intended, will nd them even
more useful than the previous editions. ese guidelines may
also serve as a resource to support education, advocacy, and
decision-making related to hemophilia treatment and the
delivery of care. In addition, they should help identify gaps
in evidence upon which the recommendations have been
formulated to help direct appropriate clin ical research in these
areas. As in the past, the electronic version of these guidelines
is available on the WFH website (http://www.w.org). ese
guidelines will be updated, added to, or modied as signicant
new data or evidence justifying change become available. is
will keep the guideline content current and cognizant of the
advances that are expected in the coming years, particularly
in the area of gene therapy for hemophilia, which will need
to be included in more detail once the ongoing clinical trials
are over and products are registered.
11
1
PRINCIPLES
OF CARE
1
Alok Srivastava
1
| Gerard Dolan
2
| Lisa Bagley
3
| Margareth C. Ozelo
4
| Emna Gouider
5
| Debbie Hum
6
|
Steven W. Pipe
7
| Bradley Rayner
8
| Alison Street
9
| Glenn F. Pierce
6
1
Department of Haematology, Christian Medical College, Vellore, India
2
Guy’s and St. Thomas’ Hospitals NHS Foundation Trust, London, UK
3
London, UK
4
INCT do Sangue Hemocentro UNICAMP, University of Campinas, Campinas, SP, Brazil
5
Medical School, University of Tunis El Manar, Hemophilia Centre, Aziza Othmana Hospital, Tunis, Tunisia
6
World Federation of Hemophilia, Montreal, QC, Canada
7
Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, Michigan, USA
8
Cape Town, South Africa
9
Monash University, Melbourne, Victoria, Australia
Introduction
•
ese principles of care aim to provide globally relevant
guidance based on current science and best practices in
hemophilia diagnosis and treatment, as identied by the
guidelines panel of the World Federation of Hemophilia
(WFH). They include core concepts, requirements,
and priorities in the delivery and management of
hemophilia care, which together constitute a framework
for implementing and advancing hemophilia treatment
programs.
• e principles build on the original tenets set out by the
WFH and the World Health Organization (WHO) in 1990
and the updated guidelines and recommendations developed
collaboratively by the WFH, WHO, and International
Society on rombosis and Haemostasis (ISTH) in 2002.
•
e principles integrate core components of principled
integrated care and primary health care, including: meeting
people’s lifetime health needs through comprehensive
preventive, curative, and rehabilitative services as well as
palliative care; addressing the broader determinants of
health through multisectoral policy and action that engages
relevant stakeholders and enables local communities
to strengthen primary health care; and empowering
individuals, families, and communities to take charge of
their own health.
•
In addition, they align with the chronic care model’s
emphasis on the need to shi from acute, episodic, and
reactive care towards care that embraces longitudinal,
preventive, community-based, and integrated approaches.
•
In addition to guiding clinical practice, principles of care
can also serve as a common foundation of understanding
for patient organizations, healthcare providers, healthcare
administrators, and policymakers; this in turn enables better
discussion and collaboration on decisions surrounding
allocation of resources for hemophilia programs, and
priorities for achieving the best standards possible within
the available resources.
•
Principles of care aim for ideal hemophilia management to
ensure that patients have access to appropriate, sustained,
and high-quality medical services and comprehensive care;
however, it should also be recognized that the priorities
and capabilities in each country determine what is practical
at any point in time.
1.1 Principle 1: National coordination
and delivery of hemophilia care
•
A coordinated hemophilia care program, administered
through a designated agency and integrated within the
existing healthcare system, improves outcomes for people
with hemophilia.
•
Optimal hemophilia care within such a program requires
the following key components:
–
comprehensive hemophilia care provided by a
multidisciplinary team of specialists;
–
a national or regional network of hemophilia
treatment centres (HTCs);
–
a national registry of patients with hemophilia;
–
robust processes for the procurement and
distribution of safe and eective therapies,
particularly clotting factor concentrates (CFCs)
and other types of hemostasis products used in
hemophilia treatment;
WFH Guidelines for the Management of Hemophilia, 3rd edition12
–
equitable access to these services and therapeutic
products; and
–
recognition of the socioeconomic and cultural
diversities within any given community, region, or
country.
Comprehensive hemophilia care
•
Treatment centres based on the multidisciplinary
comprehensive care model should be established to ensure
that people with hemophilia have access to the full range
of clinical specialties and appropriate laboratory services.
•
See Principle 7: Multidisciplinary care for hemophilia and
Chapter 2: Comprehensive Care of Hemophilia.
Network of hemophilia treatment centres
•
Hemophilia care is best provided through designated
diagnostic and treatment centres with clearly dened
treatment protocols, standards of care, and quality and
audit activities.
•
Hospitals providing clinical care for people with hemophilia
and related disorders are strongly encouraged to seek
formal designation as a hemophilia treatment centre (HTC)
or hemophilia comprehensive care centre (HCCC), as
applicable, by the local health authorities (see Table 1-1).
•
Such centres can also serve the needs of patients with
other congenital bleeding disorders.
National patient registry
•
Each country should have a national registry of patients
with hemophilia, with standardized data collection by
all hemophilia centres and centralized administration
by a nationally mandated authority, or participate in a
multinational or international registry.
•
e WFH’s World Bleeding Disorders Registry (WBDR)
provides an online platform for a network of HTCs around
the world to collect uniform and standardized data to track
treatment and management of patients, monitor patient
outcomes, and guide clinical practice. e WBDR can
be used as a patient registry for some or all HTCs within
a country.
•
Patient registries are used to collect accurate data on
people with hemophilia in terms of their treatment and
outcomes including disease severity, type of treatment,
bleeding episodes, adverse events, joint status, inhibitor
status, comorbidities, and quality of life.
•
Registry data allow analysis of standards of care and can be
used as a tool for auditing clinical and laboratory services;
this in turn can support the development of better quality
of care and facilitate resource planning and allocation.
•
Patient registries can help to advance understanding of
the variations in hemophilia treatment; describe care
patterns, including appropriateness and disparities in the
delivery and quality of care; indicate factors that inuence
prognosis and quality of life; and provide evidence on
resource utilization.
•
Adequate provision must be made for data privacy,
condentiality, and respect for human rights in compliance
with national regulations and best ethical practices.
•
It is important to ensure that the patient and/or the parent
or legal guardian (in the case of minors) understands a
registry’s purpose and uses and provides informed written
consent for the collection and sharing of data related to
the patient’s care.
•
See Chapter 2: Comprehensive Care of Hemophilia and
Chapter 11: Outcome Assessment.
National or regional procurement of
hemophilia therapies
•
Sustained availability of CFCs in sucient quantities is
strongly correlated with better outcomes for people with
hemophilia. To ensure that people with hemophilia
have reliable access to safe and eective CFCs and other
hemostasis products, countries must establish a rigorous
national or regional system for the procurement and
distribution of hemophilia therapies.
•
Hemophilia treatment relies on essential life-saving
medicines that are relatively expensive compared to
medications for other conditions.
• Setting up a national tender system or collaborating in a
multinational system for the purchase of CFCs can help
ensure that optimal products are selected at the best price.
•
e decision-making process for such tenders under the
contracting authority (typically the Ministry of Health or
other health authority) should include both well-informed
hemophilia clinicians and patient representatives.
•
e WFH’s Guide to National Tenders for the Purchase
of Clotting Factor Concentrates describes tender and
procurement systems around the world and explains
how to set up a national procurement system and carry
out tenders.
•
See Chapter 2: Comprehensive Care of Hemophilia and
Chapter 5: Hemostatic Agents.
Chapter 1: Principles of Care 13
1.2 Principle 2: Access to safe CFCs,
other hemostasis products, and
curative therapies
Safe and effective CFCs
•
People with hemophilia must have access to safe and
eective treatment with optimal ecacy in the prevention of
bleeding and treatment of any spontaneous, breakthrough,
or trauma-related bleeding. For many, this involves
treatment with specic CFCs or other hemostasis products.
•
Both virus-inactivated plasma-derived and recombinant
CFCs, as well as other hemostasis products when
appropriate, can be used for treatment of bleeding and
prophylaxis in people with hemophilia.
•
Prophylaxis is the standard of care for people with severe
hemophilia, and for some people with moderate hemophilia,
or for those with another congenital bleeding disorder
that is associated with a severe bleeding phenotype and/
or a high risk of spontaneous life-threatening bleeding.
•
Episodic CFC replacement should not be considered a
longterm option for the management of hemophilia as it
does not alter its natural history of spontaneous bleeding
and related complications.
•
e WFH’s Guide for the Assessment of Clotting Factor
Concentrates should be carefully reviewed in the context
of the healthcare system in each country and incorporated
into tender processes for procurement of hemophilia
therapies.
•
e WFH Online Registry of Clotting Factor Concentrates
lists all currently available plasma-derived and recombinant
CFCs and their product details.
•
See Chapter 5: Hemostatic Agents and Chapter 6:
Prophylaxis in Hemophilia.
Emerging therapies and potential cures
•
Emerging therapies in development with alternative modes
of delivery (e.g., subcutaneous injection) and novel targets
may overcome the limitations of standard CFC replacement
TABLE 1-1 Roles of hemophilia comprehensive care centres and hemophilia treatment centres
6
Hemophilia comprehensive care centre (HCCC) Hemophilia treatment centre (HTC)
• Provide 24- hour service with experienced staff • Provide 24- hour, appropriate hematological cover
• Provide inhibitor care and immune tolerance services •
Operate inhibitor care and immune tolerance services in
cooperation with a HCCC
•
Provide safe and effective CFCs and other hemostasis
products
•
Provide safe and effective CFCs and other hemostasis
products
•
Provide community liaison, including school and home visits
• Provide access to nursing staff, physical therapy services,
social workers, and obstetric and gynecological services
• Offer laboratory services with 24- hour assay cover •
Provide preliminary genetic counselling followed by referral
to a HCCC for full review
•
Provide access to hospital- based nursing staff, physical
therapy services, social workers, dental services, obstetric
and gynecological services, and psychosocial support
•
Provide access to HIV and hepatitis C care, through a
HCCC, if necessary
• Provide HIV and hepatitis C care •
Offer regular follow- up and home treatment in cooperation
with a HCCC
•
Provide access to a genetics laboratory and genetic
counselling
• Provide prophylaxis in cooperation with a HCCC
• Provide home treatment • Keep reliable records
• Keep reliable records • Undertake medical education
• Undertake medical education •
Collaborate with other HTCs in research and exchange
of best practices
• Initiate and participate in research
Abbreviations: CFC, clotting factor concentrate; HCCC, hemophilia comprehensive care centre; HIV, human immunodeficiency virus; HTC, hemophilia treatment centre.
WFH Guidelines for the Management of Hemophilia, 3rd edition14
therapy (i.e., need for intravenous administration, short
half-life, risk of inhibitor formation). ese emerging
therapies oer markedly improved pharmacokinetic (PK)
proles with a very low burden of administration (e.g.,
up to monthly dosing); therefore, they may help reduce
treatment burden and increase compliance. ese therapies
are discussed in Chapter 5: Hemostatic Agents, Chapter 6:
Prophylaxis in Hemophilia, and Chapter 8: Inhibitors to
Clotting Factor.
•
e development of gene therapies for hemophilia has
advanced signicantly, with product registration likely
in the near future. Several clinical trials in both people
with hemophilia A and B have demonstrated success with
a favourable safety prole to date.
•
Gene therapy should make it possible for some people
with hemophilia to aspire to and attain much better health
outcomes and quality of life than that attainable with
currently available hemophilia therapies. is will require
evaluation through long-term follow-up as part of clinical
trials and registries.
•
Given the ongoing advances transforming the hemophilia
treatment landscape, it is important to establish systems to
constantly monitor developments in emerging and gene
therapies for hemophilia and make them available as soon
as possible following approval by regulatory authorities.
•
See Chapter 5: Hemostatic Agents, Chapter 6: Prophylaxis
in Hemophilia, and Chapter 8: Inhibitors to Clotting Factor.
1.3 Principle 3: Laboratory services and
genetic diagnosis of hemophilia
Laboratory diagnosis and testing
•
e diagnosis and treatment of hemophilia require access
to laboratory facilities that are equipped with appropriate
resources and expertise to accurately perform factor assays
and other coagulation tests.
•
Screening and testing for inhibitor development, now
the most serious complication in hemophilia, is vital for
any comprehensive hemophilia treatment program to
be able to provide medical treatment and eradication of
inhibitors; however, most centres around the world do
not have inhibitor testing capacities.
•
In many resource-constrained countries, centres and
hospitals lack the appropriate technologies and capabilities
for diagnosing hemophilia. erefore, developing or
enhancing existing laboratories with the capacity to perform
coagulation tests with assured quality is an important
priority in these countries.
•
Coagulation laboratories must have well-trained laboratory
sta and appropriate resources, including suitable and
readily available reagents.
•
Ideally, coagulation laboratories should be able to provide
24-hour services for coagulation tests and factor assays and
be able to perform inhibitor assays in a timely manner.
•
It is essential to have good communication between the
laboratory and the clinical team ordering the tests to
ensure that the appropriate assays are carried out and
that the results reported are correctly evaluated and well
understood.
•
All coagulation laboratories should include quality assurance
programs and be subject to external quality assessment.
•
See Chapter 3: Laboratory Diagnosis and Monitoring –
Quality assurance.
Genetic assessment of hemophilia
•
Genetic assessment of hemophilia is important to dene
disease biology, establish diagnosis in dicult cases,
predict risk of inhibitor development, and provide prenatal
diagnosis if desired. Wherever possible, genotype analysis
should be oered to all patients with hemophilia. (See
Chapter 2: Comprehensive Care of Hemophilia and
Chapter 3: Laboratory Diagnosis and Monitoring.)
•
Genetic testing will not always identify the underlying
variant associated with the phenotype. Genetic counselling
of the person with hemophilia referred for genetic testing
should highlight this possibility.
•
e opportunity for discussion of the genetic analysis results
between the clinical and the laboratory teams involved is
an essential aspect of the genetic diagnostic service.
•
Advances in molecular genetic technologies are becoming
routinely integrated into many genetic diagnostic
laboratories. Full F8 or F9 gene screening is performed by
polymerase chain reaction (PCR) and Sanger sequencing,
or next-generation sequencing. Use of these techniques
is evolving and increasing internationally. e approach
and use of a specic technique depend on the available
technical expertise and resources. Genetic counselling must
include comprehensive discussion about the possibility of
incidental ndings in genes other than F8 or F9, depending
on the methods being used for the assessment.
•
See Chapter 2: Comprehensive Care of Hemophilia,
Chapter 3: Laboratory Diagnosis and Monitoring, Chapter 4:
Genetic Assessment, Chapter 8: Inhibitors to Clotting
Factor, and Chapter 9: Specic Management Issues.
Chapter 1: Principles of Care 15
1.4 Principle 4: Education and training
in hemophilia care
Recruitment of medical specialists
•
As hemophilia is a rare disorder in which the availability
of specialized care is a critical determinant of burden of
disease, recruitment and training of medical specialists
in hemophilia management are key to establishing,
maintaining, and advancing standards of care to reduce
morbidity and mortality among people with hemophilia in
well-resourced and resource-constrained countries alike.
•
Recruitment of physicians, hematologists, and scientists
in the area of thrombosis and hemostasis to the eld
of hemophilia is essential to ensure sustained, high-
quality medical care, together with recruitment of
medical laboratory specialists, nurses, physical therapists,
occupational therapists, and other musculoskeletal
specialists (e.g., orthopedic surgeons, rheumatologists,
and physiatrists), dentists, and psychosocial counsellors.
All are integral to multidisciplinary comprehensive care
for hemophilia and require ongoing specialist education
and development for practice in this eld.
•
Hemophilia education for allied specialists needed to help
address specic medical and health-related issues that may
arise in some patients is also important.
•
Mentorship and fellowship opportunities are valuable
and eective means to attract and retain new healthcare
providers to the eld of hemophilia.
•
A coordinated approach to advancing clinical expertise
in hemophilia (i.e., continued education, training, and
fellowship programs) based on local, regional, and/or
national needs and priorities will provide the foundation
for sustaining and improving standards of care.
•
Collaboration between hemophilia centres in resource-
constrained and well-resourced countries and support from
established expert bodies are eective avenues for advancing
hemophilia knowledge, expertise, and standards of care.
•
e WFH works in many countries around the world to help
develop and expand local, regional, and national capacities
in laboratory diagnosis and treatment of hemophilia
through its medical twinning program, humanitarian aid
program, and multidisciplinary education and training
workshops for healthcare providers.
•
See Principle 7: Multidisciplinary care for hemophilia and
Chapter 2: Comprehensive Care of Hemophilia.
1.5 Principle 5: Clinical and
epidemiological research
•
Evidence-based research in hemophilia is greatly needed,
but it is hampered by signicant challenges due to the
small size of the patient population.
•
As most aspects of clinical management of hemophilia
are empirical and lack high-level evidence, well-designed
studies to generate the necessary evidence to evaluate
current practices are needed. A mutual basic scheme, such
as the WHO’s International Classication of Functioning,
Disability and Health (ICF), ensures that disciplines are
connected by the same model.
•
Given the dierences in priorities in practice around the
world, it is important to promote locally relevant clinical
research.
•
Standardization of outcome assessment will permit
meaningful comparison across studies.
•
Priority areas for clinical research in hemophilia include
optimization of clotting factor replacement therapy; better
understanding and prevention of inhibitor formation; and
clinical data collection on existing hemophilia therapies
and clinical practices, newer therapies such as extended
half-life CFCs and non-factor hemostasis products, and
potential gene therapies.
•
Patient registries, with national and international
collaboration between centres and countries, are an
eective way to pool data to achieve the required sample
size to conduct clinical research on rare disorders such
as hemophilia.
•
e WFH’s World Bleeding Disorders Registry allows
researchers to address important questions around patient
care, compare country-specic levels of care, and use the
evidence to advocate for better hemophilia care.
•
See Chapter 5: Hemostatic Agents, Chapter 6: Prophylaxis
in Hemophilia, Chapter 8: Inhibitors to Clotting Factor,
and Chapter 11: Outcome Assessment.
1.6 Principle 6: Acute and emergency
care for bleeds
•
In critical situations, people with hemophilia need
immediate access to emergency medicines and treatment
as well as to specialist care at hospital emergency
departments. Lack of experience and knowledge of
hemophilia management among medical professionals,
particularly in emergency departments, may lead to serious
treatment-related complications.
WFH Guidelines for the Management of Hemophilia, 3rd edition16
•
erefore, it is essential to establish systems that are
accessible around the clock for the management of acute
life- or limb-threatening complications of hemophilia.
•
Treatment centres should develop protocols for emergency
care for people with hemophilia, including those with
inhibitors, that include management of serious acute
complications such as intracranial hemorrhage (ICH) and
other types of major internal hemorrhage and trauma.
(See Principle 9: Management of patients with inhibitors.)
•
People with hemophilia should not be kept waiting in
emergency departments and should be assessed immediately,
even for less serious complications which can deteriorate
while waiting. Prompt intervention is mandatory.
•
Primary physicians and HTC sta must be prepared to
attend to emergency situations and provide advice and
specialist support without delay.
•
e use of national online databases or the WBDR to
capture treatment and health-related patient data allows
for better acute and long-term management of people
with hemophilia, and the use of digital mobile devices
allows patients to record their bleeds and transmit their
information to their HTC in real time.
•
See Principle 7: Multidisciplinary care for hemophilia and
Chapter 2: Comprehensive Care of Hemophilia.
1.7 Principle 7: Multidisciplinary care for
hemophilia
•
Optimal care of people with hemophilia, especially those
with severe forms of the disorder, requires treatment and
comprehensive care provided by a multidisciplinary team
of specialists.
•
Priorities in treatment and care to ensure the best health
and quality-of-life outcomes for people with hemophilia
include:
–
prevention of bleeding and joint damage;
–
prompt management of bleeding episodes including
follow-up physical therapy and rehabilitation;
–
appropriate emergency care;
–
appropriate pain management;
–
management of musculoskeletal complications and
inhibitor development;
–
management of comorbidities;
–
regular psychosocial assessment and support as
needed; and
–
ongoing education on treatment and self-care for
people and families living with hemophilia.
Patient self-management and empowerment
•
Self-management, i.e., the ability of patients to undertake
daily management of their health and health care, is
essential in hemophilia. People with hemophilia must be
competent in controlling bleeding symptoms to preserve
their health, joint integrity, and functional independence.
Self-management allows them to minimize the short- and
long-term consequences of the disorder and can help
provide a sense of normalcy and control.
•
Key components of self-management in hemophilia
include:
–
bleed recognition;
–
record-keeping of bleeds and treatment;
–
self-administration of CFCs or other hemostasis
products;
–
self-care (i.e., nutrition and physical tness) and
medicines management (i.e., record-keeping,
treatment routines, maintenance of adequate
treatment supply, proper storage, reconstitution, and
administration of treatment products);
–
pain management;
–
risk management; and
–
participation in outcome reporting and
documentation.
•
Patient advocacy organizations have played an important
role in advancing hemophilia care around the world.
Such organizations should therefore be encouraged and
supported to cover those aspects of care which are not
covered by the healthcare system, including emphasis on
patient empowerment and working with other agencies
to advance care.
•
See Chapter 2: Comprehensive Care of Hemophilia, Chapter
7: Treatment of Specic Hemorrhages, Chapter 8: Inhibitors
to Clotting Factor, Chapter 9: Specic Management Issues,
and Chapter 10: Musculoskeletal Complications.
Transition from pediatric to adult care
•
e transition from pediatric to adult care, during which
adolescents and young adults with hemophilia gradually
assume responsibility for their own health and hemophilia
management, can be a challenge for patients and their
families.
• Treatment adherence is a key challenge at two transition
points: when young people with hemophilia switch to
self-infusion, and again when they move away from home
and assume the full responsibility of self-care.
•
Comprehensive hemophilia care should therefore include
a conscientious approach to transition of care that starts
in early adolescence and supports the development of
Chapter 1: Principles of Care 17
young people’s self-ecacy and self-management skills,
including psychosocial coping.
•
Both pediatric and adult healthcare providers must be
engaged in considering the individual needs of patients
and families to ensure a smooth transition and to ensure
the best care possible during this time.
•
Engagement of adolescents and their caregivers early in the
transition process allows time for acceptance and better
understanding of the transition from the pediatric to the
adult model of care as well as the associated reallocation
of health management and medical decision-making
responsibilities.
•
See Chapter 2: Comprehensive Care of Hemophilia –
Transition from pediatric to adult care and Chapter 9:
Specic Management Issues – Psychosocial issues.
1.8 Principle 8: Regular replacement
therapy (prophylaxis)
•
e standard of care for all patients with severe hemophilia
is regular replacement therapy (prophylaxis) with CFCs,
or other hemostasis products to prevent bleeding, started
early in life (before age 3) to prevent musculoskeletal
complications from recurrent joint and muscle bleeds.
•
Episodic (“on demand”) clotting factor replacement therapy
should no longer be considered to be a long-term treatment
option.
•
Implementation of home-based prophylaxis programs
increases compliance and allows people with hemophilia
to live relatively normal lives. ese programs should
be accompanied by education of patients, families, and
healthcare providers on the benets of prophylaxis and
the importance of adherence to treatment regimens.
• Prophylaxis in young children may be the best way for a
country to begin implementing universal prophylaxis for
people with hemophilia.
•
See Chapter 6: Prophylaxis in Hemophilia and Chapter
10: Musculoskeletal Complications.
1.9 Principle 9: Management of patients
with inhibitors
•
Systematic surveillance for inhibitors and comprehensive
management of inhibitors should be implemented for
people with hemophilia A, particularly when patients
are at highest risk during their rst 20 exposures to CFCs
(with one exposure dened as all CFCs administered within
a 24-hour period), and thereaer up to 75 exposures.
•
Eradication of inhibitors is currently best achieved through
immune tolerance induction (ITI) therapy.
•
Patients who develop inhibitors should have access to ITI
and to suitable hemostatic agents for control of bleeding
as well as surgical interventions, if needed, at specialized
centres with relevant experience.
•
Bypassing agents and other suitable treatment products
should be available for patients who do not respond to
enhanced factor dosages or ITI.
•
Given the costs and other limitations of current treatment
modalities, research and innovation in the prevention and
treatment of inhibitors are required.
•
See Chapter 5: Hemostatic Agents and Chapter 8: Inhibitors
to Clotting Factor.
1.10 Principle 10: Management of
musculoskeletal complications
•
The prevention and treatment of musculoskeletal
complications in people with hemophilia are important
to their health, autonomy, and quality of life.
•
In all cases of musculoskeletal bleeding, adequate
treatment generally requires a combination of clotting
factor replacement therapy and physical therapy with
an experienced physical therapist to achieve complete
functional recovery.
•
People with hemophilia should also have access to
musculoskeletal specialists (i.e., physical therapist,
occupational therapist, physiatrist, physical medicine/
rehabilitation specialist, rheumatologist, orthopedist,
orthopedic surgeon) with experience in hemophilia, with
annual musculoskeletal assessments and longitudinal
monitoring of their musculoskeletal outcomes and
preventive or corrective measures as needed.
•
Surgical interventions may become necessary for
musculoskeletal complications if nonsurgical measures fail
to provide satisfactory pain relief and improved function.
Orthopedic surgeons should have specic training in
surgical management of patients with hemophilia.
•
See Chapter 2: Comprehensive Care of Hemophilia and
Chapter 10: Musculoskeletal Complications.
WFH Guidelines for the Management of Hemophilia, 3rd edition18
1.11 Principle 11: Management of
specific conditions and
comorbidities
•
Specic complications and management issues may aect
people with hemophilia and their families at dierent life
stages. Treatment and care for these conditions should
be established as part of national hemophilia programs.
Carriers of hemophilia
•
Some carriers of hemophilia experience bleeding problems,
including joint hemorrhages, similar to males; in addition,
they may experience problems that are specic to women,
such as prolonged or heavy menstrual bleeding.
Symptomatic carriers are considered to have mild or
moderate hemophilia. It is therefore important to include
a gynecologist in the comprehensive care team for the
management of carriers.
•
Carriers may experience a signicant impact on various
aspects of their lives and thus require specialist care specic
to reproductive issues, including genetic counselling,
genetic testing, prenatal diagnosis and planning, newborn
testing, and psychosocial counselling.
• See Chapter 9: Specic Management Issues – Carriers.
Surgery and other invasive procedures
•
Surgeries and other invasive procedures pose particular
risks to patients with hemophilia; however, these procedures
can be performed safely with the provision of adequate
laboratory support, careful preoperative planning,
appropriate hemostasis with sucient quantities of CFCs
and other hemostasis products during and aer surgery,
and optimal postoperative recovery and rehabilitation.
•
erefore, treatment centres and hospitals should establish
protocols to ensure that people with hemophilia, with or
without inhibitors, have ready access to these services,
both in acute and elective surgery situations.
•
See Chapter 9: Specic Management Issues – Surgery and
invasive procedures.
Management of comorbidities
•
Improved life expectancy in hemophilia has led to a greater
interest in age-related disorders, with cardiovascular
disease, hypertension, and other cardiovascular risk factors
increasingly reported in adults with hemophilia.
•
e treatment of comorbidities, especially cardiovascular
diseases, is one of the most important challenges.
•
Although most evidence suggests that hemophilia, at least
the severe form, partially protects against myocardial
infarction, stroke, and venous thromboembolism, typical
cardiovascular risk factors may still be present and cause
disease despite the clotting defect.
•
People with hemophilia are equally or even more prone
to obesity, hypertension, and diabetes than the general
population.
•
Preventive strategies are needed to identify people
with hemophilia who are at higher risk of developing
cardiovascular disease in adulthood.
•
See Chapter 9: Specic Management Issues – Comorbidities.
Medical issues with aging
•
As they age, people with hemophilia require education
and preventive strategies to reduce the risks and impacts
of age-related morbidities.
•
e hemophilia team should be closely involved in the
planning and management of specialist care for people
with hemophilia with comorbidities and any complications
related to aging, to facilitate close consultation and
agreement on treatment plans.
•
Elderly patients with hemophilia should be managed in
the same way as their peers in the general population,
except for the necessary additional correction of impaired
hemostasis with CFCs.
•
Specialist services should be well versed in bleed
management and the specic treatment requirements of
people with hemophilia.
•
See Chapter 9: Specic Management Issues – Medical
issues with aging.
Management of transfusion-transmitted
infections
•
Transfusion-transmitted infections, particularly those with
the human immunodeciency and hepatitis C viruses, have
been major complications in the treatment of hemophilia
in the past.
•
It is absolutely imperative to ensure that current replacement
therapy products are well tested and virally inactivated to
avoid any chance of such infections being transmitted.
•
While the management of these conditions will not be
covered further in these guidelines, given the eectiveness
of current anti-viral therapies for both these conditions, it
is important that relevant services be universally accessible
to all patients with hemophilia who need them.
Chapter 1: Principles of Care 19
1.12 Principle 12: Outcome assessment
•
In the management of hemophilia, outcome assessment
refers to the use of specic tools designed to monitor an
individual’s disease course and to measure the consequences
of the disease and its treatment (i.e., eectiveness of
hemostatic therapy and associated complications).
•
To ensure that all consequences of the disorder are
evaluated, outcome assessment should follow the WHO’s
ICF model.
•
Standardized, validated outcome assessment is necessary
for the clinical management of individual patients, to
assess the quality of care provided, and for research or
advocacy purposes.
•
e most important indicator of the ecacy of hemostatic
therapy is frequency of bleeding, particularly joint and
muscle bleeds. Bleeding frequency is the primary parameter
for treatment decisions and is also used as a predictor of
long-term musculoskeletal outcomes.
•
In hemophilia care, the impact of bleeding on the
musculoskeletal and other systems is measured across
several domains, including body structure and function
and activities and participation. All of these domains may
be aected by contextual factors including environmental,
personal, and economic factors.
•
Multiple clinical and radiological tools are used to assess the
status of joints and specic muscle groups. Measurements
of activities and participation are either self-reported or
observed.
•
The ongoing development of hemophilia-specific
measurement and assessment tools oers opportunities
for clinicians and patients to better understand and evaluate
the nature of the impairments and functional limitations
associated with the condition.
•
Increasingly in recent years, health authorities, including
health technology assessment bodies, are relying on patient-
reported outcome data to evaluate the benets of health
interventions.
•
Despite the availability of numerous assessment options, a
core set of measures for outcome assessment in hemophilia
remains to be dened. Such a core set should ideally be
applicable to the clinical and cultural realities of hemophilia
management worldwide.
• See Chapter 11: Outcome Assessment.
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22. George LA, Sullivan SK, Giermasz A, et al. Hemophilia B gene
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27. Li T, Miller CH, Driggers J, Payne AB, Ellingsen D, Hooper WC.
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28. Lyu C, Xue F, Liu X, et al. Identication of mutations in the F8 and
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29. Manderstedt E, Nilsson R, Lind-Hallden C, Ljung R, Astermark J,
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30. Iorio A, Stonebraker JS, Chambost H, et al. Establishing the prevalence
and prevalence at birth of hemophilia in males: a meta-analytic
approach using national registries. Ann Intern Med. 2019;171(8):540-
546.
31. Pierce GF, Haar A, Ampartzidis G, et al. First-year results of an
expanded humanitarian aid programme for haemophilia in resource-
constrained countries. Haemophilia. 2018;24(2):229-235.
32. Giangrande PL, Black C. World Federation of Haemophilia programs in
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tools in haemophilia care and research: a multidisciplinary perspective.
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34. Fowler H, Lacey R, Keaney J, Kay-Jones C, Martlew V, achil J.
Emergency and out of hours care of patients with inherited bleeding
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35. Khair K, Meerabeau L, Gibson F. Self-management and skills
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36. Breakey VR, Ignas DM, Warias AV, White M, Blanchette VS, Stinson
JN. A pilot randomized control trial to evaluate the feasibility of an
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youth with haemophilia. Haemophilia. 2014;20(6):784-793.
37. Lee Mortensen G, Strand AM, Almen L. Adherence to prophylactic
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38. Breakey VR, Blanchette VS, Bolton-Maggs PH. Towards comprehensive
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2010;16(6):848-857.
39. Croteau SE, Padula M, Quint K, D’Angelo L, Neufeld EJ. Center-based
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40. Weyand AC, Pipe SW. New therapies for hemophilia. Blood.
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41. Schrijvers LH, Schuurmans MJ, Fischer K. Promoting self-management
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42. Blanchette VS, Key NS, Ljung LR, et al. Denitions in hemophilia:
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43. van den Berg HM, Fischer K, Carcao M, et al. Timing of inhibitor
development in more than 1000 previously untreated patients with
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44. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in
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of a physiotherapy exercise programme in haemophilia—a global
perspective. Haemophilia. 2010;16(Suppl 5):136-145.
46. Paroskie A, Gailani D, DeBaun MR, Sidonio RF Jr. A cross-sectional
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47. Hermans C, Kulkarni R. Women with bleeding disorders. Haemophilia.
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48. Osooli M, Doneld SM, Carlsson KS, et al. Joint comorbidities among
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Haemost. 2015;13(4):530-539.
50. Zimmermann R, Staritz P, Huth-Kuhne A. Challenges in treating
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Prevalence of hypertension (HTN) and cardiovascular risk factors in a
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2016;5(5):507-519.
SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting
Information section.
21
COMPREHENSIVE CARE
OF HEMOPHILIA
Elena Santagostino
1
| Alison Dougall
2
| Mathieu Jackson
3
| Kate Khair
4
| Richa Mohan
5
| Kim Chew
6
| Augustas Nedzinskas
7
| Margareth C. Ozelo
8
| H. Marijke van den Berg
9
| Glenn F. Pierce
10
|
Alok Srivastava
11
1
Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda Foundation,
Maggiore Hospital Policlinico, Milan, Italy, and Sobi, Basel, Switzerland
2
Special Care Dentistry Division of Child and Public Dental Health, School of Dental Science, Trinity College Dublin, Dublin Dental
University Hospital, Dublin, Ireland
3
Centre of Excellence on Partnership with Patients and the Public, Université de Montréal, Montreal, QC, Canada
4
Centre for Outcomes and Experience Research in Child Health, Illness and Disability Research Unit (ORCHID) and Great Ormond Street
Hospital for Children, London, UK
5
Empowering Minds Society for Research and Development, New Delhi, India
6
Kuala Lumpur, Malaysia
7
Ariogala, Lithuania
8
INCT do Sangue Hemocentro UNICAMP, University of Campinas, Campinas, SP, Brazil
9
PedNet Haemophilia Research Foundation, Baarn, the Netherlands
10
World Federation of Hemophilia, Montreal, QC, Canada
11
Department of Haematology, Christian Medical College, Vellore, India
All statements identied as recommendations are
consensus based, as denoted by
.
2.1 Introduction
•
Hemophilia is a rare X-linked congenital bleeding disorder
characterized by a deciency of coagulation factor VIII
(FVIII), called hemophilia A, or factor IX (FIX), called
hemophilia B. e factor deciencies are the result of
pathogenic variants in the F8 and F9 clotting factor genes.
•
e best estimates of the prevalence of hemophilia, based
on the most reliable national patient registry data available
and recent World Federation of Hemophilia (WFH) annual
global surveys, indicate that the expected number of males
with hemophilia worldwide is 1,125,000, the majority of
whom are undiagnosed, including an estimated 418,000
males with severe hemophilia.
Hemophilia A and B
•
Hemophilia A is much more common than hemophilia B.
Hemophilia A is estimated to account for 80%-85% of all
hemophilia cases; hemophilia B is estimated to account for
15%-20% of all hemophilia cases. Estimated prevalence is
17.1 cases per 100 000 males for all severities of hemophilia
A (6.0 cases for severe hemophilia A) and 3.8 cases per 100
000 males for all severities of hemophilia B (1.1 cases for
severe hemophilia B). Estimated prevalence at birth is 24.6
cases per 100 000 males for all severities of hemophilia A
(9.5 cases for severe hemophilia A) and 5.0 cases per 100
000 males for all severities of hemophilia B (1.5 cases for
severe hemophilia B).
•
Hemophilia is usually inherited through an X chromosome
with an F8 or F9 gene mutation. However, both the F8
and F9 genes are prone to new mutations, and about 30%
of all cases result from spontaneous genetic variants.
Prospective studies report that over 50% of people newly
diagnosed with severe hemophilia have no prior family
history of hemophilia.
•
Hemophilia usually aects only males who inherit an
aected maternal X chromosome. Females with hemophilia
(FVIII or FIX <40 IU/dL) are rare; in such cases, both X
chromosomes are aected or one is aected and the other
is inactive. A female with one aected X chromosome is
called a carrier of hemophilia.
•
Hemorrhages, musculoskeletal complications, and other
sequelae of hemophilia typically occur in males with
hemophilia but may also occur in a proportion of female
carriers. Since the baseline factor levels in carriers may be
normal or variably reduced, the symptoms and complications
of hemophilia are less common in females and are oen
overlooked and underdiagnosed; joint bleeds in carriers
oen remain unrecognized, leading to poorer joint outcomes
due to undiagnosed joint problems. Better diagnosis and
2
WFH Guidelines for the Management of Hemophilia, 3rd edition22
management of bleeding problems in carriers are needed.
(See Chapter 9: Specic Management Issues – Carriers.)
Clinical diagnosis
•
Hemophilia should be suspected in individuals presenting
with a history of any of these symptoms:
–
easy bruising;
–
“spontaneous” bleeding (i.e., bleeding for no
apparent/known reason), particularly into the joints,
muscles, and so tissues;
–
excessive bleeding following trauma or surgery.
•
Early symptoms of joint bleeds in children at a very young
age are a key indicator of severe hemophilia. (See also
“Bleeding manifestations” below.)
•
If hemophilia is suspected, the clinician should obtain the
patient’s bleeding history and family history of abnormal
or unexplained bleeding experienced by any siblings or
maternal male relatives (i.e., maternal cousin, uncle, or
grandfather) to assess patterns of inheritance and assist
with diagnosis.
•
Accurate diagnosis of hemophilia is essential to inform
appropriate management. A denitive hemophilia diagnosis
is based on a factor assay to demonstrate deciency of
FVIII or FIX.
•
See Chapter 3: Laboratory Diagnosis and Monitoring and
Chapter 4: Genetic Assessment.
Bleeding manifestations
•
e characteristic phenotype in hemophilia is the bleeding
tendency. e severity of bleeding manifestations in
hemophilia generally correlates with the degree of the
clotting factor deciency (see Table 2-1).
•
People with mild hemophilia may not necessarily have
abnormal or prolonged bleeding problems until they
experience serious trauma or undergo surgery.
•
People with severe hemophilia most commonly experience
bleeds into the joints, muscles, and internal organs (see
Tables 2-2 and 2-3).
•
In newborns and children with severe hemophilia less
than 2 years of age, common types of bleeding include:
–
so tissue and intramuscular bleeding;
–
bleeding associated with a medical procedure
(e.g., venipuncture, central line placement,
circumcision, neonatal heel prick);
–
mucocutaneous bleeding (e.g., oral, nasal);
–
extracranial bleeding.
• Some types of bleeds can be life-threatening and require
immediate treatment and medical attention.
•
See Table 2-2 and Chapter 7: Treatment of Specific
Hemorrhages.
Patient/caregiver education
•
People with hemophilia and family/primary caregivers
must receive comprehensive education on hemophilia
care, particularly on the prevention and treatment of bleeds
and management of musculoskeletal complications, and
training on essential skills for self-management, including
bleed recognition, self-treatment, record-keeping, dental
care, and risk management. (See 2.5 Home therapy –
Self-management, below.)
2.2 Comprehensive care
•
Comprehensive hemophilia care involves multidisciplinary
medical services necessary for the diagnosis, treatment,
and management of the condition and its complications.
ese services are typically delivered by a hemophilia
treatment centre or hemophilia comprehensive care centre,
as described in Chapter 1: Principles of Care – Principle 1:
National coordination and delivery of hemophilia care.
Comprehensive care promotes physical health, psychosocial
well-being, and quality of life for people with hemophilia
and reduces morbidity and mortality. It should
encompass family-centred care, particularly diagnosis
and management of carriers.
TABLE 2-1 Relationship of bleeding severity to clotting factor level
8
Severity Clotting factor level Bleeding episodes
Severe <1 IU/dL (<0.01 IU/mL) or <1% of normal
Spontaneous bleeding into joints or muscles, predominantly
in the absence of identifiable hemostatic challenge
Moderate 1-5 IU/dL (0.01-0.05 IU/mL) or 1-5% of normal
Occasional spontaneous bleeding; prolonged bleeding
with minor trauma or surgery
Mild
5-40 IU/dL (0.05-0.40 IU/mL) or 5-<40% of normal
Severe bleeding with major trauma or surgery; rare
spontaneous bleeding
Chapter 2: Comprehensive Care of Hemophilia 23
Key components of comprehensive care
•
Hemophilia is a rare inherited disorder that is complex
to diagnose and to manage. Optimal care, especially for
people with severe forms of the disorder, requires more
than treatment of acute bleeding.
• Priorities in hemophilia treatment and care include:
–
prevention of bleeding and joint damage;
–
prompt management of bleeding episodes including
physical therapy and rehabilitation aer joint bleeds;
–
pain management;
–
management of musculoskeletal complications;
–
prevention and management of inhibitors;
–
management of comorbidities;
–
dental care;
–
quality-of-life assessments and psychosocial support;
–
genetic counselling and diagnosis;
–
ongoing patient/family caregiver education and support.
•
Emergency care should be available at all times, with the
following essential services and resources:
–
coagulation laboratory services with the capacity to
perform accurate and precise clotting factor assays
and inhibitor testing;
–
provision of clotting factor concentrates (CFCs),
either virus-inactivated plasma-derived or
recombinant, as well as other hemostatic agents
such as desmopressin (DDAVP) and antibrinolytic
agents (tranexamic acid or epsilon aminocaproic
acid [EACA]) where available;
–
provision of safe blood components such as
fresh frozen plasma (FFP) and cryoprecipitate if
adequately screened, tested, and/or virus-inactivated
where CFCs are not available;
–
casting and/or splinting and mobility/support aids,
as needed.
• See Chapter 5: Hemostatic Agents.
Comprehensive care team
•
e wide-ranging needs of people with hemophilia and
their families are best met by a multidisciplinary team of
healthcare professionals with expertise and experience in
hemophilia, in accordance with accepted protocols and
practices and national standards of care, if available.
Patient/healthcare provider partnership and
decision-making
•
People with hemophilia are regarded as distinct core
members of the comprehensive care team who through
day-to-day self-management become experts and partners
in their own hemophilia care.
•
It is important to involve patients (and their parents/
caregivers) in decision-making; incorporate their particular
preferences, values, and personal experiences; and obtain
their concurrence with short- and long-term treatment
and management plans. All parties should engage in truly
shared decision-making through educated discussions about
available healthcare options and anticipated outcomes,
including evidence-informed guideline recommendations,
benets and risks of the various choices, and expressed
concerns and values of the patient and care-givers. ey
should work together on the development and periodic
updating of individualized treatment guidelines that the
patient/caregiver can consult at will and share with others
involved in care.
•
Increasingly, patients are not only active members of their
own healthcare team; they are becoming full partners in
the health-care team who are also involved in research,
medical education, and student training in recognition of
the value of their particular understanding and expertise.
TABLE 2-2 Sites of bleeding in hemophilia
9
Serious • Joints (hemarthrosis)
• Muscles, especially deep
compartments (iliopsoas, calf,
forearm)
• Mucous membranes of the mouth,
nose, and genitourinary tract
Life-threatening • Intracranial
• Neck/throat
• Gastrointestinal
TABLE 2-3 Approximate frequency of bleeding
at different sites
Site of bleeding
Approximate
frequency
Joints
• More common in hinged joints: ankles,
knees, elbows
• Less common in multi-axial joints:
shoulders, wrists, hips
70-80%
Muscles
10-20%
Other sites (major bleeds) 5-10%
Central nervous system <5%
WFH Guidelines for the Management of Hemophilia, 3rd edition24
Multidisciplinary team
•
e core team typically consists of a medical director, nurse
coordinator, physical therapist, laboratory specialist, and
psychosocial counsellor; all of whom should be specically
trained in the eld.
–
e medical director (normally a pediatric and/
or adult hematologist or a physician with training
and expertise in managing hemophilia and other
bleeding disorders) oversees patient management
including ordering diagnostic laboratory tests,
prescribing treatment, and monitoring patient health
and medical needs.
–
e nurse coordinator, who should have training
in the management of patients with bleeding
disorders, coordinates the provision of care by the
multidisciplinary team, educates patients and their
families, provides training for home therapy and
other aspects of care, and assesses patients and
institutes initial care where appropriate.
–
e physical therapist plays an important role in
educating people with hemophilia and their caregivers
on preventive measures, facilitating complete
functional recovery aer each bleed, and counselling
individuals about preserving musculoskeletal
health. Other musculoskeletal specialists (i.e.,
occupational therapist, physiatrist, physical medicine/
rehabilitation specialist, rheumatologist, orthopedist,
orthopedic surgeon) provide treatment for specic
musculoskeletal conditions.
–
e laboratory specialist performs specialized blood
tests to establish the diagnosis and monitor therapy,
including blood coagulation tests, factor assays, and
inhibitor assays.
–
e psychosocial counsellor (preferably a social
worker or psychologist) conducts psychosocial
assessments and provides counselling and/or
referrals to community resources.
•
e roles assumed by core team members may dier
at dierent centres, depending on the availability and
expertise of trained sta and the organization of services
within the centre.
•
e comprehensive care team should also include or have
access to dentists with hemophilia experience, and other
specialists as needed to address specic medical and
health-related issues that some people with hemophilia
and carriers may encounter, including:
–
chronic pain specialist;
–
pharmacist;
–
geneticist;
–
hepatologist;
–
infectious disease specialist;
–
immunologist;
–
gynecologist/obstetrician;
–
vocational counsellor.
•
Other medical specialists may be needed to address
comorbid conditions related to age, lifestyle, or other
circumstances. (See Chapter 9: Specic Management
Issues – Comorbidities.)
•
Detailed clinical management protocols are essential to
ensure continuity of care in the event of personnel changes
within the comprehensive care team.
•
To foster the necessary expertise and experience in
hemophilia, mentorships and fellowships can offer
opportunities for recruiting medical professionals to the
eld and advancing clinical knowledge.
RECOMMENDATION 2.2.1:
•
For people with hemophilia, the WFH recommends
coordinated delivery of comprehensive care by a
multidisciplinary team of healthcare professionals
with expertise and experience in hemophilia.
•
REMARK: e core members of the comprehensive
care team should consist of a medical director, nurse
coordinator, musculoskeletal specialists, medical
laboratory specialist, psychosocial specialist, and the
patient and family caregivers. e roles assumed by
the core team members may dier at dierent centres
depending on the availability and expertise of trained
sta and the organization of services within the centre.
RECOMMENDATION 2.2.2:
•
For people with hemophilia, the WFH recommends
availability of and access to:
–
appropriate emergency care at all times;
–
a coagulation laboratory capable of performing
clotting factor assays and inhibitor testing;
–
appropriate clotting factor concentrates (CFCs),
either plasma-derived or recombinant, as well
as other hemostatic agents such as desmopressin
(DDAVP), emicizumab, and antibrinolytics;
–
safe blood components such as fresh frozen
plasma (FFP) and cryoprecipitate that have
been adequately screened, tested, and/or virus-
inactivated if CFCs are not available;
–
casting and/or splinting for immobilization and
mobility/support aids, as needed;
Chapter 2: Comprehensive Care of Hemophilia 25
–
other specialists to address specic medical and
health-related issues that some individuals may
encounter, as needed.
RECOMMENDATION 2.2.3:
•
For all patients with hemophilia, the WFH suggests the
preparation of written clinical management protocols
to ensure continuity of care in the event of changes in
clinic personnel.
Functions of a comprehensive care program
• A comprehensive care program helps put into operation
the key principles of comprehensive care for hemophilia.
e core functions are described here.
Coordination and provision of care
•
A comprehensive care program enables centralized
coordination of care from across multidisciplinary
specialities, services, and facilities, and the provision of
inpatient care (hospital stays) and outpatient care (checkups
and other clinic visits) to patients and their families.
•
People with hemophilia require periodic monitoring and
assessment of their condition and circumstances. ey
should be evaluated at least once per year; those with
mild or moderate hemophilia may require less frequent
monitoring.
•
Referrals to other services (e.g., dentistry, surgery,
obstetrics/ gynecology) including communication of the
care management plan to all treaters and care facilities
are arranged through the program, which helps ensure
that patients receive optimal care from specialists
with appropriate hemophilia expertise. Planning and
coordination of procedures must involve patients/family
caregivers in consultation with all specialists required (e.g.,
for surgery, the anesthesiologist, surgeon, and surgical
sta including nurses).
•
Ongoing collaboration with patients and family caregivers
to develop, audit, and rene the comprehensive care
management plan is essential.
RECOMMENDATION 2.2.4:
•
For people with hemophilia, the WFH recommends
a multidisciplinary checkup including hematologic,
musculoskeletal, and quality-of-life assessments by the
core comprehensive care team members at least yearly
(every 6 months for children).
•
REMARK: Smaller centres and family physicians
can provide primary care and management of some
complications of hemophilia, in frequent consultation
with the hemophilia comprehensive care centre, especially
for patients who live a long distance from the nearest
hemophilia treatment centre.
Patient registry and data collection
•
e comprehensive care program facilitates centralized
patient data collection on sites of bleeds, types and doses
of treatment administered, complications of treatment,
and assessment of long-term musculoskeletal and other
health outcomes and patient-reported outcomes (e.g.,
bleed-related activities, acute and chronic pain, days
missed from school or work, impact of hemophilia on
activities of daily living). e WFH’s World Bleeding
Disorders Registry (WBDR) is an online platform for
use by hemophilia treatment centres around the world to
collect such data to monitor patient outcomes and guide
clinical practice.
•
Patient records should be maintained in accordance
with condentiality laws and other national regulations,
ideally in a computerized patient registry that is updated
regularly by designated clinic sta with direct or indirect
patient input.
•
Systematic data collection also serves to facilitate the
auditing of services provided by the hemophilia treatment
centre with the goal of improving care delivery and to help
the patient better manage their health condition.
•
See Chapter 9: Specic Management Issues, Chapter 10:
Musculoskeletal Complications, and Chapter 11: Outcome
Assessment.
RECOMMENDATION 2.2.5:
•
For all patients with hemophilia, the WFH recommends
systematic data collection in patient registries, where
possible, to inform allocation of resources, support
improvement of care delivery services, and promote
collaboration among centres in sharing data and
conducting research.
Clinical research
•
Basic and clinical hemophilia research should be
conducted where possible. Since the number of patients
with hemophilia at individual centres may be limited,
clinical research is best conducted in collaboration with
other hemophilia centres and national hemophilia patient
groups such as national member organizations (NMOs)
of the WFH.
WFH Guidelines for the Management of Hemophilia, 3rd edition26
Patient/caregiver education and support
•
Education and training on home therapy should be provided
where available and should ideally include supervision of
adherence to treatment.
•
Ongoing support should be provided to families and
caregivers including identifying resources and/or developing
strategies to enable them to adapt to living with hemophilia.
•
Potential challenges that patients and family members may
encounter in everyday living, particularly those related to
the management of bleeding, include:
–
changes associated with dierent stages of growth
and development (especially adolescence and aging);
–
adherence to a complex medical regimen requiring
frequent IV infusions in the midst of other
competing family needs;
–
issues with schooling and/or employment;
–
psychosocial and mental health issues;
–
bleeding problems and reproductive issues in
carriers.
•
In collaboration with hemophilia patient organizations, a
comprehensive care program helps promote and/or facilitate
hemophilia support groups, educational workshops, and
recreational activities such as hemophilia camps.
•
See 2.5 Home therapy and 2.8 Transition from pediatric
to adult care, below, and Chapter 9: Specic Management
Issues.
RECOMMENDATION 2.2.6:
•
e WFH recommends that adequate education be
provided to people with hemophilia, their family members,
and other caregivers to enable self-management and
sucient understanding of the disease for prevention of
bleeds and related complications and for life planning.
RECOMMENDATION 2.2.7:
•
For people with hemophilia and their families, the WFH
recommends promotion and/or facilitation of educational
and recreational activities in collaboration with patient
organizations, to provide them with opportunities to
discover new interests and capabilities and build a
support network with diverse members of the hemophilia
community.
2.3 Fitness and physical activity
•
Physical activity is important to promote normal
neuromuscular development and physical tness.
•
People with hemophilia may have an increased risk of low
bone mineral density compared to the general population
due to risk factors including hemophilia severity and
hemophilic arthropathy and resulting immobility. Ways
to promote bone health include preventing hemarthrosis,
regular exercise, and adequate vitamin D and calcium
intake.
•
For those with signicant musculoskeletal dysfunction,
weight-bearing activities that promote development and
maintenance of good bone density should be encouraged
to the extent their joint health permits.
•
e choice of activities should reect the individual’s
preferences/interests, physical condition and ability, local
contexts, and available resources.
•
Non-contact sports such as swimming, walking, jogging,
golf, badminton, archery, cycling, rowing, sailing, and
table tennis should be encouraged.
•
High-contact and collision sports such as soccer, hockey,
rugby, boxing, and wrestling, and high-velocity activities
such as motocross racing and skiing are not advised due
to the potential for life-threatening injuries, unless the
individual is on adequate prophylaxis to cover such activities
and is well educated on the potential risks.
•
Custom-made dental mouthguards should be used by
individuals with hemophilia for all contact sports to
prevent trauma and injury to teeth and oral so tissues.
•
Organized sports programs should be encouraged over
unstructured sports activities where protective equipment
and supervision may be lacking.
•
Ideally, individuals with hemophilia (or their family
caregivers) should consult a physical therapist before
engaging in new sports and physical activities to discuss
their appropriateness, required protective gear, prophylaxis
(factor coverage and other measures), and required physical
skills prior to beginning the activity. is is particularly
important if the individual has any joint with recurrent
bleeding (i.e., target joint).
•
Ongoing patient/caregiver education on the physical
implications of a given activity in relation to hemophilia
(i.e., joint exion, joint or muscle trauma) is important
so that they can make informed choices, adapt their self-
management accordingly, and responsibly manage the way
they participate in sports and physical activities.
•
Target joints can be protected with braces or splints
during physical activity, especially in the absence of factor
coverage.
•
See Chapter 7: Treatment of Specic Hemorrhages and
Chapter 10: Musculoskeletal Complications.
Chapter 2: Comprehensive Care of Hemophilia 27
RECOMMENDATION 2.3.1:
•
For people with hemophilia, the WFH recommends
promotion of regular physical activity and tness, with
special attention on bone health maintenance, muscle
strengthening, coordination, physical functioning,
healthy body weight, and positive self-esteem.
RECOMMENDATION 2.3.2:
•
For people with hemophilia, the WFH recommends
promotion of non-contact sports. High-contact and
collision sports and high-velocity activities should
be avoided unless the individual is on a prophylactic
regimen that is adequate to cover such activities and
is properly educated on the potential risks and other
required protective measures.
•
REMARK: e choice of sports activities should take
into consideration the individual’s physical condition
and ability, preferences and interests, local customs,
and available resources.
RECOMMENDATION 2.3.3:
•
For people with hemophilia, the WFH recommends
consultation with a physical therapist or other
musculoskeletal specialist before engaging in sports and
physical activities to discuss their appropriateness specic
to the individual’s condition and their requirement for
particular physical skills and/or protective gear.
2.4 Adjunctive management
•
Adjunctive therapies are important in the treatment of
bleeds, particularly where coagulation therapies and
hemostatic agents are limited (or unavailable), and may
lessen the amount of treatment product required.
•
First-aid measures are a key component of adjunctive
management. In addition to CFCs to raise factor levels (or
DDAVP in mild hemophilia A), the PRICE principles—
protection, rest, ice, compression, and elevation—based
on the conventional rest, ice, compression, and elevation
(RICE) protocol for injuries, may be used for joint and
muscle bleeds. Another approach, POLICE (protection,
optimum loading, ice, compression, and elevation), replaces
“rest” with “optimum loading” to focus attention on the
need to balance rest with early mobilization and gradual
weight-bearing to prevent complications associated
with immobilization. It is important to consider the
appropriateness of each of these measures for the particular
situation.
•
In recent years, there has been debate on the application of
ice, which is believed to help manage acute pain from joint
bleeding and reduce blood ow to the injured tissue. One
study suggested that the cooling eect of ice may interfere
with coagulation and slow the hemostasis process.
However, counter viewpoints note that many people with
hemophilia appreciate ice for pain relief and that, for those
without access to treatment products, ice for acute and
chronic pain may be their only “treatment” option.
•
See Chapter 7: Treatment of Specic Hemorrhages – Joint
hemorrhage – Adjunctive care.
•
Physical therapy and rehabilitation are particularly
important for functional improvement and recovery
aer musculoskeletal bleeds and for those with established
hemophilic arthropathy.
•
See Chapter 7: Treatment of Specic Hemorrhages – Joint
hemorrhage – Physical therapy and rehabilitation and
Chapter 10: Musculoskeletal Complications – Hemophilic
arthropathy and joint contractures – Physical therapy for
hemophilic arthropathy.
•
Antibrinolytic drugs are eective as adjunctive treatment
for mucosal bleeds and invasive dental procedures. (See
2.7 Dental care and management, below, and Chapter 5:
Hemostatic Agents – Other pharmacological options.)
•
Certain selective COX-2 inhibitors may be used for joint
inammation aer an acute bleed and for chronic arthritis.
(See 2.6 Pain management, below.)
•
Complementary techniques for pain management (e.g.,
meditation, distraction, mindfulness, or music therapy)
may also be helpful for those with chronic hemophilic
arthropathy. (See 2.6 Pain management, below.)
RECOMMENDATION 2.4.1:
•
For people with hemophilia with a muscle or joint bleed,
the WFH recommends following the PRICE principles
(protection, rest, ice, compression, and elevation) in
addition to increasing factor level.
RECOMMENDATION 2.4.2:
•
For people with hemophilia recovering from a joint
or muscle bleed, the WFH recommends gradual re-
initiation of physical activities under the supervision
of a physical therapist with experience in hemophilia
to assess resumption of normal motor development
and coordination.
•
REMARK: For children with hemophilia recovering
from a joint or muscle bleed, the physical therapist
and family caregiver should remain in close contact
WFH Guidelines for the Management of Hemophilia, 3rd edition28
to discuss and decide on the appropriate sports and
activities for the child’s progressive rehabilitation.
RECOMMENDATION 2.4.3:
•
For people with hemophilia with established hemophilic
arthropathy or aer recovery from musculoskeletal
bleeding, the WFH recommends physical therapy and
rehabilitation activities.
RECOMMENDATION 2.4.4:
•
For people with hemophilia, the WFH recommends
the use of antibrinolytic drugs (e.g., tranexamic acid,
epsilon aminocaproic acid [EACA]) alone or as adjuvant
treatment, particularly in controlling mucosal bleeds
and for invasive dental procedures.
2.5 Home therapy
•
Home therapy gives people with hemophilia immediate
access to CFCs or other coagulation therapies and hemostatic
agents (e.g., emicizumab, DDAVP, antibrinolytics) and
hence enables optimal early treatment, resulting in less
pain, dysfunction, and long-term disability, and signicantly
reduced hospitalization rates for hemophilic bleeding
complications, especially for those on prophylaxis compared
to episodic therapy.
•
Home therapy also offers people with hemophilia
substantially improved quality of life including less school/
work absenteeism, the ability to safely participate in a
larger variety of sports and physical activities, greater
employment stability, and greater freedom to travel.
•
Home therapy must be supervised closely by the
comprehensive care team and should only be initiated
aer comprehensive patient/caregiver education and
training.
•
Education should focus on instilling essential knowledge
of hemophilia and the basics of home therapy, including:
–
recognition of bleeds and common complications;
–
rst-aid measures;
–
dosage calculation;
–
storage, preparation, and administration of CFCs
and/or other treatment products;
–
aseptic techniques;
–
venipuncture (or access through a central venous
catheter) and self-infusion/self-injection;
–
record-keeping;
–
proper storage and disposal of needles/sharps;
–
handling of blood spills.
•
A patient/caregiver home therapy certication program
is helpful for acknowledging and ensuring readiness to
begin home therapy.
•
Treatment adherence, level of education, and understanding
of episodic and prophylactic treatment, infusion/injection
techniques, and bleed records should be reviewed and
evaluated with patients and family caregivers at clinic
checkups.
• See also “Self-management” below.
Clotting factor replacement therapy
•
Home therapy with CFCs should ideally be achieved with
products that are safe and are easily reconstituted. CFCs can
be stored at room temperature or in a domestic refrigerator,
depending on the product. People with hemophilia must
be skilled in self-infusion to minimize time to treatment
and improve their joint health outcomes.
•
Home therapy with CFCs can be started with young
children with adequate venous access and motivated family
caregivers who have undergone comprehensive training.
Older children and teenagers can learn self-infusion
with education and training from the hemophilia nurse
coordinator (or home infusion nurse, where available)
and family support.
•
See “Self-management” below and Chapter 6: Prophylaxis
in Hemophilia.
New coagulation therapies
•
e use of new innovative therapies administered via
dierent routes requires carefully planned patient/caregiver
education, training, and supervision including specic
training for those transitioning to another type of therapy
(e.g., from intravenous factor replacement therapy to
subcutaneous factor substitution therapy with emicizumab).
•
Patients and their caregivers should understand the
dierences, benets, and any risks associated with a
particular treatment. Importantly, they should be taught
how to monitor treatment and response, and under which
circumstances they should contact their healthcare provider
and/or hemophilia treatment centre (e.g., breakthrough
bleeding, upcoming surgery).
Emicizumab
•
People with hemophilia A on prophylaxis with emicizumab
may begin home therapy after proper training in
subcutaneous injection technique.
•
Emicizumab and those non-factor agents in development
dier from conventional types of prophylaxis as they do not
replace the missing coagulation factor, are administered
Chapter 2: Comprehensive Care of Hemophilia 29
subcutaneously and, in some cases, can be administered as
infrequently as once or twice monthly. Additionally, these
agents are not associated with the peak and trough curves
of protection that are now seen with factor prophylaxis
regimens.
•
Emicizumab’s subcutaneous route of administration is
already making it easier to start pediatric patients on
prophylaxis at very young ages and without the need for
central venous access devices (CVADs). Emicizumab
makes it feasible to initiate prophylaxis at birth to provide
protection of newborns and infants newly diagnosed with
severe hemophilia A; however, further research in infants
less than 1 year of age is required.
•
Emicizumab is not intended to treat acute bleeding episodes.
Breakthrough bleeding is treated with doses of CFCs (or
bypassing agents in the case of patients with inhibitors) that
are sucient to achieve hemostasis. Caution is required
when treating breakthrough bleeding episodes while on
emicizumab as several patients have developed either venous
thromboembolism or thrombotic microangiopathy with
concomitant administration of activated prothrombin
complex concentrate (aPCC). Consult the individual product
inserts for precautions and risk management guidance.
•
See Chapter 5: Hemostatic Agents, Chapter 6: Prophylaxis
in Hemophilia, and Chapter 8: Inhibitors to Clotting Factor.
Self-management
•
Self-management focuses on patient empowerment and
refers to a patient’s ability to acquire the necessary skills
and knowledge to become competent in their own care
and apply it in their daily activities to keep their condition
under control and minimize its impacts on their physical
and psychological health. For people with hemophilia,
self-management requires concrete knowledge of bleeding
mechanisms and treatment strategies (when and how to
treat and what dose to give).
• e key self-management skills required for people with
hemophilia include:
–
bleed recognition;
–
self-infusion/self-treatment skills;
–
self-care (i.e., nutrition and physical tness) and
medicines management (i.e., record-keeping,
treatment routines, maintenance of adequate
treatment supply, skills in storage, reconstitution,
and administration of treatment products);
–
pain management; and
–
risk management and conceptualizing preventive
therapy.
•
Knowledge of appropriate adjunctive therapies (e.g.,
antifibrinolytics, pain medications) and adjunctive
management (e.g., the PRICE principles) are also important
to self-management.
•
See 2.3 Fitness and physical activity, 2.4 Adjunctive
management, and 2.5 Home therapy, above, and 2.6 Pain
management, below.
Bleed recognition
•
Bleed recognition, especially of joint and muscle bleeds,
is an essential part of self-management so that prompt
treatment can be initiated to minimize the shortand long-
term impacts of bleeds. In hemophilia, a wait-and-see
approach for potential bleeds or missed doses may result
in the onset and progression of bleeding symptoms that
are not only painful but ultimately lead to joint damage.
•
It is important for family members/caregivers to be able
to recognize subtle signs of bleeds in young children with
hemophilia; in infants and young children, reluctance to
use a limb may be indicative of a joint/muscle bleed.
e signs and symptoms of common types of hemorrhage
in hemophilia are described in Chapter 7: Treatment
of Specific Hemorrhages and Chapter 11: Outcome
Assessment.
•
For those on prophylaxis with new types of coagulation
therapy, it is important to monitor and assess the ability
of patients/caregivers to recognize breakthrough bleeds
and initiate prompt episodic treatment with CFCs or
appropriate hemostatic agents.
Self-infusion/self-treatment
•
In young children, injections or infusions are normally
given by the parents and/or caregivers until the child is
old enough to switch to self-treatment.
•
Children with hemophilia typically learn to self-infuse
or self-inject in late childhood or early adolescence. Self-
infusion requires skill and expertise developed through trial
and error as well as education and support. Becoming
sucient at self-infusion is complex as it requires a one-
handed technique to perform all steps; however, most
children self-infuse at least part of the time by 12 years
of age.
•
Establishing routines, such as self-infusing at the same
time every day, can help signicantly with treatment
adherence.
RECOMMENDATION 2.5.1:
•
Patients (or caregivers of children) with hemophilia
should be taught how to manage their care at home
WFH Guidelines for the Management of Hemophilia, 3rd edition30
and be able to demonstrate understanding of how to
recognize bleeds and the ability to infuse or self-infuse,
with monitoring of venous access skills over the patient’s
lifetime.
Self-care and medicines management
•
Because people with hemophilia self-manage largely at
home, healthcare providers have to depend on the patient/
caregiver to inform them of their type of bleed episodes,
bleeding frequency, and usage of treatment products.
•
erefore, it is important for patients/caregivers to keep
accurate bleed treatment records (paper or electronic) that
include the date and site of bleeding, the dosage and lot
number of the product used, any adverse eects, bleed-
related activities, and other outcomes to be reported as
required.
•
Hemophilia treatment centres now have the option to use
electronic diaries (e-diaries) in the form of smartphone
applications, handheld wireless monitoring systems, and
online platforms that allow real-time entries and direct
data analysis. With these tools, healthcare providers no
longer need to rely on patient visits to the hemophilia
treatment centre to review paper diaries.
•
Studies on e-diaries have demonstrated that their use
increases the amount of information provided as well as
the completeness of data reporting. Remote patient record
management may also improve treatment compliance,
increase patient quality of life, support healthcare
providers in modifying treatment regimens, and improve
communication with the healthcare team.
RECOMMENDATION 2.5.2:
•
For patients with hemophilia, a detailed record of
all treatments administered (reason, batch number,
number of units, etc.) should be documented and used
to personalize treatment plans.
Risk management and conceptualizing
preventative therapy
•
Risk management requires the ability to judge and balance
chances and risks encountered in daily life, including
controlling and navigating risks that arise and distinguishing
between negative risk-taking and positive risk management.
In addition, it requires being able to self-advocate for
appropriate hemophilia care with support from the
hemophilia treatment centre such as emergency care,
surgical management, or dental treatment. (See 2.3 Fitness
and physical activity, above, 2.7 Dental care and management,
below, and Chapter 9: Specic Management Issues.)
•
In addition, healthcare providers can educate and guide
people with hemophilia in planning their daily lives to
reduce bleeding risk. Strategies may include adapting the
treatment regimen to t within other priorities (e.g., school
and sports), routines, activities, and events in their lives.
Central venous access devices
•
An implanted central venous access device can enable stable,
long-lasting venous access to make infusions easier and
may be required for administering prophylaxis or immune
tolerance induction (ITI) therapy in young children with
problematic venous access.
•
e complications and risks associated with surgical
implantation of CVADs (i.e., hospitalization, bleeding,
catheter infection, thrombosis, breakage, and/or
malfunction) need to be weighed against the advantages
of early initiation of intensive prophylaxis. Many
pediatricians and hemophilia treaters are shiing from the
use of CVADs to peripheral venous access for early initiation
of prophylaxis, starting with once-weekly prophylaxis then
gradually escalating infusion frequency, together with
more intensive caregiver training.
•
Alternatively, the use of emicizumab obviates the need
for CVADs, and it is increasingly among the treatment
options for people with hemophilia A in many countries.
(See Chapter 6: Prophylaxis in Hemophilia.)
•
e protocol used for device care (using aseptic precautions),
quality of patient/caregiver education, and user compliance
may aect frequency of infections; therefore, careful
guidelines and surveillance protocols are important to
reduce the risk of complications.
•
Parents and caregivers must be taught to keep CVADs
scrupulously clean and to ush out the catheter properly
aer each therapy administration to prevent CVAD infection
and clot formation. Fibrinolytic agents may be helpful
for preventing clotting and infections.
•
It is essential to ensure that parents and caregivers have a
thorough understanding of all aspects of home therapy and
are prepared and able to handle the issues and challenges
that commonly arise in children with hemophilia at each
development stage. (See 2.8 Transition from pediatric to
adult care, below.)
•
For patients in whom venous access is problematic, non-
factor replacement therapy that can be administered
subcutaneously (i.e., emicizumab) should be considered.
(See Chapter 6: Prophylaxis in Hemophilia – Non-factor
replacement therapy.)
Chapter 2: Comprehensive Care of Hemophilia 31
RECOMMENDATION 2.5.3:
•
For children with hemophilia, central venous access
devices could be considered to facilitate early access to
bleed treatment and prophylaxis.
2.6 Pain management
•
Acute and chronic pain are common in people with
hemophilia. Proper assessment of the cause of pain is
essential.
• See also Chapter 7: Treatment of Specic Hemorrhages.
RECOMMENDATION 2.6.1:
•
For people with hemophilia with acute or chronic pain,
the WFH recommends the use of age-appropriate pain
assessment tools to determine the cause and guide
appropriate management.
Pain caused by venous access
•
In general, no pain medication is given. If required,
application of a local anesthetic spray or cream at the
site of venous access may be helpful.
RECOMMENDATION 2.6.2:
•
For people with hemophilia with venous access pain,
discomfort or anxiety, the WFH recommends the
application of a local anesthetic spray or cream at the
site of venous access.
Pain caused by joint or muscle bleeding
•
While hemostatic treatment should be administered as
soon as possible to stop bleeding, additional medications
are oen needed for pain control (see Table 2-4).
• Other adjunctive measures may be required.
• See also Chapter 10: Musculoskeletal Complications.
RECOMMENDATION 2.6.3:
•
For people with hemophilia with acute pain due to a
joint or muscle bleed, the WFH recommends immediate
administration of clotting factor concentrates to stop
bleeding, pain medication, and adjunctive measures
such as immobilization, compression, and splinting to
minimize pain, if appropriate.
Postoperative pain
•
Intramuscular injection of analgesics should be avoided.
•
Postoperative pain management should be coordinated
with the anesthesiologist or pain specialist.
•
Initially, narcotic analgesics can be given, followed by an
oral opioid.
• When pain decreases, paracetamol/acetaminophen may
be used.
RECOMMENDATION 2.6.4:
•
For patients with hemophilia and postoperative pain, the
WFH advises proportionate management of postoperative
pain in coordination with the anesthesiologist or pain
specialist.
RECOMMENDATION 2.6.5:
•
For patients with hemophilia and postoperative
pain, the WFH recommends analgesia similar to that
used in patients without hemophilia including, as
appropriate, the use of intravenous morphine or other
narcotic analgesics, followed by an oral opioid (e.g.,
tramadol, codeine, hydrocodone, etc.) and paracetamol/
acetaminophen as pain decreases.
•
REMARK: With the exception of selective COX-2
inhibitors, NSAIDs should not be used in patients
with hemophilia.
•
REMARK: e intramuscular route for administration
of analgesia is not advised.
TABLE 2-4 Pain management strategies for
people with hemophilia
Severity
1 Paracetamol/acetaminophen
If not effective
2 COX-2 inhibitorª (e.g., celecoxib, meloxicam,
nimesulide, and others)
or
paracetamol/acetaminophen plus codeine
(3-4 times/day)
or
paracetamol/acetaminophen plus tramadol
(3-4 times/day)
3 Morphine: Use a slow-release product with a
rapid-release product as an escape analgesic.
Increase use of the slow-release product if
the rapid-release product is used more than
4 times/day.
Note: If for any reason medications have been stopped for a period
of time, individuals who have been taking and tolerating high-dose
narcotic drugs should restart the drug at a lower dose, or use a less
powerful painkiller, under the supervision of a physician.
ªCOX-2 inhibitors should be used with caution by people with
hemophilia with hypertension and renal dysfunction.
WFH Guidelines for the Management of Hemophilia, 3rd edition32
Pain due to chronic hemophilic arthropathy
•
Chronic hemophilic arthropathy develops in individuals
who have not had adequate treatment and follow-up
physical therapy and rehabilitation for joint and muscle
bleeds.
•
Pain management for chronic hemophilic arthropathy
should include functional training and adaptation, and
appropriate analgesics as detailed in Table 2-4.
•
Pain medications that may be used by people with
hemophilia for chronic hemophilic arthropathy include
paracetamol/acetaminophen, selective COX-2 inhibitors,
tramadol, and opioid analgesics. Other NSAIDs should
be avoided in people with hemophilia. Codeine should
not be administered to children under 12 years of age.
•
For individuals with disabling chronic pain due to
hemophilic arthropathy, orthopedic surgery may be
indicated.
•
See Chapter 10: Musculoskeletal Complications –
Hemophilic arthropathy.
RECOMMENDATION 2.6.6:
•
For people with hemophilia and chronic hemophilic
arthropathy in need of pain management, the WFH
recommends functional training and adaptations
alongside appropriate analgesics.
RECOMMENDATION 2.6.7:
•
For people with hemophilia and chronic hemophilic
arthropathy, the WFH recommends education on pain
management including the use of complementary pain
management techniques (e.g., meditation, distraction,
mindfulness, or music therapy).
RECOMMENDATION 2.6.8:
•
For children and adults with hemophilia with pain due to
chronic hemophilic arthropathy, the WFH recommends
the use of paracetamol/acetaminophen, selective COX-2
inhibitors, tramadol, or morphine, and avoidance of
other NSAIDs. Codeine may be used for children over 12
years of age but is contraindicated in younger children.
•
REMARK: Prolonged use of these medications may
have risks of dependence or addiction, as well as organ
damage, and must be carefully monitored.
•
REMARK: People with persistent pain should be referred
to a specialized pain management team.
RECOMMENDATION 2.6.9:
•
For patients with hemophilia with disabling pain from
chronic hemophilic arthropathy, the WFH recommends
referral to an orthopedic specialist for consideration of
orthopedic surgery.
Dental pain
•
People with hemophilia experiencing dental pain should
always be referred for a professional dental consultation.
Proportionate pain management measures should be
applied (see Table 2-4).
RECOMMENDATION 2.6.10:
•
For children and adults with hemophilia, the WFH
recommends interim management of dental or orofacial
pain according to a proportionate approach for pain
relief and referral to a dental care professional for
assessment.
2.7 Dental care and management
•
Maintaining good oral health and preventing dental
problems is of great importance in people with hemophilia
to prevent oral diseases and conditions such as gingivitis,
dental caries, and periodontal diseases which may cause
serious gum bleeding, especially in those with severe/
moderate hemophilia, and to avoid the need for major
dental surgery.
•
Since prolonged bleeding aer dental treatment can cause
severe or even life-threatening complications, people with
hemophilia are a priority group for preventive dental and
oral health care.
•
It is important to ensure that people with hemophilia have
access to dental treatment and regular preventive dental
care at a designated dental care centre with expertise in
the management of people with hemophilia according to
evidence-based dental protocols.
•
See also Chapter 7: Treatment of Specic Hemorrhages
– Oral hemorrhage.
RECOMMENDATION 2.7.1:
•
For children and adults with hemophilia, the WFH
recommends provisions for access to regular preventive
dental and oral health care as part of comprehensive
hemophilia care.
RECOMMENDATION 2.7.2:
•
For children with hemophilia, the WFH recommends
referral to a designated dental care centre at the time of
the rst tooth eruption (around 6 months of age) or by
age 1 in order to reduce the complications, morbidity,
Chapter 2: Comprehensive Care of Hemophilia 33
costs, and health and psychosocial impacts associated
with oral diseases in people with hemophilia.
RECOMMENDATION 2.7.3:
•
For adults with hemophilia, the WFH recommends
facilitating access to appropriate adult dental services and
procedures, with regular dental assessments throughout
their lives to monitor and safeguard oral health using
evidence-based and personalized preventive dental
protocols.
RECOMMENDATION 2.7.4:
•
For people with hemophilia, the WFH recommends
preventive dental and oral care as a priority to ensure
optimal oral health and hygiene to prevent periodontal
disease and dental caries, which predispose to gum
bleeding, dental pain, tooth loss, chewing diculties,
and social impacts.
Oral care
•
Optimal oral hygiene is essential to prevent periodontal
disease and dental caries, which predispose to gum bleeding,
dental pain, tooth loss, chewing diculties, and social
impacts (e.g., halitosis and low self-esteem). is
involves the use of oral hygiene products and toothbrushes
which can be adapted based on individual needs.
•
Dental pain occurring spontaneously or with facial swelling
usually indicates the presence of advanced stages of oral
disease and/ or infection and should trigger a professional
dental consultation. Short-term pain control should be
achieved as described (see 2.6 Pain management, above),
with paracetamol/acetaminophen as the drug of choice
to manage toothache in children.
RECOMMENDATION 2.7.5:
•
For all people with hemophilia, the WFH recommends
education on the importance of good oral hygiene to
prevent dental problems and complications, including
instructions for twice-daily brushing of the teeth using
a so- or medium-texture toothbrush and uoridated
toothpaste to remove plaque deposits; the toothpaste
should not be rinsed away but rather retained (“spit, but
don’t rinse”) aer brushing to maximize uoride benet.
•
REMARK: e use of dental oss or interdental brushes
should be encouraged to ensure complete plaque removal.
•
REMARK: Individuals with elbow or shoulder restrictions
may benet from modied or electric toothbrushes and
ossing aids.
RECOMMENDATION 2.7.6:
•
For children with hemophilia 6 years of age and younger,
the WFH recommends parental/caregiver supervision
of toothbrushing.
Dental surgery and invasive procedures
•
Before any dental surgery or other invasive procedure
within the oral cavity, hemostasis management should
be individually planned under the advisement of a
hematologist.
•
Systemic or topical antibrinolytics (i.e., tranexamic acid or
EACA) are eective as adjunct treatment in the management
of dental interventions pre- and postoperatively and have
the potential to reduce the need for factor replacement
therapy.
•
Antibiotics should only be prescribed if clinically indicated
for management of infection.
•
Local hemostatic measures such as wound suture, topical
antibrinolytics, oxidized cellulose, and brin sealant
should be used as appropriate whenever possible following
a dental extraction.
•
Patients must be advised to immediately report any
prolonged bleeding and/or diculty speaking, swallowing,
or breathing following dental surgery to the hematologist/
dental surgeon as this can be life-threatening. ose who
are not in hospital must report to the nearest emergency
centre without delay.
•
For many dental procedures, adequate local anesthesia
is necessary, and most dental injections can be delivered
safely.
•
Higher-risk intramuscular oral injections may require
systemic hemostatic measures. ese measures should
be established preoperatively under advisement of a
hematologist.
•
Alternative low-risk routes of delivery such as
intraligamentary single-tooth anesthesia (STA) or buccal
inltration injections are eective alternatives to inferior
alveolar nerve blocks (IDB).
•
Other nonsurgical dental procedures carry variable levels
of bleeding risk. Most restorative dental procedures such as
dental llings are low risk and can be carried out without
the need for factor replacement therapy.
•
Minimally invasive buccal inltration or intraligamentary
injections and techniques to protect so tissues should
be used, and standard local measures to aid mucosal
hemostasis should be applied as appropriate.
•
Professional dental cleanings can be provided with the
use of antibrinolytic agents, if necessary.
WFH Guidelines for the Management of Hemophilia, 3rd edition34
RECOMMENDATION 2.7.7:
•
For patients with hemophilia, the WFH recommends that
dental extraction or other invasive procedures within the
oral cavity (e.g., dental implantation, periodontal surgery,
or gum biopsy) be performed only with a personalized
plan for hemostasis management in consultation with
a hematologist.
RECOMMENDATION 2.7.8:
•
For patients with hemophilia, the WFH recommends
the use of systemic or topical tranexamic acid or epsilon
aminocaproic acid (EACA) as adjunct treatment in
the management of dental interventions pre- and
postoperatively, to reduce the need for factor replacement
therapy.
RECOMMENDATION 2.7.9:
•
For patients with hemophilia requiring dental extractions,
the WFH recommends local hemostatic measures.
Typical procedures include wound suture, topical use of
antibrinolytics, oxidized cellulose, and brin sealant,
applied as appropriate.
•
REMARK: Patients should be advised to maintain a
so diet and undertake careful brushing around the
wound site for a minimum of 3-5 days postoperatively
to avoid disturbing the clot and
wound healing within the tooth socket.
RECOMMENDATION 2.7.10:
•
For patients with hemophilia, the WFH recommends
appropriate local anesthesia for dental treatments as
an essential part of pain and anxiety management.
Most dental injections pose a low risk for patients with
hemophilia when delivered by a dental care professional
using local anesthesia with a vasoconstrictor, and when
the agent is delivered slowly with a single-use ne-gauge
needle.
RECOMMENDATION 2.7.11:
•
For patients with hemophilia requiring higher-risk
intramuscular oral injections commonly associated
with the provision of surgical dentistry (such as inferior
alveolar dental block [IDB], superior alveolar nerve block,
or injections in the oor of the mouth or vascular lingual
tissues), the WFH recommends systemic hemostatic
measures preoperatively to avoid the risk of hematoma.
ese measures should be established in consultation
with the hematologist.
•
REMARK: e availability and eectiveness of alternative
low-risk routes of local anesthetic delivery (such as
intraligamentary single-tooth anesthesia, or buccal
inltration injections with 4% articaine) are eective
alternatives to IDB and permit dental procedures in
primary and permanent mandibular molar teeth.
RECOMMENDATION 2.7.12:
•
For patients with hemophilia, the WFH recommends
the use of antibrinolytic agents as eective adjunct
treatment in the management of dental hygiene therapies
that facilitates access to regular dental care delivered
by a dental hygienist.
RECOMMENDATION 2.7.13:
•
In patients with hemophilia, the WFH asserts that the
presence of blood-borne infections does not aect the
safety of dental treatment as stringent universal cross-
infection procedures are now mandatory across all
disciplines of dentistry and recommends the provision
of full dental services regardless of infectivity or
immunological status.
2.8 Transition from pediatric to adult care
•
At dierent life stages, people with hemophilia and their
caregivers go through transitions that involve transfer of
care beyond the family, such as when a young person with
hemophilia starts school, a new sport or leisure activities,
and adolescence, and when moving from pediatric to
adult medical care, moving away from home, starting new
relationships, and making career choices.
•
Parents and/or caregivers typically assume primary
responsibility for the management of care for children and
adolescents with hemophilia; in particular, for administering
treatment and maintaining adherence to therapeutic
regimens.
•
Two transition periods are particularly challenging for
treatment adherence: when adolescents switch to self-
treatment; and when young adults move away from home
and assume full responsibility for self-care. Many children
and adolescents with hemophilia on prophylaxis who
receive excellent comprehensive care do not experience
the serious sequelae of their disorder, which may result
in complacency in young adulthood.
•
Ideally, young people with hemophilia should obtain
the necessary knowledge and skills for self-management
before transitioning to adult care; however, many young
Chapter 2: Comprehensive Care of Hemophilia 35
people still require parental assistance with hemophilia
care even in their later teenage years.
•
Adherence to prophylaxis has been found to be suboptimal
in many adolescents (13-17 years of age) and young adults
(18-30 years of age) with hemophilia.
•
In general, the main barriers to adherence to prophylaxis
include high perceived burden of treatment; no or low
burden of bleeds and symptoms; venous access diculties;
and viewing prophylaxis as complicated and time-
consuming.
•
In adolescents and young adults with hemophilia in
particular, barriers to treatment adherence include:
–
low symptom burden;
–
forgetfulness and lack of basic self-management
skills such as treatment routines;
–
lack of knowledge about hemophilia, including low
perceived benet of prophylaxis;
–
inability to identify and act on bleeds;
–
disease denial;
–
the desire to be “normal”;
–
perceived negative impact on activities and social
participation;
–
lack of transition planning;
–
diculties with self-treatment; and
–
challenges communicating with a hemophilia
treatment centre to receive optimal care.
•
e transition to adulthood, with increased independence
in living situations (e.g., living alone or away at college/
university) and nancial responsibilities, may be particularly
challenging for young adults with hemophilia.
•
Hemophilia treatment centres and healthcare providers
can play an important role in helping young people with
hemophilia maintain treatment adherence as they make
the transition to adulthood, by ensuring that patient
education encompasses knowledge and technical skills
and development of self-ecacy and self-management
skills including psychosocial coping.
•
As no definitive systematic approach to transition
from pediatric to adult care has yet been dened, the
comprehensive care team should continuously assess and
follow up on individual needs, preferences, and barriers
to treatment adherence with age-appropriate, tailored
support.
• Key components of transition strategies include:
–
development of a structured transition plan;
–
monitoring with systematic assessments of a patient’s
readiness;
–
individualized support; and
–
added support when switching to self-treatment or
moving away from home.
•
In addition, readiness self-assessment tools, such as the
HEMO-Milestones tool, may be useful for promoting
a standardized approach to assess self-management
competency.
•
Outcome indicators for assessing the eectiveness of
transition from pediatric to adult hemophilia care include:
–
measurement of adherence;
–
any change in bleeding rate;
–
self-ecacy skills;
–
hemophilia knowledge;
–
patient and caregiver satisfaction;
–
time gap between last pediatric and rst adult clinic
visit; and
–
number of emergency room or hospital
admissions.
•
Self-management programs available on the Internet may
also help to support young people with hemophilia in their
transition to adult care.
•
See Chapter 6: Prophylaxis in Hemophilia and Chapter
11: Outcome Assessment.
RECOMMENDATION 2.8.1:
•
Children and adolescents with hemophilia should
be supported with ongoing education and skills
development, including the ability to self-infuse and
other self-ecacy skills, to gain necessary hemophilia
knowledge for self-management of their condition before
they make the transition from pediatric to adult care.
•
REMARK: e comprehensive care team should support
young patients and their families through the transition
period. When possible, the rst visit should be performed
by both the pediatric and adult hematologists.
RECOMMENDATION 2.8.2:
•
For adolescents with hemophilia on prophylaxis, the
WFH recommends individual education and training,
ideally from a hemophilia nurse coordinator, to ensure
adequate knowledge of hemophilia, and to support
prophylaxis adherence and self-care management.
is should include understanding measurements of
adherence, as well as factors and risks that can lead to
changes in bleeding rates.
RECOMMENDATION 2.8.3:
•
For adolescents 12-18 years of age with hemophilia,
the WFH recommends age-specic hemophilia camps
to foster peer group support and develop their self-
infusion skills and understanding of the importance
of adherence to treatment.
WFH Guidelines for the Management of Hemophilia, 3rd edition36
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45. Khair K, Meerabeau L, Gibson F. Self-management and skills
acquisition in boys with haemophilia. Health Expect. 2015;18(5):1105-
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46. Genentech. HEMLIBRA® (emicizumab-kxwh) injection for
subcutaneous use [U.S. prescribing information]. South San Francisco,
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47. Shima M, Nogami K, Nagami S, et al. A multicentre, open-label
study of emicizumab given every 2 or 4 weeks in children with severe
haemophilia A without inhibitors. Haemophilia. 2019;25(6):979-987.
48. Pierce GF, Hart DP, Kaczmarek R. WFH Coagulation Product Safety,
Supply, and Access (CPSSA) Committee of the World Federation of
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agents in newborns and infants [letter to the editor]. Haemophilia.
2019;25(5):e334-e335.
49. European Medicines Agency. European public assessment report:
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summary_en.pdf. Accessed February 13, 2020.
50. Blanchette VS, Key NS, Ljung LR, et al. Denitions in hemophilia:
communication from the SSC of the ISTH. J romb Haemost.
2014;12(11):1935-1939.
51. Lee Mortensen G, Strand AM, Almen L. Adherence to prophylactic
haemophilic treatment in young patients transitioning to adult care: a
qualitative review. Haemophilia. 2018;24(6):862-872.
52. Sholapur NS, Barty R, Wang G, Almonte T, Heddle NM. A survey of
patients with haemophilia to understand how they track product used
at home. Haemophilia. 2013;19(5):e289-e295.
53. Banchev A, Goldmann G, Marquardt N, et al. Impact of telemedicine
tools on record keeping and compliance in haemophilia care.
Hamostaseologie. 2019;39(4):347-354.
54. Mondorf W, Eichler H, Fischer R, et al. Smart Medication, an electronic
diary for surveillance of haemophilia home care and optimization of
resource distribution. Hamostaseologie. 2019;39(4):339-346.
55. Leone JR. Utility of a wireless, handheld monitoring system in
the management of hemophilia patients. Comput Inform Nurs.
2011;29(9):521-522.
56. Cuesta-Barriuso R, Lopez-Pina JA, Nieto-Munuera J, Sagarra-Valls
G, Panisello-Royo JM, Torres-Ortuno A. Eectiveness of the Medtep
Hemophilia online platform for adherence to prophylactic treatment
in haemophilia patients: results from a 1-year observational study.
Haemophilia. 2018;24(3):452-459.
57. Neunert CE, Miller KL, Journeycake JM, Buchanan GR. Implantable
central venous access device procedures in haemophilia patients
without an inhibitor: systematic review of the literature and institutional
experience. Haemophilia. 2008;14(2):260-270.
58. Valentino LA, Ewenstein B, Navickis RJ, Wilkes MM. Central venous
access devices in haemophilia. Haemophilia. 2004;10(2):134-146.
59. Ljung R. e risk associated with indwelling catheters in children with
haemophilia. Br J Haematol. 2007;138(5):580-586.
60. Ragni MV, Journeycake JM, Brambilla DJ. Tissue plasminogen activator
to prevent central venous access device infections: a systematic
review of central venous access catheter thrombosis, infection and
thromboprophylaxis. Haemophilia. 2008;14(1):30-38.
61. Khair K, Ranta S, omas A, Lindvall K. PedNet study group.
e impact of clinical practice on the outcome of central venous
access devices in children with haemophilia. Haemophilia.
2017;23(4):e276-e281.
62. Gouw SC, van den Berg HM, Fischer K, et al. Intensity of factor
VIII treatment and inhibitor development in children with severe
hemophilia A: the RODIN study. Blood. 2013;121(20):4046-4055.
63. Roussel NA. Gaining insight into the complexity of pain in patients with
haemophilia: state-of-the-art review on pain processing. Haemophilia.
2018;24(Suppl 6):3-8.
64. Lander JA, Weltman BJ, So SS. EMLA and amethocaine for reduction of
children’s pain associated with needle insertion. Cochrane Database Syst
Rev. 2006;3:CD004236.
65. Rogers TL, Ostrow CL. e use of EMLA cream to decrease
venipuncture pain in children. J Pediatr Nurs. 2004;19(1):33-39.
66. Celik G, Ozbek O, Yilmaz M, Duman I, Ozbek S, Apiliogullari S.
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controlled, crossover study. Int J Med Sci. 2011;8(7):623-627.
67. Vallejo L, Pardo A, Gomis M, Gallach JE, Perez S, Querol F. Inuence of
aquatic training on the motor performance of patients with haemophilic
arthropathy. Haemophilia. 2010;16(1):155-161.
68. Humphries TJ, Kessler CM. Managing chronic pain in adults
with haemophilia: current status and call to action. Haemophilia.
2015;21(1):41-51.
69. Holstein K, Klamroth R, Richards M, et al. Pain management in patients
with haemophilia: a European survey. Haemophilia. 2012;18(5):743-752.
70. Rattray B, Nugent DJ, Young G. Celecoxib in the treatment of
haemophilic synovitis, target joints, and pain in adults and children
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71. Tsoukas C, Eyster ME, Shingo S, et al. Evaluation of the ecacy and
safety of etoricoxib in the treatment of hemophilic arthropathy. Blood.
2006;107(5):1785-1790.
72. Eyster ME, Asaad SM, Gold BD, Cohn SE, Goedert JJ, Second
Multicenter Hemophilia Study Group. Upper gastrointestinal bleeding
in haemophiliacs: incidence and relation to use of non-steroidal anti-
inammatory drugs. Haemophilia. 2007;13(3):279-286.
73. Rodriguez-Merchan EC. Musculoskeletal complications of hemophilia.
HSSJ. 2010;6(1):37-42.
74. Scully C, Diz Dios P, Giangrande P. Oral Care for People with
Hemophilia or a Hereditary Bleeding Tendency, 2nd ed.. Treatment of
Hemophilia Monograph No. 27. Montreal, Canada: World Federation
of Hemophilia; 2008. https://www1.w.org/publication/les/pdf-1164.
pdf. Accessed November 21, 2019.
75. Kalsi H, Nanayakkara L, Pasi KJ, Bowles L, Hart DP. Access to primary
dental care for patients with inherited bleeding disorders. Haemophilia.
2012;18(4):510-515.
76. Friedman M, White B, Dougall AJ. An audit of the protocol for the
management of patients with hereditary bleeding disorders undergoing
dental treatment. J Disab Oral Health. 2009;10(4):151-155
77. American Academy of Pediatric Dentistry. Guideline on caries-risk
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Pediatr Dent 2015;37(Special issue):132-139.
78. Tonetti MS, Jepsen S, Jin L, Otomo-Corgel J. Impact of the global
burden of periodontal diseases on health, nutrition and wellbeing of
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79. Nakagawa Y, Shimada Y, Kinai E, et al. Long-handle toothbrush
for haemophiliacs with severe elbow arthropathy. Haemophilia.
2015;21(6):e481-e483.
80. Hermans C, Altisent C, Batorova A, et al. Replacement therapy for
invasive procedures in patients with haemophilia: literature review.
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658.
81. Coetzee MJ. e use of topical crushed tranexamic acid tablets
to control bleeding aer dental surgery and from skin ulcers in
haemophilia. Haemophilia. 2007;13(4):443-444.
82. Franchini M, Rossetti G, Tagliaferri A, et al. Dental procedures in adult
patients with hereditary bleeding disorders: 10 years experience in three
Italian hemophilia centers. Haemophilia. 2005;11(5):504-509.
83. Hewson I, Makhmalbaf P, Street A, McCarthy P, Walsh M. Dental
surgery with minimal factor support in the inherited bleeding disorder
population at the Alfred Hospital. Haemophilia. 2011;17(1):e185-e188.
84. Dougall A, Pughe G. A multi centre prospective study audited the
outcome of adverse events following buccal inltration injections for
patients with a range of bleeding disorders. Haemophilia. 2016;22:82.
WFH Guidelines for the Management of Hemophilia, 3rd edition38
85. Dougall A, Apperley O, Smith G, Madden L, Parkinson L, Daly B.
Safety of buccal inltration local anaesthesia for dental procedures.
Haemophilia. 2019;25(2):270-275.
86. Dougall A, Hayes M, Daly B. A systematic review of the use of local
analgesia in medically compromised children and adolescents. Eur Arch
Paediatr Dent. 2017;18(5):331-343.
87. Breakey VR, Ignas DM, Warias AV, White M, Blanchette VS, Stinson
JN. A pilot randomized control trial to evaluate the feasibility of an
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youth with haemophilia. Haemophilia. 2014;20(6):784-793.
88. Witkop M, Guelcher C, Forsyth A, et al. Treatment outcomes, quality of
life, and impact of hemophilia on young adults (aged 18-30 years) with
hemophilia. Am J Hematol. 2015;90(Suppl 2):S3-S10.
89. Campbell F, Biggs K, Aldiss SK, et al. Transition of care for adolescents
from paediatric services to adult health services. Cochrane Database Syst
Rev. 2016;4:CD009794.
90. Croteau SE, Padula M, Quint K, D’Angelo L, Neufeld EJ. Center-based
quality initiative targets youth preparedness for medical independence:
HEMO-Milestones tool in a comprehensive hemophilia clinic setting.
Pediatr Blood Cancer. 2016;63(3):499-503.
91. Sun HL, Breakey VR, Straatman L, Wu JK, Jackson S. Outcomes
indicators and processes in transitional care in adolescents with
haemophilia: a Delphi survey of Canadian haemophilia care providers.
Haemophilia. 2019;25(2):296-305.
SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting
Information section.
39
Steve Kitchen
1
| Francisco de Paula Careta
2
| Silmara A. de Lima Montalvão
3
| Emna Gouider
4
|
Radoslaw Kaczmarek
5
| Claude T. Tagny
6
| Pierre Toulon
7
| Glenn F. Pierce
8
| Alok Srivastava
9
1
Department of Coagulation, Sheffield Haemophilia and Thrombosis Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
2
Department of Pharmacy and Nutrition, Federal University of Espirito Santo Alegre, Alegre, ES, Brazil
3
INCT do Sangue Hemocentro UNICAMP, University of Campinas, Campinas, SP, Brazil
4
Medical School, University of Tunis El Manar, Hemophilia Centre, Aziza Othmana Hospital, Tunis, Tunisia
5
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
6
Department of Hematology, Faculty of Medicine and Biomedical Sciences, University of Yaounde I and University Teaching Hospital of
Yaoundé, Yaoundé, Cameroon
7
Service d’Hématologie Biologique, Université Côte d’Azur and Hôpital Pasteur – CHU Nice, Nice, France
8
World Federation of Hemophilia, Montreal, QC, Canada
9
Department of Haematology, Christian Medical College, Vellore, India
All statements identied as recommendations are
consensus based, as denoted by
.
3.1 Introduction
•
Different bleeding disorders may have very similar
symptoms; therefore, a correct diagnosis is essential to
ensure that a patient receives the appropriate treatment.
•
An accurate diagnosis can only be made with the support
of a comprehensive and reliable laboratory service. is
is dependent on the laboratory following strict protocols
and procedures, which require:
–
knowledge and expertise in coagulation laboratory
testing;
–
use of the correct equipment and reagents; and
–
quality assurance (QA).
•
For detailed information on technical aspects and specic
instructions on screening tests and factor assays, please
consult Diagnosis of Hemophilia and Other Bleeding
Disorders: A Laboratory Manual, current edition, published
by the World Federation of Hemophilia (WFH).
RECOMMENDATION 3.1.1:
•
e WFH recommends that testing for diagnosis and
monitoring of hemophilia must be carried out by sta
with knowledge and experience in coagulation laboratory
testing using equipment and reagents that have been
validated for this specic purpose.
•
REMARK: Details of laboratory tests for the diagnosis
and monitoring of hemophilia are described in the WFH
laboratory manual.
3.2 Coagulation laboratory testing
Principles of diagnosis
•
Diagnosis of hemophilia is based on the following three
principles:
–
understanding the clinical features of hemophilia
and the appropriateness of the clinical diagnosis;
–
using screening tests such as prothrombin time (PT)
and activated partial thromboplastin time (APTT)
or platelet function tests to identify the potential
cause of bleeding (keeping in mind that normal
screening test results do not exclude the possibility
of a clinically relevant bleeding disorder being
present); and
–
conrming the diagnosis by factor assays and other
appropriate specic investigations.
Technical aspects
Preparation of the patient prior to taking a blood
sample
•
Fasting is not necessary before collection of blood for
investigation of possible bleeding disorders.
•
Whenever possible, patients should avoid medications that
can aect test results such as acetylsalicylic acid (ASA),
which can severely aect platelet function for 7-10 days.
3
LABORATORY DIAGNOSIS
AND MONITORING
WFH Guidelines for the Management of Hemophilia, 3rd edition40
•
Levels of factor VIII (FVIII) and von Willebrand factor
(VWF) may be temporarily elevated by strenuous exercise,
stress, or inammation enough to aect the accuracy
of diagnosis. Factor VIII/ VWF levels increase during
pregnancy.
RECOMMENDATION 3.2.1:
•
In preparation for collection of a blood sample for
determination of prothrombin time (PT), activated
partial thromboplastin time (APTT), or FVIII/FIX
activity, the WFH advises that patients with hemophilia
may maintain their regular diet—overnight fasting is
not necessary prior to blood draw.
•
REMARK: High levels of lipid in the plasma may
aect the determination of clotting times when using
coagulometers with optical systems.
RECOMMENDATION 3.2.2:
•
In preparation for collection of a blood sample for
determination of APTT or FVIII/FIX activity, the
WFH recommends that patients with hemophilia avoid
strenuous exercise prior to blood draw.
•
REMARK: Strenuous exercise or stress can temporarily
elevate FVIII activity of patients with mild hemophilia
A into the reference range; therefore, patients should
be rested for a few minutes prior to venipuncture.
Sample collection
•
e blood sample should be collected as per standard
guidelines.
•
The sample should preferably be collected near the
laboratory to ensure quick transport, and it should remain
capped during transport.
•
Results of tests can change according to the interval
between collection and testing and according to sample
storage conditions. Higher temperatures (>25°C) lead
to loss of FVIII activity over time, whereas cold storage
(2-8°C) may lead to cold activation of several proteolytic
systems. Storage of blood samples before processing
at 2-8°C can lead to loss of FVIII and VWF sucient to
cause unaected patients to be misdiagnosed with von
Willebrand disease (VWD).
•
Specific guidance is available in relation to sample
collection. Venipuncture must be aseptic, and the sample
must be collected within 1 minute of tourniquet application
without prolonged venous stasis.
•
Blood should be withdrawn into a plastic syringe or an
evacuated collection system. e needle should be 19-
21 gauge for adults and 22-23 gauge for small children.
Collection through peripheral venous catheters or non-
heparinized central venous catheters can be successful for
many hemostasis tests.
•
Blood from an indwelling catheter should be avoided for
some coagulation tests, particularly if platelet aggregation
testing is being performed.
•
Frothing of the blood sample should also be avoided. It is
only necessary to discard the rst 2 mL of blood collected
if blood is collected through a catheter.
•
e sample should be collected in citrate tubes containing
0.105M-0.109M (c3.2%) aqueous trisodium citrate
dihydrate, maintaining the proportion of blood to citrate at
a 9:1 ratio. If the tube contains less than 90% of the target
volume, results may be adversely aected, and prolongation
of PT and APTT is expected when tubes contain less than
80% of target volume.
•
Patients with an elevated hematocrit above 55% have a
reduced plasma volume leading to an exponential increase
in PT and APTT with increasing hematocrit, which can be
avoided by adjusting the ratio of blood to anticoagulant.
•
Results of some PT and APTT tests are dierent if samples
are collected into 3.8% trisodium citrate. e sample
should be mixed promptly and adequately with citrate
solution by gentle inversion 3 or 4 times.
•
If platelet-poor plasma (PPP) is frozen for future testing, the
storage conditions aect the stability of the frozen material.
If the sample is frozen at −70°C, it may be stored for up
to six months. Storage at −20°C is usually inadequate.
•
Frozen samples must be thawed rapidly in a water bath for
4-5 minutes at 37°C to avoid formation of cryoprecipitate.
Preparation of platelet-poor plasma (PPP)
• Most coagulation tests require the use of PPP.
• PPP should be prepared as per standard guidelines.
•
The residual platelet count in PPP depends on the
centrifugation conditions including adverse eects on
platelet function testing if refrigerated centrifuges are
used since cold can activate platelets.
•
PPP may be kept at room temperature (20-25°C) prior
to testing.
•
Plasma that has been hemolyzed during collection and
processing should not be used for platelet function testing,
APTT testing, or related testing, irrespective of which
method and instrument are used for analysis. PT
and brinogen testing are less aected, and only gross in
vitro hemolysis may be relevant. Adding hemolysate
to plasma in vitro may give misleading results.
•
Sample acceptance criteria should take into account the
risks from rejection (and delayed or missing test results)
Chapter 3: Laboratory Diagnosis and Monitoring 41
against the risks of acceptance and testing (and the degree
to which sample artefacts may or may not inuence clinical
management).
RECOMMENDATION 3.2.3:
•
For the diagnosis and monitoring of hemophilia A and
B, the WFH recommends that blood samples be labelled
immediately with the patient’s rst and last name, an
identication number or date of birth, and the date
and time of specimen collection. is should be done
before leaving the side of the patient.
• REMARK: ere is no consensus on whether the tube
should be labeled immediately before or immediately
aer blood collection.
RECOMMENDATION 3.2.4:
•
The WFH recommends that blood samples for
determination of PT, APTT, or FVIII/FIX activity
be collected in citrate tubes containing 0.105-0.109M
(around 3.2%) aqueous trisodium citrate dihydrate,
capped during processing, and kept at 18-25°C during
transport and storage. Blood samples should be
centrifuged at ambient temperature for a minimum
of 1700 g for at least 10 minutes, and either be analyzed
within 8 hours of collection (4 hours for FVIII:C) or
stored deep frozen at −35°C or lower.
• REMARK: Storage of citrated whole blood samples at
2-8°C should be avoided as this may result in loss of
FVIII activity.
•
REMARK: Platelet poor plasma (PPP) samples can be
stored at −35°C for up to 3 months and at −70°C for
up to 6 months prior to determination of FVIII/FIX
activity. Storage of PPP at −20°C is usually inadequate.
Freezers with auto-defrost should not be used to store
PPP prior to determination of PT, APTT, or FVIII/
FIX activity.
RECOMMENDATION 3.2.5:
•
The WFH recommends that blood samples for
determination of PT, APTT, or FVIII/FIX activity
should be rejected and replaced if the collection tube
contains less than 80% of the target ll volume.
•
REMARK: If the collection tube contains between 80%
and 90% of its target ll volume, the results obtained
using certain methods may have minor artefactual
prolongation of PT and APTT and minor artefactual
reduction in FVIII/FIX activity.
RECOMMENDATION 3.2.6:
•
The WFH recommends that blood samples for
determination of APTT or FVIII/FIX activity should
be rejected and replaced if in vitro hemolysis or clotting
have occurred during the collection and processing of
the sample.
•
REMARK: e impact of in vitro hemolysis on PT is
insucient to aect patient management.
•
REMARK: Samples from patients with in vivo hemolysis
that have been collected for determination of PT, APTT,
or FVIII/FIX activity can be accepted and tested.
Endpoint detection
•
Many laboratories now have some form of semior fully
automated coagulation analyzers. Accurately detecting
the clotting endpoint using a manual technique requires
considerable expertise, particularly if clotting time is
prolonged or if brinogen concentration is low, and the
clot is thin and wispy.
•
For manual testing, the tube should be tilted 3 times every
5 seconds through an angle of approximately 90° during
observation. e tube should be immersed in a water bath
at 37°C between tilting.
Screening tests
•
Platelet count, PT, and APTT may be used to screen a
patient suspected of having a bleeding disorder.
•
e sensitivity of both PT and APTT tests to factor
deciencies are inuenced by the type of reagents used
to perform the test.
RECOMMENDATION 3.2.7:
•
For laboratory investigation of patients being assessed
due to clinical suspicion of hemophilia A, the WFH
recommends that prothrombin time testing also be
performed using a laboratory reagent containing human
tissue factor.
•
REMARK: Hemophilia A is sometimes excluded despite
clinical suspicion of its presence. Such cases may have
other factor deciencies. Some patients with certain FVII
defects may have symptoms similar to mild hemophilia
but may display normal PT and FVII activity if the
laboratory reagent contains non-human tissue factor
so that the diagnosis would be missed.
RECOMMENDATION 3.2.8:
•
For laboratory investigation of patients being assessed
due to clinical suspicion of hemophilia, the WFH
recommends that an APTT result within the reference
WFH Guidelines for the Management of Hemophilia, 3rd edition42
range not be used to rule out the presence of mild
hemophilia A or B.
•
REMARK: In some cases of mild hemophilia A or B,
APTT may be within the normal range.
•
Bleeding time testing lacks sensitivity and specicity, and
it is also prone to performance-related errors. erefore,
other tests of platelet function such as platelet aggregometry
are preferred when available.
•
Based on the results of these tests, the category of bleeding
disorder may be partially characterized to guide subsequent
analysis (see Table 3-1).
•
ese screening tests may not detect abnormalities in
patients with mild bleeding disorders, including some
variants of VWD, some cases of genetically conrmed
mild hemophilia A or B, defects of platelet function, FXIII
deciency, and those rare defects of brinolysis which may
be associated with a bleeding tendency.
Correction studies
•
Abnormal screening tests may be further investigated
using correction or mixing studies.
•
Correction or mixing studies using pooled normal
plasma (PNP) may help to dene whether prolonged
coagulation times are due to factor deciency or circulating
anticoagulants or inhibitors.
•
e APTT of a patient/normal plasma mix may initially be
normal and then progressively prolonged on incubation
in the presence of a time-dependent inhibitor (e.g., many
acquired autoantibodies against FVIII), although this
pattern can be variable in cases with complex kinetics.
•
Correction studies with FVIII/FIX-decient plasma may
be used to identify the particular deciency if a factor
assay is not available.
RECOMMENDATION 3.2.9:
•
e WFH recommends that an APTT result within the
normal range obtained in a sample containing an equal
volume mixture of patient and pooled normal plasma
that was analyzed immediately aer preparation of
that mixture should not be used to rule out the possible
presence of an FVIII inhibitor.
•
REMARK: e APTT of an equal volume mixture of
patient and pooled normal plasma becomes substantially
prolonged over a period of 1 to 2 hours of incubation
at 37°C if the patient sample contains a neutralizing
anti-FVIII inhibitor.
Factor assays
•
Several types of FVIII assay including chromogenic and
uorogenic clotting assays are available. One-stage
clotting assays based on APTT are the most commonly
used techniques in most regions.
•
FVIII- and FIX-decient plasma must completely lack
FVIII and FIX, respectively, i.e., it must contain < 1 IU/
dL and have normal levels of other clotting factors.
•
e level of clotting factors in pooled normal plasma
varies substantially between pools, therefore, a system
of international units (IUs) has been established for
continuity and traceability. Factor levels are reported in
international units, either per mL or per decilitre (IU/dL).
If IU/dL is used, then results are not interchangeable with
percentage (%) of pooled normal plasma.
•
Use of a single test plasma dilution leads to assay inaccuracy
in the presence of some inhibitors, including lupus
anticoagulants (LA), specic high-responding factor
inhibitors, and some anticoagulant drugs, and leads to
assay imprecision.
•
Assay calibration method can aect the quality of results.
When assaying test samples from patients with moderate
or severe hemophilia, an extended or separate calibration
curve may be needed. It is not acceptable to simply extend
the calibration curve by extrapolation without analyzing
additional dilutions of the calibration plasma.
•
Some cases of genetically conrmed mild hemophilia
A show normal FVIII activity when a one-stage assay is
TABLE 3-1 Interpretation of screening tests
Possible diagnosis PT APTT Platelet count
Normal Normal Normal Normal
Hemophilia A or B Normal Prolongedª Normal
VWD Normal Normal or Prolongedª Normal or reduced
Platelet defect Normal Normal Normal or reduced
Abbreviations: APTT, activated partial thromboplastin time; PT, prothrombin time; VWD, von Willebrand disease.
ªThe same pattern can occur in the presence of FXI, FXII, prekallikrein, or high molecular weight kininogen deficiencies.
Chapter 3: Laboratory Diagnosis and Monitoring 43
used for diagnosis but reduced activity in chromogenic
and two-stage clotting assays. e reverse can also
occur. is means that more than one type of FVIII
assay is needed to detect all forms of mild hemophilia A.
•
All patients with reduced FVIII activity and a possible
diagnosis of hemophilia A should have a full laboratory
assessment to rule out VWD. is is especially important
to dierentiate VWD Normandy from mild hemophilia
A since both have a normal level of VWF antigen usually
associated with a reduced FVIII activity.
•
Chromogenic FIX assays are becoming more available,
and one study has reported that a chromogenic FIX assay
may correlate better with the clinical picture than a one-
stage assay in some hemophilia B cases.
•
rombin generation tests have been used in characterizing
hemophilia but are not in widespread use.
RECOMMENDATION 3.2.10:
•
For laboratory investigation of patients being assessed
due to clinical suspicion of hemophilia A, the WFH
recommends the use of both the one-stage FVIII assay and
the chromogenic FVIII:C assay in the initial diagnostic
workup.
•
REMARK: Both assays should be performed even if
the result of one of the two assays shows FVIII activity
within the normal range.
•
REMARK: e one-stage FVIII assay requires the use
of FVIII-decient plasma containing less than 1 IU/dL
(<1%) FVIII activity and normal levels of other clotting
factors that can inuence APTT (brinogen, FII, FV,
FIX, FX, FXI, FXII, prekallikrein, and HMWK).
RECOMMENDATION 3.2.11:
•
For laboratory investigation of patients being assessed
due to clinical suspicion of hemophilia B, the WFH
recommends the use of the one-stage FIX assay in the
initial diagnostic workup.
•
REMARK: Data are currently insucient to make
recommendations on the role of the chromogenic FIX
assay in the initial diagnostic workup of hemophilia B.
•
REMARK: e one-stage FIX assay requires the use
of FIX-decient plasma containing less than 1 IU/dL
(<1%) FIX activity and normal levels of other clotting
factors that can inuence APTT (brinogen, FII, FV,
FVIII, FX, FXI, FXII, prekallikrein, and HMWK).
RECOMMENDATION 3.2.12:
•
For one-stage or chromogenic FVIII/FIX assays, the
reference/ standard plasma used for calibration, whether
commercially or locally prepared, must be traceable to
a WHO international standard, and results should be
reported in international units (IUs).
•
REMARK: Results should be reported as IU/mL or IU/dL.
•
REMARK: In principle, percentage is the appropriate
unit of activity only when the assay is performed using
pooled normal plasma as the reference plasma whose
activity is not traceable back to a WHO international
standard.
RECOMMENDATION 3.2.13:
•
For laboratory investigation due to clinical suspicion
of hemophilia using one-stage FVIII/FIX assays, the
WFH recommends analysis using 3 dierent dilutions
of test plasma samples.
•
REMARK: e results of the test and standard plasma
dilutions should be compared by parallel-line analysis.
One way to assess this is to calculate the coecient of
variation (CV) of the 3 results using the equation CV =
([standard deviation/ mean] × 100). If the CV of the 3
results is less than 15%, then the average of the 3 results
should be reported. If the CV is greater than 15%, the
results should be scrutinized. Presence of pathological
inhibitors against specic clotting factors or lupus
anticoagulants can interfere with some one-stage FVIII
and FIX assays. Some therapeutic anticoagulants can
also show this interference eect. In all of these settings,
factor activity increases in the assay as the plasma is
increasingly diluted. Factor activity is underestimated
when the plasma is diluted less, and a more accurate
activity result is obtained when the test plasma is diluted
more.
RECOMMENDATION 3.2.14:
•
In populations where lupus anticoagulant occurs,
the WFH recommends the use of an APTT reagent
insensitive to lupus anticoagulant to perform one-stage
FVIII/FIX assays.
RECOMMENDATION 3.2.15:
•
For all one-stage FVIII/FIX assays, only the clotting
times of test sample dilutions that are within the range
covered by the calibration curve should be used to
calculate FVIII/FIX activity in the test sample.
•
REMARK: When assaying test samples from patients
with moderate or severe hemophilia A or B, an extended
or additional calibration curve may be needed. It is
not acceptable to extend the calibration curve by
WFH Guidelines for the Management of Hemophilia, 3rd edition44
extrapolation without analyzing additional dilutions
of the reference/calibration plasma.
RECOMMENDATION 3.2.16:
•
For all types of FVIII and FIX assays, an internal quality
control (IQC) sample should be included with each
batch of test samples analyzed. Results should only
be released for patient management purposes aer
conrmation that the IQC result is within the target
range for that material.
•
REMARK: A description of how to set target ranges for
IQC materials and handle out-of-range IQC results is
available in the WFH laboratory manual.
RECOMMENDATION 3.2.17:
•
For internal quality control samples with FVIII/FIX
activity in the range of 50-150 IU/dL, the between-assay
coecient of variation should be less than 10%.
•
REMARK: Some studies have shown use of a stored
calibration curve to be associated with higher between-
assay CVs than use of a new calibration curve generated
alongside patient samples.
Post-FVIII/FIX infusion monitoring
•
Lower than expected recovery and/or reduced half-life
of infused clotting factor concentrates (CFCs) may be an
early indicator of the presence of inhibitors.
•
For samples containing FVIII or FIX CFCs, results of FVIII
or FIX assays may vary according to whether a one-stage
or chromogenic assay is used for analysis and sometimes
according to the specic reagents or kits used in the assay.
•
If factor assays are used to conrm ecacy of treatment or
to make dose adjustments, bear in mind that some assays
are unsuitable for monitoring some products.
•
Using an assay that markedly overestimates activity
compared to the expected results from the labelled potency
of the concentrate could lead to undertreatment and
clinical risk.
•
A full consensus on the tolerable degree of dierence in
results from dierent assays before patient management is
adversely aected has not been established at the time of
this writing; in the meantime, assays that give results that
dier by more than 25-30% from the labelled potency of
the concentrate vial are best avoided or, in any case, should
not be used without taking account of such dierences.
•
Routine in-house assays can be used for post-infusion
monitoring, provided that the local assay system (method
and reference/ calibrator) is included in the manufacturer’s
guidance. Any local assay should be veried for use with
the specic CFC being used.
•
A number of articles have reviewed the published evidence
related to use of specic assays for monitoring specic
extended half-life (EHL) and unmodied CFCs.
•
One-stage assays used to monitor the single-chain
recombinant FVIII molecule lonoctocog alfa (Afstyla®)
underestimated relative potency by 45% whereas
chromogenic assay recovered the expected values
which led to a recommendation that chromogenic assay
is preferred, and that one-stage assay results should be
multiplied by a conversion factor of 2 to determine the
patient’s FVIII activity level. Such an approach did not
fully correct for reagent dierences, and some experts
have specically recommended against using an assay
known to give discrepant values and multiplying the
result by a correction factor in this way. Since there may
be lot-to-lot variation in reagents used for factor assays,
any such conversion factor should be veried for the lot
numbers in use.
•
ere are numerous published assay studies comparing
results in samples containing CFCs including EHL FVIII
and FIX concentrates. Despite this, there are a number
of one-stage and chromogenic assay reagents that have
not been studied for use with some CFCs at the time of
this writing. e reader is referred to the references in
Table 3-2 (FVIII) and Table 3-3 (FIX) to see the evidence
supporting the recommendations below.
RECOMMENDATION 3.2.18:
•
For monitoring replacement therapy with FVIII or FIX
concentrates, the WFH recommends that laboratories
use a FVIII/FIX assay that has been validated for use
with the specic concentrate used for treatment.
•
REMARK: This recommendation is particularly
important for modied molecular forms of FVIII and
FIX.
RECOMMENDATION 3.2.19:
•
For monitoring replacement therapy with plasma-derived
FVIII concentrates, the WFH recommends use of a
one-stage or chromogenic FVIII assay calibrated with
a plasma standard traceable to a WHO international
standard.
RECOMMENDATION 3.2.20:
•
For monitoring replacement therapy with clotting factor
concentrates containing full-length recombinant FVIII,
the WFH recommends use of a one-stage or chromogenic
Chapter 3: Laboratory Diagnosis and Monitoring 45
TABLE 3-2 Publications with data related to the use of different FVIII assays in the presence of
recombinant and modified factor VIII concentrates
Product type Brand name
International non-
proprietary name References
Full-length recombinant Advate
®
, Kogenate
®
FS,
Kovaltry
®
Octocog alfa Church (2018)
66
, Kitchen (2016)
67
, Kitchen
(2016)
68
, Turecek (2016)
69
BDD FVIII NovoEight
®
Turoctocog alfa Viuff (2011)
70
BDD FVIII ReFacto AF
®
Moroctocog alfa Kitchen (2016)
68
, Jacquemin (2018)
71
, Cauchie
(2013)
72
, Morfini (2003)
73
, Ingerslev (2004)
74
,
Santoro (2009)
75
BDD FVIII fused to Fc
portion of IgG1
Elocta
®
/Eloctate
®
Efmoroctocog alfa Powell (2012)
76
, McCue (2015)
77
, Sommer
(2014)
78
, Kitchen (2019)
79
B-domain-truncated FVIII
with site-specific 40 kDa
polyethylene glycol moiety
Esperoct
®
Turoctocog alfa pegol Hillarp (2017)
80
, Pickering (2016)
81
, Persson
(2019)
82
, Ezban (2019)
83
, Hegemann (2019)
84
,
Tiefenbacher (2019)
85
BDD FVIII with site-specific
60 kDa polyethylene glycol
Jivi
®
Damoctocog alfa pegol Church (2018)
66
, Gu (2014)
86
Full-length recombinant
FVIII with non-site-specific
20 kDa pegylation
Adynovate
®
/Adynovi
®
Rurioctocog alfa pegol Turecek (2016)
69
, Bulla (2017)
87
, Weber (2017)
88
Single-chain recombinant
FVIII
Afstyla
®
Lonoctocog alfa St Ledger (2018)
62
, Bowyer (2017)
64
Recombinant BDD porcine
FVIII
Obizur
®
Susoctocog alfa Turecek (2016)
69
, Vanguru (2018)
89
Note: Therapeutic products are denoted by both their international non-proprietary name and their brand name because of the latter’ s more
common usage and recognition by the community.
Abbreviations: BDD, B-domain- deleted; FVIII, factor VIII; kDA, kilodalton.
TABLE 3-3 Publications with data related to the use of different FIX assays in the presence of
recombinant and modified factor IX concentrates
Product type Brand name
International non-
proprietary name References
Recombinant Not identified Not identified Wilmot (2014)
90
Recombinant FIX fused to
Fc portion of IgG1
Alprolix
®
Eftrenonacog alfa Kershaw (2018)
54
, Sommer (2014)
91
,
Bowyer (2019)
92
Recombinant fusion
protein linking FIX to
albumin
Idelvion
®
Albutrepenonacog alfa Horn (2019)
51
, Bowyer (2019)
92
Recombinant FIX with
site-directed 40 kDa
pegylation
Refixia
®
/Rebinyn
®
Nonacog beta pegol Bowyer (2016)
52
, Rosen (2016)
93
, Tiefenbacher
(2017)
94
, Ezban (2019)
95
Note: Therapeutic products are denoted by both their international non-proprietary names and their brand names because of the latter’ s more
common usage and recognition by the community.
Abbreviations: FIX, factor IX; IgG1, immunoglobulin G1; kDA, kilodalton.
WFH Guidelines for the Management of Hemophilia, 3rd edition46
FVIII assay calibrated with a plasma standard traceable
to a WHO international standard.
RECOMMENDATION 3.2.21:
•
For monitoring replacement therapy with efmoroctocog
alfa (recombinant FVIII fused with human
immunoglobulin G1 [rFVIIIFc]; Elocta®/Eloctate®), the
WFH recommends use of a one-stage or chromogenic
FVIII assay calibrated with a plasma standard traceable
to a WHO international standard.
RECOMMENDATION 3.2.22:
•
For monitoring replacement therapy with turoctocog alfa
pegol (recombinant B-domain-truncated FVIII with a
site-specic 40-kDa polyethylene glycol group [N8-GP];
Esperoct®), the WFH recommends use of a chromogenic
FVIII assay or APTT-based one-stage FVIII assay with
validated reagents, including some ellagic acid activator
reagents (Actin®, Actin® FS, SynthAFax™, DG Synth™)
and some silica activator reagents (Pathromtin® SL,
SynthASil™), calibrated with a plasma standard traceable
to a WHO international standard.
•
REMARK: One-stage FVIII assays with APTT-SP™,
STA®-PTT Automate, or TriniCLOT™ APTT HS reagents
signicantly underestimate true FVIII activity of N8-GP
and should not be used.
RECOMMENDATION 3.2.23:
•
For monitoring replacement therapy with damoctocog
alfa pegol (recombinant B-domain-deleted FVIII with
a site-specic 60 kDa branched polyethylene glycol
group [BDD-rFVIII]; Jivi®), the WFH recommends
use of a chromogenic FVIII assay or APTTbased one-
stage FVIII assay with validated reagents, including
the ellagic acid activator reagent Actin® FSL and some
silica activator reagents (Pathromtin® SL, SynthASil™),
calibrated with a plasma standard traceable to a WHO
international standard.
•
REMARK: One-stage FVIII assays with the ellagic
acid activator reagent Actin® FS or the kaolin activator
reagent C.K. Prest® signicantly overestimate true FVIII
activity and should not be used. One-stage FVIII assays
with APTT-SP™ and STA®-PTT Automate reagents
signicantly underestimate true FVIII activity and
should not be used.
RECOMMENDATION 3.2.24:
•
For monitoring replacement therapy with rurioctocog
alfa pegol (full-length recombinant FVIII with non-
site-specic 20-kDa polyethylene glycol; Adynovate®/
Adynovi®), the WFH advises that more laboratory assay
studies are required to inform recommendations about
laboratory monitoring.
•
REMARK: ere are conicting ndings in the literature
assessing the use of one-stage and chromogenic FVIII
assays in samples containing rurioctocog alfa pegol.
RECOMMENDATION 3.2.25:
•
For monitoring replacement therapy with lonoctocog alfa
(single-chain recombinant FVIII [rVIII-SingleChain];
Afstyla®), the WFH recommends use of a chromogenic
FVIII assay calibrated with a plasma standard traceable
to a WHO international standard.
•
REMARK: e summary of product characteristics
recommends chromogenic assays. It also states that
the one-stage FVIII assay result underestimates the
FVIII activity level by approximately 45% compared to
the chromogenic assay result, and suggests that if the
one-stage assay is used, the result should be multiplied
by a factor of 2.
RECOMMENDATION 3.2.26:
•
For monitoring replacement therapy with plasma-
derived FIX concentrates, the WFH recommends use
of a one-stage or chromogenic FIX assay calibrated with
a plasma standard traceable to a WHO international
standard.
RECOMMENDATION 3.2.27:
•
For monitoring replacement therapy with clotting factor
concentrates containing unmodied recombinant FIX,
the WFH recommends use of a one-stage FIX assay
calibrated with a plasma standard traceable to a WHO
international standard.
•
REMARK: Chromogenic FIX assays have been reported
to underestimate the FIX activity of recombinant FIX
concentrate.
RECOMMENDATION 3.2.28:
•
For monitoring replacement therapy with
erenonacog alfa (recombinant FIX fused with human
immunoglobulin G1 [rFIXFc]; Alprolix®), the WFH
recommends use of a chromogenic FIX assay or APTT-
based one-stage FIX assay with validated reagents,
including some ellagic acid activator reagents (Actin®,
Actin® FS, Actin® FSL), some silica activator reagents
(Pathromtin® SL, SynthASil™), and a polyphenol activator
Chapter 3: Laboratory Diagnosis and Monitoring 47
reagent (Cephascreen®), calibrated with a plasma standard
traceable to a WHO international standard.
•
REMARK: One-stage FIX assays with STA®-PTT
Automate or kaolin activator (C.K. Prest®) reagents
signicantly underestimate true rFIXFc (Alprolix®)
activity and should not be used.
RECOMMENDATION 3.2.29:
•
For monitoring replacement therapy with
albutrepenonacog alfa (recombinant FIX fused with
recombinant human albumin [rFIX-FP]; Idelvion®),
the WFH recommends use of an APTT-based one-
stage FIX assay with validated reagents, including some
silica activator reagents (Pathromtin® SL, SynthASil™),
calibrated with a plasma standard traceable to a WHO
international standard.
•
REMARK: One-stage FIX assays with the ellagic acid
activator reagent Actin® FS or the kaolin activator reagent
C.K. Prest® signicantly underestimate true rFIX-FP
(Idelvion®) activity and should not be used. One-stage
assays with the ellagic acid activator SynthAFax™ reagent
or chromogenic FIX assays signicantly overestimate true
rFIX-FP (Idelvion®) activity and should not be used.
RECOMMENDATION 3.2.30:
•
For monitoring replacement therapy with nonacog beta
pegol (recombinant FIX with a 40-kDa polyethylene
glycol moiety [N9-GP]; Rexia®/Rebinyn®), the WFH
recommends use of a chromogenic FIX assay or APTT-
based one-stage FIX assay with validated reagents,
including the ellagic acid activator reagent SynthAFax™
or the polyphenol activator Cephascreen®, calibrated with
a plasma standard traceable to a WHO international
standard.
•
REMARK: Most one-stage FIX assays signicantly
overestimate or underestimate true FIX activity of
N9-GP and should not be used. One-stage assays using
the ellagic acid activator reagent SynthAFax™ or the
polyphenol activator reagent Cephascreen®, are suitable
for monitoring therapy with N9-GP.
Emicizumab
•
Emicizumab is an engineered bispecic antibody that
binds both human FIX/FIXa and FX/FXa and which is
not regulated by the mechanisms that regulate FVIII but
which acts as a FVIII mimetic.
•
e APTT is considerably shortened by emicizumab
to within or below the reference range irrespective of
reagents used, which means that emicizumab aects all
APTT-based laboratory tests and assays.
•
Emicizumab signicantly interferes in chromogenic
FVIII assays utilizing human FIXa and FX but not those
using FIXa and FX of bovine origin. Local verication is
needed for chromogenic kits containing bovine FX and
human FIXa.
•
Emicizumab can be measured and reported in g/mL
using a modied one-stage assay with higher test sample
dilution (in assay buer) and calibrated with emicizumab-
specic calibrators.
RECOMMENDATION 3.2.31:
•
For patients receiving emicizumab in whom conrmation
of expected emicizumab levels is required, the WFH
recommends use of a modied one-stage assay including
an additional pre-dilution step of test plasma and assay
calibration with specic emicizumab calibrators.
•
REMARK: Even at subtherapeutic levels of emicizumab,
APTT may be normal or subnormal in patients with
severe hemophilia A with or without inhibitors.
RECOMMENDATION 3.2.32:
•
For determination of FVIII activity in patients with
hemophilia A receiving emicizumab, the WFH
recommends use of a chromogenic FVIII assay containing
bovine FX.
•
REMARK: At therapeutic levels, emicizumab aects
any chromogenic FVIII assay containing FX of human
origin. Emicizumab may also aect chromogenic FVIII
assays containing FIXa of human and FX of bovine
origin but only at emicizumab levels higher than those
expected in patients receiving recommended doses.
RECOMMENDATION 3.2.33:
•
For determination of FVIII inhibitor levels in patients
receiving emicizumab, the WFH recommends use of
a chromogenic FVIII assay containing bovine FX.
RECOMMENDATION 3.2.34:
•
For patients with a suspected neutralizing anti-
emicizumab antibody, the WFH recommends measuring
emicizumab levels using a modied one-stage assay
including an additional pre-dilution step of test
plasma and assay calibration with specic emicizumab
calibrators.
•
REMARK: Validated anti-drug antibody assays may
also be used for this purpose, if available.
WFH Guidelines for the Management of Hemophilia, 3rd edition48
Inhibitor testing
•
e most frequently encountered functional inhibitors of
hemostasis are lupus anticoagulants, which are not directed
against specic clotting factors and whose presence should
be excluded prior to specic factor inhibitor testing.
•
Results of APTT testing on mixtures of test and normal
plasma can be dicult to interpret, particularly since in
acquired hemophilia there may initially be a full correction
of APTT even in the presence of a potent specic anti-FVIII
antibody. If anti-FVIII antibody is present, the APTT of
this mixture will be prolonged with incubation.
•
Most FVIII inhibitors that develop secondary to replacement
therapy in patients with hemophilia A show a characteristic
pattern: the APTT of a patient/PNP mixture is intermediate,
i.e., between the APTTs of the two materials, and it is
further prolonged when the mixture is incubated at 37°C
for 1-2 hours.
•
Conrmation that an inhibitor is directed against a specic
clotting factor requires a specic inhibitor assay.
•
Quantication of the inhibitor titer is performed in the
laboratory, preferably using the Nijmegen-modied
Bethesda assay for FVIII inhibitor testing, because this
modication oers improved specicity and sensitivity
over the original Bethesda assay.
•
e results of Bethesda inhibitor assays can be aected by
the use of dierent dilutions of test sample before those
dilutions are mixed with normal plasma.
•
For patients treated with FVIII or FIX, washout is no
longer necessary if a heat neutralization modication of
the Nijmegen-Bethesda assay is used, which inactivates
FVIII/FIX in the sample to allow detection of the
inhibitor. is is not required if FVIII/FIX is
<5 IU/dL in the test sample since this low level will not
have a signicant eect on inhibitor titer calculations.
•
Dierent types of FVIII assays can be used to determine the
FVIII during the Nijmegen-Bethesda inhibitor assay.
e protocol for the US national inhibitor program requires
a chromogenic assay to be used when positive FVIII
inhibitor results below 2.0 BU are observed. If there is
suspicion of lupus anticoagulant or if the sample contains
therapeutic anticoagulants such as heparin or direct FXa
or FIIa inhibitors, it may be useful to conrm inhibitor
presence using a chromogenic assay to measure residual
factor activity (instead of a one-stage assay).
•
An inhibitor titer of ≥ 0.6 BU/mL should be considered
clinically signicant.
•
Some non-neutralizing anti-FVIII antibodies which are
not detected by the Nijmegen-Bethesda assay may be
clinically relevant because they may increase the clearance
of FVIII and can be measured by ELISA.
RECOMMENDATION 3.2.35:
•
For determination of anti-FVIII inhibitors in a sample
containing greater than 5 IU/dL FVIII activity, the
WFH recommends that prior to testing, the sample
be heated to 56°C for 30 minutes and centrifuged at
ambient temperature for a minimum of 1700 g for at
least 5 minutes.
•
REMARK: e quantication limit of the Nijmegen-
Bethesda FVIII inhibitor assay is around 0.6 BU/mL.
•
REMARK: e Nijmegen-Bethesda FVIII inhibitor
assay requires use of buered pooled normal plasma
as a source of FVIII, which is then mixed with an equal
volume of FVIII-decient plasma to prepare the control
mixture.
RECOMMENDATION 3.2.36:
•
For determination of anti-FIX inhibitors in a sample
containing greater than 5 IU/dL FIX activity, the WFH
recommends that prior to testing, the sample be heated
at 56°C for 30 minutes and centrifuged at ambient
temperature for a minimum of 1700 g for at least 5
minutes.
RECOMMENDATION 3.2.37:
•
For quantication of anti-FVIII inhibitors, the WFH
recommends that the Nijmegen-Bethesda assay be used.
•
REMARK: Bethesda assays detect neutralizing antibodies.
A small proportion of anti-FVIII antibodies are non-
neutralizing, shorten the half-life of infused FVIII, and
are not detected by Bethesda assays.
•
REMARK: e Nijmegen modication describes a
specic method for buering pooled normal plasma;
other buering methods may be suitable.
RECOMMENDATION 3.2.38:
•
For quantication of FVIII and FIX inhibitors, the
WFH recommends that only residual FVIII/FIX activity
between 25% and 75% of the FVIII/FIX in the control
mixture be used to calculate inhibitor concentrations.
•
REMARK: e most accurate inhibitor results are
obtained when the residual FVIII/FIX activity is close
to 50% of the level in the control mixture.
RECOMMENDATION 3.2.39:
•
For quantication of low-titer anti-FVIII inhibitors
(<2 BU/mL), the WFH recommends use of a chromogenic
Chapter 3: Laboratory Diagnosis and Monitoring 49
Nijmegen-Bethesda FVIII assay to measure residual
FVIII activity.
•
REMARK: Use of a chromogenic Nijmegen-Bethesda
FVIII assay instead of a one-stage FVIII assay
provides greater specificity and reduces possible
variability in measurement of residual FVIII leading
to underestimation to the extent that a false positive
inhibitor is reported when no inhibitor is present.
Gene therapy
•
Discrepancies between results of one-stage and chromogenic
assays have been reported aer both FVIII and FIX gene
therapy.
•
Results of one-stage FVIII assays were approximately 1.65-
fold higher and 1.5-fold higher than chromogenic
assays for two dierent therapies with B-domain–deleted
(BDD) FVIII, which is in contrast to CFC-containing
BDD FVIII where chromogenic results are higher than
one-stage assay results.
•
Results of one-stage FIX assays varied according to reagents
used but were higher than results obtained in chromogenic
FIX assays in patients who had received FIX gene therapy
with a high specic activity FIX Padua variant.
RECOMMENDATION 3.2.40:
•
For quantication of FVIII activity in recipients of gene
transfer, the WFH advises that more research is necessary
to determine the relative accuracy of chromogenic and
one-stage assays in predicting hemostatic protection.
•
REMARK: e one-stage assay appears to consistently
produce FVIII activity results that are approximately 1.6-
fold greater than those obtained with the chromogenic
assay for multiple FVIII transgene products. Correlation
with both plasma and recombinant FVIII-specic
activity and clinical response may be needed for accurate
determination of FVIII activity in recipients.
RECOMMENDATION 3.2.41:
•
For quantication of FIX activity in recipients of gene
transfer, the WFH advises that more research is necessary
to determine the relative accuracy of chromogenic and
one-stage assays in predicting hemostatic protection.
•
REMARK: FIX Padua (R338L) has been utilized for FIX
gene therapy because it has a higher specic activity than
native FIX. e one-stage assay appears to consistently
produce FIX Padua activity results that are approximately
1.6-fold greater than those obtained with the chromogenic
assay. Correlation with both plasma and recombinant
FIX-specic activity is needed for accurate determination
of FIX Padua activity in recipients.
Trained personnel
•
A laboratory scientist/technologist with an interest in
coagulation must have an in-depth understanding of the
tests in order to achieve accurate results.
•
In some cases, it may be benecial to have a laboratory
scientist/ technologist who has had further training in a
specialist centre.
3.3 Use of correct equipment and
reagents
Equipment
•
e basic laboratory equipment requirements include a
37°C ± 0.5°C water bath for rapid thawing of frozen samples
and for performing manual tests on any samples where
automated analysis has failed, and calibrated automated
pipettes.
•
Plastic and glass consumables used in coagulation testing
should not be re-used.
•
Automated coagulometers oer signicant advantages
over manual methods of some semi-automates including
improved accuracy precision, repertoire and in some cases
automatic detection of pre-analytical problems.
Selection of coagulometers
•
Important considerations in the selection of coagulometers
include:
–
test repertoire;
–
operational requirements including service and
breakdown response;
–
throughput;
–
comparability between the results on the primary
analyzer and any back-up methods;
–
compatibility with blood sample tubes and plasma
storage containers in local use; and
–
safety.
•
Information is required in relation to the performance
characteristics of the system. is can be obtained from
a variety of sources including the published literature and
manufacturers’ data, but it may also require some form
of local assessment. Detailed guidance on selection and
assessment of analyzers is available.
WFH Guidelines for the Management of Hemophilia, 3rd edition50
Reagents
•
It is good practice to ensure continuity of the supply of
a chosen reagent, with attention paid to continuity of
batches and long shelf life. is may be achieved by asking
the supplier to batch hold for the laboratory, if possible.
•
Dierent reagent brands may have dierent sensitivities
and should not be run side by side, unless this is done for
a specic purpose.
•
A normal reference range should be dened for all methods.
Practical guidance on this is published, and for APTT
must take into account the sample collection and processing
conditions used locally.
3.4 Quality assurance
•
Quality assurance covers all aspects of the diagnosis process
from sample taking, separation and analysis, and internal
quality control (IQC) through to reporting of the result
and ensuring that it reaches the appropriate clinician
within an appropriate time.
Internal quality control
•
Internal quality control is used to establish whether a
series of techniques and procedures is being performed
consistently over a period of time.
•
IQC measures are taken to ensure that the results of
laboratory investigations are reliable enough to assist
clinical decision-making, monitor therapy, and diagnose
hemostatic abnormalities.
•
Graphical display of quality control results, for example in
the form of Levey-Jennings charts, may facilitate review
of trends in IQC results.
External quality assessment
•
External quality assessment (EQA) helps to identify the
degree of agreement between the local laboratory results
and those obtained by other centres.
•
e WFH International External Quality Assessment
Scheme (IEQAS) is specically designed to meet the
needs of hemophilia treatment centres worldwide. is
scheme includes analyses relevant to the diagnosis and
management of bleeding disorders. Details of this scheme,
which is operated in conjunction with the U.K. National
External Quality Assessment Service (UK NEQAS) for
Blood Coagulation in Sheeld, U.K., can be obtained
from the WFH.
•
In order for a laboratory to attain a high level of testing
reliability and to participate successfully in an external
quality assessment program, the laboratory must have
access to appropriate reagents and techniques and an
appropriate number of adequately trained sta.
RECOMMENDATION 3.4.1:
•
The WFH strongly recommends that coagulation
laboratories implement quality assurance programs for
all laboratory systems to ensure quality adherence and
the reliability of laboratory blood testing procedures and
reporting for the diagnosis and treatment of hemophilia.
RECOMMENDATION 3.4.2:
•
For hemostasis screening tests, the WFH recommends
performing internal quality controls with at least two
levels of internal quality control samples (normal and
abnormal plasma samples) for all test batches at least
daily.
RECOMMENDATION 3.4.3:
•
e WFH strongly recommends that clinical laboratories
routinely participate in external quality assessment
for each assay used for the diagnosis and treatment of
hemophilia.
•
REMARK: Participation in the WFH International
External Quality Assessment Scheme (IEQAS) enables
laboratories to improve and standardize laboratory
testing for hemophilia.
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autoimmune antibody responses to FVIII characterized by surface
plasmon resonance. PLoS ONE. 2013;8(5):e61120.
119. Verbruggen B, Novakova I, Wessels H, Boezeman J, van den Berg M,
Mauser-Bunschoten E. e Nijmegen modication of the Bethesda
assay for factor VIII: C inhibitors: improved specicity and reliability.
romb Haemost. 1995;73(2):247-251.
120. Blanchette VS, Key NS, Ljung LR, et al. Denitions in hemophilia:
communication from the SSC of the ISTH. J romb Haemost.
2014;12(11):1935-1939.
121. Klintman J, Hillarp A, Berntorp E, Astermark J. Long-term anti-
FVIII antibody response in Bethesda-negative haemophilia A
patients receiving continuous replacement therapy. Br J Haematol.
2013;163(3):385-392.
122. Patil R, Chandrakala S, Parihar A, Mohite A, Shetty S. Role of lupus
anticoagulants in immediate acting inhibitor positivity in congenital
haemophilia A patients. romb Res. 2018;172:29-35.
123. Batty P, Moore GW, Platton S, et al. Diagnostic accuracy study of a
factor VIII ELISA for detection of factor VIII antibodies in congenital
and acquired haemophilia A. romb Haemost. 2015;114(4):804-811.
124. Hoauer CJ, Whelan SF, Hirschler M, et al. Anity of FVIII-specic
antibodies reveals major dierences between neutralizing and
nonneutralizing antibodies in humans. Blood. 2015;125(7):1180-1188.
125. Klintman J, Hillarp A, Doneld S, Berntorp E, Astermark J. Antibody
formation and specicity in Bethesda-negative brother pairs with
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126. Sahud M, Zhukov O, Mo K, Popov J, Dlott J. False-positive
results in ELISA-based anti FVIII antibody assay may occur with
lupus anticoagulant and phospholipid antibodies. Haemophilia.
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127. Irigoyen MB, Primiani L, Felippo M, et al. A ow cytometry evaluation
of anti-FVIII antibodies: correlation with ELISA and Bethesda assay.
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128. Kim SY, Kang SY, Lee WI. Comparative measurement of FVIII
inhibitors in hemophilia A patients using ELISA and the Bethesda assay.
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129. Rangarajan S, Walsh L, Lester W, et al. AAV5-factor VIII gene transfer
in severe hemophilia A. N Engl J Med. 2017;377(26):2519-2530.
130. Konkle BA, Stine K, Visweshwar N, et al. Updated follow-up of the Alta
study, a phase 1/2, open label, adaptive, dose-ranging study to assess
the safety and tolerability of SB-525 gene therapy in adult patients with
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131. Robinson M, George LA, Samelson-Jones BJ, et al. Activity of a FIX-
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chromogenic assay systems following PF-06838435 (SPK-9001) gene
delivery. Blood. 2018;132(Supplement 1):2198.
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programme, 2003-2008. Haemophilia. 2009;15(2):571-577.
SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting
Information section.
55
4
Megan Sutherland
1
| Carlos De Brasi
2
| Barbara A. Konkle
3
| Shrimati Shetty
4
| Glenn F. Pierce
5
|
Alok Srivastava
6
1
Manchester University Hospitals NHS Foundation Trust, Manchester, UK
2
Sección Genética Molecular de la Hemofilia, Instituto de Investigaciones Hematologicas and Instituto de Medicina Experimental,
CONICET – Academia Nacional de Medicina, Buenos Aires, Argentina
3
Bloodworks Northwest and Division of Hematology, Department of Medicine, University of Washington, Seattle, WA, USA
4
ICMR – National Institute of Immunohaematology, KEM Hospital, Mumbai, India
5
World Federation of Hemophilia, Montreal, QC, Canada
6
Department of Haematology, Christian Medical College, Vellore, India
All statements identied as recommendations are
consensus based, as denoted by
.
4.1 Introduction
•
Genetic assessment of hemophilia is important in dening
disease biology, establishing diagnosis in dicult cases,
predicting risk of inhibitor development, identifying female
carriers, and providing prenatal diagnosis, if desired.
•
Genotype analysis should be oered to all people with
hemophilia and their “at-risk” female family members.
•
Genetic testing strategies are led by the phenotypic
parameters measured by the coagulation laboratory in
addition to the family pedigree. erefore, it is essential that
the data are made available to the genetic testing laboratory.
An accurate interpretation of the underlying variant(s)
detected is dependent on the supporting phenotypic data
and family history for the patient.
•
Genetic counselling for people with hemophilia and their
families is an essential requirement prior to genetic testing.
is includes obtaining informed consent from the patient,
parent, or legal guardian, requiring both permission to
carry out testing as well as education to ensure that they
fully understand the testing procedure, the benets and
limitations of the test, and possible consequences of the
test results.
•
Genetic counselling should also provide information and
advice about prenatal diagnosis (PND), management of
pregnancy and delivery in hemophilia carriers, and pre-
implantation genetic diagnosis (PGD). It is important to
be aware of and follow the relevant laws governing such
procedures in the country where the service is being
provided.
•
Genetic testing will not always identify the underlying
variant associated with the hemophilia phenotype.
Genetic counselling should highlight this possibility to
the individual referred for genetic testing. (See Chapter 9:
Specic Management Issues – Carriers – Genetic counselling
– Psychosocial support.)
•
Genetic diagnostic laboratories should adhere to strict
protocols and procedures, which require:
–
knowledge and expertise in genetic laboratory
testing;
–
use of the correct investigative platforms;
–
knowledge and expertise in the interpretation of
the genetic variants identied in association with
hemophilia;
–
use of the correct interpretative platforms for
investigation of variants;
–
use of the correct nomenclature for description of
variants and the correct classication systems for
determining pathogenicity of variants;
–
internal quality control procedures;
–
participation in periodic accreditation, where
available; and
–
participation in external quality assessment schemes
(EQAS), where available.
•
e interpretation of the results of genetic testing should
be performed by scientists who have knowledge and
expertise in hemophilia genetics.
•
e opportunity for discussion of the genetic results
between the ordering clinician and reporting scientist is
an essential provision of the genetic diagnostic service.
RECOMMENDATION 4.1.1:
•
For people with hemophilia, the WFH recommends
that genetic testing be oered to identify the specic
GENETIC
ASSESSMENT
WFH Guidelines for the Management of Hemophilia, 3rd edition56
underlying genetic variant associated with their disorder.
RECOMMENDATION 4.1.2:
•
For obligate carriers of hemophilia and “at-risk” female
relatives of people with hemophilia or potential carriers
of hemophilia, the WFH recommends that genetic
testing be oered for the previously identied genetic
variant in the F8 or F9 gene.
RECOMMENDATION 4.1.3:
•
For females with low phenotypic coagulation FVIII or
FIX levels, the WFH recommends that investigation
of the genetic/epigenetic basis of the phenotype be
oered.
RECOMMENDATION 4.1.4:
•
For obligate carriers of hemophilia and “at-risk” female
relatives of people with hemophilia or potential carriers
of hemophilia, the WFH recommends the inclusion
of a detailed family pedigree to support the genetic
testing referral.
RECOMMENDATION 4.1.5:
•
For individuals with suspected hemophilia and potential
carriers of hemophilia, the WFH strongly recommends
that phenotypic screening for FVIII or FIX levels, von
Willebrand factor (VWF) antigen, and VWF activity
testing be performed prior to referral for genetic testing.
RECOMMENDATION 4.1.6:
•
For people with hemophilia, obligate carriers of
hemophilia, “at-risk” female relatives, or individuals
with low coagulation factor levels, the WFH strongly
recommends detailed genetic counselling prior to
oering genetic testing.
•
REMARK: Genetic counselling should include a
discussion of the experimental limits of the molecular
results according to the availability of practical
approaches.
•
REMARK: Genetic counselling should include a
discussion of the possibility of incidental ndings in
genes other than F8 or F9, if the methodology used
by the investigating laboratory (e.g., next generation
sequencing [NGS]) may detect such genetic variations.
•
REMARK: Genetic counselling should be performed
by a genetic counsellor when available. If no genetic
counsellor is available, a medical professional with
knowledge of genetics in hemophilia can provide genetic
counselling.
RECOMMENDATION 4.1.7:
•
For all patients referred for genetic testing, the WFH
strongly recommends that informed consent be obtained
from the patient, parent, or legal guardian. is requires
both permission to carry out testing and education to
ensure that they fully understand the testing procedure,
the benets and limitations of the test, and possible
consequences of the test results.
•
REMARK: Written informed consent may need to be
obtained and documented by the clinician or genetic
counsellor in compliance with local policies and practices.
4.2 Indications for genetic assessment
•
Genetic testing is generally sought in all aected cases
(probands) and “at-risk” female relatives within the family.
•
Ideally, the disease-causing variant should rst be identied
in the proband or the obligate carrier. All other potential
carriers may subsequently be screened for this variant to
conrm or exclude the carrier status.
•
If neither the proband nor the obligate carrier are available
for testing, the genetic assessment may still be performed
in potential carriers; however, when a disease-causing
variant is not detected, it should be clearly mentioned in
the report that failure to detect genetic variants with the
existing techniques does not exclude the carrier status.
•
Carriers of hemophilia exhibit a wide range of factor levels,
with approximately 30% having levels <40 IU/dL. Women
and girls with low or borderline levels can experience a
range of bleeding symptoms, usually consistent with mild
hemophilia, but hemarthrosis and more severe bleeding
symptoms can occur.
•
Besides the heterozygosity for the disease-causing variant,
low factor levels in carriers of hemophilia may be attributed
to other epigenetic factors such as X-chromosome
inactivation (XCI) or the ABO blood group system.
•
Pregnant women who are conrmed carriers of an F8 or F9
variant may be oered non-invasive testing to determine
the sex of the fetus they are carrying in order to inform
subsequent options for prenatal diagnosis in a male fetus.
is is achieved through analysis of cell-free fetal DNA
in the maternal plasma.
•
Prenatal diagnosis may be oered to all conrmed carriers
of an F8 or F9 variant who are carrying a male fetus in
Chapter 4: Genetic Assessment 57
early pregnancy by chorionic villus sampling or in late
pregnancy by late-gestation amniocentesis, in order to
guide the management of the delivery or to terminate
the pregnancy in case of an aected fetus. Genetic
counselling should include a discussion of the risk of the
PND procedure to the pregnancy.
•
Pre-implantation genetic diagnosis may be oered to
conrmed carriers of an F8 or F9 variant in order to select
an embryo that will not result in the birth of a male with
hemophilia.
•
It is important to be aware of and follow the relevant
laws governing genetic counselling and pre-implantation
genetic diagnosis in the country where the services are
being provided.
• Among all the genetic risk factors, the nature of disease-
causing variants in both F8 and F9 has been found to be
the strongest risk factors for inhibitor development. Null
variants, i.e., variants which result in total absence of the
protein (large deletions, duplications, insertions, inversions,
nonsense mutations, and splice-site variants), have shown
the strongest association with inhibitors as compared to
other variants (small in-frame deletions, duplications,
insertions, missense mutations). e response to
immune tolerance induction (ITI) therapy has also been
reported to be associated with the disease-causing variants
with the latter group showing good response to ITI as
compared to patients carrying null variants.
•
Some of the gene manipulation techniques (e.g., nonsense
mutation suppression and gene editing) may require prior
information of the disease-causing variants.
• Genetic assessment may be oered to:
–
all cases with clinically suspected hemophilia
or hemophilia cases with conrmed laboratory
diagnosis;
–
all obligate carriers to identify the molecular variant
for possible future prenatal diagnosis;
–
all at-risk female family members to establish
carrier status, which is critical for optimal prenatal
counselling and testing if indicated, or to oer pre-
implantation genetic diagnosis;
–
all symptomatic females (with low FVIII or FIX
levels) with no family history;
–
predict the risk of inhibitor development in
individuals with hemophilia;
–
predict the response to ITI therapy;
–
ascertain the feasibility of some gene manipulation
techniques.
• See Chapter 3: Laboratory Diagnosis and Monitoring.
RECOMMENDATION 4.2.1:
•
For people with suspected or established hemophilia
undergoing genetic testing, the WFH recommends that
the index case (pro-band) be genotyped to identify the
underlying genetic variant.
RECOMMENDATION 4.2.2:
•
For obligate carriers of hemophilia and “at-risk” female
relatives of the aected proband or potential carrier of
hemophilia, the WFH recommends genetic counselling
about their risk of being a carrier.
RECOMMENDATION 4.2.3:
•
For all obligate carriers of hemophilia and “at-risk”
female relatives of people with hemophilia or potential
carriers of hemophilia, the WFH recommends that
phenotypic coagulation factor levels be measured.
RECOMMENDATION 4.2.4:
•
For all obligate carriers of hemophilia and “at-risk”
female relatives of people with hemophilia, the WFH
recommends that genetic testing be oered for the
previously identied genetic variant in the F8 or F9
gene.
RECOMMENDATION 4.2.5:
•
For females with low phenotypic coagulation FVIII or
FIX levels, the WFH recommends that investigation
of the genetic/epigenetic basis of the phenotype be
oered.
RECOMMENDATION 4.2.6:
•
For pregnant females who are carriers of an F8 or
F9 variant and are carrying a male fetus, the WFH
recommends that prenatal diagnosis (PND) be oered
to determine the hemophilia status of the fetus.
•
REMARK: Genetic counselling should include a
discussion of the risk of the PND procedure to the
pregnancy.
•
REMARK: It is important to be aware of and follow the
relevant laws governing such procedures in the country
where the service is being provided.
RECOMMENDATION 4.2.7:
•
For families who wish to be prepared for a child with
hemophilia before birth or who wish to terminate an
aected fetus, the WFH recommends that prenatal
diagnosis (PND) by chorionic villus sampling or
amniocentesis be oered.
WFH Guidelines for the Management of Hemophilia, 3rd edition58
•
REMARK: It is important to be aware of and follow the
relevant laws governing such procedures in the country
where the service is being provided.
•
REMARK: PND may be oered in early pregnancy or
in late pregnancy by late-gestation amniocentesis in
order to guide the management of the delivery of an
aected child.
RECOMMENDATION 4.2.8:
•
For people with suspected or established hemophilia, the
WFH recommends that genetic testing be performed;
knowledge of the genetic variant may help predict the
risk of inhibitor development, response to immune
tolerance induction (ITI), and depth of phenotype
severity, as well as determine the availability of gene
manipulation techniques.
4.3 Strategy for genetic testing of
probands
•
Worldwide, approximately 30-45% of patients with severe
hemophilia A show an unusual type of structural variant
(SV), a large DNA inversion aecting the F8 intron 22
(i.e., the intron 22 inversion, Inv22).
•
e F8 intron 22 inversion originates almost exclusively
from male germ cells by an event of homologous
recombination between large inverted repeated sequences.
Reported evidence in the literature supports the fact that
almost all mothers of patients with the Inv22 are carriers
and that the Inv22 is the most prevalent cause for severe
hemophilia A worldwide.
•
A second recurrent inversion event causing approximately
2% of severe hemophilia A phenotypes worldwide is the
F8 intron 1 inversion (Inv1).
•
e remaining patients with severe, moderate, or mild
hemophilia A (i.e., uninformative for the common F8
inversions), as well as all patients with hemophilia B,
generally have small variants in F8 or F9, such as single
nucleotide substitutions, small insertions, duplications or
deletions, or, less frequently, large copy number variations
(CNVs).
•
Information about F8 and F9 variants is compiled in
internationally accessible databases, such as those developed
by the Centers for Disease Control and Prevention (CDC),
named CDC Hemophilia A Mutation Project (CHAMP)
and CDC Hemophilia B Mutation Project (CHBMP;
http://www.cdc.gov/ncbddd/hemophilia/champs.html),
and by the European Association for Haemophilia and
Allied Disorders (EAHAD) for F8 and F9.
RECOMMENDATION 4.3.1:
•
For male probands, the WFH recommends that genetic
testing be directed by the proband’s baseline phenotypic
coagulation factor level, which indicates the severity of
the disorder.
–
In patients with severe hemophilia A (FVIII:C
<1 IU/dL) or moderate hemophilia A with lower-
borderline factor activity levels (FVIII:C 1-3 IU/
dL), analysis of the F8 intron 22 inversion and the
F8 intron 1 inversion should be performed rst.
–
Patients with severe hemophilia A in whom
recurrent inversions (i.e., F8 intron 22 and intron
1 inversions) cannot be detected should undergo
screening and characterization of small variants,
including single nucleotide variants (SNV) and
small insertion, duplication, or deletion variants
covering the essential regions of F8 including
the 26 exons, exon/intron boundaries, and 5'
and 3' untranslated regions. If these tests are
still uninformative, patients should be screened
for copy number variants (CNV) including
large F8 deletions, duplications, or complex
rearrangements.
–
In patients with moderate (FVIII:C 1-5 IU/dL)
or mild (FVIII:C 5-40 IU/dL) hemophilia A,
screening and characterization of small variants
(i.e., SNV and small insertions, duplications,
or deletions) covering the essential regions
of F8 including the 26 exons, exon/intron
boundaries, and 5' and 3' untranslated regions
should be performed rst. If these tests are still
uninformative, patients should be screened for F8
CNV.
–
In all patients with hemophilia B (i.e., patients with
severe [FIX:C <1 IU/dL], moderate [FIX:C 1-5 IU/
dL], and mild [FIX:C 5-40 IU/dL] hemophilia B),
screening and characterization of small variants
(i.e., SNV and small insertions, duplications, or
deletions) covering the essential regions of F9
including the 8 exons, exon/intron boundaries, and
5' and 3'untranslated regions should be performed
rst. If these tests are still uninformative, patients
should be screened for F9 CNV.
Chapter 4: Genetic Assessment 59
4.4 Techniques for genetic assessment
•
The F8 gene is localized to the long arm of the X
chromosome at Xq28. F8 spans 187 kb of genomic DNA
and consists of 26 exons encoding a mRNA of 9.0 kb. e
mature FVIII protein has 2,332 amino acids.
•
The F9 gene is localized to the long arm of the X
chromosome at Xq27. F9 spans 33 kb of DNA and comprises
8 exons. F9 mRNA is 2.8 kb and encodes a pre-pro-protein
of 461 amino acids that is post-translationally processed
to yield a mature protein of 415 amino acids.
•
Dierent techniques (e.g., Southern blot, long-range and
inverse-shiing polymerase chain reaction [PCR]) can be used
for detection of the recurrent F8 intron 22 inversion.
e recurrent F8 intron 1 inversion can be detected by double
PCR or by inverse-shiing PCR. e approach and use
of a specic technique depend on the available technical
expertise and resources. All results should be conrmed
by repeat analytical testing of the DNA sample.
•
Depending on the availability of resources, full F8 or F9
gene screening is performed by PCR and Sanger sequencing,
or next-generation sequencing (NGS), for the detection of
missense, nonsense, splice-site, small and large deletions,
duplications, and insertions. Where resources are
limited, laboratories may choose a cost-eective screening
approach prior to Sanger sequencing, e.g., by heteroduplex
analysis using conformation sensitive gel electrophoresis
(CSGE).
•
When choosing an analytical technique, laboratories
must be aware of the sensitivity and specicity of the
approach used and the turn-around time for producing
an interpretive report. All results should be conrmed by
repeat analytical testing of the DNA sample.
•
e presence of a variant should be conrmed in both
5' (forward) and 3' (reverse) directions, specically in
heterozygous carriers, when analyzing variants detected
using Sanger sequencing.
•
In case of no amplication in a particular exon or in a
contiguous stretch during PCR, a large DNA deletion
may be suspected. is should be conrmed by standard
approaches such as gap-PCR or techniques which can
detect gene dosage or CNVs such as multiplex ligation-
dependent probe amplication (MLPA) or quantitative
real-time PCR on the deleted region. e conventional
Sanger sequencing techniques are not sensitive to pick up
CNVs in the case of carriers.
•
When a disease-causing variant is not detected, large
duplications or insertions may be suspected. ese can be
detected by applying the same methods as those employed
for identifying large deletions, as described above.
•
e technical approach for CNV analysis may depend on
the resources available to the laboratory. According to the
practical limitations of the technique, results should be
provided with an estimation of error, if applicable.
•
High-throughput sequencing techniques, e.g., NGS, should
only be used aer it is established that structural variants
can be detected by the technique.
•
All results of genetic testing should be conrmed by
independent testing of the DNA sample. is may be
accomplished either through a repeat of the original assay
or by using a dierent methodology, e.g., using Sanger
sequencing to conrm an NGS result.
•
During the technical process of taking a sample for prenatal
diagnosis, the fetal sample may get contaminated with
maternal blood which can lead to misdiagnosis. Dierent
techniques can be used for maternal cell contamination
testing depending on the available technical expertise and
resources. For example, multiple autosomal short tandem
repeat (STR) markers may be used. When choosing
an analytical technique, laboratories must be aware of the
sensitivity and specicity of the approach used and the
turn-around time for producing an interpretive report.
RECOMMENDATION 4.4.1:
•
For people with severe hemophilia A, or moderate
hemophilia A with lower-borderline factor activity levels
(FVIII:C 1-3 IU/dL), the WFH recommends testing for
the F8 intron 22 inversion and F8 intron 1 inversion in
the rst line of genetic testing.
•
REMARK: Dierent techniques can be used for detection
of the F8 intron 22 inversion and intron 1 inversion
depending on the available technical expertise and
resources.
•
REMARK: All results should be confirmed by
independent analytical testing of the DNA sample.
RECOMMENDATION 4.4.2:
•
For people with severe hemophilia A who are negative
for the common F8 intron 22 inversion and F8 intron
1 inversion variants, the WFH recommends full gene
screening of the essential regions of F8, including the
26 exons, splice boundaries, promoter, and 5' and 3'
untranslated regions.
•
REMARK: For example, depending on the availability
of resources, full F8 gene screening may take the form of
polymerase chain reaction (PCR) and Sanger sequencing
or next generation sequencing (NGS). Where resources
WFH Guidelines for the Management of Hemophilia, 3rd edition60
are limited, laboratories may choose a cost-eective
screening approach prior to Sanger sequencing.
•
REMARK: When choosing an analytical technique,
laboratories must be aware of the sensitivity and
specicity of the approach used and the turn-around
time for producing an interpretive report.
•
REMARK: e presence of a variant should be conrmed
in both 5' (forward) and 3' (reverse) directions,
specically in heterozygous carriers, when analyzing
variants detected using Sanger sequencing.
•
REMARK: All results should be confirmed by
independent analytical testing of the DNA sample.
RECOMMENDATION 4.4.3:
•
For people with hemophilia B, the WFH recommends full
gene screening of the essential regions of F9, including
the 8 exons, splice boundaries, promoter, and 5' and 3'
untranslated regions.
•
REMARK: For example, depending on the availability
of resources, full F9 gene screening may take the form of
polymerase chain reaction (PCR) and Sanger sequencing
or next generation sequencing (NGS). Where resources
are limited, laboratories may choose a cost-eective
screening approach prior to Sanger sequencing.
•
REMARK: When choosing an analytical technique,
laboratories must be aware of the sensitivity and
specicity of the approach used and the turn-around
time for producing an interpretive report.
•
REMARK: e presence of a variant should be conrmed
in both 5' (forward) and 3' (reverse) directions,
specically in heterozygous carriers, when analyzing
variants detected using Sanger sequencing.
•
REMARK: All results should be confirmed by
independent analytical testing of the DNA sample.
RECOMMENDATION 4.4.4:
•
For people with hemophilia A or B in whom no variant is
detectable on inversion analysis or full gene sequencing,
the WFH recommends that a large deletion or duplication
event be investigated.
•
REMARK: Copy number variation (CNV) analysis
may be performed using various validated techniques
dependent on the resources available to the laboratory.
According to the practical limitations of the technique,
results should be provided with an estimation of error,
if applicable.
•
REMARK: All results should be confirmed by
independent analytical testing of the DNA sample.
RECOMMENDATION 4.4.5:
•
For prenatal testing, the WFH recommends maternal
cell contamination testing of the fetal sample.
•
REMARK: Dierent techniques can be used for maternal
cell contamination testing depending on the available
technical expertise and resources. For example, multiple
autosomal short tandem repeat (STR) markers may
be used.
•
REMARK: When choosing an analytical technique,
laboratories must be aware of the sensitivity and
specicity of the approach used and the turn-around
time for producing an interpretive report.
4.5 Classification and description of
variants
•
e American College of Medical Genetics and Genomics
(ACMG) guidelines were developed to provide a
standardized approach and terminology for classication
of genetic variants in Mendelian disorders. When applied
across laboratories, they provide clinicians with useful
information on the likelihood that the variant impacts
gene function.
• Genetic diagnostics are critically dependent on accurate
and standardized descriptions and sharing of genetic
variants. e Human Genome Variation Society (HGVS)
maintains a sequence variant nomenclature system for this
purpose (http://www.HGVS.org/varnomen). Providing
corresponding F8 or F9 legacy nomenclature can be helpful
to the clinician for comparison to prior patient or family
clinical reports.
RECOMMENDATION 4.5.1:
•
e WFH recommends that variants be classied per the
American College of Medical Genetics and Genomics
(ACMG) guidelines.
•
REMARK: ClinGen, a U.S. National Institutes of Health-
funded resource dedicated to building a central resource
that denes the clinical relevance of genes and variants,
has assembled an international expert committee to
apply ACMG recommendations to F8 and F9 variants,
which should produce more hemophilia-specific
recommendations.
RECOMMENDATION 4.5.2:
•
e WFH recommends that variants be described
using the Human Genome Variation Society (HGVS)
nomenclature.
Chapter 4: Genetic Assessment 61
4.6 Interpretive reports
•
Clinical laboratory reports should include information to
allow correct identication of the patient and specimen,
report the variant using standardized nomenclature with
a genome reference, note limitations of the assay, and
provide an interpretation of the ndings in a manner that
will be helpful to the ordering clinician.
RECOMMENDATION 4.6.1:
•
e WFH recommends that interpretive reports contain:
–
patient information including patient name, date
of birth, ordering clinician, date of specimen
collection, diagnosis, baseline factor level, and
family pedigree;
–
description of the assay(s), references to the
literature (if applicable), limitations of the test,
and the genome reference sequence used for
analysis;
–
results including DNA variant(s) in Human
Genome Variation Society (HGVS) nomenclature
and American College of Medical Genetic and
Genomics (ACMG) variant classication; and
–
interpretation of test results in a format
useful to the ordering clinician, including
recommendations for follow-up testing if
indicated, implications of test results for patients
and family members, and the role of genetic
counselling.
RECOMMENDATION 4.6.2:
•
For all interpretive reports for all individuals undergoing
genetic testing for hemophilia, the WFH recommends
that the ordering clinician and reporting scientist be
available to discuss the potential phenotypic consequences
of the reported genotype, as required.
4.7 Strategies if causative variant is not
detected
•
Approximately 0.6% of patients with severe hemophilia A
and 2.9% of patients with moderate or mild hemophilia
A will have no identiable genetic variant in F8 genomic
DNA using current diagnostic methods, i.e., covering all
coding and regulatory regions of F8 but not deep intronic
sequences.
•
Approximately 1.1% of patients with moderate or mild
hemophilia B will have no identiable genetic variant in
F9 genomic DNA using current diagnostic methods that
exclude the screening of deep intronic sequences.
•
In patients with a clear diagnosis of hemophilia A and no
pathogenic variant identied in the F8 coding sequences,
analysis of intronic regions by sequencing or targeted
massively parallel sequencing (MPS) to the whole F8 is
an option to detect and analyze deep intronic variants
involved in splicing defects, which are suspected to account
for most of these patients’ phenotypes. Deep intronic
variants should be interpreted with caution, and functional
analysis of these variants would be desirable to demonstrate
their pathogenicity.
•
NGS platforms have been designed to cover dierent
needs. Among them, the My Life, Our Future platform
(https://www.mylifeourfuture.org) simultaneously analyzes
all small variants and the prevalent inversions causing
hemophilia A and B; the romboGenomics platform
(http://thrombo.cambridgednadiagnosis.org.uk) analyzes
63 genes associated with thrombotic, coagulation, and
platelet disorders; and the 23-gene NGS panel for inherited
bleeding coagulation disorders analyzes 23 genes known
to be associated with inherited bleeding disorders. e
latter two approaches complement the variant screening
with a separate testing of F8 inversions. Due to the wide
range of genes under analysis, the latter two platforms
are particularly useful to investigate the hidden cause of
bleeding in a patient lacking a proper diagnosis.
•
Whole-genome sequencing (WGS) can be considered
noting any limitations in detecting structural variation.
Linkage analysis may be considered for family studies.
•
Complex genomic rearrangements may be considered in
some individuals who present with an atypical phenotype.
ese patients, in whom a large genomic deletion including
part or all of F8 or F9 is suspected, should be referred to a
geneticist to evaluate the possible utility of a pangenomic
study. e presence of a contiguous gene syndrome can be
analyzed by cytogenetic microarray analysis.
•
In patients with a conrmed diagnosis of hemophilia
A and no F8 exonic or intronic pathogenic variant
detected, identication of specic micro-RNA expression
imbalances, either by ncRNA microarrays or RNA-seq
(MPS-based transcriptome), may represent the cause for
F8 downregulation and hemophilia A expression.
However, further research is still necessary to determine
the actual role of microRNAs in the pathogenesis of
hemophilia A.
•
Germline and somatic mosaicism may complicate any
genetic assessment in hemophilia.
WFH Guidelines for the Management of Hemophilia, 3rd edition62
•
In some cases, when testing for the familial variant in the
mother of a patient with hemophilia, the variant will not
be detected. In this instance, the possibility of mosaicism
should be considered.
•
In hemophilia A-aected probands where the mode
of inheritance is not conclusive, or in low-level female
probands, other potential diagnoses that need to be
investigated include:
–
type 2N VWD if only low FVIII:C level on the
phenotypic screen has been assessed;
–
combined FV and FVIII deciency caused by
pathogenic variants aecting LMAN1 or MCFD2
genes;
–
other types of VWD.
• See Chapter 3: Laboratory Diagnosis and Monitoring.
•
As X-chromosome-linked recessive disorders, hemophilia A
and B aect hemizygous males while heterozygous females
(carriers) do not typically express hemophilia symptoms.
However, in cases of symptomatic carriers, abundant
evidence has indicated that non-random and extremely
skewed X-chromosome inactivation plays central roles in
hemophilia pathogenesis. Furthermore, hemophilia
expression in female heterozygous carriers is caused by
the phase of the X-chromosome inactivation skewing,
preferentially silencing the normal F8 allele.
RECOMMENDATION 4.7.1:
•
For people in whom a strong diagnosis of hemophilia is
certain but no F8 or F9 variant is detected using current
diagnostic genetic testing, the WFH recommends that
other genetic causes be considered (e.g., deep intronic
variants).
• REMARK: Current testing techniques are expected to
evolve in the near future to include next generation
sequencing (NGS) and whole genome sequencing (WGS).
•
REMARK: NGS and WGS techniques should only be
used aer it is established that structural variants can
be detected by the technique.
RECOMMENDATION 4.7.2:
•
For “at-risk” female relatives of people with hemophilia
in whom the familial variant is not detected using
standard diagnostic genetic testing, particularly in
females with one aected child, the WFH recommends
that the possibility of mosaicism be considered and
discussed during genetic counselling.
RECOMMENDATION 4.7.3:
•
For people with hemophilia A in whom the mode of
inheritance is not conclusive, and in whom no inversion
or variant is detected by current diagnostic testing, the
WFH recommends that other potential diagnoses be
investigated, including type 2N von Willebrand disease
(VWD), combined FV and FVIII deciency, or other
types of VWD.
RECOMMENDATION 4.7.4:
•
For symptomatic females with low phenotypic coagulation
FVIII or FIX levels in whom just one pathogenic variant
is found, the WFH recommends performing investigative
tests for an X-chromosome inactivation pattern, if
locally available.
4.8 Quality assurance
•
Quality assurance (QA), as described in Chapter 3:
Laboratory Diagnosis and Monitoring – Quality assurance,
is an umbrella term used to describe all measures taken to
ensure the reliability of laboratory testing and reporting.
In genetic testing, this covers all aspects of the diagnostic
process from nucleic acid extraction and genetic analysis,
to the description and classication of the variant(s)
detected, and the production of an interpretive report to
the ordering clinician.
•
Internal Quality Control (IQC) of genetic tests should
routinely be performed to ensure the validity of any
variant(s) detected.
•
Genetics laboratories are strongly advised to participate in
External Quality Assessment Schemes (EQAS) to ensure
that the quality of their results identied, classied, and
interpreted, are in agreement with those obtained by other
laboratories. is may be by a formal EQAS or an informal
sample exchange between laboratories. Formal EQAS for
genomics are provided by, for example, Genomics Quality
Assessment (GenQA), and specically for hemophilia
genetic assessment by the U.K. National External Quality
Assessment Service (UK NEQAS) for Blood Coagulation.
•
Genetic diagnostic laboratories should undergo
periodic accreditation, if available, by an approved body.
Accreditation assesses the laboratory against internationally
agreed standards to ensure high-quality provision of the
genetic diagnostic service.
•
e formation of Genetics Laboratory Networks for those
providing genetic assessment of hemophilia, either within
Chapter 4: Genetic Assessment 63
countries or between those in regions of the world, enables
an opportunity for sharing of good practice and expertise.
RECOMMENDATION 4.8.1:
•
The WFH recommends that genetic diagnostic
laboratories should undergo periodic accreditation, if
available, by an approved body.
RECOMMENDATION 4.8.2:
•
e WFH recommends that internal quality control (IQC)
of genetic tests be performed and recorded routinely
within the laboratory.
RECOMMENDATION 4.8.3:
•
e WFH recommends that laboratories participate
in external quality assessment schemes (EQAS) for the
genetic tests they provide.
•
REMARK: Participation in an EQAS ensures the
provision of a test that is robust and reliable. is may
be through participation in a formal EQAS or an informal
sample exchange between laboratories.
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89. Sun P, Ma L, Diao G, Li CQ, Lin FZ. Application of indirect linkage
analysis and direct genotyping to hemophilia A carrier detection in
Sichuan, China. Genet Mol Res. 2015;14(3):8229-8235.
90. Jourdy Y, Chatron N, Carage ML, et al. Study of six patients with
complete F9 deletion characterized by cytogenetic microarray:
role of the SOX3 gene in intellectual disability. J romb Haemost.
2016;14(10):1988-1993.
91. Jourdy Y, Chatron N, Fretigny M, et al. Molecular cytogenetic
characterization of ve F8 complex rearrangements: utility for
haemophilia A genetic counselling. Haemophilia. 2017;23(4):e316-e323.
92. Janczar S, Kosinska J, Ploski R, et al. Haemophilia A and cardiovascular
morbidity in a female SHAM syndrome carrier due to skewed X
chromosome inactivation. Eur J Med Genet. 2016;59(1):43-47.
93. Lannoy N, Hermans C. Review of molecular mechanisms at distal Xq28
leading to balanced or unbalanced genomic rearrangements and their
phenotypic impacts on hemophilia. Haemophilia. 2018;24(5):711-719.
94. Sarachana T, Dahiya N, Simhadri VL, et al. Small ncRNA expression-
proling of blood from hemophilia A patients identies miR-1246 as a
potential regulator of factor 8 gene. PLoS ONE. 2015;10(7):e0132433.
95. Rosset C, Vieira IA, Salzano FM, Bandinelli E. A germline variant
aects putative miRNA-binding sites at the F8 3'UTR and acts as a
potential haemophilia A phenotype modier in Southern Brazilian
patients. Haemophilia. 2016;22(4):e327-e329.
96. Jankowska KI, McGill J, Pezeshkpoor B, Oldenburg J, Atreya CD, Sauna
ZE. Clinical manifestation of hemophilia A in the absence of mutations
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hemophilia A: a fairly common event. Am J Hum Genet. 2001;69(1):75-
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1042.
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SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting
Information section.
66
5
HEMOSTATIC
AGENTS
Steven W. Pipe
1
| Manuel Carcao
2
| Kim Chew
3
| Radoslaw Kaczmarek
4
| Steve Kitchen
5
|
Johnny Mahlangu
6
| Margareth C. Ozelo
7
| Ekawat Suwantaroj
8
| Jerzy Windyga
9
| Glenn F. Pierce
10
|
Alok Srivastava
11
1
Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, Michigan, USA
2
Department of Paediatrics, University of Toronto, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada
3
Kuala Lumpur, Malaysia
4
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
5
Department of Coagulation, Sheffield Haemophilia and Thrombosis Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield,
UK
6
Department of Molecular Medicine and Haematology, University of the Witwatersrand, National Health Laboratory Service,
Johannesburg, South Africa
7
INCT do Sangue Hemocentro UNICAMP, University of Campinas, Campinas, SP, Brazil
8
Bangkok, Thailand
9
Department of Hemostasis Disorders and Internal Medicine, Laboratory of Hemostasis and Metabolic Diseases, Institute of Hematology
and Transfusion Medicine, Warsaw, Poland
10
World Federation of Hemophilia, Montreal, QC, Canada
11
Department of Haematology, Christian Medical College, Vellore, India
All statements identied as recommendations are
consensus based, as denoted by
.
5.1 Introduction
•
Dierent types of hemostatic agents and coagulation
therapies are available for the management of hemophilia.
e wide range of product classes and types in use around
the world reects the evolution of hemophilia treatment
products and the variations in local healthcare resources
and capacities.
• Clotting factor concentrates (CFCs) are the treatment of
choice for people with hemophilia as they are very safe and
eective for treating and preventing bleeds. ere are two
main types of CFCs: virally inactivated plasma-derived
products made from plasma donated by human blood
donors; and recombinant products manufactured using
genetically engineered cells and recombinant technology.
•
e development of non-factor replacement therapies such
as emicizumab has recently begun to oer an alternative
treatment approach as such products become available
in clinical practice.
•
However, access to CFCs and emicizumab is limited in
many parts of the world; in some countries, healthcare
providers oen rely on locally produced blood products
such as cryoprecipitate and fresh frozen plasma (FFP) for
hemophilia treatment. However, these blood products
are less eective than CFCs and may contain viral and
bacterial pathogens. For this reason, where available,
viral-inactivated plasma-derived or recombinant CFCs
are preferred over cryoprecipitate and FFP.
•
Although advances have been made in the safety of such
blood products, the WFH’s position is that the products
of choice for hemophilia treatment are industrially
manufactured CFCs where they fulll the requirements
for pharmaceutical Good Manufacturing Practice (GMP).
•
e comprehensive WFH Guide for the Assessment of
Clotting Factor Concentrates describes the key elements that
aect the quality, safety, ecacy, licensing, and regulation
of factor products and the important principles involved in
selecting suitable products for the treatment of hemophilia.
•
e WFH also publishes and regularly updates the WFH
Online Registry of Clotting Factor Concentrates, which lists
all currently available products and their manufacturing
details.
RECOMMENDATION 5.1.1:
•
For patients with hemophilia, the WFH does not express
a preference for recombinant over plasma-derived
clotting factor concentrates.
•
REMARK: e choice between these classes of product
must be made according to local criteria including
availability, cost, and patient preferences.
Chapter 5: Hemostatic Agents 67
5.2 Product selection
•
Product selection should evaluate key requirements
including product safety and quality, purity, viral
inactivation, and ecacy.
Safety and quality
•
Currently manufactured plasma-derived CFCs produced
to GMP standards have an exemplary safety record
with respect to lipid-enveloped viruses, such as human
immunodeciency virus (HIV) and hepatitis C virus (HCV).
•
Product safety is the result of comprehensive measures
and improvements in several areas including:
–
donor selection (exclusion of at-risk donors);
–
screening of donations, including nucleic acid testing
(NAT);
–
a number of in-process viral inactivation and/or
removal steps, notably solvent-detergent and heat
treatment, and nanoltration for the removal of
some non-enveloped viruses and prions; and
–
post-marketing surveillance.
•
As new information evolves in this field, decision-
makers need to always be aware of current scientic
recommendations regarding choice of CFCs for people
with hemophilia.
•
When selecting plasma-derived CFCs, both plasma quality
and the manufacturing process need to be considered. e
WFH emphasizes the importance of assessment by the
ocial agencies responsible for protecting and promoting
public health (i.e., national regulatory authorities, health
agencies, or ministries of health) to ensure the quality,
safety, and ecacy of plasma-derived treatment products
for hemophilia.
• Two issues require special consideration:
–
purity of product; and
–
viral inactivation/elimination.
Purity
•
Purity of CFCs refers to the percentage of the desired
ingredient (i.e., factor VIII [FVIII] or factor IX [FIX])
relative to the other ingredients in the product.
•
ere is no universally accepted classication of products
based on purity, and CFCs on the market vary widely in
their purity. eir “specic activity” may be expressed
in international units (IU) per milligram (mg) and, for
example, can range from 10 to >100 IU/mg for FVIII.
•
Some products have high or very high purity at one stage
in the production process but are subsequently stabilized
by albumin, which decreases their nal purity.
•
In rare cases, lower-purity CFCs may give rise to adverse
or allergic reactions. Patients who experience repeated
allergic reactions with a particular product may benet
from the administration of an antihistamine immediately
prior to infusion or from the use of a higher-purity CFC.
•
Plasma-derived FVIII CFCs may contain variable amounts
of von Willebrand factor (VWF). erefore, it is important
to ascertain a product’s VWF content (as most commonly
measured by VWF activity assay) if it is used for the
treatment of von Willebrand disease (VWD) and not
hemophilia A.
•
For treatment of FIX deciency, a product containing
only FIX is more appropriate than prothrombin complex
concentrates (PCCs). PCCs also contain other clotting
factors such as factors II, VII, and X, some of which
may become activated during manufacture and may
predispose the patient to thromboembolism. Current
PCCs are considered safer than earlier products due to
the inclusion of coagulation inhibitors such as heparin,
antithrombin, and proteins C, S, and Z. Nevertheless, with
intensive treatment (e.g., during perioperative management),
prothrombotic clotting factors may accumulate in the plasma
and increase the risk for thromboembolic complications.
•
e viral safety of CFCs is not related to their purity,
provided that adequate viral elimination measures are
in place.
Viral inactivation/elimination
•
In-process viral inactivation is the single largest contributor
to the safety of plasma-derived CFCs.
•
Typically, two complementary or orthogonal-specic
viral reduction steps are incorporated into the CFC
manufacturing process. ese measures should follow
the regulations set by ocial regulatory agencies.
•
Solvent-detergent treatment is highly eective against
lipid-enveloped viruses such as hepatitis B virus (HBV),
HCV, and HIV, but this treatment does not inactivate non-
lipid-enveloped viruses such as hepatitis A virus (HAV)
and human parvovirus B19.
•
Heat treatment is generally eective against a broad range
of viruses, both with and without a lipid envelope, including
HAV and human parvovirus B19. However, the degree of
inactivation is dependent upon the temperature, time, and
whether heating occurs in the dry or wet state.
•
As non-enveloped viruses currently pose a greater challenge
than enveloped viruses to viral elimination during the
manufacturing process, any viral reduction/inactivation
process should ideally inactivate both lipid-enveloped and
non-lipid-enveloped viruses.
WFH Guidelines for the Management of Hemophilia, 3rd edition68
•
Inactivation of prions in plasma-derived CFCs is not
possible because the necessary techniques denature
coagulation factors; nor is there a reliable screening
test for variant Creutzfeldt–Jakob disease (vCJD). e
risk of prion-mediated disease through plasma-derived
products is currently being addressed by exclusion of
at-risk donors, leukoreduction of donations, and plasma
fractionation manufacturing steps including precipitation,
chromatography, and ltration.
RECOMMENDATION 5.2.1:
•
For people with hemophilia, the WFH recommends
the use of products that have been accepted by the
ocial regulatory agencies responsible for protecting
and promoting public health with consideration given
to the plasma quality (i.e., purity of the product) and
the manufacturing process (i.e., viral inactivation/
elimination).
•
REMARK: A plasma-derived product created by a
process that incorporates two viral reduction steps
should not automatically be considered better than one
that only has one specic viral inactivation step. If only
one step is used, this step should preferably inactivate
viruses with and without lipid envelopes. Most recently,
licensed products use two orthogonal viral inactivation/
elimination steps.
•
REMARK: Current prothrombin complex concentrates
should be considered safer than earlier products due to
the inclusion of coagulation inhibitors such as heparin,
antithrombin, and proteins C, S, and Z.
Efficacy
•
Product potency (the biological activity in terms of the
concentration or amount of the drug required to produce a
dened eect) and ecacy (the ability of a drug to produce
a desired therapeutic eect in patients) are also important
features for consideration in product selection.
•
Plasma-derived and conventional recombinant FVIII and
FIX CFCs with standard half-life (SHL) have been proven
to have similarly high clinical ecacy.
•
Recombinant CFCs with extended half-life (EHL) are
engineered to provide longer-lasting therapy than SHL
CFCs. (See “Extended half-life products” below.)
5.3 Clotting factor concentrates (CFCs)
•
The main treatment for severe hemophilia is CFC
replacement therapy with plasma-derived or recombinant
CFCs as they provide convenient high doses of clotting
factor for the treatment and prevention of bleeds.
•
See also Chapter 2: Comprehensive Care of Hemophilia,
Chapter 6: Prophylaxis in Hemophilia, Chapter 7:
Treatment of Specic Hemorrhages, and Chapter 9: Specic
Management Issues.
FVIII CFCs
•
All currently marketed plasma-derived and recombinant
FVIII products are listed in the WFH Online Registry of
Clotting Factor Concentrates. Consult the individual
product inserts for details.
Dosage/administration
•
FVIII CFCs are available in vials labelled with the product
potency expressed in IU, ranging from approximately
250-3000 IU per vial.
•
In the absence of an inhibitor, each IU of plasma-derived
or recombinant SHL FVIII per kilogram of body weight
infused intravenously will raise the plasma FVIII level by
approximately 2 IU/dL. is raise (also called recovery) is
dependent on several individual factors; most importantly,
the body mass index (BMI). It is higher in patients with a
high BMI and lower in those with a low BMI.
•
e half-life of SHL FVIII is approximately 12 hours in
adults; its half-life is shorter in younger children and
increases with age.
•
To calculate dosage, multiply the patient’s weight in
kilograms by the FVIII level in IU/dL desired, then multiply
by 0.5.
–
Example: 50 kg × 40 (IU/dL level desired) × 0.5 =
1000 IU of FVIII.
•
See Chapter 7: Treatment of Specic Hemorrhages and
refer to Table 7-2 for CFC replacement for dierent types
of hemorrhage.
•
FVIII CFCs should be infused slowly over several minutes
as specied in the product insert. e patient’s peak
factor level should be measured 15-30 minutes aer the
infusion to verify the expected FVIII activity level of the
dose given.
•
For patients undergoing surgery or those with severe bleeds
that require frequent infusions, laboratory monitoring of
FVIII levels is necessary, including measurement of FVIII
trough level to aid in the calculation of subsequent doses.
(See Chapter 3: Laboratory Diagnosis and Monitoring –
Factor assays, and Chapter 9: Specic Management Issues
– Surgery and invasive procedures.)
•
Subsequent doses should ideally be based on the FVIII
half-life and on the factor recovery in the individual
Chapter 5: Hemostatic Agents 69
patient for a particular product. However, the half-life
in individual patients cannot be predicted simply from
patient characteristics such as age and body weight and
typically requires empiric determination.
•
Guidelines for pharmacokinetic (PK) studies on new FVIII
CFCs include 10-11 blood samplings taken over a period
of 32-48 hours (additional samplings over up to 96 hours
or longer for EHL FVIII). However, for dose tailoring in
routine practice, useful PK parameters can be estimated
from population PK models which enable Bayesian
estimation of individual PK from limited samples.
•
See Chapter 6: Prophylaxis in Hemophilia and Chapter
7: Treatment of Specic Hemorrhages.
RECOMMENDATION 5.3.1:
•
For people with hemophilia receiving FVIII concentrates
who would benet from optimization of prophylaxis,
the WFH recommends individualized pharmacokinetic
monitoring.
•
REMARK: Peak factor level should be measured 15-30
minutes aer the infusion to verify calculated dose.
Plasma half-life can be determined via full PK (10-11
blood samplings taken over a period of 32-96 hours), or
with limited sampling in combination with population
PK estimates.
•
Continuous infusion of CFCs avoids peaks and troughs
and may be advantageous and more convenient in certain
clinical situations (e.g., major surgery or severe bleeding
episodes in patients with low-responding inhibitors).
However, the use of specically designated pumps and
knowledge of the stability of the particular CFC aer
reconstitution within the infusion device are required.
•
Continuous infusion may allow a reduction in factor
clearance, dosage, and the total quantity of CFCs used.
It can potentially be more cost-eective for patients with
severe hemophilia, depending on the doses used for
continuous and intermittent bolus infusions. However,
caution should be exercised if considering continuous
infusion for patients with mild hemophilia as this has been
associated with an increased risk of the development of
inhibitors, although the contribution of continuous
infusion alone may be confounded by the presence of
high-risk pathogenic variants in mild hemophilia A.
•
Doses for continuous infusion should be adjusted based on
frequent factor assays (usually once a day) and calculation of
clearance, noting that clearance of factor may be increased
immediately aer surgery or with severe bleeding (e.g.,
blood loss of >500 mL), whereby additional boluses of
CFCs may be required to maintain eective levels. For some
CFCs, stability can be demonstrated for up to 12 hours
aer preparing the solution; thus, continuous infusion
over several hours is possible.
RECOMMENDATION 5.3.2:
•
For patients with hemophilia receiving FVIII concentrates
where steady-state hemostatic correction is necessary for a
prolonged period of time (e.g., perioperative management
or in the case of a severe bleeding episode in a patient
with a low-responding inhibitor), the WFH recommends
consideration for use of continuous infusion.
•
REMARK: Continuous infusion may lead to a reduction
in the total quantity of clotting factor concentrates
used and can be more cost-eective in patients with
severe hemophilia. However, this cost-eectiveness
comparison can depend on the doses used for continuous
and intermittent bolus infusions.
•
REMARK: Continuous infusion requires the use of
specically designated pumps and knowledge of the
stability of the particular clotting factor concentrate aer
reconstitution within the infusion device, and patients
must be monitored frequently for pump failure.
FIX CFCs
•
All currently marketed plasma-derived and recombinant
FIX products are listed in the WFH Online Registry of
Clotting Factor Concentrates. Consult the individual
product inserts for details.
• FIX CFCs are categorized into two classes:
–
Pure FIX CFCs, which may be plasma-derived or
recombinant (see below for information on EHL FIX
CFCs);
–
FIX CFCs that also contain factors II, VII, IX, and
X, known as prothrombin complex concentrates
(PCCs), which are nowadays only rarely used.
•
Whenever possible, the use of pure FIX concentrates is
preferable for the treatment of hemophilia B as they
are associated with a reduced risk of thrombosis and
disseminated intravascular coagulation compared to PCCs,
particularly in the following instances:
–
surgery;
–
liver disease;
–
intensive exposure, i.e., prolonged therapy at high
doses;
–
previous thrombosis or known thrombotic tendency;
–
concomitant use of drugs known to have
thrombogenic potential, including antibrinolytic
agents.
WFH Guidelines for the Management of Hemophilia, 3rd edition70
•
See Chapter 9: Specic Management Issues – Surgery and
invasive procedures.
RECOMMENDATION 5.3.3:
•
For treatment of FIX deficiency in patients with
hemophilia B, the WFH recommends a product
containing only FIX rather than prothrombin complex
concentrates (PCCs), which also contain other clotting
factors, such as factors II, VII, and X, some of which
may become activated during manufacture and may
predispose the patient to thromboembolism.
•
REMARK: Pure FIX products have reduced risk of
thrombosis or disseminated intravascular coagulation,
compared to what was observed with large doses of
older-generation PCCs.
•
REMARK: Current PCCs are considered safer than earlier
products due to the inclusion of coagulation inhibitors
such as heparin, antithrombin, and proteins C, S, and
Z. Nevertheless, in cases of intensive treatment (e.g.,
perioperative management), prothrombotic clotting
factors may accumulate in plasma and may increase the
risk for thromboembolic complications. When PCCs
are used in high doses in order to normalize FIX levels,
thromboprophylaxis should be considered.
RECOMMENDATION 5.3.4:
•
For hemophilia B patients requiring prolonged therapy
at high doses, the use of pure FIX concentrates is
recommended over prothrombin complex concentrates.
RECOMMENDATION 5.3.5:
•
For hemophilia B patients undergoing surgery, the
use of pure FIX concentrates is recommended over
prothrombin complex concentrates.
RECOMMENDATION 5.3.6:
•
For hemophilia B patients with liver disease, the use of
pure FIX concentrates is recommended over prothrombin
complex concentrates.
RECOMMENDATION 5.3.7:
•
For hemophilia B patients with previous thrombosis
or known thrombotic tendency, the use of pure FIX
concentrates is recommended over prothrombin complex
concentrates.
RECOMMENDATION 5.3.8:
• For hemophilia B patients concomitantly using drugs
known to have thrombogenic potential, including
antibrinolytic agents, the use of pure FIX concentrates is
recommended over prothrombin complex concentrates.
Dosage/administration
•
FIX CFCs are available in vials labelled with the product
potency, ranging from approximately 250-4000 IU per vial.
•
In the absence of an inhibitor, each IU of plasma-derived
or recombinant SHL FIX per kilogram of body weight
infused intravenously will raise the plasma FIX level by
approximately 1 IU/dL.
•
e half-life of SHL FIX is approximately 18-24 hours.
Guidelines for PK studies on FIX CFCs include at least 8
blood samplings taken over a period of 72 hours (additional
samplings over up to 2 weeks for EHL FIX). However, for
dose tailoring in routine practice, useful PK parameters
can be estimated from population PK models which
enable Bayesian estimation of individual PK from limited
samples.
RECOMMENDATION 5.3.9:
•
For patients with hemophilia B receiving FIX concentrates
who would benet from optimization of prophylaxis,
the WFH recommends pharmacokinetic monitoring.
•
REMARK: Peak factor level should be measured 15-30
minutes aer the infusion to verify calculated dose.
Plasma half-life can be determined via full PK (10-11
blood samplings taken over a period of 1-2 weeks), or
with limited sampling in combination with population
PK estimates.
• Unmodied recombinant FIX (rFIX) CFCs have a lower
recovery than plasma-derived FIX CFCs, such that each
unit of FIX infused per kilogram of body weight will raise
FIX activity by approximately 0.8 IU/dL in adults and 0.7
IU/dL in children under 15 years of age.
•
To calculate dosage, multiply the patient’s weight in
kilograms by the FIX level in IU/dL desired.
–
Example: 50 kg body weight × 40 (IU/dL level
desired) = 2000 IU of plasma-derived FIX.
–
For rFIX, the dose is calculated as 2000 IU ÷ 0.8
(or 2000 IU × 1.25) = 2500 IU for adults, and
2000 IU ÷ 0.7 (or 2000 IU × 1.43) = 2860 IU for
children.
Chapter 5: Hemostatic Agents 71
•
See Chapter 7: Treatment of Specic Hemorrhages and
refer to Table 7-2 for practice patterns with CFCs for
dierent types of hemorrhage.
•
FIX CFCs should be infused slowly over several minutes
as specied in the product insert. e patient’s peak FIX
level should be measured approximately 15-30 minutes
aer infusion to verify the expected FIX activity of the
dose given.
•
For patients undergoing surgery or those with severe bleeds
that require frequent infusions, laboratory monitoring
of FIX levels is required including measurement of FIX
trough level to aid in the calculation of subsequent doses.
(See Chapter 3: Laboratory Diagnosis and Monitoring –
Factor assays, and Chapter 9: Specic Management Issues
– Surgery and invasive procedures.)
•
Puried FIX CFCs may also be administered by continuous
infusion (as with FVIII CFCs).
•
Allergic reactions may occur with infusions of both
recombinant and plasma-derived FIX CFCs (in
approximately 2%-4% of cases). ese are oen associated
with anti-FIX inhibitors.
Extended half-life products
Rationale for development of EHL CFCs
•
e frequency of infusions using SHL CFCs is associated
with an increased burden of treatment and oen leads to
poor adherence to prophylaxis regimens. Annualized
bleeding rates (ABRs) are not always zero with prophylaxis
with SHL CFCs, and joint disease can still appear in young
adults. EHL products were developed to address the
need to reduce the treatment burden of prophylaxis and
to maintain higher factor trough levels to improve bleed
prevention.
Mechanisms of half-life extension
• Fusion technologies and PEGylation are successful half-
life extension strategies in hemophilia.
•
Fusion technologies rescue endocytosed proteins from
intracellular degradation pathways through interaction
with the neonatal Fc receptor.
•
PEGylation reduces interaction with clearance receptors.
•
All currently marketed EHL products are listed in the WFH
Online Registry of Clotting Factor Concentrates. Consult
the individual product inserts for details.
•
Dierent types of recombinant and modied forms of
FVIII and FIX are summarized in Chapter 3: Laboratory
Diagnosis and Monitoring – Tables 3-2 and 3-3.
•
e WFH recommendations on EHL products were
structured accordingly:
–
e emphasis was on the absence of “clinical safety
issues” and not on preclinical observations from
animal models with unclear implications.
–
e WFH recognizes that evaluation of both clinical
and preclinical observations of EHL products has
led to divergence in regulatory approval for some
PEGylated products, which has impacted their
licensing for prophylaxis and pediatric application in
some geographies.
–
Regarding allergic reactions, these are, albeit rarely,
observed for all infusion treatment products and
have been observed with fusion proteins as well.
–
Regarding anti-PEG antibodies, there is no
published evidence to support that these have
clinical safety implications in patients with
hemophilia.
RECOMMENDATION 5.3.10:
•
For patients with hemophilia A or B, there is no evidence
for any clinical safety issues in persons with hemophilia to
recommend a preference among the various mechanisms
of action (e.g., PEGylation, Fc-fusion, albumin-fusion)
used to extend the half-life of clotting factor concentrates.
Pharmacokinetic properties of EHL products
•
For EHL FVIII products, half-life extension has been limited
to 1.4- to 1.6-fold (or approximately 19 hours) that of SHL
FVIII products. EHL FIX products have a much longer
half-life at 3- to over 5-fold that of SHL FIX products.
•
e prolonged half-life of EHL products translates to
dosing twice per week or every 3 days in most cases for
FVIII, and once every 7-14 days for FIX.
•
Clearance of EHL products in adolescents and adults is
similar, as was observed for SHL products, and half-life
is shorter in pediatric populations.
•
EHL FIX products do not demonstrate the lower factor
recovery observed with standard rFIX products. Some
EHL FIX products show much higher recovery, suggesting
extravascular distribution of a lower proportion of EHL
FIX. Accordingly, clinical assessment of ecacy should
supplement assessment of plasma PK measurements.
•
Modication of these molecules has introduced variations
in their activity measurements in routine coagulation
assays. us, clinicians should follow the recommendations
accompanying a product’s regulatory approval regarding
the optimal assays to be used for laboratory monitoring.
WFH Guidelines for the Management of Hemophilia, 3rd edition72
(See Chapter 3: Laboratory Diagnosis and Monitoring –
Factor assays.)
Safety and efficacy of EHL products
•
All registered EHL products have been shown to be
ecacious in the prevention and treatment of bleeds in
children, adolescents, and adults. Over 90% of bleeds were
successfully treated with a single administration, and the
ecacy in bleed prevention resulted in ABRs <4-5 across
all EHL products. Hemostatic ecacy was demonstrated
in a variety of minor and major surgeries.
•
In previously treated children, adolescents, and adults,
no increased risk of new inhibitor development has been
observed in those receiving EHL FVIII/FIX products; all
clinical trials in previously treated patients (PTPs) have
demonstrated either no inhibitor development or very low
incidence rates that were within regulatory safety limits.
•
EHL products have been given to previously untreated
patients (PUPs), either as part of clinical PUP studies or
outside of studies. Although inhibitor development has
been reported in such settings, no substantial dierence
in levels of inhibitor development has been observed with
EHL compared to SHL products. However, no completed
trial in PUPs has yet been published in full.
Approaches to dosing with EHL products
•
Although EHL CFCs extend the time until patients reach
the minimum trough levels required to avoid spontaneous
bleeds, there is signicant interpatient variability related
to age, body mass, blood group, VWF level, bleeding
phenotype, physical activity level, joint status, and
compliance. Accordingly, there is no consensus on
standardized dosing with EHL CFCs nor management
of patients receiving EHL products.
•
Each of the following approaches has established ecacy
in clinical trials with EHL CFCs:
–
xed programmatic prophylaxis (xed dose and
interval, e.g., once weekly for FIX, twice weekly for
FVIII);
–
PK-tailored prophylaxis (dose tailored to target
trough level, given at xed intervals);
–
phenotypic-tailored prophylaxis (variable dose and
interval tailored according to bleeding pattern and
activity);
–
dose/frequency-tailored prophylaxis (dose and/or
frequency tailored according to target trough level
and interval, e.g., higher dose and longer interval).
•
To transition from SHL to EHL factor replacement therapy,
dose frequency is typically lowered from 3 to 2 times
weekly for FVIII, and from twice weekly to once every
7-10 days for FIX.
•
PK-driven dosing allows more individualized prophylaxis.
Population PK tools are in development to aid the
implementation of individualized prophylaxis in clinical
practice. Once an individual’s PK prole is generated, the
dose and treatment frequency required to obtain a desired
trough level can be estimated. e target trough level needs
to be customized to the needs of the individual patient
within their healthcare system’s parameters and exibilities.
•
See Chapter 6: Prophylaxis in Hemophilia – Extended
half-life factor prophylaxis.
RECOMMENDATION 5.3.11:
•
Patients with hemophilia who are transitioning from
standard half-life clotting factor concentrates to extended
half-life clotting factor concentrates would typically
require decreased dose frequencies, but EHL products
may also be used to maintain higher trough levels to
optimize prophylaxis.
•
REMARK: Pharmacokinetic-guided dosing as per
Recommendations and 5.3.9 provides for more
individualized prophylaxis.
5.4 Bypassing agents
•
Bypassing agents are used for the treatment and prevention
of bleeding complications in patients with hemophilia
A or B who develop FVIII or FIX alloantibodies (called
inhibitors) that typically neutralize the function of infused
CFCs. ese agents are based on dierent mechanisms of
action to achieve hemostasis, thereby bypassing the need
for FVIII or FIX replacement to treat and prevent bleeds.
Recombinant activated factor VIIa (rFVIIa)
•
Recombinant activated factor VIIa (rFVIIa) is a bypassing
agent that promotes coagulation through tissue factor-
dependent and independent pathways. rFVIIa binds
to tissue factor to activate FX and FIX and allows the
coagulation cascade to resume.
Activated prothrombin complex concentrate
(aPCC)
•
Activated prothrombin complex concentrate (aPCC) is
used to treat patients with hemophilia A with inhibitors.
aPCC contains mainly non-activated FII (prothrombin),
FIX, FX, and mainly activated FVII.
Chapter 5: Hemostatic Agents 73
•
See Chapter 8: Inhibitors to Clotting Factor for more
information on bleed management for patients with
inhibitors.
RECOMMENDATION 5.4.1:
•
For people with hemophilia A with an inhibitor requiring
treatment for acute bleeding complications or surgery,
the WFH recommends that a bypassing agent be used.
•
REMARK: Bypassing agents include recombinant
activated factor VIIa or activated prothrombin complex
concentrate.
RECOMMENDATION 5.4.2:
•
For patients with hemophilia B and an inhibitor with a
history of anaphylaxis to FIX-containing clotting factor
concentrates, recombinant activated factor VIIa must
be administered as activated prothrombin complex
concentrate cannot be used.
RECOMMENDATION 5.4.3:
• e WFH recommends that patients with hemophilia
with an inhibitor should be considered for regular
prophylaxis to prevent bleeding events.
• In addition to bypassing agents, non-factor replacement
therapies (e.g., emicizumab) are becoming available that
oer new treatment paradigms including for the treatment
of inhibitors.
•
See 5.7 Non-factor replacement therapies, below; and
Chapter 6: Prophylaxis in Hemophilia – Prophylaxis using
non-factor replacement therapies.
5.5 Other plasma products
•
Cryoprecipitate and FFP are not normally subjected to
viral inactivation procedures (such as heat or solvent-
detergent treatment) and consequently carry an increased
risk of transmission of viral pathogens, which is signicant
with repeated infusions. However, the WFH recognizes
the necessity of the continued use of cryoprecipitate and
FFP in some parts of the world where they are the only
available or aordable treatment options.
•
Certain steps can be taken to minimize the risk of
transmission of viral pathogens. ese include:
–
quarantining plasma until the donor has been tested
or even retested for antibodies to HIV, HCV, and the
surface antigens of the hepatitis B virus (HBsAg)—a
practice that is dicult to implement in countries
where the proportion of repeat donors is low;
–
NAT testing to detect viruses—a technology that
has a potentially much greater relevance for the
production of cryoprecipitate than for CFCs, as the
latter are subjected to viral inactivation steps.
•
Allergic reactions are more common following infusion
of cryoprecipitate than CFC. (For use of antihistamine
prophylaxis, see “Safety and quality” above.)
RECOMMENDATION 5.5.1:
•
For patients with hemophilia, the WFH strongly
recommends the use of viral-inactivated plasma-derived
or recombinant clotting factor concentrates in preference
to cryoprecipitate or fresh frozen plasma.
•
REMARK: e WFH supports the use of CFCs in
preference to cryoprecipitate or FFP due to concerns
about quality, safety, and ecacy. However, the WFH
recognizes the reality that they are still widely used in
countries around the world where they are the only
available or aordable treatment options.
Fresh frozen plasma (FFP)
•
As fresh frozen plasma contains all coagulation factors, it
is sometimes used to treat coagulation factor deciencies.
• Cryoprecipitate is preferable to FFP for the treatment of
hemophilia A. However, as FFP and cryo-poor plasma
contain FIX, albeit in low concentrations, they can be used
for the treatment of hemophilia B in countries unable to
aord plasma-derived FIX CFCs.
RECOMMENDATION 5.5.2:
•
For patients with hemophilia, fresh frozen plasma is
not recommended due to concerns about the safety
and quality.
•
REMARK: However, the WFH recognizes the as yet
unavoidable reality of their continued use in some parts
of the world where it is the only available or aordable
treatment option.
•
It is possible to apply some forms of virucidal treatment to
packs of FFP (including solvent-detergent treatment). e
use of treated packs is recommended; however, virucidal
treatment may have some impact on coagulation factors. e
large-scale preparation of pooled solvent-detergent–treated
plasma has also been shown to reduce the proportion of
the largest multimers of VWF, which is important for
VWD, but is irrelevant for treatment of hemophilia A.
WFH Guidelines for the Management of Hemophilia, 3rd edition74
Dosage/administration
• One mL of FFP contains 1 unit of factor activity.
•
It is generally dicult to achieve FVIII levels higher than
30 IU/ dL with FFP alone.
•
FIX levels above 25 IU/dL are dicult to achieve. A starting
FFP dose of 15-20 mL/kg is acceptable.
Cryoprecipitate
•
Cryoprecipitate is the insoluble concentrate of high
molecular weight plasma proteins that precipitate when
frozen plasma is slowly thawed at 1-60°C.
•
Cryoprecipitate contains signicant quantities of FVIII
(about 3-10 IU/mL), VWF, brinogen, and FXIII but not
FIX nor FXI. e resultant supernatant is called cryo-poor
plasma and contains other coagulation factors such as
factors VII, IX, X, and XI.
•
The use of viral inactivation procedures is strongly
encouraged.
•
e manufacture of small pool, viral-inactivated (solvent-
detergent–treated) cryoprecipitate has been described,
although this provides safety only for lipid-enveloped
viruses.
RECOMMENDATION 5.5.3:
•
For patients with hemophilia, cryoprecipitate is not
recommended due to concerns about the safety and
quality.
•
REMARK: e use of cryoprecipitate can only be justied
in situations where clotting factor concentrates are not
available as there is no proven advantage for their use over
CFCs. It is strongly encouraged that viral-inactivation
procedures be used, if available.
Dosage/administration
•
A bag of cryoprecipitate made from 1 unit of FFP (200-
250 mL) may contain 70-80 units of FVIII in a volume
of 30-40 mL.
5.6 Other pharmacological options
•
In addition to CFCs, other agents can be of great value in
a signicant proportion of cases. ese include:
–
desmopressin (DDAVP);
–
tranexamic acid; and
–
epsilon aminocaproic acid (EACA).
•
See also Chapter 2: Comprehensive Care of Hemophilia,
Chapter 7: Treatment of Specic Hemorrhages, and Chapter
9: Specic Management Issues.
Desmopressin (DDAVP)
•
Desmopressin (1-deamino-8-D-arginine vasopressin, also
known as DDAVP) is a synthetic analogue of vasopressin
that boosts plasma levels of FVIII and VWF.
•
DDAVP may be the treatment of choice for patients with
mild or moderate hemophilia A when FVIII can be raised
to an appropriate therapeutic level because it avoids the
expense and potential hazards of using CFC including the
risk of FVIII inhibitor development.
•
DDAVP does not aect FIX levels and is of no value in
hemophilia B.
•
ere are signicant dierences in individual patient
response to DDAVP. e response to intranasal DDAVP
is more variable and therefore less predictable.
•
DDAVP is particularly useful in the treatment and
prevention of bleeding in carriers of hemophilia A.
•
DDAVP is not licensed for use in pregnancy, but it has been
used with caution in pregnant carriers during labour and
delivery. Its use should be avoided in preeclampsia and
eclampsia because of the already high levels of VWF.
(See Chapter 9: Specic Management Issues – Carriers.)
•
e decision to use DDAVP must be based on both the
patient’s baseline FVIII activity, the increment achieved,
and the duration of treatment required.
Dosage/administration
•
ough DDAVP may be given subcutaneously, it is primarily
administered by intravenous infusion or nasal spray. It is
important to choose the correct preparation of DDAVP
because some lower-dose preparations are used for other
medical purposes.
• Appropriate preparations include:
–
4 g/mL for intravenous use;
–
15 g/mL for intravenous and subcutaneous use;
–
150 g per metered dose as nasal spray.
•
A single dose of 0.3 g/kg body weight, either via
intravenous or subcutaneous administration, can be
expected to boost the FVIII level 3- to 6-fold.
•
For intravenous use, DDAVP is usually diluted in at least
50-100 mL of physiological saline and given by slow
infusion over 20-30 minutes.
•
e peak response is seen approximately 60 minutes aer
either intravenous or subcutaneous administration.
•
Children should generally not be given DDAVP more
than once per day; in adults under close supervision,
twice-daily dosing may be considered. With subsequent
dosing, therapeutic response decreases (tachyphylaxis) and
the risk of complications rises; thus, in general, DDAVP
should not be used for more than 3 consecutive days.
Chapter 5: Hemostatic Agents 75
•
CFCs may be needed when higher factor levels are required
for a prolonged period.
•
Rapid DDAVP infusion may result in tachycardia, ushing,
tremor, and abdominal discomfort.
•
A single metered intranasal DDAVP spray of 1.5 mg/mL
in each nostril is appropriate for an adult. For patients
with a body weight of less than 40 kg, a single dose in one
nostril is sucient.
•
Some patients may nd the intranasal preparation of
DDAVP dicult to use, and it may be less ecacious than
DDAVP given subcutaneously.
•
Because DDAVP is an antidiuretic agent, water retention,
hyponatremia, and even seizures may occur in patients
receiving large amounts of hypotonic intravenous or
oral uids, necessitating uid restriction during DDAVP
treatment. is is especially important in the context
of home treatment of minor bleeding episodes and peri-
operatively, when large quantities of infusions are used—
patients/caregivers should be instructed to restrict uids
aer DDAVP use.
• DDAVP should be used with caution in young children,
and it is contraindicated in children under 2 years of age.
For young pediatric inpatients (i.e., postoperative patients),
hypotonic intravenous uids should be avoided and total
uid intake should be reduced to 75% of maintenance
requirements in the 24 hours aer use of DDAVP. Plasma
osmolality and sodium levels should be measured before
and aer DDAVP use in young children, especially if
more than one dose is used over a 24-hour period.
•
Hyponatremia is uncommon in most adults treated with
DDAVP. However, hypotension is commonly observed in
both children and adults, and children under 2 years of age
have an increased risk of seizures secondary to cerebral
edema caused by water retention/ hyponatremia. Other
side eects of DDAVP include headache, ushing, fatigue,
and tachycardia. Given the vasoactive eect of DDAVP,
caution should be exercised if it is used in patients with
hypertension that is not completely controlled by therapy.
ese side eects may occur more oen aer intravenous
administration.
•
ere are case reports of thrombosis (including myocardial
infarction) aer infusion of DDAVP. It should be used with
caution in patients with a history or risk of cardiovascular
disease.
RECOMMENDATION 5.6.1:
•
For patients with mild or moderate hemophilia A
and carriers of hemophilia A, the WFH recommends
considering desmopressin (DDAVP) as an option for
treatment.
•
REMARK: e WFH recommends testing DDAVP
prior to therapeutic use to evaluate the individual FVIII
response. e decision to use DDAVP must be based
on the patient’s baseline FVIII activity, the increment
achieved, and the duration of treatment required.
•
REMARK: In general, the most common adverse events
observed are tachycardia, ushing, tremor, abdominal
discomfort, and headache, especially during rapid
infusion, and are mostly mild and transient. However,
hypotension and/or severe hyponatremia can also occur.
•
REMARK: For pregnant women during labour and
delivery, the WFH recommends caution in the use of
DDAVP, and it should be avoided in pre-eclampsia and
eclampsia.
•
REMARK: With more than 3 consecutive days of dosing,
the therapeutic response may decrease (tachyphylaxis)
and the risk of complications rises; thus, clotting factor
concentrates may be needed when higher factor levels
are required for a prolonged period.
RECOMMENDATION 5.6.2:
•
For adults, the WFH recommends DDAVP not be
used for more than 3 consecutive days and only under
close supervision. If DDAVP is administered twice in
a single day, subsequent daily dosing should be limited
to once per day.
•
REMARK: In general, the most common adverse events
observed are tachycardia, ushing, tremor, abdominal
discomfort, and headache, especially during rapid
infusion. However, hypotension and/or hyponatremia
can also occur.
•
REMARK: With more than 3 consecutive days of dosing,
the therapeutic response may decrease (tachyphylaxis)
and the risk of complications rises; thus, clotting factor
concentrates may be needed when higher factor levels
are required for a prolonged period.
RECOMMENDATION 5.6.3:
•
For children, the WFH recommends using no more
than 1 dose of DDAVP per day for no more than 3
consecutive days.
•
REMARK: In general, the most common adverse events
observed are tachycardia, ushing, tremor, abdominal
discomfort, and headache, especially during rapid
infusion. However, hypotension and/or hyponatremia
can also occur.
WFH Guidelines for the Management of Hemophilia, 3rd edition76
•
REMARK: With more than 3 consecutive days of dosing,
the therapeutic response may decrease (tachyphylaxis)
and the risk of complications rises; thus, clotting factor
concentrates may be needed when higher factor levels
are required for a prolonged period.
RECOMMENDATION 5.6.4:
•
For children under 2 years of age, the WFH alerts
that DDAVP is contraindicated due to increased risk
of seizures as consequences of water retention and
hyponatremia.
RECOMMENDATION 5.6.5:
•
For patients at risk of cardiovascular disease or
thrombosis, the WFH recommends that DDAVP should
be used with caution due to the risk of thromboembolism
and myocardial infarction.
Tranexamic acid
•
Tranexamic acid is an antifibrinolytic agent that
competitively inhibits the activation of plasminogen to
plasmin. It promotes clot stability and is useful as adjunctive
therapy for some types of hemophilic bleeding.
•
Treatment with tranexamic acid alone is of no value in the
prevention of hemarthroses in hemophilia.
•
Tranexamic acid is useful for treating supercial so
tissue and mucosal bleeds (e.g., oral bleeding, epistaxis,
and menorrhagia).
• Tranexamic acid is particularly valuable in the setting of
dental surgery and may be used to control oral bleeding
associated with eruption or shedding of teeth.
•
See also Chapter 2: Comprehensive Care of Hemophilia
and Chapter 7: Treatment of Specic Hemorrhages.
Dosage/administration
•
Tranexamic acid is usually given as oral tablets (25 mg/kg/
dose) 3-4 times daily. It can also be given by intravenous
infusion (10 mg/kg/dose) 2-3 times daily. It is also available
as an oral rinse.
•
Gastrointestinal upset (nausea, vomiting, or diarrhea)
may rarely occur as a side eect of tranexamic acid, but
these symptoms usually resolve if the dosage is reduced.
When administered intravenously, tranexamic acid must
be infused slowly as rapid injection may result in dizziness
and hypotension.
•
A syrup formulation of tranexamic acid is also available
for pediatric use. If this is not obtainable, a tablet can be
crushed nely and dissolved in clean water for topical use
on bleeding mucosal lesions.
•
Tranexamic acid is commonly prescribed for 7 days
following dental extractions to prevent postoperative
bleeding.
•
Tranexamic acid is excreted by the kidneys, and the dose
must be reduced if there is renal impairment in order to
avoid toxic accumulation.
•
e use of tranexamic acid is contraindicated for the
treatment of hematuria as its use may prevent dissolution of
clots in the ureter, leading to serious obstructive uropathy
and potentially permanent loss of renal function.
• Tranexamic acid is also contraindicated in the setting of
thoracic surgery where it may result in the development
of insoluble hematomas.
•
Tranexamic acid may be given alone or together with
standard doses of CFCs including bypassing agents such
as aPCC and rFVIIa.
•
Tranexamic acid is contraindicated in patients with
hemophilia B receiving PCCs, as it increases the risk of
thromboembolism.
RECOMMENDATION 5.6.6:
•
For patients with hemophilia, the WFH recommends that
antibrinolytics are a valuable alternative to use alone
or as adjuvant treatment, particularly in controlling
mucocutaneous bleeding (e.g., epistaxis, oral and
gastrointestinal bleeding, and menorrhagia) and for
dental surgery and eruption or shedding of teeth.
•
REMARK: Antibrinolytics can be used with standard
doses of clotting factor concentrates, including
bypassing agents. However, they should not be used
with prothrombin complex concentrates due to the
increased risk of thromboembolism.
RECOMMENDATION 5.6.7:
•
For patients with hematuria, the WFH recommends
against the use of antibrinolytics, as it is contraindicated
in these patients due to increased risk of obstructive
uropathy.
RECOMMENDATION 5.6.8:
•
For patients with renal impairment, the WFH
recommends reduced dosing of antibrinolytics and
close monitoring.
Epsilon aminocaproic acid
•
Epsilon aminocaproic acid is similar to tranexamic acid
but is less widely used as it has a shorter plasma half-life,
lower potency, and higher toxicity.
Chapter 5: Hemostatic Agents 77
•
See also Chapter 2: Comprehensive Care of Hemophilia
and Chapter 7: Treatment of Specic Hemorrhages.
Dosage/administration
•
In adults, EACA is typically administered orally
(100 mg/kg/dose up to a maximum of 2 g/dose) or
intravenously (100 mg/kg/dose up to a maximum of 4
g/dose) every 4-6 hours up to a maximum of 24 g/day.
•
A 250 mg/mL syrup formulation of EACA is also available.
•
Gastrointestinal upset is a common complication with
EACA use; reducing the dose oen alleviates this side eect.
•
Myopathy is a rare adverse reaction specically reported
in association with EACA therapy (but not tranexamic
acid) and typically occurs aer administration of high
doses for several weeks.
•
e myopathy associated with EACA use is oen painful
and associated with elevated levels of creatine kinase and
even myoglobinuria. Full resolution may be expected once
EACA treatment is stopped.
5.7 Non-factor replacement therapies
•
For the past ve decades, the focus of hemophilia therapies
has been on replacing the missing clotting factor protein;
however, recombinant technology combined with improved
basic understanding of coagulation biochemistry is currently
shiing the treatment paradigm.
Rationale and mechanisms of action
•
New and emerging innovative therapeutics have been
developed with alternative modes of delivery (e.g.,
subcutaneous), targets that overcome the limitations of
current clotting factor replacement therapy (i.e., intravenous
administration, short half-life, risk of inhibitor formation),
and markedly improved PK proles with a very low burden
of administration (e.g., up to monthly dosing), which may
increase compliance.
Substitution therapy
•
Substitution therapy diers from factor replacement therapy
in that it is based on the use of an alternative hemostatic
agent to substitute for clotting factor. e factor mimetic,
emicizumab, is the rst and only licensed substitution
therapy at the time of this publication.
•
Emicizumab is a chimeric bispecic antibody directed
against the enzyme FIXa and the zymogen FX that mimics
the cofactor function of FVIII in patients with hemophilia
A, with or without inhibitors. Emicizumab binds to FIX,
FIXa, FX, and FXa; however, it is its anity to FIXa and
FX that promotes FIXa-catalyzed FX activation and tenase
formation.
•
e key benets of emicizumab are its subcutaneous route
of administration, long half-life, high ecacy in bleed
prevention, and reduction of the frequency of bleeding
episodes in patients with or without FVIII inhibitors.
•
As emicizumab diers biochemically from FVIII, many
questions remain regarding its long-term impact on joint
pathology and immunogenicity in non-inhibitor patients.
•
Emicizumab is not intended to treat acute bleeding episodes.
Caution is required when treating breakthrough bleeding
episodes while on emicizumab as several patients have
developed either venous thromboembolism or thrombotic
microangiopathy with concomitant administration of
aPCC. Consult the hemophilia treatment centre and
risk management guidance.
RECOMMENDATION 5.7.1:
•
For patients with hemophilia A with an inhibitor, the
WFH recommends that emicizumab should be used
for regular prophylaxis.
•
REMARK: For patients with hemophilia A with no
inhibitor, the WFH recommends that emicizumab can
be used for regular prophylaxis.
Hemostatic rebalancing agents
•
e hemostatic system regulates the balance between
procoagulants (e.g., clotting factors) and natural
anticoagulants (e.g., antithrombin, tissue factor pathway
inhibitor [TFPI], and activated protein C). Bleeding
disorders result from a deciency of the procoagulants,
whereas deciencies of the natural anticoagulants are
associated with increased thrombotic risk.
•
Hemophilia has typically been treated by replacing the
missing procoagulant protein or with bypassing agents
(i.e., when inhibitors are present). However, inhibiting the
natural anticoagulants can also restore hemostasis. is has
been observed naturally as co-inheritance of thrombophilic
risk factors can moderate the clinical phenotype of severe
hemophilia A. In addition, thrombin generation is increased
with co-inheritance of hemophilia with some forms of
thrombophilia (e.g., protein C deciency).
•
Fitusiran is an RNA interference therapy that specically
targets antithrombin messenger RNA to suppress the
production of antithrombin in the liver. is therapy has
the advantage of subcutaneous administration, prolonged
duration of action and, due to its mechanism of action, it
WFH Guidelines for the Management of Hemophilia, 3rd edition78
could be used in both hemophilia A and B patients with
or without inhibitors.
•
For prevention of bleeding, suppression of antithrombin
by 75% is most eective. Breakthrough bleeding can be
treated with FVIII/FIX replacement or with bypassing
agents, but lower doses must be used to minimize the risk
of excessive procoagulant activity.
•
Anti-TFPI antibodies represent another modality in
clinical trials. Dierent anti-TFPI antibodies are currently
in development, all of which bind to the K2 domain or to
both the K1 and K2 domains of TFPI, thus rescuing FXa
and FVIIa from inhibition. ese therapies may also
be administered subcutaneously and restore hemostasis
in both hemophilia A and B patients with or without
inhibitors, but their duration of action is limited by target-
mediated drug disposition. e use of tusiran requires
close monitoring to minimize risk of thrombosis. Two
anti-TFPI clinical programs are ongoing, while two others
have seen evidence of thrombotic complications. One
clinical program has been stopped and one halted due to
these adverse events.
•
See also Chapter 2: Comprehensive Care of Hemophilia,
Chapter 6: Prophylaxis in Hemophilia, Chapter 8: Inhibitors
to Clotting Factor, and Chapter 9: Specic Management
Issues.
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SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting
Information section.
81
6
PROPHYLAXIS IN
HEMOPHILIA
Manuel Carcao
1
| H. Marijke van den Berg
2
| Emna Gouider
3
| Kate Khair
4
| Manuel A. Baarslag
5
|
Lisa Bagley
6
| Francisco de Paula Careta
7
| Rolf C. R. Ljung
8
| Margaret V. Ragni
9
| Elena Santagostino
10
| Glenn F. Pierce
11
| Alok Srivastava
12
1
Department of Paediatrics, University of Toronto, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada
2
PedNet Haemophilia Research Foundation, Baarn, the Netherlands
3
Medical School, University of Tunis El Manar, Hemophilia Centre, Aziza Othmana Hospital, Tunis, Tunisia
4
Centre for Outcomes and Experience Research in Child Health, Illness and Disability Research Unit (ORCHID) and Great Ormond Street
Hospital for Children, London, UK
5
Bemmel, the Netherlands
6
London, UK
7
Department of Pharmacy and Nutrition, Federal University of Espirito Santo Alegre, Alegre, ES, Brazil
8
Department of Clinical Sciences – Pediatrics, Lund University, Lund, Sweden
9
Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
10
Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda Foundation,
Maggiore Hospital Policlinico, Milan, Italy, and Sobi, Basel, Switzerland
11
World Federation of Hemophilia, Montreal, QC, Canada
12
Department of Haematology, Christian Medical College, Vellore, India
is chapter discusses prophylaxis for people with hemophilia
in the absence of inhibitors to factor VIII or IX. For prophylaxis
for patients with inhibitors, see Chapter 8: Inhibitors to Clotting
Factor.
All statements identied as recommendations are consensus
based, as denoted by
.
6.1 Introduction
•
Prophylaxis in hemophilia consists of regular administration
of therapeutic products aimed at maintaining hemostasis
to prevent bleeding, especially joint hemorrhages, which
would lead to arthropathy and disability. Prophylaxis
should enable people with hemophilia to lead healthy
and active lives including participation in most physical
and social activities (at home, school, work, and in the
community), similar to the non-hemophilic population.
•
Prophylaxis with clotting factor concentrates (CFCs) is
referred to as regular replacement therapy; it stands in
contrast to episodic replacement therapy (also known as
on-demand therapy), which is dened as the administration
of CFCs only at the time of a bleed. Episodic therapy,
regardless of the doses used, while essential in reducing
the pain and debilitating impact of individual bleeds, does
not alter the bleeding prole signicantly and hence does
not change the natural history of hemophilia leading to
musculoskeletal damage and other complications due to
bleeding.
•
erefore, the use of prophylaxis is always recommended
over episodic therapy. In countries with healthcare
constraints and for patients with limited access to CFCs,
less intensive prophylaxis regimens may be used. (See 6.9
Health economics of prophylaxis.) Still, in all countries
the ideal is for patients to not experience any bleeds (i.e.,
achieve “zero” bleeds).
•
With the advent of innovative non-factor replacement
therapies, which for the most part can be administered
subcutaneously, prophylaxis is being redened as the
regular administration (intravenously, subcutaneously,
or otherwise) of a hemostatic agent/ agents to enhance
hemostasis and eectively prevent bleeding in people
with hemophilia.
RECOMMENDATION 6.1.1:
•
For patients with hemophilia A or B with a severe
phenotype (note that this may include patients with
moderate hemophilia with a severe phenotype), the
WFH strongly recommends that such patients be on
prophylaxis sucient to prevent bleeds at all times,
but that prophylaxis should be individualized, taking
into consideration patient bleeding phenotype, joint
WFH Guidelines for the Management of Hemophilia, 3rd edition82
status, individual pharmacokinetics, and patient self-
assessment and preference.
•
REMARK: Individualizing prophylaxis means that if
patients continue to experience bleeds, their prophylaxis
regimen should be escalated (in dose/frequency or both)
to prevent bleeding.
•
REMARK: In countries with signicant healthcare
constraints, the WFH still advocates for the use of
prophylaxis over episodic therapy but recognizes that
less intensive prophylaxis may be used.
•
See 6.9 Health economics of prophylaxis and 6.10 Low-
dose prophylaxis for patients with limited access to CFCs.
Standard half-life factor replacement therapy
•
Prophylaxis has conventionally been dened as the regular
intravenous (IV) infusion of the missing clotting factor VIII
(FVIII) in people with hemophilia A and factor IX (FIX)
in people with hemophilia B, given in order to increase
the FVIII/FIX level with the intent to prevent bleeding.
e focus of this conventional denition of prophylaxis
has been on preventing joint bleeds and maintaining
musculoskeletal health.
•
e objective of prophylaxis has been to convert a person
with severe hemophilia (baseline FVIII/FIX level <1 IU/dL
[1%]) to a bleeding phenotype typical of moderate or mild
hemophilia by maintaining factor levels above 1 IU/dL
(1%) at all times.
•
is was based on the observation that people with
moderate hemophilia seldom experienced spontaneous
bleeding and had much better preservation of joint function.
•
However, there has been increasing recognition and
evidence that factor trough levels of 1-3 IU/dL (1%-3%)
are insucient to totally prevent bleeds in all people with
hemophilia and allow occasional clinical and subclinical
bleeds, resulting in gradual progression of joint disease
over a lifespan.
•
In general, the higher the factor levels at all times, the less
the bleeding. For every 1% increase in baseline factor levels
(in people with hemophilia not on prophylaxis), there is a
decrease in bleeding frequency, and when baseline FVIII:C
levels are above 15 IU/dL (15%), spontaneous bleeding is
uncommon. e same is thought to apply with FIX:C
levels, although this has been less well studied. Similarly,
it has been shown that the more time spent with FVIII
levels below 1 IU/dL (1%), the higher the rate of break-
through bleeds during prophylaxis.
Extended half-life factor replacement therapy
• e use of extended half-life (EHL) CFCs ts within the
denition of conventional factor prophylaxis but allows
for more ambitious prophylaxis than simply converting
an individual from a severe to a moderate phenotype.
•
is is particularly the case with some EHL FIX products
which allow individuals to have FIX levels in a non-
hemophilic range (>40 IU/dL [40%]) for a substantial
proportion of time and levels in the mild hemophilia range
(5-40 IU/dL [5%-40%]) just prior to the next infusion.
•
While prophylaxis with CFCs has been the mainstay of
hemophilia treatment for many decades, the treatment
landscape is changing with the development of new types
of therapies.
Non-factor replacement therapy
•
Non-factor replacement therapy diers from clotting factor
replacement therapy in that it provides hemostasis through
a dierent mechanism than FVIII/FIX replacement. e
rst, and at the time of this publication, the only licensed
non-factor replacement therapy for hemophilia A is
emicizumab. Emicizumab mimics the cofactor activity
of FVIII. It is administered subcutaneously once weekly,
and in some cases can be administered as infrequently
as once every 2 or 4 weeks. (See 6.5 Prophylaxis with
non-factor replacement therapy.)
Basic definitions and concepts in prophylaxis
with CFCs
•
Prophylaxis has been characterized according to when it
is initiated and according to its intensity. ese denitions
apply to both hemophilia A and B. (See Tables 6-1 and 6-2.)
Initiation of prophylaxis: timing and approach
•
Age at initiation of prophylaxis has been a strong predictor
of long-term clinical outcomes.
•
People with hemophilia initiated on early prophylaxis
(i.e., primary or secondary prophylaxis) have shown the
best long-term outcomes. (See Table 6-1 for prophylaxis
denitions.) Furthermore, early initiation of prophylaxis also
reduces the risk and incidence of intracranial hemorrhage
(ICH), which is highest in very young children.
•
Long-term cohort studies have shown that a small number
of joint bleeds occurring early in life prior to the start of
prophylaxis may (in some patients) ultimately result in
hemophilic arthropathy.
•
Regular prophylaxis begun at a young age and given in
appropriate doses should therefore be considered the
Chapter 6: Prophylaxis in Hemophilia 83
standard of care to treat hemophilia until an alternate
long-term therapy such as gene therapy is available.
•
ere have been various approaches regarding how to
initiate conventional prophylaxis with IV factor replacement
therapy. e two main ways (high-dose prophylaxis and
low-dose escalating prophylaxis) are mainly dierentiated
in the frequency of CFC administration and less so in the
doses used.
•
Escalating frequency prophylaxis, which starts with less
intense prophylaxis (e.g., once-weekly infusions), followed
by an increase in frequency, has enabled young children
and their families to gradually adapt to the burdens of
prophylaxis (e.g., peripheral venous infusion). You ng
children commenced on low-dose escalating prophylaxis
need to be followed closely, and strong consideration
should be given to escalating prophylaxis quickly (either
all patients or according to bleeding symptoms) in order
to prevent bleeding and resulting morbidity.
•
Starting with less intense prophylaxis and then gradually
escalating may improve family acceptance of starting
prophylaxis early and may improve adherence to
prophylaxis. is approach also appears to result in less need
for placement of central venous access devices (CVADs).
However, patients on less intenseprophylaxis are at a higher
risk of bleeding until escalation of prophylaxis occurs.
• For people with hemophilia A, starting with small doses
of FVIII CFC therapy may have the additional (unproven)
benet of decreasing inhibitor development, as large and
frequent doses of FVIII early on have been associated
with an increase in the rate of inhibitor development.
•
People with severe/moderate hemophilia who have had a
life-threatening bleed in early childhood should, however,
not be placed on escalating dose prophylaxis but instead
be started immediately on high-dose prophylaxis.
•
How to start and when to start prophylaxis with either
standard half-life (SHL) or extended half-life (EHL) CFCs
is not signicantly dierent. In both cases, prophylaxis
should be commenced early by starting with a high-dose/
high-frequency approach or a low-frequency approach,
followed by escalation of frequency.
•
With EHL CFCs, less frequent infusions (e.g., once weekly)
may be sucient for many individuals, particularly those
with severe hemophilia B receiving EHL FIX CFCs. As
EHL CFCs must still be given intravenously, they remain
TABLE 6-1 Conventional factor prophylaxis for hemophilia A and B defined according to when
prophylaxis is initiated
1
Primary prophylaxis • Regular continuous prophylaxis started in the absence of documented joint disease,
determined by physical examination and/or imaging studies, and before the second
clinically evident joint bleed and 3 years of age
Secondary prophylaxis • Regular continuous prophylaxis initiated after 2 or more joint bleeds but before the onset
of joint disease; this is usually at 3 or more years of age
Tertiary prophylaxis • Regular continuous prophylaxis initiated after the onset of documented joint disease.
Tertiary prophylaxis typically applies to prophylaxis commenced in adulthood
TABLE 6-2 Conventional factor prophylaxis with standard half-life clotting factor defined according
to its intensity
Prophylaxis intensity Hemophilia A Hemophilia B
High-dose prophylaxis
4
25-40 IU FVIII/kg every 2 days
(>4000 IU/kg per year)
40-60 IU FIX/kg twice per week
(>4000 IU/kg per year)
Intermediate-dose prophylaxis 15-25 IU FVIII/kg 3 days per week
(1500-4000 IU/kg per year)
20-40 IU FIX/kg twice per week
(2000-4000 IU/kg per year)
Low-dose prophylaxis (with escalation
of dose intensity, as needed)
a
10-15 IU FVIII/kg 2-3 days per week
(1000-1500 IU/kg per year)
10-15 IU FIX/kg 2 days per week
(1000-1500 IU/kg per year)
Abbreviations: FIX, factor IX; FVIII, factor VIII; IU, international unit; kg, kilogram.
ªShould only be taken as the starting point of replacement therapy to be tailored, as possible, to prevent bleeding.
WFH Guidelines for the Management of Hemophilia, 3rd edition84
dicult to administer in very young children with poor
peripheral venous access.
•
Time to initiation of prophylaxis with non-factor
replacement agents has not been well studied. Since
emicizumab is administered subcutaneously, challenges
of venous access are mitigated. It may be started at a similar
time as CFC prophylaxis initiation, or perhaps earlier,
although data are still very limited. Further research on
initiation of emicizumab in newborns is needed.
•
See Tables 6-1 and 6-2, above, and Chapter 3: Laboratory
Diagnosis and Monitoring – Inhibitor testing.
RECOMMENDATION 6.1.2:
•
For pediatric patients with severe hemophilia A or B,
the WFH recommends early initiation of prophylaxis
with clotting factor concentrates (standard or extended
half-life FVIII/FIX) or other hemostatic agent(s) prior
to the onset of joint disease and ideally before age 3,
in order to prevent spontaneous and break-through
bleeding including hemarthroses which can lead to
joint disease.
RECOMMENDATION 6.1.3:
•
For adolescents and adults with hemophilia who show
evidence of joint damage and have not as yet been
on prophylaxis, the WFH recommends commencing
tertiary prophylaxis in order to reduce the number
of hemarthroses, spontaneous and break-through
bleeding, and slow down the progression of hemophilic
arthropathy.
Intensity of prophylaxis
•
Although intensity of prophylaxis has generally been
referred to as high, intermediate, and low dose, it should
be appreciated that intensity is a function of both dose and
frequency and that high dose usually refers to a combination
of both high doses and high frequencies, while low dose
usually refers to a combination of lower doses and lower
frequencies, although not always.
•
See 6.6 Fixed/non-tailored factor prophylaxis regimens,
below, and 6.7 Tailored factor prophylaxis regimens, below.
6.2 Benefits of prophylaxis
Prophylaxis using clotting factor concentrates
•
All forms of prophylaxis (high/intermediate/low dose with
CFCs or prophylaxis with non-factor replacement agents,
e.g., emicizumab) provide superior benets over episodic
therapy. Conventional high-dose and intermediate-dose
prophylaxis, initiated early in life, have been associated with
over 90% reduction in joint bleeding rates, annualized joint
bleeding rates (AJBRs) below 3 per year, and a signicant
reduction in joint deterioration and degenerative joint
disease.
•
Prophylaxis also provides protection from other types
of hemorrhages in hemophilia, including preventing or
substantially reducing the risk of intracranial hemorrhage.
•
Longer-term benefits include reduction of chronic
musculoskeletal pain, functional limitations and disability,
need for orthopedic surgery, hospitalization, emergency
room visits, and reduced length of hospital stays; all of this
leads to greater participation (i.e., regular attendance) in
educational, recreational, and professional activities, with
improved quality of life.
•
Because of these benets, the World Health Organization
(WHO), the World Federation of Hemophilia (WFH), and
many national and international hemophilia organizations
have endorsed early prophylaxis as the standard of care
for children with a severe phenotype hemophilia and
recommend that prophylaxis be continued lifelong.
Additionally, adults with severe phenotype hemophilia
(if not already on prophylaxis) should initiate prophylaxis
as well.
Prophylaxis using non-factor replacement
therapies
•
Emicizumab prophylaxis in a number of clinical trials
has been shown to be associated with very low rates of
bleeding (an annualized bleeding rate [ABR] of 1.5) and
ABRs lower than what patients previously reported while
on prophylaxis with CFCs. More research is needed
regarding long-term outcomes with emicizumab. Data
on the use of other non-factor therapies for prophylaxis
are at present much more limited.
RECOMMENDATION 6.2.1:
•
For patients with severe phenotype hemophilia A or
B, especially children, the WFH recommends regular
long-term prophylaxis as the standard of care to prevent
hemarthrosis and other spontaneous and breakthrough
bleeding, maintain musculoskeletal health, and promote
quality of life. When prophylaxis is not feasible, episodic
therapy is essential treatment for acute hemorrhages,
but it will not prevent long-term joint damage.
•
REMARK: In the long term, early and regular prophylaxis
for children reduces hemarthrosis and other hemophilic
bleeding, produces better health and joint outcomes,
Chapter 6: Prophylaxis in Hemophilia 85
reduces the number of hospital visits and admissions,
and may avert the need for orthopedic interventions,
including surgery, in the future.
6.3 Standard half-life factor prophylaxis
•
All SHL CFCs (i.e., plasma-derived and recombinant)
have essentially similar pharmacokinetic properties. e
short half-life of SHL CFCs results in the need for frequent
venipunctures for prophylaxis (3-4 times per week for
FVIII and 2-3 times per week for FIX); this oen leads
to the need for CVADs in young children and to reduced
adherence in older children/adults.
•
With SHL CFCs, it is dicult to achieve factor trough
levels much higher than 1 IU/dL (1%); to do so would
require very frequent infusions (possibly daily) that many
patients are likely unwilling or unable to do.
•
Individual factor levels in people with hemophilia on
prophylaxis are determined by:
–
the prophylaxis regimen (dose and frequency) that
individuals are on;
–
their individual pharmacokinetic (PK) handling of
factor (factor recovery and half-life/clearance); and
–
the PK characteristics of the CFC product used. (See
Table 6-3.)
RECOMMENDATION 6.3.1:
•
For patients with severe phenotype hemophilia A or B,
prophylaxis with clotting factor concentrates (either
standard or extended half-life) is recommended at a dose
and dosing interval (dependent on the pharmacokinetic
[PK] properties of the clotting factor concentrate) that
allow them to at all times have sucient circulating
factor to prevent hemarthrosis, and spontaneous and
breakthrough bleeding, based on their individual needs
and lifestyles and preserve musculoskeletal function.
•
REMARK: In the past, a trough factor level of 1 IU/dL
(1%) was deemed an adequate goal. Now recognizing
that with a 1% trough level, patients remain at risk of
bleeding, most clinicians would prefer to target higher
trough levels (>3%-5%, or higher). Recent studies show
that such trough levels achieve less bleeding. However,
the trade-o is that higher trough levels may require
higher doses or more frequent infusions of clotting factor
concentrates. is should therefore be personalized
based on the individual’s activities, lifestyle, and PK
handling of factor.
Time of day dosing for SHL CFCs
•
Timing of prophylactic doses is important particularly for
conventional CFCs with shorter half-lives (i.e., SHL FVIII/
FIX). Due to the short half-life of SHL CFCs, conventional
prophylaxis produces a sinusoidal curve of factor peaks
and troughs, corresponding to times when patients can
safely be more active and times when they cannot.
•
As people are more likely to be active during the day, it
makes logical sense for most to infuse SHL CFCs in the
mornings rather than in the evenings.
RECOMMENDATION 6.3.2:
•
For patients who are adherent to their prescribed
prophylaxis regimen but still experience breakthrough
bleeds, the WFH recommends escalation of prophylaxis
with measurement of trough levels and, if required,
orthopedic interventions as appropriate.
•
REMARK: Any patient who fails to respond to adequate
factor replacement therapy aer past responsiveness
should be tested for inhibitor development prior to
escalation of therapy.
6.4 Extended half-life factor prophylaxis
• e limitations of prophylaxis with SHL CFCs led to the
recent development, introduction, and increasing use of
EHL CFCs.
Half-life/clearance
•
Current EHL FVIII CFCs show modest improvement
(1.4- to 1.6-fold) in half-life/clearance in comparison to
SHL FVIII CFCs, with no signicant dierences in PK
properties between these EHL FVIIIs. (Note that there
is one EHL FVIII still in clinical trials [BIVV001] that
shows a 3- to 4-fold half-life extension.) By contrast, EHL
FIX CFCs show greatly improved half-lives (3- to 5-fold
longer) in comparison to SHL FIX, but unlike with EHL
FVIIIs, there are signicant dierences in the PK properties
between EHL FIX CFCs.
Dose
•
It is not as yet determined what constitutes high-,
intermediate-, and low-dose prophylaxis with EHL CFCs
and whether these denitions should be revised, given that
much higher factor trough levels can be obtained with
EHL CFCs, particularly with EHL FIXs. For the most part,
EHL FVIIIs have similar recoveries as SHL FVIIIs, and
hence doses used for prophylaxis will be similar. Certain
WFH Guidelines for the Management of Hemophilia, 3rd edition86
EHL FIX products show higher recoveries on the basis
of less extravascular distribution than SHL FIX; for these
products, lower doses might be used for prophylaxis.
It has been hypothesized that dierences in extravascular
distribution of FIX between various EHL and SHL FIX
CFCs may be important in the protective eect that these
CFCs deliver. Further research into this is necessary.
Frequency of dosing
•
Overall, EHL CFCs allow people with hemophilia to
reduce the number of infusions needed to still achieve
levels of protection similar to SHL CFCs, or allow them to
increase their factor trough levels and achieve higher levels
of bleed protection with a similar number of infusions,
or a combination of both. Modest reductions in infusion
frequency or modest increases in factor trough levels
(likely not both) may be accomplished with EHL FVIII
concentrates.
•
Some (but not all) EHL FIX concentrates permit patients
to infuse much less frequently (e.g., once every 7-14 days)
and still maintain FIX trough levels of ≥10%-20% or
infuse weekly or more frequently and achieve FIX trough
levels of 20%, 30%, or potentially higher levels. e only
caveat to this is that dierences in extravascular distribution
of FIX may be important in the protective eect of FIX.
Time of day dosing for EHL CFCs
•
e longer the half-life of a product, the less critical the
timing of infusions. is is particularly the case with some
EHL FIX concentrates. (See Table 6-4.)
RECOMMENDATION 6.4.1:
•
For patients with severe phenotype hemophilia A or
B using EHL FVIII or FIX concentrates, the WFH
recommends prophylaxis with EHL clotting factor
concentrates at sucient doses and dosing intervals to
prevent hemarthroses and spontaneous and breakthrough
bleeding and preserve joint function.
6.5 Prophylaxis with non-factor
replacement therapy
•
Note: Emicizumab is the only licensed non-factor
replacement product available at the time of publication.
•
e development of new non-factor hemostatic therapies
in hemophilia is causing a reconsideration of the concepts
and denitions of prophylaxis. ese new non-factor
therapies include emicizumab, a FVIII mimetic already
in clinical use for hemophilia A, and others still in
development including agents that inhibit natural
endogenous anticoagulants (antithrombin, tissue factor
pathway inhibitor [TFPI], and activated protein C).
TABLE 6-3 Variables that affect factor levels (applies to both SHL and EHL clotting factors) in people
with hemophilia
Variables Impacts on factor levels
Most important
Frequency of dosing
a
• Doubling frequency of infusions (without changing the dose/infusion) provides on average
5 half-lives of additional coverage
Half-life/clearance
b
• Doubling half-life provides on average 5 half-lives of additional coverage
Least important
Dose • Doubling dose provides 1 half-life of additional coverage
Recovery • Doubling recovery provides 1 half-life of additional coverage
Note: This table is adapted from Carcao (2015).
29
Abbreviations: CFC, clotting factor concentrate; EHL, extended half-life; FIX, factor IX; SHL, standard half-life.
a
Frequent small doses of CFC are generally much more efficient than infrequent large doses. Daily prophylaxis would be the most efficient
prophylaxis regimen with SHL CFCs, as it would allow for use of relatively small doses of CFC and yet permit high factor levels to be maintained.
However, such a regimen may be very difficult to adhere to, particularly for younger patients.
b
Known variables that impact half-life/clearance of FVIII include blood group (O vs non-O) and von Willebrand factor levels; less is known as to
what contributes to individual differences in pharmacokinetic handling of FIX. For the most part, individual factor recovery and half-lives increase
with age. This may result in older patients needing a lower dose per infusion to maintain similar factor trough levels.
Chapter 6: Prophylaxis in Hemophilia 87
•
Emicizumab and those non-factor agents in development
dier from conventional types of prophylaxis as they do not
replace the missing coagulation factor, are administered
subcutaneously, and in some cases can be administered
as infrequently as once every 2 or 4 weeks. Additionally,
these agents are not associated with the peak and trough
curves of protection that we now see with factor prophylaxis
regimens.
•
There have already been extensive clinical trials of
emicizumab in patients with hemophilia A with and without
inhibitors that attest to the safety and bleed protection
with this agent. (For emicizumab use in patients with
inhibitors, see Chapter 8: Inhibitors to Clotting Factor.)
•
Emicizumab is already making it easier to start patients on
prophylaxis at an earlier age and without the need for CVADs.
is may cause a re-evaluation of what constitutes primary
prophylaxis (see Table 6-1), as perhaps prophylaxis can be
commenced much earlier than usual. is could reduce the
risk of bleeding that now occurs in very young children
(ages 6-12 months) prior to the usual commencement
of prophylaxis. Further research on the safety of
emicizumab in this very young population is required.
•
Non-factor products should allow for less burdensome
prophylaxis, which might improve adherence and
might lead to increased uptake of prophylaxis among
patients not currently on prophylaxis (including those
with moderate hemophilia), permitting them increased
participation in social and sports activities. e above is
already demonstrated by the increasing uptake and usage
of emicizumab.
•
All of these developments are transforming the concepts
of prophylactic intensity. No longer can one refer to high-
dose prophylaxis as prophylaxis that results in factor
trough levels of 1%-3%.
RECOMMENDATION 6.5.1:
•
For patients with severe phenotype hemophilia A without
inhibitors, prophylaxis with emicizumab will prevent
hemarthrosis, spontaneous, and breakthrough bleeding.
•
REMARK: e WFH however notes that there are very
little long-term data on patient outcomes with such an
approach and recommends that such data be obtained.
•
See also Chapter 5: Hemostatic Agents and Chapter 8:
Inhibitors to Clotting Factor.
6.6 Fixed/non-tailored factor
prophylaxis regimens
•
Many factor prophylaxis regimens have been developed
and promulgated by dierent groups. ese regimens can,
in general, be categorized as non-tailored/xed-dose (“one
size ts all”) or tailored prophylaxis regimens.
TABLE 6-4 Documented benefits of EHL CFCs
Benefits of lower infusion frequency Benefits of higher factor trough levels
• Fewer clinic visits or home care nurse visits when
commencing patients on prophylaxis, possibly leading
to earlier start of prophylaxis
• More effective prophylaxis—higher level of prevention
of bleeds (both clinically evident and subclinical
microbleeds) while maintaining similar dosing schedules
• Less need for CVADs leading to some cost savings and
reduced morbidity
• Potentially greater level of sports participation
(possibly including sports that have traditionally been
discouraged) without incurring a substantially increased
risk of bleeding
• Less burdensome infusion schedules (dosing days and
times):
fewer morning infusions
fewer infusions on work/school days
• Increased uptake of prophylaxis among patients not
currently on prophylaxis
Note: This table is adapted from Carcao (2015).
29
Abbreviations: CFC, clotting factor concentrate; CVADs, central venous access devices; EHL, extended half-life.
WFH Guidelines for the Management of Hemophilia, 3rd edition88
“One size fits all” SHL factor prophylaxis
regimens
High-dose and intermediate-dose prophylaxis
•
The high-dose prophylaxis approach involves the
administration of usually 25-40 IU/kg per dose given every
other day or 3 times per week (for SHL FVIII concentrates)
or twice per week (for SHL FIX concentrates) in order to
ensure protection from spontaneous and breakthrough
bleeds. Intermediate-dose prophylaxis is dierentiated
from high-dose prophylaxis mainly in that lower doses
are used (15-25 IU/kg) but generally at similar or almost
similar infusion frequencies. (See Tables 6-2 and 6-5.)
•
High-dose regimens are associated with a higher need for
CVADs in children. ese can empower parents to be able
to manage their child’s hemophilia at home such that they
no longer rely on regular trips to the hospital. ey also
make treatment less stressful for young patients, potentially
improving adherence. However, there is expense and
discomfort associated with the insertion of CVADs, and
there is an appreciable frequency of complications (i.e.,
infection, thrombosis, and mechanical device failure) which
oen lead to hospitalization and CVAD replacement.
Consequently, CVADs should be viewed as a temporary
aid and kept in place only for the minimum time possible
to transition to using peripheral veins.
•
As a result of a greater appreciation of CVAD complications,
there has been a shi away from starting high-dose
prophylaxis immediately in young children. More and
more young children with severe phenotype hemophilia
have been commenced on escalating prophylaxis regimens
that start with once-weekly prophylaxis and then gradually
escalate frequency of infusions regardless of bleeding
phenotype.
•
In patients who have experienced a life-threatening bleed,
doses of CFC or non-factor therapy used for prophylaxis
should be adequate to prevent further bleeding; however,
optimal doses to achieve this goal remain to be dened.
TABLE 6-5 Advantages and disadvantages of fixed “one size fits all” SHL factor prophylaxis regimens
Regimen Advantages Disadvantages
High dose/high
frequency
• Ensures that, on average, patients with
hemophilia will have at all times measurable
FVIII/FIX levels; i.e., levels above 1 IU/dL (1%)
• Ensures that virtually all individuals receive
enough treatment to prevent virtually all
bleeds
• Achieves lowest AJBRs and best long-term
joint outcomes
• Offers benefits for very active individuals
• May be associated with adherence and
convenience issues due to increased infusion
demands on patients
• Is associated with highest factor utilization
and consequently highest cost
• Results in high need for CVADs or AVFs
• May overtreat some individuals who have
a milder phenotype which may negatively
impact adherence
• Is not ideal for resource-constrained
countries
Intermediate
dose/
intermediate
frequency
• Reduces AJBRs by approximately 90% to
<1 per year
• Is less expensive than high-dose prophylaxis
and consequently affordable in more countries
• Provides quality of life and activity participation
rates comparable to high-dose prophylaxis
• Might be best for adolescents and adults
• Results in undertreatment of some patients
• Leads to slightly worse long-term MSK
outcomes
Low dose/low
frequency
• Is the least expensive of the fixed regimens
and consequently affordable in more countries
• Reduces the incidence of bleeding by ~80% or
more in comparison to episodic therapy and
can achieve AJBRs of around <3 per year
20
• Has unknown long-term effect on MSK
outcomes which are likely worse than those
achieved with intermediate-/high-dose
regimens
Note: This table is adapted from Carcao (2015).
29
Abbreviations: AJBR, annual joint bleeding rate; AVF, arteriovenous fistula; CVAD, central venous access device; FIX, factor IX; FVIII, factor VIII;
MSK, musculoskeletal; SHL, standard half- life.
Chapter 6: Prophylaxis in Hemophilia 89
RECOMMENDATION 6.6.1:
•
For patients with moderate/severe hemophilia A or B,
especially those who have experienced a life-threatening
bleed (e.g., intracranial hemorrhage [ICH]), the WFH
recommends prophylaxis with FVIII or FIX concentrates
or with a non-factor therapy (e.g., emicizumab for
hemophilia A) in order to prevent a recurrent life-
threatening bleed. is is particularly important during
the rst 3-6 months following an ICH as the risk of
recurrence is highest during this period.
•
REMARK: As inhibitor development is associated with
intense exposure as would occur in the setting of an
ICH, such patients require good clinical monitoring
of treatment response and frequent laboratory testing
for inhibitors.
RECOMMENDATION 6.6.2:
•
For patients with hemophilia and venous access
diculties that impede regular clotting factor concentrate
infusions, the WFH recommends insertion of a central
venous access device (CVAD) to facilitate prophylactic
clotting factor concentrate infusions. Another currently
available option is the use of emicizumab while in the
future there may be other subcutaneous non-factor
therapies that become available.
Low-dose prophylaxis
•
Low-dose prophylaxis involves the administration of
factor replacement therapy at either less frequent intervals
(generally once-weekly or twice-weekly prophylaxis) or
using lower doses or a combination of both.
• In well-resourced countries, low-dose prophylaxis tends
to be low-frequency prophylaxis with usual doses. is
oen is used as a way of initiating prophylaxis and is then
followed by escalation of frequency to a higher degree of
protection.
• Some centres choose to escalate only those patients who
demonstrate breakthrough bleeds on less intense prophylaxis
(escalation tailored to bleeding phenotype approach);
other centres choose to escalate all patients rapidly to
more intense prophylaxis regardless of bleeding phenotype
(escalation regardless of bleeding phenotype approach)
to provide greater protection.
•
In resource-constrained countries, low-dose prophylaxis
tends to focus on the use of smaller doses. is is a way for
patients in these countries to start receiving prophylaxis
but at lower cost. To minimize cost, the focus tends to
be on minimizing the doses used while keeping infusion
frequencies similar.
•
is allows replacement therapy with annual consumption
similar to episodic treatment but with a much lower rate
of spontaneous bleeds.
•
Advantages and disadvantages of xed “one size ts all”
SHL factor prophylaxis regimens are shown in Table 6-5.
6.7 Tailored factor prophylaxis regimens
•
Tailored prophylaxis regimens are individualized to the
needs of each patient; this means that individuals get a
prophylaxis regimen tailored to their needs rather than
a generic regimen received by all. Ideally, this allows for
the “right amount of prophylaxis to be given to the right
patient.” is has the potential to more eciently allocate
CFCs such that they will not be “wasted” on patients
who may not require as much and yet not be denied to
patients who require more. (See 6.9 Health economics of
prophylaxis, below.)
•
Prophylaxis can be tailored in dierent ways. is applies
to both hemophilia A and B. (See Tables 6-2 and 6-6).
•
Dierences in disease phenotype as well as dierences
in individual PK handling of factor form the basis of the
rationale for tailoring prophylaxis to the individual.
• Advantages and disadvantages of both xed prophylaxis
regimens and tailored prophylaxis regimens are shown in
Table 6-5 (xed-dose regimens) and Table 6-6 (tailored
regimens). ere is likely no one regimen that is best for
all patients and for all economies.
•
e ultimate goal of all prophylaxis therapy should be the
same— to have no spontaneous bleeding.
• See Chapter 11: Outcome Assessment.
Variables that affect bleeding phenotype
•
People with hemophilia exhibit signicant phenotypic
heterogeneity in bleeding; this inter-individual variability
is seen even among people with severe hemophilia with
comparable baseline factor levels.
•
e bleeding phenotype results from the combined eect
of the individual patient’s genotypic prole (including
hemophilia genotype, genetic profiles for all other
hemostatic factors, and other genetic traits), joint health
status, and behavioral characteristics. (See Table 6-7.)
•
It has been noted that people with hemophilia who suer
recurrent bleeds at a young age and develop joint damage
(target joints) will usually require much higher factor
trough levels to prevent bleeding in the future.
WFH Guidelines for the Management of Hemophilia, 3rd edition90
TABLE 6-6 Tailoring prophylaxis to patient needs
Tailoring approach Advantages Disadvantages
Pharmacokinetics
• Involves undertaking at least a
minimal PK evaluation of patients
and then adjusting the dose/
frequency of factor infusions in
order to achieve in each patient a
predetermined factor trough level.
• Can be estimated with population
PK modeling (e.g., WAPPS-Hemo)
a
using Bayesian analysis
• Recognizes that hemophilia
patients have different PK handling
of factor which will impact on
prophylaxis needs.
• Matches the amount of CFCs given
to a patient with their PK perceived
needs, ensuring that every patient
is receiving a sufficient amount of
treatment to attain similar factor
levels.
• Does not force patients to
experience bleeds in order to
declare their prophylaxis needs.
• May result in substantial savings
in factor consumption as patients
would receive targeted amounts
needed to achieve certain factor
trough levels.
• Allows for individualizing
prophylaxis with aging as PKs
change with patient age. PK
assessments will require repeating
with aging
48
• Requires patients to undergo at
least a minimal PK evaluation.
• Requires expertise in interpreting
results of PK.
• Focuses solely on one attribute
that contributes to bleeding (PK
handling of factor) and ignores
other differences between
patients, including physical activity
levels. Sports participation may
be better supported by attention
to factor levels at the time of
participation rather than by factor
trough levels alone.
• May lead to overtreatment in some
patients who might do well with
lower factor trough levels, and may
lead to undertreatment of some
patients (e.g., very active patients)
who might need higher factor
trough levels
Clinical factors (bleeding phenotype
and physical activity patterns)
• Involves selection of a starting
regimen, which can be of any
frequency, and patients are
carefully monitored for bleeding.
Dose and frequency are adjusted
(escalated or de-escalated) as
needed to suppress excessive
clinical bleeding with the minimum
intensity of prophylaxis
• Recognizes that patients with
hemophilia are heterogeneous,
not just in PK handling of factor
but in many other aspects (some
unknown) that contribute to
bleeding and MSK outcomes.
• Better matches the amount of
prophylaxis to the needs of the
patient, potentially saving at a
population level a certain amount
of CFCs.
• Suited to transitional stages in
life, e.g., escalating prophylaxis
in early childhood; de-escalating
prophylaxis in adulthood.
• Allows very young children to
become accustomed to receiving
IV infusions when escalating
prophylaxis and might allow the
avoidance of CVADs
• Forces patients to experience
bleeds to declare their bleeding
phenotype and prophylaxis needs
• Depends heavily on the bleeding
criteria used to adjust treatment.
Although some patients may
tolerate some bleeds without long-
term joint damage, other patients
(particularly young children) are
much more susceptible; in these
patients, even one or a few bleeds
might contribute to long-term joint
damage.
• Puts patients at risk of a serious
bleed (e.g., ICH) while escalating
prophylaxis.
• Requires constant adaptation of
prophylaxis to physical activity
patterns which may be difficult
if physical activity patterns are
frequently changing
Note: This table is adapted from Carcao (2015).
29
Abbreviations: CFC, clotting factor concentrate; CVADs, central venous access devices; ICH, intracranial hemorrhage; IV, intravenous; MSK,
musculoskeletal; PK, pharmacokinetic.
a
Available at: http://www.wapps-hemo.org.
47
Chapter 6: Prophylaxis in Hemophilia 91
•
Inter-individual dierences in the balance between positive
and negative regulators of coagulation lead to dierential
bleeding risks.
•
Furthermore, activity levels can vary greatly over a
person’s lifetime. Young children may be constantly and
unpredictably active while older children and adults may
be much less active and when active may engage in planned
physical activities less likely to cause bleeding.
• Consequently, a patient’s prophylaxis regimen may need
to change over time, particularly with changes in activity
levels. Hence, prophylaxis may be individualized over a
person’s lifetime.
•
Some of this individualization might have to do with
individual lifestyle; some people who tend to be more
sedentary may opt for fewer infusions leading to a lower
degree of protection, while more active individuals may
opt for more frequent infusions and a higher level of
protection. is leads to increased inter-patient and intra-
patient individualization of prophylaxis as patients age.
•
All of the factors described above contribute to the
wide variability in clinical phenotype among people
with hemophilia. is variability in inherent bleeding
phenotype is demonstrated in the wide range of ages at
which children experience their rst joint bleed, which
may vary from <1 year to about 6 years with a median of
around 2 years of age. Age at rst joint bleed has been
shown in several studies to predict bleeding phenotype
in later years as reected in subsequent annual clotting
factor utilization and arthropathy rates, wherein patients
who had their rst joint bleed at a later age required less
treatment and developed less arthropathy.
6.8 Adherence and patient/caregiver
education
•
Despite the benefits of prophylaxis, adherence has
traditionally been a signicant problem. ere are many
reasons for reduced adherence to prophylaxis. e main
reason is likely the burden of administering CFCs both
intravenously and frequently. is results in venous access
diculties (particularly in young children but also in
older adults with signicant arthropathy and potentially
extinguished veins) and child/family resistance to the
time-consuming nature of conventional prophylaxis.
•
Another reason for reduced adherence stems from the fact
that prophylaxis is designed mainly to prevent long-term
complications from hemophilia. ere may be a lack of
comprehension on the part of the patient/caregiver of the
long-term complications of hemophilia that can occur if
prophylaxis is not commenced at a young age and a lack of
appreciation of the benets of prophylaxis. (See Chapter
2: Comprehensive Care of Hemophilia – Transition from
pediatric to adult care.)
•
e consequences of reduced adherence are reduced
eectiveness of prophylaxis; in the extreme, reduced
adherence leads to cessation of prophylaxis and places
the patient at signicant risk of bleeding. is problem of
reduced adherence is seen in both well-resourced countries
as well as in countries with more constrained resources.
•
With SHL CFCs, missed or delayed prophylaxis doses
immediately increase the bleeding risk; thus missed/delayed
doses account for a substantial proportion of breakthrough
bleeds. With EHL CFCs, the consequences of a missed
dose may be even greater; however, there is much more
margin for a dose to be simply delayed rather than missed.
TABLE 6-7 Factors that affect bleeding phenotype and contribute to inter-patient phenotypic
variability
Genetic differences Non-genetic differences
• Hemophilic variants • Levels and patterns of activity
• Levels of other procoagulant and anticoagulant proteins • Functional ability and physical coordination (i.e.,
strength, flexibility, balance, stability, mobility)
• Inflammatory responses that might impact a person’s
susceptibility to joint damage from bleeding
• Risk-taking behaviors
• Body build (i.e., muscle status)
• Presence or absence of existing target joints or
established hemophilic arthropathy
• Occurrence of trauma
WFH Guidelines for the Management of Hemophilia, 3rd edition92
•
EHL CFCs may improve adherence by allowing treatment
to be administered less oen and at less burdensome times
(evenings rather than mornings and weekends rather
than weekdays). is is particularly the case with some
EHL FIX CFCs.
•
Emicizumab, which may be administered weekly, biweekly,
or every 4 weeks, should improve adherence even further;
this needs to be studied. e impact of other non-factor
therapies, if they are found to be eective and safe and
become clinically available, will also need to be studied.
•
Prophylaxis is a team eort that relies on ongoing patient/
caregiver education and consultation. e hemophilia
treatment centre care team plays a key role in teaching the
patient/family about prophylaxis, about the importance of
maintaining a paper or electronic diary of bleeding episodes
and amount of CFC or other therapy administered, and
about the importance of adhering to the treatment plan.
•
A key component of prophylaxis has been teaching patients/
families how to infuse intravenous therapies at home; this is
referred to as home therapy. (See Chapter 2: Comprehensive
Care of Hemophilia – Home therapy.)
•
Regular checkups throughout a lifetime at the hemophilia
treatment centre are important to review the prophylaxis
plan together, including the type of therapy, dosage, and
frequency, with adjustments according to the patient’s
body weight, bleeding patterns, or other factors.
•
e above are integral requirements for eective prophylaxis.
Other requirements for eective prophylaxis are noted in
Table 6-8.
RECOMMENDATION 6.8.1:
•
For patients with severe phenotype hemophilia A or B
on prophylaxis, the WFH recommends that patients/
caregivers be taught to maintain timely and accurate
records of bleeding episodes and treatment and be
followed in hemophilia treatment centres.
6.9 Health economics of prophylaxis
•
CFCs have generally been quite expensive and have usually
accounted for over 90% of the cost of hemophilia care.
is has historically led to prophylaxis in the short term
being considerably more expensive than episodic factor
replacement therapy.
•
Cost of prophylaxis is very sensitive to the cost of CFCs
and to the intensity (frequency and dose) of prophylaxis.
In the long term, some of the cost of early and routine
prophylaxis may be mitigated by decreased healthcare
costs in adulthood due to better joint health outcomes
which may diminish hemarthroses and other hemophilic
bleeding and therefore reduce the number of hospital
visits and admissions over the years as well as diminish
or eliminate the need for costly orthopedic surgery in
the future.
•
By contrast, the direct costs of episodic therapy increase over
time because numerous joint bleeds lead to joint damage
and greater susceptibility to bleeding, oen resulting in
greater need for episodic CFC infusions and for orthopedic
surgery in later years.
•
ere are considerable long-term personal and societal
indirect costs stemming from people with hemophilia not
being on prophylaxis, including absenteeism from school
or work and limitations in vocational opportunities for
adults with hemophilic arthropathy.
•
e development of new therapies for hemophilia will likely
have considerable economic ramications. Historically,
when new therapies are introduced, they tend to be more
expensive than existing available “older therapies.”
•
However, they oen lead to a drop in the price of “older
therapies.” is may lead to the increased uptake of
prophylaxis (and possibly high-dose prophylaxis) with older
CFCs where their reduced prices may make conventional
prophylaxis much more aordable and more widely
available.
•
Furthermore, many countries have achieved substantial
decreases in CFC prices through national and regional
tenders.
TABLE 6-8 Basic requirements for effective
prophylaxis
• Reliable, uninterrupted supply of prophylactic
treatments (clotting factor concentrates and/or non-
factor therapies)
• Consistent, expert monitoring (clinical and laboratory)
of prophylaxis and its effectiveness
• Home therapy, preferably administered by the
patient/caregiver
• Good patient understanding of the value of
prophylaxis
• Good patient adherence to prophylaxis
Chapter 6: Prophylaxis in Hemophilia 93
6.10 Low-dose prophylaxis for patients
with limited access to CFCs
•
For over two decades, prophylaxis has been the standard
of care in most well-resourced countries but was seldom
undertaken in resource-constrained countries as it was
deemed to not be aordable at the doses conventionally
used. In the early 2000s, a number of observational studies
showed the benets of low-dose factor prophylaxis (i.e.,
reduced bleeds and better preservation of joint health) over
episodic factor replacement therapy, without a dramatic
increase in cost. Consequently, it became recognized
that low-dose factor prophylaxis should also be the preferred
way of managing patients even in resource-constrained
countries.
•
Showing the benets of low-dose prophylaxis regimens over
episodic therapy can be an important step in convincing
stakeholders in resource-constrained countries to gradually
transition patients with hemophilia from episodic therapy
to prophylaxis.
•
For those countries with healthcare constraints where
prophylaxis may potentially be instituted gradually, the
WFH’s position is that it is most essential to initiate
prophylaxis in young children since prevention of target
joint development may oer marked long-term joint
health benets.
RECOMMENDATION 6.10.1:
•
For patients with severe phenotype hemophilia A or B
in countries with healthcare constraints, the WFH still
strongly recommends prophylaxis (even when the only
option is using lower factor doses) over episodic factor
therapy to reduce hemarthroses and other spontaneous
and breakthrough bleeding and better preserve joint
function.
6.11 New definitions of prophylaxis
•
With emicizumab and potentially with other non-
factor therapies in the future, as well as with EHL CFCs
(particularly EHL FIX), new denitions for prophylaxis
are required. Modern prophylaxis denitions will need to
be inclusive of a wide variety of hemostatic agents with
diverse mechanisms of action and modes of administration.
•
e WFH proposes the following as a new denition
of prophylaxis based on outcomes rather than doses of
therapeutic products or time for initiation of the treatment
regimen: the regular administration of a hemostatic agent/
agents with the goal of preventing bleeding in people with
hemophilia while allowing them to lead active lives and
achieve quality of life comparable to non-hemophilic
individuals.
6.12 Future research questions to be
addressed
•
Prophylaxis in the future will create new challenges and
need for research studies, including:
–
how to assess the pharmacodynamic eects and
pharmacokinetics of new therapies, considering that
monitoring is more complex than simply measuring
FVIII or FIX levels;
–
how to assess the intensity of prophylaxis with
emicizumab and potentially other non-factor
therapies, especially given current challenges in
monitoring such therapies;
–
how to manage breakthrough bleeds and surgical
procedures in patients on prophylaxis with
emicizumab and potentially other non-factor
therapies;
–
how best to monitor short- and long-term clinical
outcomes and adverse events with these new
products as they may be associated with outcomes
and adverse events not previously encountered;
–
how to approach inhibitor development
(traditionally the greatest threat to managing
hemophilia) and inhibitor eradication in the face
of emicizumab and potentially other non-factor
therapies;
–
how best to select a hemostatic therapy or a
combination of therapies tailored to an individual
patient.
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factor IX Fc fusion protein in hemophilia B. New Engl J Med.
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31. Santagostino E, Martinowitz U, Lissitchkov T, et al. Long-acting
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35. Chowdary P, Kearney S, Regnault A, Hoxer CS, Yee DL. Improvement
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36. Staord DW. Extravascular FIX and coagulation. romb J.
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38. Rath T, Baker K, Dumont JA, et al. Fc-fusion proteins and FcRn:
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39. Metzner HJ, Pipe SW, Weimer T, Schulte S. Extending the
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of emicizumab prophylaxis given every 4 weeks in people with
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factor VIII Fc fusion protein in severe hemophilia A. Blood.
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43. Chozie NA, Primacakti F, Tulaar A, Setiabudy R, Prasetyo M, Gatot
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Chapter 6: Prophylaxis in Hemophilia 95
46. Verma SP, Dutta TK, Mahadevan S, et al. A randomized study of very
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48. Ljung R, Auerswald G, Benson G, et al. Novel coagulation factor
concentrates: issues relating to their clinical implementation and
pharmacokinetic assessment for optimal prophylaxis in haemophilia
patients. Haemophilia. 2013;19(4):481-486.
49. Brummel-Ziedins KE, Wolberg AS. Global assays of hemostasis. Curr
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50. van Dijk K, van der Bom J, Lenting P, et al. Factor VIII half-life
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51. van Dijk K, Fischer K, van der Bom JG, Grobbee DE, van den Berg HM.
Variability in clinical phenotype of severe haemophilia: the role of the
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52. Pollmann H, Richter H, Ringkamp H, Jurgens H. When are children
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53. Carcao M, Chambost H, Ljung R. Devising a best practice approach
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haemophilic treatment in young patients transitioning to adult care: a
qualitative review. Haemophilia. 2018;24(6):862-872.
55. O’Mahony B, Noone D, Prihodova L. Survey of coagulation factor
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Management of haemophilia in the developing world. Haemophilia.
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57. Srivastava A. Factor replacement therapy in haemophilia—are there
models for developing countries? Haemophilia. 2003;9(4):391-396
58. Gouider E, Rauchensteiner S, Andreeva T, et al. Real-life evidence
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recombinant FVIII concentrate: a non-interventional study in emerging
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SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting
Information section.
96
7
TREATMENT OF SPECIFIC
HEMORRHAGES
Johnny Mahlangu
1
| Gerard Dolan
2
| Alison Dougall
3
| Nicholas J. Goddard
4
| Enrique D. Preza
Hernández
5
| Margaret V. Ragni
6
| Bradley Rayner
7
| Jerzy Windyga
8
| Glenn F. Pierce
9
| Alok Srivastava
10
1
Department of Molecular Medicine and Haematology, University of the Witwatersrand, National Health Laboratory Service,
Johannesburg, South Africa
2
Guy’s and St. Thomas’ Hospitals NHS Foundation Trust, London, UK
3
Special Care Dentistry Division of Child and Public Dental Health, School of Dental Science, Trinity College Dublin, Dublin Dental
University Hospital, Dublin, Ireland
4
Department of Trauma and Orthopaedics, Royal Free Hospital, London, UK
5
Mexico City, Mexico
6
Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
7
Cape Town, South Africa
8
Department of Hemostasis Disorders and Internal Medicine, Laboratory of Hemostasis and Metabolic Diseases, Institute of Hematology
and Transfusion Medicine, Warsaw, Poland
9
World Federation of Hemophilia, Montreal, QC, Canada
10
Department of Haematology, Christian Medical College, Vellore, India
All statements identied as recommendations are
consensus based, as denoted by
.
7.1 Introduction
•
The primary clinical hallmarks of hemophilia are
prolonged spontaneous and/or traumatic hemorrhages,
most commonly within the musculoskeletal system
and predominantly intra-articular bleeding into the
large synovial joints, i.e., the ankles, knees, and elbows,
and frequently into the shoulder, wrist, and hip joints.
Hemophilic bleeding is also common in muscle and mucosal
so tissues, and less common in other so tissues, the
brain, and internal organs. Without adequate treatment,
such internal bleeds may lead to serious complications
and even become life-threatening.
•
Bleeding symptoms and tendencies depend on the patient’s
hemophilia severity and clotting factor level.
•
People with mild hemophilia may not necessarily have
abnormal or prolonged bleeding problems requiring
clotting factor replacement therapy until they experience
serious trauma or undergo surgery. ose with moderate
hemophilia may experience occasional spontaneous
bleeding and/or prolonged bleeding with minor trauma or
surgery. (See Chapter 2: Comprehensive Care of Hemophilia
– Table 2-1: Relationship of bleeding severity to clotting
factor level.)
•
In general, the main treatment for bleeding episodes in
patients with severe hemophilia is prompt clotting factor
replacement therapy and rehabilitation. However, dierent
types of bleeds and bleeding at particular anatomical sites
may require more specic management with additional
measures. It is important to consult the appropriate
specialists for the management of bleeds related to specic
sites. (For discussion and recommendations on muscle
hemorrhages and acute and chronic complications related to
musculoskeletal bleeding, see Chapter 10: Musculoskeletal
Complications – Muscle hemorrhage.)
•
e aim of management of specic hemorrhages is not only
to treat the bleed, but also to prevent bleed recurrence, limit
complications, and restore tissue and/or organ function
to a pre-bleed state.
• Diagnosing a specic bleed correctly is the rst step and
may require a combination of clinical evaluation, laboratory
assessment, and imaging investigations.
•
In most instances in hemophilia care, therapeutic
intervention may precede diagnostic workup of the patient.
e objective of early intervention is to limit the extent of
bleeding and to reduce bleeding complications.
•
e amount of hemostatic agent used for bleed treatment
and duration of treatment depends on the site and severity
of bleeding.
•
More and more hemophilia A patients are being treated
with emicizumab prophylaxis; this therapy is not intended
for treatment of acute bleeding episodes and breakthrough
bleeding (bleeding that occurs between prophylactic doses).
Chapter 7: Treatment of Specific Hemorrhages 97
•
For breakthrough bleeding in patients without inhibitors
on emicizumab, factor VIII (FVIII) infusion at doses
expected to achieve hemostasis should be used. To date,
no cases of thrombosis or thrombotic microangiopathy
have been reported in this setting.
•
Patients with inhibitors on emicizumab experiencing acute
bleeds should be treated with recombinant activated factor
VIIa (rFVIIa) at doses expected to achieve hemostasis. e
use of activated prothrombin complex concentrate (aPCC)
should be avoided in inhibitor patients on emicizumab
experiencing breakthrough bleeding. If the use of aPCC is
not avoidable, lower doses of aPCC can be used with close
monitoring of the patient for development of thrombosis
and/or thrombotic microangiopathy.
•
For inhibitor patients not on emicizumab, standard doses
of rFVIIa or aPCC should be used.
Patient/caregiver education
•
Since most bleeds in hemophilia occur outside of
hemophilia treatment centres, ongoing patient/family
caregiver education is an essential component of bleed
management.
•
It is important for healthcare providers to educate patients
and caregivers on bleed recognition and treatment, on
hemophilia self-care and self-management, and on potential
bleeding risks and complications associated with dierent
circumstances and at dierent stages of development. (See
Chapter 2: Comprehensive Care of Hemophilia – Home
therapy – Self-management.)
•
Patient and caregiver education should include instruction
on the limitations and potential side eects of hemostatic
agents and on when to consult healthcare providers for
guidance and further intervention.
7.2 Joint hemorrhage
•
e onset of bleeding into a joint is oen experienced
by patients as a sensation “aura”, described as a tingling
sensation and tightness within the joint that precedes
the appearance of clinical signs. A joint hemorrhage
(hemarthrosis) is dened as an episode characterized by
a combination of any of the following:
–
increasing swelling or warmth of the skin over the
joint;
–
increasing pain; or
–
progressive loss of range of motion or diculty in
using the limb as compared with baseline.
•
e loss of range of motion associated with joint hemorrhage
limits both exion and extension.
Clotting factor replacement therapy
•
e goal in the treatment of acute hemarthrosis is to stop
the bleeding as soon as possible. Treatment should ideally
be given as soon as the patient suspects a bleed and before
the onset of overt swelling, loss of joint function, and pain.
•
Clotting factor concentrate (CFC) should be administered
immediately at a dose sucient to raise the patient’s factor
level high enough to stop the bleeding. (See Table 7-2.)
•
In the acute setting, bleeding evaluation should include
bleeding history assessment, physical examination, and
pain assessment. Ultrasound may be a useful tool to aid
in the assessment of early hemarthrosis.
•
Response to treatment is demonstrated by a decrease in
pain and swelling, and an increase in range of motion of the
joint. e denitions listed in Table 7-1 are recommended
for the assessment of response to treatment of an acute
hemarthrosis.
RECOMMENDATION 7.2.1:
• Hemophilia patients with severe hemarthrosis should
be treated immediately with intravenous clotting factor
concentrate replacement infusion(s) until there is bleed
resolution.
RECOMMENDATION 7.2.2:
•
Hemophilia patients with moderate or mild joint bleeding
should be given 1 intravenous infusion of clotting factor
concentrate, repeated if clinically indicated, depending
on the resolution of the bleed.
•
If bleeding continues over the next 6-12 hours, a revised plan
of assessment including further diagnostic assessment (i.e.,
factor assays) and/or intensication of factor replacement
therapy should be adopted.
•
Depending on the response to the rst dose of treatment,
a further dose(s) 12 hours aer the initial loading dose for
hemophilia A (if using standard half-life FVIII) or aer 24
hours for hemophilia B (if using standard half-life factor
IX [FIX]) may be required to achieve full resolution.
(See Table 7-2.)
•
e need for a further dose of extended half-life FVIII or
FIX will also depend on the product half-life.
•
Aer an initial moderate to excellent response to hemostatic
treatment, a new bleed is dened as a bleed occurring over
72 hours aer stopping treatment for the original bleed
for which treatment was initiated.
WFH Guidelines for the Management of Hemophilia, 3rd edition98
•
A target joint is a single joint in which three or more
spontaneous bleeds have occurred within a consecutive
6-month period.
•
If symptoms and signs of bleeding persist despite normally
appropriate and adequate interventions, the presence of
inhibitors or alternative diagnoses such as septic arthritis
or fracture should be considered. (See Chapter 8: Inhibitors
to Clotting Factor.)
Pain management
•
Acute hemarthrosis may be extremely painful, and prompt
administration of clotting factor replacement and eective
analgesia are key aspects of pain management.
•
Analgesics for use in people with hemophilia include
paracetamol/acetaminophen, selective COX-2 inhibitors
(but not other NSAIDs), tramadol, or opioids. (See
Chapter 2: Comprehensive Care of Hemophilia – Pain
management.)
•
Many patients may require opioid analgesia; any usage of
opioids should be under the guidance of a pain specialist,
as even well-intentioned eorts may lead to medication
addiction.
•
Long-term use of opioid analgesics should be carefully
monitored but preferably avoided because of the chronic
nature of bleeding episodes in people with severe hemophilia
and the risks of medication addiction.
•
See Chapter 2: Comprehensive Care of Hemophilia – Pain
management.
RECOMMENDATION 7.2.3:
•
In hemophilia patients with hemarthrosis, severity of
pain should be graded and monitored according to
the World Health Organization (WHO) pain scale.
RECOMMENDATION 7.2.4:
•
Hemophilia patients with pain due to hemarthrosis
should be given analgesic medication according to the
severity of the pain.
RECOMMENDATION 7.2.5:
•
In hemophilia patients with severe pain, management
of such pain should include opioids based on clinical
symptoms to an extent that the patient is comfortable
to weight bear or use the joint as much as possible
without any pain.
Adjunctive care
•
A key element of managing the symptoms of hemarthrosis
is RICE (rest, ice, compression, elevation). In hemophilia
care, immobilization is also considered to be an aspect of
this approach; therefore, PRICE, which includes the concept
of “protection” of the injured area, is oen recommended.
Compression may help to reduce the risk of rebleeding.
However, as prolonged rest can negatively aect joint
function through reduction in muscle strength, the acronym
POLICE, which replaces “rest” with “optimal loading”,
has been put forward to encourage clinicians to establish
a balance between rest, early mobilization, and weight-
bearing to prevent unwanted complications associated with
immobilization, while minimizing rebleeding leading to
synovitis and cartilage damage.
•
e application of ice has been shown to reduce acute
hemarthrosis-related pain; however, it has been suggested
that a decrease in intra-articular temperature could interfere
with coagulation in the presence of acute tissue lesions.
e use of ice without direct skin contact for short periods
of 15-20 minutes soon aer bleeding occurs is considered
TABLE 7-1 Definitions of response to treatment
Excellent • Complete pain relief and/or complete resolution of signs of continuing bleeding after the initial
infusion within 8 h and not requiring any further factor replacement therapy within 72 h after onset of
bleeding
Good • Significant pain relief and/or improvement in signs of bleeding within approximately 8 h after a single
infusion but requiring more than 1 dose of factor replacement therapy within 72 h for complete
resolution
Moderate • Modest pain relief and/or improvement in signs of bleeding within approximately 8 h after the initial
infusion and requiring more than 1 infusion within 72 h but without complete resolution
None • No or minimal improvement, or condition worsens, within approximately 8 h after the initial infusion
Notes: The above definitions of response to treatment of an acute hemarthrosis refer to treatment with standard half-life products in inhibitor-
negative individuals with hemophilia. These definitions may require modification for inhibitor patients receiving bypassing agents as hemostatic
coverage and patients who receive extended half-life clotting factor concentrates. Modifications may be required for studies where patients
receive a priori multidose clotting factor concentrate infusions for treatment of acute joint/muscle bleeds as part of an enhanced episodic
treatment program. Adapted from Blanchette et al. (2014).
3
Chapter 7: Treatment of Specific Hemorrhages 99
acceptable but should not exceed 6 hours. (See Chapter
2: Comprehensive Care of Hemophilia – Adjunctive
management.)
•
During a joint bleed, semi-exion is usually the most
comfortable position, and any attempt to change this
position oen exacerbates pain.
•
Depending on the site of the joint bleed, elevating the
aected joint, if tolerated and comfortable, may help
reduce hemarthrosis-related swelling.
•
Rest, in the case of a hip, knee, or ankle bleed, or the use of
a sling for an elbow, shoulder, or wrist bleed, is advisable to
immobilize a joint with severe bleeding until pain resolves.
•
As soon as the pain and swelling begin to subside, the
patient can change the position of the aected joint from
a position of rest to a position of function, gently and
gradually increasing mobilization of the joint.
•
Patients with hip, knee, or ankle joint bleeds should be
restricted from weight-bearing until complete pre-bleed
joint range of motion and function are restored and acute
pain and inammation symptoms have dissipated. It
is advisable to avoid weight-bearing for 1 week, with
the use of walking aids (e.g., crutches, walker) to assist
progressive weight-bearing under the guidance of a
member of the comprehensive care team with experience
in musculoskeletal rehabilitation aer a bleed. Pain can
also be used to guide resumption of weight-bearing.
•
ese adjunctive measures will not stop joint bleeding
but can help manage and reduce symptoms of pain and
inammation.
•
See also Chapter 2: Comprehensive Care of Hemophilia
– Adjunctive management.
RECOMMENDATION 7.2.6:
•
Hemophilia patients with hemarthrosis should
be managed using the RICE approach (Rest, Ice,
Compression, and Elevation) in addition to clotting
factor concentrate replacement.
•
REMARK: e WFH recognizes that in some regions
of the world, RICE may be the only initial treatment
available or the best treatment available in the absence
of an adequate supply of CFCs or other hemostatic
agents.
.
RECOMMENDATION 7.2.7:
•
In hemophilia patients with hemarthrosis, weight-
bearing should be avoided until the symptoms improve
to an extent that the patient is comfortable to weight
bear without signicant pain.
RECOMMENDATION 7.2.8:
•
In hemophilia patients, use of opioid analgesia in
managing pain should be limited in duration, as much
as possible.
Physical therapy and rehabilitation
•
Physical therapy and rehabilitation for the management of
patients with hemophilia refers to the use of exibility and
strength training, proprioceptive/sensorimotor retraining,
and balance and functional exercises to restore or preserve
joint and muscle function.
•
orough assessment of acute joint bleeding followed by
physical therapy tailored to the individual’s clinical situation
is essential to achieve a signicant degree of success.
•
Ideally, physical therapy should be undertaken under
adequate factor or hemostatic coverage. If hemostatic
coverage is not available, physical therapy should be applied
cautiously and exercises should be initiated judiciously.
•
It is important to carefully monitor the aected joint
throughout physical therapy and assess whether hemostatic
treatment is needed to prevent recurrence of bleeding.
•
Rehabilitation should include both active and passive
range of motion exercises.
•
The patient should continue active exercises and
proprioceptive training until complete pre-bleed joint
range of motion and functioning are restored and signs
of acute synovitis have dissipated.
RECOMMENDATION 7.2.9:
•
In hemophilia patients with hemarthrosis, physical
therapy exercises performed under clotting factor
coverage should begin as soon as the pain symptoms
stop.
RECOMMENDATION 7.2.10:
•
In hemophilia patients with hemarthrosis, the aim of
physical therapy should be to return joint function to
the pre-bleed state.
Arthrocentesis
•
Arthrocentesis (removal of blood from a joint) may be
considered for patients with hemophilia experiencing
prolonged or worsening bleeding symptoms including:
–
tense, painful hemarthrosis that shows no
improvement within 24 hours of the initial infusion
(this is particularly the case for bleeding into the hip
joint due to the particular anatomy of the hip joint);
or
–
clinical suspicion of infection/septic arthritis.
WFH Guidelines for the Management of Hemophilia, 3rd edition100
•
Inhibitors should be considered as a possible reason for
persistent bleeding despite adequate factor replacement
therapy, and the presence of inhibitors should be assessed
before arthrocentesis is attempted.
•
For hemophilia patients with inhibitors, other appropriate
hemostatic agents should be used to provide hemostatic
coverage for the procedure, as needed. (See “Management
of bleeding” in Chapter 8: Inhibitors to Clotting Factor.)
•
Arthrocentesis should always be done under strictly aseptic
conditions to avoid introducing intra-articular infections.
•
When necessary, arthrocentesis should only be performed
under factor coverage, with factor activity levels of at least
30-50 IU/dL maintained for 48-72 hours. Arthrocentesis
should not be done in circumstances where such factor
coverage (or equivalent coverage with other hemostatic
agents) is not available.
•
A large-bore needle, at least 16 gauge, should be used.
e joint should be immobilized with mild compression
following arthrocentesis, and weight-bearing should be
restricted until the remaining blood is absorbed or absence
of pain permits mobilization.
•
Arthrocentesis should be followed by carefully supervised
physical therapy and rehabilitation.
• See also Chapter 10: Musculoskeletal Complications.
RECOMMENDATION 7.2.11:
•
For hemophilia patients without inhibitors on factor
replacement therapy presenting with joint hemorrhage
and persistent pain, arthrocentesis is recommended only
if there is a tense, painful hemarthrosis or suspicion of
infection. Routine arthrocentesis is not advised.
•
REMARK: In many healthcare settings, arthrocentesis
is not common practice because of fear of introducing
intra-articular infection.
7.3 Central nervous system and
intracranial hemorrhage
•
All head injuries, conrmed or suspected, signicant
headaches including headaches lasting for several hours,
and somnolence in some instances, must be treated as
possible intracranial bleeds. Sudden severe back pain
may be a symptom of bleeding around the spinal cord.
•
In the event of signicant head trauma or clinical suspicion
of central nervous system and/or intracranial hemorrhage,
immediate treatment with CFC infusion is required without
waiting for further symptoms to develop or for laboratory
or radiologic evaluation.
RECOMMENDATION 7.3.1:
•
In hemophilia patients presenting with suspected central
nervous system bleeds or bleed-related symptoms, clotting
factor replacement therapy should be administered
immediately before investigations are performed.
•
Immediately administer appropriate clotting factor
replacement therapy as soon as signicant trauma or
symptoms occur, before any other intervention, and
maintain factor level until etiology is dened. If a bleed
is conrmed, maintain the appropriate factor level for
10-14 days. (See Table 7-2.)
•
Immediate medical evaluation and hospitalization are
required, including a computed tomography (CT) scan
or magnetic resonance imaging (MRI) of the brain
and neurological consultation as soon as possible.
Ultrasound examination may be considered in children.
RECOMMENDATION 7.3.2:
•
In patients with hemophilia presenting with suspected
central nervous system bleeding that could be life-
threatening, clotting factor replacement therapy should
be administered immediately before investigations are
performed and continued until the bleed resolves.
•
REMARK: In patients with hemophilia who have been
treated for central nervous system bleeding, secondary
prophylaxis is recommended to prevent bleed recurrence.
•
Intracranial hemorrhage may be an indication for secondary
prophylaxis (short-term prophylaxis for 3-6 months or
even lifelong), especially where a relatively high risk of
bleed recurrence has been observed (e.g., in the presence
of human immunodeciency virus [HIV] infection).
7.4 Throat and neck hemorrhage
•
Bleeding into the throat or neck may be due to local
pathology, trauma, or severe coughing, and may present
with swelling or pain. is is a medical emergency because
it can lead to airway obstruction. If indicated, gently
elevate the head to help reduce airway obstruction due
to the hemorrhage.
•
Treat immediately with CFC to raise the patient’s factor
level when signicant trauma or bleeding symptoms occur
in the throat and neck area, without any delay that could
occur while awaiting full evaluation. (See Table 7-2.)
Chapter 7: Treatment of Specific Hemorrhages 101
•
Immediate hospitalization and medical evaluation by a
specialist otolaryngologist is required.
•
Protective factor levels should be maintained until
symptoms resolve. (See Table 7-2.)
RECOMMENDATION 7.4.1:
•
In hemophilia patients with throat and neck bleeding,
clotting factor replacement therapy should be
administered immediately and critical care evaluation
sought.
RECOMMENDATION 7.4.2:
•
In hemophilia patients with throat and neck bleeding,
including injury of the tongue, clotting factor replacement
therapy should continue until the bleeding symptoms
have resolved.
•
To prevent oral hemorrhage in patients with severe
tonsillitis, prophylaxis with CFCs, desmopressin (DDAVP;
for those with mild or moderate hemophilia A), or
antibrinolytics (epsilon aminocaproic acid [EACA]
and tranexamic acid) are advised in addition to bacterial
culture and treatment with appropriate antibiotics.
RECOMMENDATION 7.4.3:
•
In hemophilia patients with throat and neck bleeding
and local infection, antibrinolytics should be started to
treat the bleed and antibiotics to treat the infection.
7.5 Gastrointestinal/abdominal
hemorrhage
•
Acute gastrointestinal (GI) hemorrhage may present
as hematemesis, hematochezia (rectal passage of fresh
blood), or melena.
•
In a patient with liver disease, the rst sign of GI bleeding
may be hepatic encephalopathy, as the failing liver cannot
process the high protein load of GI bleeding.
• Any sign of GI bleeding and/or acute hemorrhage in the
abdomen requires immediate medical evaluation. All
patients with GI bleeds should be hospitalized.
RECOMMENDATION 7.5.1:
•
In hemophilia patients with gastrointestinal bleeding,
factor levels should be raised immediately and the
underlying etiology of the bleed identied and treated.
•
GI bleeds must be treated as soon as possible following
injury and/or the onset of the earliest symptoms with clotting
factor replacement therapy to raise the patient’s factor level,
with factor levels maintained until hemorrhaging has
stopped and the etiology of the hemorrhage is dened.
(See Table 7-2.)
RECOMMENDATION 7.5.2:
•
Hemophilia patients with gastrointestinal bleeding
should be prescribed antibrinolytics.
•
Antibrinolytics are oen eective adjunctive therapy
for both patients with hemophilia A and hemophilia B.
Concurrent use with aPCC or prothrombin complex
concentrate (PCC) may be used with caution in some
patients.
• Treat the origin of the hemorrhage as indicated.
•
Monitor hemoglobin levels regularly and treat anemia or
shock as needed. Perform endoscopy, if clinically indicated,
in any patient with dropping hemoglobin levels. In GI
bleeding, the investigation of choice is endoscopy.
•
In patients with advanced liver disease, ammonia levels
should be monitored, and treatment to prevent clinical
encephalopathy with lactulose or a similar agent should
be initiated.
RECOMMENDATION 7.5.3:
•
In hemophilia patients with gastrointestinal bleeding,
endoscopic and radiologic imaging should be performed
to identify all sites of bleeding.
RECOMMENDATION 7.5.4:
•
In hemophilia patients with gastrointestinal bleeding,
hemoglobin levels should be monitored regularly.
•
An acute abdominal (including retroperitoneal) hemorrhage
can present with abdominal pain and distension and can be
mistaken for a number of infectious or surgical conditions.
It may also present as a paralytic ileus.
•
Abdominal bleeds must be treated immediately to raise
and maintain the patient’s factor levels until the etiology
can be dened.
•
Perform a clinical assessment of the patient with a physical
examination, pain assessment, and history taking including
bleed history. An ultrasound and/or CT scan can identify
the site and extent of abdominal bleeding.
•
Determine appropriate treatment in consultation with a
specialist. (See Table 7-2.)
WFH Guidelines for the Management of Hemophilia, 3rd edition102
7.6 Renal hemorrhage
•
Bleeding in the kidneys (renal hemorrhage) can occur
spontaneously or following injury.
•
Urinary tract bleeding may be the rst sign of malignancy
in the bladder, particularly in older patients.
•
Symptoms may include abdominal pain and swelling,
severe ank and back pain, and hematuria.
•
Patients with mild painless hematuria can be treated
with complete bed rest and vigorous hydration (3 L/
m body surface area/ day), with or without clotting
factor replacement as feasible, for 48 hours unless there
is concurrent renal or cardiac impairment. Avoid DDAVP
when hydrating intensively.
• All renal bleeding should be treated as urgent.
RECOMMENDATION 7.6.1:
•
For hemophilia patients with urinary tract hemorrhage,
the site of bleeding should be identied and clotting
factor replacement therapy should be administered
immediately.
RECOMMENDATION 7.6.2:
•
Hemophilia patients with renal bleeding should be
given adequate hydration and prescribed bed rest until
bleeding stops.
•
If there is pain or persistent gross hematuria, it is important
to watch for clots and urinary obstruction. Avoid use
of antibrinolytic agents.
RECOMMENDATION 7.6.3:
•
In hemophilia patients with renal bleeding,
antibrinolytics should not be administered.
RECOMMENDATION 7.6.4:
•
In hemophilia patients with renal bleeding, clotting
factor replacement therapy should continue until the
bleeding is resolved.
•
Refer the patient to a urologist for evaluation of a local
cause if hematuria (gross/macroscopic or microscopic
hematuria) persists or if there are repeated episodes. (See
Table 7-2.)
7.7 Ophthalmic hemorrhage
•
Bleeding in the eye (ophthalmic hemorrhage) is uncommon
unless associated with trauma or infection of the eye.
•
Eye bleeds should be treated immediately to raise the
patient’s factor level, with factor levels maintained until
the etiology of the bleed can be dened, followed by
appropriate treatment in consultation with a specialist.
RECOMMENDATION 7.7.1:
•
In hemophilia patients with ophthalmic bleeding,
clotting factor levels should be raised immediately and
the patient evaluated by an ophthalmologist.
RECOMMENDATION 7.7.2:
•
In hemophilia patients with ophthalmic bleeding, regular
physical examination should be carried out every 6-8
hours for the duration of the ophthalmic bleed.
•
REMARK: Imaging may be included as clinically
indicated.
.
RECOMMENDATION 7.7.3:
•
In hemophilia patients with ophthalmic bleeding,
treatment and monitoring should be continued until
the bleeding is resolved.
•
Refer the patient for evaluation by an ophthalmologist as
soon as possible. (See Table 7-2.)
7.8 Oral hemorrhage
•
e most common causes of bleeding in the mouth (oral
hemorrhage) are dental extraction, gingival bleeding (oen
due to poor oral hygiene), and trauma.
•
Gum bleeding is a sign of inammatory gum disease
(gingivitis) and is preventable and treatable in people with
hemophilia. It is not caused by the underlying congenital
bleeding disorder itself.
•
Early referral to a dental professional for assessment and
appropriate periodontal treatment and advice will reduce
bleeding aer brushing, prevent progression of gum disease,
and reduce the likelihood of early tooth loss and risk of
associated systemic eects.
•
Other less common causes of bleeding from the mouth
may include: self-injury, shedding of deciduous (baby)
teeth, and recent dental surgery without appropriate
hemostatic measures in place.
Chapter 7: Treatment of Specific Hemorrhages 103
•
Bleeding following loss of baby teeth is not usually
prolonged if recognized and treated early. Direct pressure
should be applied on the tooth socket using a damp gauze
swab and maintained for at least 15-30 minutes. Parents/
caregivers should be advised that if bleeding persists for
longer than 6 hours, they should consult their hemophilia
treatment centre for additional support.
• A carefully planned preoperative hemostatic care plan is
advised for patients with hemophilia about to undergo oral
surgery or invasive dental procedures to avoid postoperative
bleeding.
RECOMMENDATION 7.8.1:
•
In hemophilia patients with oral bleeding, the site of
bleeding should be identied and direct pressure and/
or sutures applied, if possible.
RECOMMENDATION 7.8.2:
•
In hemophilia patients with oral bleeding,
antibrinolytics should be prescribed and administered
at appropriate dosages.
•
Antibrinolytic agents should be used with caution in
patients with hemophilia B who are being treated with
large doses of PCC or in patients with inhibitors being
treated with aPCC.35,36
RECOMMENDATION 7.8.3:
•
In hemophilia patients with persistent oral bleeding,
clotting factor replacement therapy should be
administered along with local measures such as sutures
and topical adrenaline application to stop the bleeding.
•
Patients who experience prolonged bleeding from the mouth
should seek early consultation with their hemophilia team
in association with the dentist or oral and maxillofacial
surgeon to determine the source and severity of bleeding.
•
If there has been unexpected bleeding following a carefully
planned invasive dental procedure, laboratory tests should
be performed alongside management of oral bleeding to
identify possible causes, e.g., the presence of an inhibitor
or platelet function defect due to medication.
•
Persistent oral bleeding should be managed using staged
local and/or systemic measures including:
–
direct pressure on the area using a damp gauze swab,
maintained for at least 15-30 minutes;
–
local anesthesia with adrenaline/epinephrine to aid
local vasoconstriction;
–
sutures for wound closure;
–
application of local hemostatic agents, e.g., oxidized
cellulose, thrombin, brin sealant, or similar;
–
use of oral or topical antibrinolytics as a
mouthwash or paste;
–
systemic treatment of choice, e.g., CFC replacement,
DDAVP, or antibrinolytic therapy as directed by the
hemophilia team; and
–
monitoring of vital signs and treatment for anemia,
if required.
•
Once hemostasis is achieved, stringent postoperative
management will reduce risk of rebleeding.
• Patients with hemophilia should be advised to:
–
use systemic and/or topical antibrinolytic agents for
5-7 days;
–
refrain from sports and intensive exercises for 3-5
days;
–
eat a so diet with no vigorous mouth rinsing for 3-5
days;
–
refrain from or reduce smoking for at least 24 hours;
and
–
consider use of a so splint to protect the wound
longer term, if required.
•
See also Chapter 2: Comprehensive Care of Hemophilia
– Dental care and management.
7.9 Epistaxis
•
Bleeding from the nose (epistaxis) can occur with injury
or irritation to the nasal mucous membrane.
•
People with hemophilia may experience frequent and
prolonged nosebleeds which can be minor nuisances or
major events that require medical attention in the hospital
or emergency room.
•
Clotting factor replacement therapy is oen not necessary
unless bleeding is severe or recurrent.
RECOMMENDATION 7.9.1:
•
In hemophilia patients with epistaxis, the head should
be elevated and cold compression applied to the Little’s
area of the nose.
RECOMMENDATION 7.9.2:
•
In hemophilia patients with epistaxis, nasal packing
should be avoided as it can cause bleeding when removed.
However, in practice, nasal packing is used extensively.
WFH Guidelines for the Management of Hemophilia, 3rd edition104
RECOMMENDATION 7.9.3:
•
In hemophilia patients with epistaxis, gauze soaked
in an antibrinolytic agent may be used in addition to
clotting factor replacement therapy.
•
Patients with acute epistaxis must receive rst aid treatment
as follows:
–
Place the patient’s head in a forward position to
avoid swallowing of blood and have the patient
gently blow out weak clots.
–
Apply rm continuous pressure with a gauze soaked
in ice water to the anterior nasal septum, i.e., Little’s
area, for 5-10 minutes.
–
An antibrinolytic agent applied locally using a
soaked gauze is helpful.
•
Nasal packing is contraindicated because the vascular
endothelial lining is destroyed upon removal of the packing
material, and hemostasis will be challenged. Cauterization
is an eective alternative.
•
For epistaxis specifically related to allergies, upper
respiratory infections, or seasonal changes, administer
antihistamines and decongestant medications if indicated.
•
For epistaxis caused by infection, administer antibiotics
if indicated.
•
If epistaxis is prolonged or occurs frequently, evaluate for
anemia and treat appropriately.
•
For patients with severe and recurrent nosebleeds, specialist
consultation and preventative measures are recommended.
Consultation with an otolaryngologist is advisable if
nosebleeds are persistent or recurrent.
•
In severe or persistent cases, therapeutic occlusion of the
arterial supply to the nose may be indicated.
• Preventive measures to reduce risk of epistaxis include:
–
increasing the humidity of the environment;
–
applying gels (e.g., petroleum jelly or saline drops/
gel) to the nasal mucosa to preserve moisture, or
administering saline spray;
–
adhering to prescribed medications such as
antihistamines, decongestant medications, and
antibiotics as directed.
RECOMMENDATION 7.9.4:
•
In hemophilia patients with persistent epistaxis, vital
signs and hemoglobin levels should be monitored until
the bleeding stops (usually within 24-48 hours).
RECOMMENDATION 7.9.5:
•
In hemophilia patients with recurrent epistaxis, the
underlying pathology should be identied immediately
and treated. Decongestants and antihistamines should
help if bleeding is related to allergy, and antibiotics should
be administered if bleeding is related to infection.
7.10 Lacerations and abrasions
•
Lacerations and abrasions are external bleeds caused by
supercial or deep cuts or scrapes to the surface of the skin.
• Supercial lacerations should be treated with rst aid.
• For deep lacerations, raise the patient’s factor level, then
suture the wound if appropriate. (See Table 7-2.)
RECOMMENDATION 7.10.1:
•
In hemophilia patients with lacerations and abrasions,
clotting factor replacement therapy should be
administered and the wound sutured immediately, if
appropriate, in consultation with appropriate surgeons.
•
Hemostatic coverage should be considered for suture
removal, if the risk of bleeding is considered high.
7.11 Soft tissue hemorrhage
•
A so tissue hemorrhage (hematoma) occurs in muscles,
ligaments, tendons, and subcutaneous spaces.
•
Common so tissue injuries are oen caused by a sprain
or strain, a blow resulting in a contusion, or overuse of
a particular body part. Symptoms depend on the site of
hemorrhage.
•
Clotting factor replacement therapy may not be necessary
for most supercial so tissue bleeding. e application
of rm pressure and ice may be helpful.
•
Open compartmental hemorrhage, such as in the
retroperitoneal space, scrotum, buttocks, or thighs, can
result in extensive blood loss. If this situation is suspected,
immediate clotting factor replacement therapy is required
to decrease bleeding as well as ice and adjunct treatment to
reduce pain, tissue metabolism, edema, and inammation.
•
Evaluate the patient for severity of hemorrhage and possible
distal neurovascular involvement. Rule out possible trauma
to spaces containing vital organs, such as the head or
abdomen.
•
Continued evaluation should be considered to avoid
compartment syndrome.
•
Monitor hemoglobin levels and vital signs regularly until
bleeding has stopped and/or function is restored.
• See also Chapter 10: Musculoskeletal Complications.
Chapter 7: Treatment of Specific Hemorrhages 105
TABLE 7-2 Practice patterns: peak plasma factor levels and duration of administration
Hemophilia A Hemophilia B
Lower-dose
practice pattern
Higher-dose
practice pattern
Lower-dose
practice pattern
Higher-dose
practice pattern
Type of
hemorrhage
Peak factor
level (IU/dL)
Treatment
duration (d)
Peak factor
level (IU/dL)
Treatment
duration (d)
Peak factor
level (IU/dL)
Treatment
duration (d)
Peak factor
level (IU/dL)
Treatment
duration (d)
Joint 10-20 1-2
a
40-60 1-2
a
10-20 1-2
a
40-60 1-2
a
Superficial muscle/
no NV compromise
(except iliopsoas)
10-20 2-3
a
40-60 2-3
a
10-20 2-3
a
40-60 2-3
a
Iliopsoas or deep muscle with NV injury or substantial blood loss
Initial 20-40 1-2 80-100 1-2 15-30 1-2 60-80 1-2
Maintenance 10-20 3-5
b
30-60 3-5
b
10-20 3-5
b
30-60 3-5
b
Intracranial
Initial 50-80 1-3 80-100 1-7 50-80 1-3 60-80 1-7
Maintenance 20-40 8-14 50 8-21 20-40 8-14 30 8-21
30-50 4-7 – – 30-50 4-7 – –
Throat and neck
Initial 30-50 1-3 80-100 1-7 30-50 1-3 60-80 1-7
Maintenance 10-20 4-7 50 8-14 10-20 4-7 30 8-14
Gastrointestinal
Initial 30-50 1-3 80-100 7-14 30-50 1-3 60-80 7-14
Maintenance 10-20 4-7 50 10-20 4-7 30
Renal 20-40 3-5 50 3-5 15-30 3-5 40 3-5
Deep laceration 20-40 5-7 50 5-7 15-30 5-7 40 5-7
Surgery (major)
Pre-op 60-80 80-100 50-70 60-80
Post-op
c
30-40 1-3 60-80 1-3 30-40 1-3 40-60 1-3
20-30 4-6 40-60 4-6 20-30 4-6 30-50 4-6
10-20 7-14 30-50 7-14 10-20 7-14 20-40 7-14
Surgery (minor)
Pre-op 40-80 50-80 40-80 50-80
Post-op
d
20-50 1-5 30-80 1-5 20-50 1-5 30-80 1-5
Notes: In this table, the desired peak factor levels of CFC replacement shown for treatment of hemorrhages at different anatomical sites represent
the ranges in global practice patterns depending on available resources. Importantly, it should be recognized that the goal of such treatment is
effective control of bleeding and should be the same everywhere in the world. Lower CFC replacement levels require much closer observation
for effectiveness of bleeding control, with a potentially greater chance of requiring additional CFC replacement to achieve the target plasma
level as well as the hemostatic and musculoskeletal outcomes.
Abbreviations: CFC, clotting factor concentrate; NV, neurovascular.
a
May be longer if response is inadequate.
b
Sometimes longer as secondary prophylaxis during physical therapy.
c
The duration of treatment refers to sequential days post-surgery. Type of CFC and patient’s response to CFC should be taken into account.
d
Depending on procedure; the number of doses would depend on the half-life of the CFC used.
WFH Guidelines for the Management of Hemophilia, 3rd edition106
7.12 Practice patterns in CFC
replacement
•
e desired peak plasma factor levels shown in Table 7-2
reect the range of practice in the community and have
been part of the WFH guidelines since 2005. Over this
long period, they have helped guide clinical care as well
as research, particularly for surgical hemostasis, without
any reported safety concerns. More research is needed to
critically evaluate these practices.
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12. Stephensen D, Bladen M, McLaughlin P. Recent advances in
musculoskeletal physiotherapy for haemophilia. er Adv Hematol.
2018;9(8):227-237.
13. Lobet S, Hermans C, Lambert C. Optimal management of hemophilic
arthropathy and hematomas. J Blood Med. 2014;5:207-218.
14. Forsyth AL, Zourikian N, Valentino LA, Rivard GE. e eect of
cooling on coagulation and haemostasis: should “Ice” be part of
treatment of acute haemarthrosis in haemophilia? Haemophilia.
2012;18(6):843-850.
15. Gilbert MS. Musculoskeletal complications of haemophilia: the joint.
Haemophilia. 2000;6(Suppl 1):34-37.
16. Blamey G, Forsyth A, Zourikian N, et al. Comprehensive elements
of a physiotherapy exercise programme in haemophilia—a global
perspective. Haemophilia. 2010;16(Suppl 5):136-145.
17. Gomis M, Querol F, Gallach JE, Gonzalez LM, Aznar JA. Exercise and
sport in the treatment of haemophilic patients: a systematic review.
Haemophilia. 2009;15(1):43-54.
18. Heijnen L, Buzzard BB. e role of physical therapy and rehabilitation
in the management of hemophilia in developing countries. Semin
romb Hemost. 2005;31(5):513-517.
19. Ingram GI, Mathews JA, Bennett AE. Controlled trial of joint aspiration
in acute haemophilic haemarthrosis. Ann Rheum Dis. 1972;31(5):423.
20. Rodriguez-Merchan EC. Aspects of current management: orthopaedic
surgery in haemophilia. Haemophilia. 2012;18(1):8-16.
21. Hermans C, de Moerloose P, Fischer K, Holstein K, Klamroth R,
Lambert T et al., European Haemophilia erapy Standardisation Board.
Management of acute haemarthrosis in haemophilia A without inhibitors:
literature review, European survey and recommendations. Haemophilia
2011;17:383– 92.
22. Ljung RC. Intracranial haemorrhage in haemophilia A and B. Br J
Haematol. 2008;140(4):378-384.
23. Nakar C, Cooper DL, DiMichele D. Recombinant activated factor
VII safety and ecacy in the treatment of cranial haemorrhage in
patients with congenital haemophilia with inhibitors: an analysis of the
Hemophilia and rombosis Research Society Registry (2004-2008).
Haemophilia. 2010;16(4):625-631.
24. Witmer CM, Manno CS, Butler RB, Rani LJ. e clinical management
of hemophilia and head trauma: a survey of current clinical practice
among pediatric hematology/oncology physicians. Pediatr Blood
Cancer. 2009;53(3):406-410.
25. Traivaree C, Blanchette V, Armstrong D, Floros G, Stain AM, Carcao
MD. Intracranial bleeding in haemophilia beyond the neonatal
period—the role of CT imaging in suspected intracranial bleeding.
Haemophilia. 2007;13(5):552-559.
26. Patiroglu T, Ozdemir MA, Unal E, et al. Intracranial hemorrhage
in children with congenital factor deciencies. Childs Nerv Syst.
2011;27(11):1963-1966.
27. Zanon E, Iorio A, Rocino A, et al. Intracranial haemorrhage in the
Italian population of haemophilia patients with and without inhibitors.
Haemophilia. 2012;18(1):39-45.
28. Singleton T, Kruse-Jarres R, Leissinger C. Emergency department care
for patients with hemophilia and von Willebrand disease. J Emerg Med.
2010;39(2):158-165.
29. Bush MT, Roy N. Hemophilia emergencies. J Emerg Nurs.
1995;21(6):531-538; quiz 538-540.
30. Guthrie TH Jr, Sacra JC. Emergency care of the hemophiliac patient.
Ann Emerg Med. 1980;9(9):476-479.
31. Kouides PA, Fogarty PF. How do we treat: upper gastrointestinal
bleeding in adults with haemophilia. Haemophilia. 2010;16(2):360-362.
32. Mittal R, Spero JA, Lewis JH, et al. Patterns of gastrointestinal
hemorrhage in hemophilia. Gastroenterology. 1985;88(2):515-522.
33. Quon DV, Konkle BA. How we treat: haematuria in adults with
haemophilia. Haemophilia. 2010;16(4):683-685.
34. Ghosh K, Jijina F, Mohanty D. Haematuria and urolithiasis in patients
with haemophilia. Eur J Haematol. 2003;70(6):410-412.
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as a complication of the use of epsilon aminocaproic acid: a case report
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SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting
Information section.
107
INHIBITORS TO
CLOTTING FACTOR
8
Margaret V. Ragni
1
| Erik Berntorp
2
| Manuel Carcao
3
| Carmen Escuriola Ettingshausen
4
|
Augustas Nedzinskas
5
| Margareth C. Ozelo
6
| Enrique D. Preza Hernández
7
| Andrew Selvaggi
8
|
H. Marijke van den Berg
9
| Glenn F. Pierce
10
| Alok Srivastava
11
1
Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
2
Malmö Centre for Thrombosis and Haemostasis, Lund University, Malmö, Sweden
3
Department of Paediatrics, University of Toronto, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada
4
Haemophilia Centre Rhein Main, Frankfurt-Mörfelden, Germany
5
Ariogala, Lithuania
6
INCT do Sangue Hemocentro UNICAMP, University of Campinas, Campinas, SP, Brazil
7
Mexico City, Mexico
8
Melbourne, Australia
9
PedNet Haemophilia Research Foundation, Baarn, the Netherlands
10
World Federation of Hemophilia, Montreal, QC, Canada
11
Department of Haematology, Christian Medical College, Vellore, India
All statements identied as recommendations are consensus
based, as denoted by
.
is chapter describes inhibitor formation, one of the most
serious complications in hemophilia treatment, and provides
key denitions and guidance on inhibitor screening, testing,
and treatment. e management of hemophilia A inhibitors
and hemophilia B inhibitors is discussed separately given the
dierences in inhibitor incidence and treatment.
All recommendations on product use in this chapter are
made under the assumption that a specic product is available
in a particular country, region, or healthcare system.
8.1 Introduction
•
“Inhibitors” in hemophilia are IgG alloantibodies to
exogenous clotting factor VIII (FVIII) or factor IX (FIX)
that neutralize the function of infused clotting factor
concentrates (CFCs). Inhibitors are detected and quantied
by the Nijmegen-modied Bethesda assay.
•
e presence of a new inhibitor should be suspected in
any patient with hemophilia who fails to respond clinically
to CFC replacement therapy, particularly in previously
responsive patients. (See 8.2 Inhibitor screening, below.)
•
Inhibitors are more frequently encountered in patients
with severe disease than in those with moderate or
mild hemophilia, and more commonly in patients with
hemophilia A than in those with hemophilia B. Controlling
bleeds is a greater challenge in hemophilia patients with
inhibitors than in those without inhibitors. Inhibitors to
FVIII or FIX are associated with a higher disease burden,
including increased risk of musculoskeletal complications,
pain, physical limitations, and treatment challenges, all of
which may impact a patient’s physical functioning, capacity
for physical activities, and quality of life.
•
In addition, the immune response to FVIII and FIX products
is poorly understood and, in the absence of evidence, there
remain areas of evolving and sometimes ambiguous or
conicting information on inhibitor management.
•
Furthermore, while new therapies and strategies for inhibitor
treatment and eradication are emerging that may oer
benets, the long-term clinical outcomes remain unknown.
•
Signicant dierences exist between hemophilia A and
hemophilia B regarding inhibitor incidence, management,
and response to immune tolerance induction (ITI) and
alternative hemostatic agents. erefore, in this chapter,
hemophilia A inhibitors and hemophilia B inhibitors are
discussed separately.
Patient/caregiver education
•
Ongoing patient and family caregiver education and
psychosocial support are essential components of the
management of hemophilia patients with inhibitors given
the complexity and challenges of this serious complication. It
is vital for clinicians, patients, caregivers, and the hemophilia
treatment centre team to maintain good communication
through a well-coordinated plan of care.
WFH Guidelines for the Management of Hemophilia, 3rd edition108
8.2 Inhibitor screening
•
Inhibitors are measured by the Bethesda assay or the
Nijmegen-modied Bethesda assay.
•
e denition of a positive inhibitor is a Bethesda titer of
>0.6 Bethesda units (BU) for FVIII and ≥0.3 BU for FIX.
•
Inhibitor measurement may be performed during
replacement therapy by assays utilizing heat treatment
techniques. (See Chapter 3: Laboratory Diagnosis and
Monitoring – Coagulation laboratory testing – Inhibitor
testing.)
•
A low-responding inhibitor is an inhibitor <5.0 BU, whereas
a high-responding inhibitor is an inhibitor ≥5.0 BU.
•
Low-responding inhibitors tend to be transient; a transient
inhibitor is dened as a positive inhibitor that drops
below the denition threshold within 6 months of initial
documentation without any change in treatment regimen
and despite antigenic challenge with CFCs. A suspected
inhibitor should be conrmed by repeat laboratory testing,
documenting poor factor recovery and/or shortened half-
life (t½) of less than 6 hours in hemophilia A (in the case of
standard half-life FVIII CFCs) and 9 hours in hemophilia
B (in the case of standard half-life FIX CFCs).
•
High-responding inhibitors tend to be persistent and may
fall or become undetectable aer a long period without
CFC exposure; however, they increase 3-5 days aer re-
challenge with CFCs (anamnestic response).
•
It is critical to detect inhibitors early to ensure appropriate
treatment. At least half of inhibitor cases are detected
by routine inhibitor screening aer initial exposures
to CFCs, while the rest are detected aer there is poor
clinical response to CFC replacement therapy (i.e., when
factor recovery and/or half-life are not as expected) when
treating or preventing a bleed.
•
Inhibitor testing should be performed before major surgery
and if there is suboptimal response to CFC replacement
therapy in the post-operative period; and in any
patient who fails to respond to adequate CFC replacement
therapy aer past responsiveness. (See Table 8-1.)
•
It is particularly important to perform routine inhibitor
screening during the time of greatest risk for inhibitor
development, at least every 6-12 months after CFC
replacement therapy is initiated, and annually thereaer.
While some advocate more frequent screening, this
remains controversial with few data to support the benet
of this approach.
•
Screening should be performed in any patient, regardless
of age or disease severity, who is intensively treated (i.e.,
for more than 5 consecutive days) and within 4 weeks
of the last infusion.
•
See also 8.3 Hemophilia A and FVIII inhibitors – Inhibitor
incidence and 8.4 Hemophilia B and FIX inhibitors –
Inhibitor incidence, below; and Chapter 3: Laboratory
Diagnosis and Monitoring – Coagulation laboratory
testing – Inhibitor testing.
RECOMMENDATION 8.2.1:
•
For patients with newly diagnosed hemophilia A, the
WFH recommends regular inhibitor screening at least
every 6-12 months, and then annually.
•
REMARK: In general, more frequent screening should
be considered for recurrent bleeds or target joints that
occur despite standard factor replacement.
•
REMARK: is recommendation places greater value
on early inhibitor diagnosis in patients with severe
hemophilia and late diagnosis in adulthood in patients
with less severe disease, such as aer intensive exposure
to clotting factor concentrate, for example aer surgery.
• REMARK: e requirement for frequent blood draws
was considered in relationship to the potential morbidity
of uncontrolled or life-threatening bleeds.
RECOMMENDATION 8.2.2:
•
For patients with hemophilia A who receive clotting
factor concentrate for more than 5 consecutive days,
the WFH suggests inhibitor screening within 4 weeks
of the last infusion.
TABLE 8-1 Indications for inhibitor testing
• After initial factor exposure
• After intensive factor exposure, e.g., daily exposure
for more than 5 days
7,15
• For recurrent bleeds or target joint bleeds, despite
adequate CFC replacement therapy
7,12-14
• For failure to respond to adequate CFC replacement
therapy
7,12,14
• For lower than expected factor recovery or half-life
after CFC replacement therapy
7,12-14
• For suboptimal clinical or laboratory response to CFC
replacement therapy
9
• Before surgery
1,7,11
• For suboptimal post-operative response to CFC
replacement therapy
7,12-14
Abbreviation: CFC, clotting factor concentrate.
Chapter 8: Inhibitors to Clotting Factor 109
RECOMMENDATION 8.2.3:
•
For patients with hemophilia A who have poor or no
response to adequate clotting factor replacement therapy,
or who have lower than expected factor recovery or
half-life, the WFH suggests inhibitor screening.
RECOMMENDATION 8.2.4:
• For patients with hemophilia A who undergo surgery,
the WFH suggests inhibitor screening preoperatively
in order to determine if an inhibitor is present which, if
present, may require non-FVIII-containing therapy.
RECOMMENDATION 8.2.5:
•
For patients with newly diagnosed hemophilia B, the
WFH recommends regular inhibitor screening at least
every 6-12 months, and then annually.
•
REMARK: In general, more frequent inhibitor screening
should be considered when recurrent bleeds or target
joints occur despite adequate factor replacement.
• REMARK: Because inhibitor incidence is much lower
in hemophilia B than in hemophilia A, experience and
evidence are limited.
•
REMARK: is recommendation places greater value
on early inhibitor diagnosis to avoid uncontrolled
bleeds and bleeding complications. e requirement
for frequent blood draws was considered in relationship
to the potential morbidity of uncontrolled or life-
threatening bleeds.
RECOMMENDATION 8.2.6:
•
For patients with hemophilia B who are treated with
clotting factor concentrate for more than 5 consecutive
days, the WFH suggests inhibitor screening within 4
weeks of the last infusion.
RECOMMENDATION 8.2.7:
• For patients with hemophilia B who fail to respond to
adequate clotting factor replacement therapy or who
have lower than expected factor recovery or half-life,
the WFH suggests inhibitor screening.
RECOMMENDATION 8.2.8:
•
For patients with hemophilia B who develop an allergic
reaction to FIX therapy, including anaphylaxis or
nephrotic syndrome, the WFH suggests inhibitor
screening to determine if an inhibitor is present.
RECOMMENDATION 8.2.9:
•
For patients with severe hemophilia B who undergo
major surgery, the WFH suggests preoperative inhibitor
screening.
8.3 Hemophilia A and FVIII inhibitors
Genetic and environmental risk factors
•
Inhibitors are more frequently encountered in persons
with severe hemophilia A than in those with moderate
or mild forms of the disease.
• Other risk factors for inhibitor formation in hemophilia
A include family history of inhibitors, black African
ancestry, Hispanic ancestry, genetic variants such as
type of mutation and polymorphic immune regulatory
genes, and high-intensity factor exposure (e.g., intensive
CFC replacement therapy for a severe early bleed, central
nervous system bleed, surgery, or trauma).
(See Table 8-2.)
•
Product type (i.e., plasma-derived FVIII CFCs with or
without von Willebrand factor or recombinant FVIII
CFCs) may contribute to inhibitor risk in hemophilia A
patients; however, this is not well understood and remains
controversial.
Inhibitor incidence
•
Inhibitory antibodies develop with a cumulative incidence
of approximately 30% among previously untreated patients
with hemophilia A, of which 79% occur within the rst
20 exposures and the remainder, 21%, within the rst 75
exposures. An exposure is dened as any 24-hour period
in which a FVIII/FIX-containing product is given.
•
Inhibitor rates vary by study and may be underestimated
in studies in which not all subjects are previously untreated
patients (PUPs) and in whom follow-up is incomplete.
TABLE 8-2 Potential risk factors for inhibitors
• Race
9,10,15
• Family history
9,10,15
• Genotype, immune regulatory genes
9,16,17,20,25
• Hemophilia severity
9,10,12,14,19,25
• CFC replacement intensity
9,12,14-16,18,20
• CFC type
6,16,21
Abbreviation: CFC, clotting factor concentrate.
WFH Guidelines for the Management of Hemophilia, 3rd edition110
•
The incidence of inhibitors in mild and moderate
hemophilia A patients is 5%-10%, lower than in those
with severe hemophilia. ese inhibitors typically occur
at an older age and oen aer intensive FVIII exposure,
e.g., for surgery or severe bleeds. In most cases, these
are low-responding inhibitors; high-responding inhibitors
are less common in such patients.
•
Most cases of mild and moderate hemophilia A are caused
by missense mutations, which in general are associated
with a low rate of inhibitor development, although there
are a few exceptions.
Disease burden
•
Children and adults with persistent FVIII inhibitors typically
have higher rates of hospitalization, greater treatment
costs, and higher mortality rates than those without
inhibitors. Development of new non-factor replacement
therapies may reduce this burden in the future.
•
Bleeding manifestations in mild and moderate hemophilia A
patients with inhibitors are predominantly mucocutaneous,
urogenital, and gastrointestinal bleeding, reminiscent of
bleeding symptoms in patients with acquired hemophilia
A (due to autoantibodies to FVIII). Consequently, the
risk of severe complications or even death from serious
bleeding may still be signicant in these patients. e
mortality rate among mild and moderate hemophilia A
patients with inhibitors is reported to be ve times greater
than among those without inhibitors.
•
Despite the availability of non-factor replacement therapies
for hemophilia patients who develop inhibitors, there has
been a consensus that patients with inhibitors should
undergo a trial of ITI, when possible, in order to eradicate
the inhibitor.
•
e availability of non-factor replacement therapies (e.g.,
emicizumab) that are eective in bleed prevention in
patients with FVIII inhibitors has raised questions about
whether such agents should be used before, during, aer,
or in place of ITI. is remains controversial, however, as
there are insucient data to resolve this question.
Management of bleeding
•
Management of bleeding in hemophilia patients with
inhibitors must be carried out in consultation with a
hemophilia treatment centre and sta experienced in
inhibitor treatment. (See Table 8-3.)
•
Choice of treatment product should be based on inhibitor
titer, clinical response to the product, site and nature of
the bleed, and product availability by country.
RECOMMENDATION 8.3.1:
•
For patients with hemophilia A and FVIII inhibitors
who develop an acute bleed, the WFH recommends
that treatment be based on whether the inhibitor is
low-responding or high-responding.
Therapeutic options for FVIII inhibitor patients
CFC replacement therapy
•
For low-responding inhibitors, FVIII CFC replacement
therapy is preferred for acute bleeds if measurable factor
levels are achieved. Careful monitoring for clinical
ecacy is needed, as higher doses may be required to
achieve hemostasis.
•
In the absence of a rational and validated dosing algorithm,
the following formula is used to estimate the amount of
FVIII needed as a loading dose to neutralize the inhibitor:
–
[body weight (kg) × 80 × [(1 − hematocrit)
× antibody titer (BU)]
•
An additional 50 IU/kg above the calculated loading dose
is added to achieve a measurable FVIII activity.
TABLE 8-3 Treatment of acute bleeds in hemophilia A patients with inhibitors
Hemophilia A Low-responding inhibitors High-responding inhibitors
Agent • FVIII
31,a
• rFVIIa or aPCC
33,40,47,b
or FVIII
39,c
Monitoring • FVIII activity (FVIII:C) assay • Thromboelastography or thrombin generation assay
46,d
Abbreviations: aPCC, activated prothrombin complex concentrate; FVIII, factor VIII; FVIII:C, FVIII activity; rFVIIa, recombinant activated factor VIIa.
a
Will require higher, more frequent dosing if half-life is shortened.
b
In patients on emicizumab prophylaxis, aPCC should be avoided or used with caution at lower doses because of the thrombotic microangiopathy
risk (black box warning). Caution is also urged when rFVIIa is used in patients on emicizumab who have risk factors for thrombosis because of
risk of myocardial infarction or pulmonary embolism.
c
In patients with high-responding inhibitors with a currently low inhibitor titer, FVIII may be considered, with close monitoring for an anamnestic
response.
d
The thrombin generation assay is not state-of-the-art monitoring and is unavailable in most laboratories, but increasingly being used to assess
response.
Chapter 8: Inhibitors to Clotting Factor 111
•
FVIII levels should be measured 15 minutes after
completion of the bolus, and adjustment to reach target
levels is necessary because there is substantial individual
variation.
•
For high-responding inhibitors, bypass agent therapy
(recombinant activated factor VIIa [rFVIIa] or activated
prothrombin complex concentrate [aPCC]) or porcine
FVIII should be used to treat bleeds.
RECOMMENDATION 8.3.2:
•
For patients with hemophilia A and inhibitors who have
acute bleeds, the WFH recommends FVIII concentrate
for those with low-responding inhibitors, and a bypassing
agent (recombinant factor VIIa [rFVIIa] or activated
prothrombin complex concentrate [aPCC]) for those
with high-responding inhibitors.
•
REMARK: In those receiving non-factor therapy for
prophylaxis (e.g., emicizumab), the WFH prefers
rFVIIa over aPCC because of the risk of thrombotic
microangiopathy when aPCC is used with emicizumab.
•
REMARK: In patients receiving emicizumab who receive
FVIII concentrate, the WFH recommends bovine reagent
chromogenic FVIII assays (bovine FX in kit reagent) to
measure plasma FVIII:C activity and inhibitor titer levels.
•
REMARK: Caution is urged when rFVIIa is used in
patients receiving emicizumab who have risk factors
for thrombosis (e.g., past venous thromboembolism,
obesity, smoking, chronic infection, inammation) due
to the risk of acute non-ST segment elevation myocardial
infarction (non-STEMI) and pulmonary embolism.
•
For patients with high-responding inhibitors whose titers
have fallen to undetectable or low levels, standard FVIII
CFC replacement may be used in an emergency for up to
3-5 days, at more frequent dosing due to the shorter half-
life, until an anamnestic response occurs. When the latter
occurs, further treatment with FVIII CFCs is typically no
longer eective, and bypass agent therapy is needed.
is underscores the need for close FVIII monitoring.
•
e factor substitution therapy, emicizumab, is increasingly
used to prevent hemorrhage in FVIII inhibitor patients.
is agent is eective for preventing bleeds (prophylaxis)
in hemophilia A inhibitor patients but is not indicated
for treating bleeds. us, breakthrough bleeds require
treatment with FVIII CFCs (for low-responding inhibitors)
as described above, or hemostatic bypassing agents
(for high-responding inhibitors), as described below.
Conventional bypassing agents include rFVIIa and aPCC,
which have been shown to be eective as prophylaxis
and for treatment of bleeds.
Conventional hemostatic bypassing agents
•
Treatment with bypassing agents typically consists of
one dose of aPCC or two doses of rFVIIa. e ecacy of
two doses of rFVIIa (90-270 g/kg) or one dose of aPCC
(75-85 unit/kg) is comparable in the management of joint
bleeding. Notably, however, some patients may respond
better to one agent than the other, highlighting the need
to individualize therapy. (See Table 8-3.)
•
However, if hemostasis is unsatisfactory with rFVIIa or
aPCC as single agents, each may be alternated every 6
hours. (See Table 8-4.)
•
Combination/sequential bypass agent treatment should be
used only in treatment centres with extensive experience
in managing hemophilia patients with inhibitors; close
monitoring for thrombosis and disseminated intravascular
coagulation is required.
•
It is estimated that aPCC leads to an anamnestic response
in approximately 30% of patients with FVIII inhibitors
due to the presence of FVIII in aPCC.
•
While rFVIIa or aPCC may be used to treat bleeds in
both hemophilia A and B patients with inhibitors, there
has been concern about using aPCC, which contains FIX,
in patients with FIX inhibitors who manifest anaphylaxis
to FIX. is, however, is not an issue for patients with
FVIII inhibitors.
•
Caution: rombosis or thrombotic microangiopathy
may occur in patients receiving emicizumab who are also
receiving aPCC. us, aPCC should be avoided in
patients on emicizumab except in patients unresponsive
to rFVIIa or when rFVIIa is unavailable, and with aPCC
dosing not above 50 IU/kg and no more than 100 IU/kg
total per day.
RECOMMENDATION 8.3.3:
•
For patients with hemophilia A and low-responding
inhibitors who develop an acute bleed, the WFH
recommends a FVIIIcontaining product or, if the
hemostatic response is poor, the WFH recommends
rFVIIa or aPCC. For those receiving emicizumab
prophylaxis who develop an acute bleed, the WFH
prefers rFVIIa over aPCC to avoid the risk of thrombotic
microangiopathy.
•
REMARK: Caution is urged when rFVIIa is used in
patients receiving emicizumab who have risk factors for
thrombosis (e.g., past venous thromboembolism, obesity,
WFH Guidelines for the Management of Hemophilia, 3rd edition112
smoking, chronic infection, inammation) due to the
risk of acute non-STEMI and pulmonary embolism.
•
REMARK: e WFH recommends bovine reagent-based
chromogenic FVIII assays (bovine FX in kit reagent)
to measure plasma FVIII:C activity and inhibitor titer
levels.
RECOMMENDATION 8.3.4:
•
For patients with hemophilia A and high-responding
FVIII inhibitors receiving emicizumab who develop
an acute bleed, the WFH prefers rFVIIa over aPCC to
avoid the risk of thrombotic microangiopathy.
•
REMARK: Caution is urged when rFVIIa is used in
patients receiving emicizumab who have risk factors
for thrombosis (e.g., past venous thromboembolism,
obesity, smoking, chronic infection, inammation)
due to the risk of arterial thromboembolism, e.g., acute
non-STEMI and pulmonary embolism.
•
REMARK: e WFH recommends bovine reagent-based
chromogenic FVIII assays (bovine FX in kit reagent)
to measure plasma FVIII:C activity and inhibitor titer
levels.
Emicizumab
•
e factor substitution therapy, emicizumab, a bispecic
monoclonal antibody and FVIII mimic, has been licensed
for bleed prevention in patients with hemophilia A with
and without inhibitors. Patients on emicizumab who
experience breakthrough bleeds require episodic treatment
with FVIII CFCs or with hemostatic bypassing agents, as
described above.
•
Several phase 3 clinical trials and post-marketing experience
have shown that emicizumab is eective prophylaxis in
adults and children with inhibitors. As emicizumab
is injected subcutaneously every 1, 2, or 4 weeks, the
burden of prophylaxis is much less than with bypassing
agents. Emicizumab reduces morbidity, complications,
and hospitalization, and is cost-eective.
•
Prophylaxis dosing with emicizumab consists of an
induction period of 3.0 mg/kg/week for 4 weeks by
subcutaneous injection. is is followed thereaer by
1.5 mg/kg/week or alternative dosing schedules including
3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks.
•
As emicizumab interferes with the measurement of FVIII:C
and FVIII inhibitors using the one-stage FVIII assay, a
specic chromogenic assay using bovine reagents is used
to detect inhibitors to FVIII.
RECOMMENDATION 8.3.5:
•
For patients with hemophilia A and inhibitors who
receive emicizumab, the WFH recommends bovine
chromogenic assays (bovine FX in kit reagent) to monitor
inhibitor levels.
•
Close monitoring of clinical response to emicizumab and
laboratory monitoring of inhibitor titer level is advised
with a chromogenic Bethesda assay using bovine reagents.
•
In patients receiving emicizumab who have risk factors for
thrombosis, e.g., past venous thromboembolism, obesity,
smoking, chronic infection, or inammation, rFVIIa
should be used with caution due to the potential risk of
acute non-STEMI and pulmonary embolism.
RECOMMENDATION 8.3.6:
•
For patients with hemophilia A and inhibitors receiving
emicizumab, the WFH recommends close clinical
monitoring for thrombosis, adverse reactions, and
thrombotic microangiopathy.
•
REMARK: Caution is urged when rFVIIa is used in
patients receiving emicizumab who have risk factors
for thrombosis (e.g., past venous thromboembolism,
obesity, smoking, chronic infection, inammation)
due to the risk of acute non-STEMI and pulmonary
embolism.
RECOMMENDATION 8.3.7:
• As emicizumab is used to prevent, but not treat, acute
bleeds in patients with hemophilia A and inhibitors, the
WFH recommends clotting factor replacement therapy
for acute bleeds.
TABLE 8-4 Sequential bypass agent therapy
alternating rFVIIa and aPCC
37
6:00 AM 90 μg/kg rFVIIa
9:00 AM 50 U/kg aPCC
12:00 PM 90 μg/kg rFVIIa
3:00 PM 50 U/kg aPCC
6:00 PM 90 μg/kg rFVIIa
9:00 PM 50 U/kg aPCC
12:00 AM 90 μg/kg rFVIIa
3:00 AM 50 U/kg aPCC
6:00 AM 90 μg/kg rFVIIa
Abbreviations: aPCC, activated prothrombin complex concentrate;
rFVIIa, recombinant factor VIIa.
Chapter 8: Inhibitors to Clotting Factor 113
RECOMMENDATION 8.3.8:
•
For patients with hemophilia A and inhibitors
receiving emicizumab who have an acute bleed, the
WFH recommends clotting factor replacement therapy
including FVIII for those with low-responding inhibitors;
the WFH prefers rFVIIa over aPCC for those with
high-responding FVIII inhibitors due to the risk of
thrombotic microangiopathy.
•
REMARK: Caution is urged when rFVIIa is used in
patients receiving emicizumab who have risk factors
for thrombosis (e.g., past venous thromboembolism,
obesity, smoking, chronic infection, inammation)
due to the risk of acute non-STEMI and pulmonary
embolism.
RECOMMENDATION 8.3.9:
•
For patients with hemophilia A and inhibitors receiving
emicizumab who have an acute bleed, the WFH prefers
rFVIIa over aPCC, because of the risk of thrombotic
microangiopathy.
•
REMARK: e WFH suggests following black box
warnings for emicizumab and maintaining vigilance
as new evidence develops.
•
REMARK: Caution is urged when rFVIIa is used in
patients receiving emicizumab who have risk factors for
thrombosis (e.g., past venous thromboembolism, obesity,
smoking, chronic infection, inammation) due to the
risk of acute non-STEMI and pulmonary embolism.
rombotic risks may last for up to 6 months during
which plasma levels of emicizumab may persist.
Therapies in clinical trials
•
Extended half-life rFVIIa may have a role in the management
of bleeds in hemophilia patients with inhibitors, although
investigations have been in vitro and early-phase clinical
trials.
•
Non-factor therapies such as tusiran, an investigational
RNA interference agent that targets antithrombin (siRNA-
AT), and tissue factor pathway inhibitors (anti-TFPI),
are in clinical trials on bleed prevention in patients with
inhibitors. ese are not expected to be eective in episodic
treatment of bleeds.
Surgery and invasive procedures
•
Inhibitor testing of patients with hemophilia of all types of
severity is advised prior to surgery and invasive procedures.
Special precautions must be taken in hemophilia patients
with inhibitors undergoing surgery: factor coverage, bypass
agent treatment, and follow-up must be determined and
planned in advance.
•
Close monitoring of clinical response to bypass agent
therapy is required, specically monitoring for safety, i.e.,
thrombosis or consumptive coagulopathy.
•
Once hemostasis is achieved and maintained on a selected
regimen for 3-5 days, these agents may be tapered over
1-3 weeks. However, it is recognized that the dose and
taper schedule must be individualized for each patient,
as variability exists in individual response to bypass agent
therapy.
•
Adjusted-dose continuous infusion is another option
in surgery and invasive procedures, for which clearance
should be calculated every day with dose adjustment
accordingly.
•
Combination/sequential bypass agent treatment should be
considered in those with poor response to one bypassing
agent. Sequential use (i.e., alternating rFVIIa and aPCC
every 3 hours) has been shown to improve ecacy over
single bypass agent therapy and allows for lower total daily
dose of aPCC, potentially reducing thrombotic risk.
Sequential regimens should be used only in treatment
centres with extensive experience in managing hemophilia
patients with inhibitors, with close monitoring for
thrombosis and disseminated intravascular coagulation.
(See Table 8-4.)
RECOMMENDATION 8.3.10:
•
For patients with hemophilia A and low-responding
FVIII inhibitors who undergo surgery or an invasive
procedure, the WFH suggests higher, more frequent
FVIII product dosing than usual due to the short half-
life of FVIII.
•
REMARK: e WFH also recognizes adjusted-dose
FVIII continuous infusion as an option.
RECOMMENDATION 8.3.11:
•
For patients with hemophilia A and high-responding
FVIII inhibitors who undergo surgery or an invasive
procedure, the WFH recommends bypass agent therapy
(rFVIIa or aPCC) at the discretion of the clinician.
If single-agent bypass fails, sequential bypass agent
treatment, i.e., rFVIIa alternating with aPCC, is another
therapeutic approach. e WFH also recommends close
clinical monitoring for thrombosis.
RECOMMENDATION 8.3.12:
•
For patients with hemophilia A and inhibitors receiving
emicizumab who undergo major surgery or an invasive
WFH Guidelines for the Management of Hemophilia, 3rd edition114
procedure, the WFH recommends a FVIII-containing
product for those with low-responding inhibitors. e
WFH prefers rFVIIa over aPCC for those with high-
responding inhibitors due to the risk of thrombotic
microangiopathy. e WFH makes no recommendations
on specic dose, frequency, or duration as there are
insucient data.
•
REMARK: Caution is urged when rFVIIa is used in
patients receiving emicizumab who have risk factors
for thrombosis (e.g., past venous thromboembolism,
obesity, smoking, chronic infection, inammation)
due to the risk of acute non-STEMI and pulmonary
embolism.
RECOMMENDATION 8.3.13:
•
For patients with hemophilia A and inhibitors receiving
emicizumab who undergo minor surgery or an invasive
procedure, the WFH recommends either low-dose or
no clotting factor replacement therapy.
•
REMARK: Caution is urged when rFVIIa is used in
patients receiving emicizumab who have risk factors
for thrombosis (e.g., past venous thromboembolism,
obesity, smoking, chronic infection, inammation)
due to the risk of acute non-STEMI and pulmonary
embolism.
RECOMMENDATION 8.3.14:
•
For patients with hemophilia A and inhibitors receiving
emicizumab who undergo major surgery or an invasive
procedure, the WFH recommends close clinical
monitoring for thrombosis, consumptive coagulopathy,
or thrombotic microangiopathy.
RECOMMENDATION 8.3.15:
•
For patients with hemophilia A and inhibitors who use
bypass agent therapy, the WFH recommends clinical
monitoring and consideration for laboratory monitoring
with thrombin generation and other coagulation tests,
but more data are needed to recommend the latter.
Immune tolerance induction
•
Inhibitor eradication by immune tolerance induction
therapy is successful in 70%-80% of patients with severe
hemophilia A.
•
Response to ITI may be less favourable in patients with
moderate/ mild hemophilia A.
RECOMMENDATION 8.3.16:
•
For patients with hemophilia A who develop persistent
low-responding inhibitors, the WFH suggests that
immune tolerance induction (ITI) be considered.
•
Successful ITI is dened as a persistently negative Bethesda
titer, accompanied by normal pharmacokinetics, including
factor recovery >66% and half-life >6 hours for standard
FVIII CFCs. Once successful ITI is achieved, FVIII
prophylaxis may be initiated or resumed.
•
ere is general consensus that failure of ITI is the inability
to achieve successful tolerance within 2-3 years of initiation
of an ITI regimen.
RECOMMENDATION 8.3.17:
•
For patients with hemophilia A and persistent inhibitors
who fail immune tolerance induction (ITI) or never
underwent ITI, the WFH recommends emicizumab
prophylaxis over bypass agent prophylaxis (rFVIIa
or aPCC), as emicizumab is more eective in bleed
prevention and simpler to administer, as it is given
weekly and subcutaneously.
• When to initiate ITI has been a topic of debate. Registry
data from the 1990s and 2000s showed success was highest
when ITI was begun in patients with low inhibitor titers
(<10 BU). us, clinicians adopted a policy of waiting
to start ITI until inhibitor titers had fallen to <10 BU;
however, more recently, clinicians have begun to initiate
ITI immediately aer inhibitor detection no matter the
titer, with good response.
•
e optimal regimen (product or dose) for ITI remains
to be dened. In the International ITI Trial, there was no
dierence in ecacy between a low-dose/low-frequency
regimen (50 IU/kg FVIII 3 times weekly) and a high-dose/
high-frequency regimen (200 IU/kg daily), but the low-dose/
low-frequency regimen required a longer time to achieve
tolerance and more bleeds occurred during that period,
particularly in the rst 3-6 months of ITI. For this reason,
the trial was stopped early, with subsequent clinician
preference for the high-dose/high-frequency regimen.
•
While on ITI, if patients experience frequent bleeding,
bypass agent prophylaxis (rFVIIa, aPCC) or emicizumab
prophylaxis may be instituted. Emicizumab prophylaxis
has been associated with a signicantly greater reduction
in bleeding rates than bypass agent prophylaxis.
•
It may be possible to delay or avoid ITI altogether with
emicizumab prophylaxis, given the very low bleeding rates
seen with this agent, but controversy continues and data
Chapter 8: Inhibitors to Clotting Factor 115
are scarce. (See “erapeutic options for FVIII inhibitor
patients – Emicizumab” above.)
•
Few data exist on the use of extended half-life factor
therapies or ancillary non-factor therapies for ITI.
Preliminary data from small case series and observational
studies have shown that extended half-life CFCs are
eective in some patients with inhibitors, including those
with high-responding inhibitors and those who have
previously failed ITI with standard half-life CFCs or were
never tolerized, and may shorten duration of ITI.
Data from a small case series found FVIII 100 IU/kg
three times weekly plus emicizumab prophylaxis is safe
and associated with a decline in inhibitor titer. Larger,
randomized studies are needed to conrm these ndings.
•
Because ITI requires frequent infusions (up to once daily),
it generally requires good venous access. In young children
with small veins and/or poor access, a central venous access
device (CVAD) is usually required for ITI. However, CVAD
use is associated with complications such as infection
and/or thrombosis. For this reason, emicizumab, which
is administered subcutaneously and requires no IV access,
has been considered a simpler option than standard ITI
and, it may allow for lower dose/lower frequency FVIII
CFC infusions when used with ITI or instead of ITI,
although this is unproven. is remains controversial as
there are no data regarding inhibitor risk if episodic CFC
replacement therapy is required for breakthrough bleeds
during emicizumab prophylaxis.
•
Whether emicizumab should be initiated before, during,
aer, or instead of ITI is unknown, and answering this
question will require clinical trials. As emicizumab diers
biochemically from FVIII, many questions remain regarding
its long-term impact on joint pathology, immunogenicity,
and cost-eectiveness in non-inhibitor patients.
•
Although there has been interest in the use of
immunosuppressive and immunomodulatory therapies
in hemophilia patients with inhibitors, the role of these
agents is not yet dened, and as there is no consensus
regarding these agents in the management of inhibitor
patients, clinical trials are needed.
FVIII prophylaxis after immune tolerance
induction
•
Aer successful ITI in hemophilia A patients with inhibitors,
FVIII prophylaxis with close monitoring of clinical response
should be initiated.
•
At least one extended half-life CFC, rFVIIIFc, has been
evaluated for its tolerogenic potential in the prevention
of inhibitor formation and in the induction of immune
tolerance. At this time, data on the impact of extended
half-life therapies are limited.
Product switching
•
While there is controversy regarding inhibitor development
in those switching CFC products, including rare case
reports, data from large studies indicate there is no evidence
supporting increased risk.
RECOMMENDATION 8.3.18:
•
For patients with hemophilia A who switch to another
type or brand of factor product, the WFH has no
preference for the choice of specic type of therapy, as
current evidence indicates product switching does not
increase risk of inhibitor development.
•
REMARK: e WFH encourages product choice based
on potential advantages, such as simpler administration,
safety, ecacy, and personal preferences.
•
REMARK: e WFH supports prospective data collection
on inhibitor formation by product, particularly before
and aer switching products.
RECOMMENDATION 8.3.19:
• For patients with severe hemophilia A and inhibitors,
the WFH recommends emicizumab over bypass agent
prophylaxis to reduce bleeding episodes, as emicizumab
appears to be superior to bypass prophylaxis.
8.4 Hemophilia B and FIX inhibitors
Genetic and environmental risk factors
•
FIX inhibitors are almost exclusively seen in patients with
severe hemophilia B and very rarely in the milder forms.
•
Inhibitors in patients with severe hemophilia B are rare
and occur most commonly in those with null variants,
in which no endogenous clotting factor is produced, in
most cases due to large deletion, frame-shi, and nonsense
variants. ere is no known ancestral predilection to
inhibitor development in hemophilia B.
•
Inhibitor formation in hemophilia B is not thought to
be related to type of FIX CFC, and it has been reported
in those receiving plasma-derived and recombinant FIX
CFCs alike.
Inhibitor incidence
•
Inhibitor formation in patients with hemophilia B occurs
infrequently, with a cumulative incidence of up to 5%.
WFH Guidelines for the Management of Hemophilia, 3rd edition116
•
e development of an FIX inhibitor is considered the
most serious complication in patients with hemophilia B,
due not only to loss of response to FIX replacement, but
also to the associated risks of anaphylaxis and nephrotic
syndrome.
•
Inhibitor detection in hemophilia B is similar to that
in hemophilia A, with most inhibitors occurring aer
a median of 9-11 exposures, and before 20 exposures,
typically before 2 years of age.
•
Treatment strategies for FIX inhibitors are similar to those
for FVIII inhibitors; specically, they focus on controlling
hemostasis and eradicating the inhibitor.
•
It is recommended that because of the severity of
complications, patients with hemophilia B should be
followed closely and screened for inhibitors every 6-12
months aer initiating CFC replacement therapy, and
annually thereaer.
Disease burden
Anaphylaxis to FIX
•
Inhibitor formation in patients with hemophilia B is overall
associated with a similar disease burden as in hemophilia
A but may also be associated with allergic reaction to FIX
CFCs. Anaphylaxis occurs in 50% of hemophilia B patients
with inhibitors, and more frequently in those with null
mutations. Such reactions may be the rst symptom of
FIX inhibitor development.
•
Newly diagnosed severe hemophilia B patients, particularly
those with a family history of severe hemophilia B with
inhibitors and/ or with genetic variants predisposing
to inhibitor development, should be treated in a clinic
or hospital setting capable of managing severe allergic
reactions for the initial 10-20 exposures to FIX CFCs, with
emergency equipment available to treat anaphylaxis.
Reactions may also occur later but may be less severe.
RECOMMENDATION 8.4.1:
•
For patients with hemophilia B who develop anaphylaxis
to FIX therapy, the WFH recommends screening for an
inhibitor to FIX, as an allergic reaction may be the rst
sign of inhibitor development.
RECOMMENDATION 8.4.2:
•
For patients with hemophilia B and a family history
of inhibitors or risk factors for inhibitor development,
the WFH recommends monitoring initial infusions in
a clinic or hospital setting capable of managing severe
allergic reactions.
RECOMMENDATION 8.4.3:
•
For patients with hemophilia B who develop anaphylaxis
to FIX therapy, the WFH recommends screening for
nephrotic syndrome, as it is more common in FIX
inhibitor patients with allergic reactions to FIX.
RECOMMENDATION 8.4.4:
•
For patients with hemophilia B and inhibitors and an
allergic reaction/anaphylaxis to FIX therapy, the WFH
recommends rFVIIa to treat acute bleeds but is against
use of aPCC as it contains FIX and may cause or worsen
an allergic reaction.
•
REMARK: For patients with hemophilia B and inhibitors
and allergic reaction to FIX therapy, the WFH indicates
there are insucient data to recommend desensitization
by small, repeated doses of FIX, intravenously or
subcutaneously, and recognizes that in some, this
approach may worsen an allergic reaction or cause
anaphylaxis. If undertaken, FIX desensitization should
be performed with caution and under close supervision
by experts only.
RECOMMENDATION 8.4.5:
•
For patients with hemophilia B and inhibitors
who develop anaphylaxis to FIX therapy, the WFH
recommends bypass therapy with rFVIIa over aPCC,
as aPCC contains FIX and may cause or worsen an
allergic reaction.
Management of bleeding
•
Management of bleeding in hemophilia patients with
inhibitors must be carried out in consultation with a
hemophilia treatment centre and sta experienced in
inhibitor treatment.
•
Treatment of bleeding in hemophilia B patients with
inhibitors should be individualized. Choice of treatment
product should be based on inhibitor titer, clinical response
to the product, previous infusion reactions, site and nature
of the bleed, and product availability by country.
RECOMMENDATION 8.4.6:
•
For patients with hemophilia B and inhibitors who
develop an acute bleed, the WFH recommends treatment
based on whether the inhibitor is low-responding or
high-responding and whether there is a history of
allergic reactions.
Chapter 8: Inhibitors to Clotting Factor 117
Therapeutic options for patients with FIX
inhibitors
CFC replacement therapy
•
For those with low-responding inhibitors, specic FIX
CFC replacement therapy may be used if there is adequate
inhibitor neutralization to control bleeding. Because
allergic reactions and anaphylaxis may occur in up to
50% of hemophilia B patients with inhibitors, close
monitoring is essential.
RECOMMENDATION 8.4.7:
•
For patients with hemophilia B and low-responding
FIX inhibitors, the WFH recommends use of a FIX-
containing product to treat acute bleeds, as long as
there is no allergic reaction to FIX.
•
For hemophilia B patients with high-responding inhibitors
or those with low-responding inhibitors who develop
allergic reactions or anaphylaxis, the bypassing agent
rFVIIa may be used to control bleeding. As aPCC contains
FIX, it may trigger or worsen an allergic or anaphylactic
response; for that reason, aPCC should be avoided in
hemophilia B patients. However, in the absence of such a
reaction, aPCC has shown similar ecacy in controlling
acute bleeding.
RECOMMENDATION 8.4.8:
•
For patients with hemophilia B and high-responding
FIX inhibitors, the WFH prefers rFVIIa over aPCC to
treat acute bleeds, as aPCC contains FIX and may cause
or worsen an allergic reaction.
Conventional hemostatic bypassing agents
•
Alternative hemostatic agents for prevention of spontaneous
or traumatic bleeds (prophylaxis) in hemophilia B inhibitor
patients include rFVIIa, or, in the absence of an allergic/
anaphylactic reaction to FIX, aPCC.
•
Bypass agent prophylaxis in inhibitor patients is not as
eective nor as convenient as standard factor prophylaxis
is in patients without inhibitors.
•
For hemostasis, bypass agent therapy with rFVIIa constitutes
the standard approach. In general, aPCC may increase
risk of anaphylaxis because of FIX content and should be
avoided in those with hemophilia B inhibitors (see above).
Both agents are eective in treating 90% of musculoskeletal
bleeds and can be used in major and minor prophylaxis.
(See Table 8-5.)
•
As there are no reliable laboratory assays to monitor
bypass agent therapy, careful monitoring of hemoglobin
levels, blood loss, wound healing, and clinical response to
treatment is advised, including patient-reported outcomes
and subjective patient feedback.
RECOMMENDATION 8.4.9:
•
For patients with hemophilia B and inhibitors who use
bypass agent therapy, the WFH recommends clinical
monitoring and consideration for laboratory monitoring
with thrombin generation and other coagulation tests,
although more data are needed to recommend the
latter.
Therapies in clinical trials
•
Several emerging non-factor therapies are in clinical
trials for bleed prevention in hemophilia B patients with
inhibitors, including tusiran (siRNA-AT3) and anti-
TFPI. ese therapies may provide a less invasive
route and/or lower frequency of dosing and, if safe and
eective, may be adopted into use.
•
An extended half-life rFVIIa with in vitro hemostasis is
in early clinical trials for bleed prevention in patients with
hemophilia B and inhibitors. is therapy may reduce
the frequency of dosing and, if safe and eective, may be
adopted into use.
Immune tolerance induction
•
Because inhibitor prevalence is low in hemophilia B,
experience with ITI is limited. e principles of treatment
are similar to those in hemophilia A, but the success rate
is lower, especially in patients with an allergic reaction
to FIX. e latter may require FIX desensitization before
attempting ITI, although few data are available regarding
the ecacy or safety of this approach.
•
Hemophilia B inhibitor patients with a history of severe
allergic reactions to FIX may develop nephrotic syndrome,
which may be irreversible. In some patients undergoing
ITI, nephrotic syndrome may develop; close monitoring is
required even aer ITI is completed, as nephrotic syndrome
may persist.
•
ere is little evidence regarding when or whether to initiate
ITI in hemophilia B patients aer inhibitor detection;
however, some have initiated a high-dose/high-frequency
FIX regimen until tolerance is achieved, i.e., the inhibitor
titer is persistently negative and factor recovery and half-life
return to normal. However, there is no supporting evidence,
and this approach is based on experience with hemophilia A
inhibitor management. Clinical and laboratory monitoring
WFH Guidelines for the Management of Hemophilia, 3rd edition118
is important, especially for development of allergic reactions
or nephrotic syndrome.
•
Little is known about the role of immunosuppressive
agents in hemophilia B patients with inhibitors, as few
data are available; thus, there is no consensus regarding
their use in these patients.
RECOMMENDATION 8.4.10:
•
For patients with hemophilia B and inhibitors, the
WFH is unable to make a recommendation on the use
of immune tolerance induction, as experience with ITI
in hemophilia B is limited.
•
REMARK: In patients with hemophilia B and
inhibitors in whom ITI is attempted, high-dose factor
replacement protocols should be followed similar to
what is recommended for hemophilia A, with strong
consideration for the use of immunosuppression. It
should be noted the risk of nephrotic syndrome may
increase with high-dose ITI.
FIX prophylaxis after immune tolerance
induction
•
Aer successful immune tolerization in hemophilia
B patients with inhibitors (dened as the return to a
persistently negative inhibitor titer), FIX prophylaxis with
close monitoring of clinical response should be initiated.
Surgery and invasive procedures
•
Inhibitor testing is advised in patients with hemophilia
B prior to surgery and invasive procedures. Special
precautions, as noted above in the “Management of
bleeding” section, must be taken in hemophilia B patients
with inhibitors, including monitoring for allergic reactions
and nephrotic syndrome.
•
In those with low-responding inhibitors, standard FIX
CFC coverage may be considered if high enough levels
are achieved. In those with high-responding inhibitors or
in those with a history of allergic reactions to FIX CFCs,
treatment with the bypassing agent rFVIIa is advised,
recognizing the risk of an allergic reaction or worsening of
such a reaction in those who experience allergic reactions
to FIX when treated with aPCC due to its FIX content.
•
If hemostasis is unsatisfactory with rFVIIa or aPCC used as
single agents, these agents may be alternated, recognizing
this is based on a small observational study and also
recognizing the risk for allergic reaction or worsening of
an allergic reaction with aPCC due to FIX content.
•
Close perioperative monitoring of clinical response to
bypass agent therapy is required, particularly for thrombosis
or consumptive coagulopathy. (See Recommendation 8.4.9
on clinical monitoring of bypass agent therapy, above.)
•
Once hemostasis is achieved and maintained on a bypass
agent regimen for 3-5 days, use of these agents may be
tapered over a week or more.
RECOMMENDATION 8.4.11:
•
For patients with hemophilia B and low-responding
FIX inhibitors who undergo surgery, the WFH has no
preference for type of FIX products, but recommends
more frequent dosing due to the short FIX half-life.
RECOMMENDATION 8.4.12:
•
For patients with hemophilia B and FIX inhibitors who
undergo surgery, the WFH recommends rFVIIa over
aPCC, as aPCC contains FIX and may cause or worsen
an allergic reaction.
RECOMMENDATION 8.4.13:
•
For patients with hemophilia B and inhibitors and an
allergic reaction to FIX who undergo surgery, the WFH
prefers rFVIIa over aPCC as aPCC contains FIX and
may cause or worsen an allergic reaction.
TABLE 8-5 Treatment of acute bleeds in hemophilia B patients with inhibitors
Hemophilia B Low-responding inhibitors High-responding inhibitors
Agent • FIX
20,a
• rFVIIa or aPCC
27,b
Monitoring • FIX activity (FIX:C) assay • Thromboelastography or thrombin generation assay
46,c
Abbreviations: aPCC, activated prothrombin complex concentrate; FIX, factor IX; FVIII, factor VIII; rFVIIa, recombinant activated factor VIIa.
a
Will require higher, more frequent dosing if half-life is shortened.
b
In patients with FIX inhibitors, there is high risk for allergic reaction and nephrotic syndrome with FIX-containing products, e.g., aPCC, and
caution is urged; however, in those with an allergic reaction or nephrotic syndrome with FIX-containing products, aPCC should be avoided
since it contains FIX.
c
The thrombin generation assay is not state-of-the-art monitoring and is unavailable in most laboratories, but increasingly being used to assess
response.
Chapter 8: Inhibitors to Clotting Factor 119
RECOMMENDATION 8.4.14:
•
For patients with hemophilia B and inhibitors who
undergo surgery or an invasive procedure, the WFH
recommends close clinical monitoring for thrombosis
or consumptive coagulopathy.
Product switching
•
While there is controversy regarding risk of inhibitor
development in patients with hemophilia B switching
FIX CFC products, including rare case reports, there is a
lack of evidence supporting this risk.
RECOMMENDATION 8.4.15:
•
For patients with hemophilia B who switch to another
type or brand of factor product, the WFH has no
preference in the choice of specic type of therapy, as
current evidence indicates product switching does not
increase the risk of inhibitor development, but rigorous
controlled trials are lacking.
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16. Gouw SC, van den Berg HM, Fischer K, et al. Intensity of factor
VIII treatment and inhibitor development in children with severe
hemophilia A: the RODIN study. Blood. 2013;121(20):4046-4055.
17. Castaman G, Fijnvandraat K. Molecular and clinical predictors of
inhibitor risk and its prevention and treatment in mild hemophilia A.
Blood. 2014;124(15):2333-2336.
18. Fischer K, Lassila R, Peyvandi F, et al. Inhibitor development in
haemophilia according to concentrate: four-year results from the
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19. Hay CR. Factor VIII inhibitors in mild and moderate-severity
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20. Chitlur M, Warrier I, Rajpurkar M, Lusher JM. Inhibitors in factor IX
deciency a report of the ISTH-SSC international FIX inhibitor registry
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21. Carcao M, Re W, Ewenstein B. e role of previously untreated
patient studies in understanding the development of FVIII inhibitors.
Haemophilia. 2016;22(1):22-31.
22. van den Berg HM, Fischer K, Carcao M, et al. Timing of inhibitor
development in more than 1000 previously untreated patients with
severe hemophilia A. Blood. 2019;134(3):317-320.
23. Eckhardt CL, Menke LA, van Ommen CH, et al. Intensive peri-
operative use of factor VIII and the Arg593–>Cys mutation are risk
factors for inhibitor development in mild/moderate hemophilia A. J
romb Haemost. 2009;7(6):930-937.
24. Hashemi SM, Fischer K, Moons KG, van den Berg HM. Improved
prediction of inhibitor development in previously untreated patients
with severe haemophilia A. Haemophilia. 2015;21(2):227-233.
25. Eckhardt CL, van Velzen AS, Peters M, et al. Factor VIII gene (F8)
mutation and risk of inhibitor development in nonsevere hemophilia A.
Blood. 2013;122(11):1954-1962.
26. Eckhardt CL, Loomans JI, van Velzen AS, et al. Inhibitor development
and mortality in non-severe hemophilia A. J romb Haemost.
2015;13(7):1217-1225.
27. Ljung RCR. How I manage patients with inherited haemophilia A and B
and factor inhibitors. Br J Haematol. 2018;180(4):501-510.
28. Colvin BT, Astermark J, Fischer K, et al. European principles of
haemophilia care. Haemophilia. 2008;14(2):361-374.
29. Teitel J, Berntorp E, Collins P, et al. A systematic approach to controlling
problem bleeds in patients with severe congenital haemophilia A and
high-titre inhibitors. Haemophilia. 2007;13(3):256-263.
30. Berntorp E, Shapiro A, Astermark J, et al. Inhibitor treatment in
haemophilias A and B: summary statement for the 2006 international
consensus conference. Haemophilia. 2006;12(Suppl 6):1-7.
31. Kempton CL, White GC 2nd. How we treat a hemophilia A patient with
a factor VIII inhibitor. Blood. 2009;113(1):11-17.
32. Young G, Liesner R, Chang T, et al. A multicenter, open-label phase 3
study of emicizumab prophylaxis in children with hemophilia A with
inhibitors. Blood. 2019;134(24):2127-2138.
33. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in
hemophilia A with inhibitors. N Engl J Med. 2017;377(9):809-818.
34. Konkle BA, Ebbesen LS, Erhardtsen E, et al. Randomized, prospective
clinical trial of recombinant factor VIIa for secondary prophylaxis in
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hemophilia patients with inhibitors. J romb Haemost. 2007;5(9):1904-
1913.
35. Leissinger C, Gringeri A, Antmen B, et al. Anti-inhibitor coagulant
complex prophylaxis in hemophilia with inhibitors. N Engl J Med.
2011;365(18):1684-1692.
36. Astermark J, Doneld SM, DiMichele DM, et al. A randomized
comparison of bypassing agents in hemophilia complicated by an
inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. Blood.
2007;109(2):546-551.
37. Seaman CD, Ragni MV. Sequential bypassing agents during major
orthopedic surgery: a new approach to hemostasis. Blood Adv.
2017;1(17):1309-1311.
38. Seaman CD, Ragni MV. Emicizumab use in major orthopedic surgery.
Blood Adv. 2019;3(11):1722-1724.
39. Dimichele D. Inhibitors: resolving diagnostic and therapeutic dilemmas.
Haemophilia. 2002;8(3):280-287.
40. HEMLIBRA® (emicizumab-kxwh) injection for subcutaneous use [U.S.
prescribing information]. South San Francisco, CA: Genentech; Revised
10/2018.
41. Mahlangu J, Oldenburg J, Paz-Priel I, et al. Emicizumab prophylaxis
in patients who have hemophilia A without inhibitors. N Engl J Med.
2018;379(9):811-822.
42. Young G. Implementing emicizumab in hemophilia inhibitor
management: emicizumab should be prescribed aer tolerance. Blood
Adv. 2018;2(20):2780-2782.
43. Pipe SW, Shima M, Lehle M, et al. Ecacy, safety, and pharmacokinetics
of emicizumab prophylaxis given every 4 weeks in people with
haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised
phase 3 study. Lancet Haematol. 2019;6(6):e295-e305.
44. Oldenburg J, Mahlangu JN, Bujan W, et al. e eect of emicizumab
prophylaxis on health-related outcomes in persons with haemophilia A
with inhibitors: HAVEN 1 Study. Haemophilia. 2019;25(1):33-44.
45. Nogami K, Soeda T, Matsumoto T, Kawabe Y, Kitazawa T, Shima M.
Routine measurements of factor VIII activity and inhibitor titer in the
presence of emicizumab utilizing anti-idiotype monoclonal antibodies. J
romb Haemost. 2018;16(7):1383-1390.
46. Tripodi A, Chantarangkul V, Novembrino C, Peyvandi F. Advances in
the treatment of hemophilia: implications for laboratory testing. Clin
Chem. 2019;65(2):254-262.
47. Gundabolu K, Goldsweig A, Bhatt VR, Koepsell SA, Harper JL. ST-
segment elevation myocardial infarction (STEMI) and pulmonary
embolism in a hemophilia A patient receiving emicizumab and
recombinant activated factor VII. Haemophilia. 2020;26:e5-e8.
48. Bar-Ilan A, Livnat T, Homann M, et al. In vitro characterization of
MOD-5014, a novel long-acting carboxy-terminal peptide (CTP)-
modied activated FVII. Haemophilia. 2018;24(3):477-486.
49. Gruppo RA, Malan D, Kapocsi J, et al. Phase 1, single-dose escalating
study of marzeptacog alfa (activated), a recombinant factor VIIa
variant, in patients with severe hemophilia. J romb Haemost.
2018;16(10):1984-1993.
50. Pasi KJ, Rangarajan S, Georgiev P, et al. Targeting of antithrombin in
hemophilia A or B with RNAi therapy. N Engl J Med. 2017;377(9):819-
828.
51. Eichler H, Angchaisuksiri P, Kavakli K, et al. A randomized trial of
safety, pharmacokinetics and pharmacodynamics of concizumab in
people with hemophilia A. J romb Haemost. 2018;16(11):2184-2195.
52. Coppola A, Windyga J, Tufano A, Yeung C, Di Minno MN. Treatment
for preventing bleeding in people with haemophilia or other congenital
bleeding disorders undergoing surgery. Cochrane Database Syst Rev.
2015;(2):CD009961.
53. Coppola A, Di Minno MN, Santagostino E. Optimizing management
of immune tolerance induction in patients with severe haemophilia
A and inhibitors: towards evidence-based approaches. Br J Haematol.
2010;150(5):515-528.
54. DiMichele DM, Hoots WK, Pipe SW, Rivard GE, Santagostino E.
International workshop on immune tolerance induction: consensus
recommendations. Haemophilia. 2007;13(Suppl 1):1-22.
55. Nakar C, Manco-Johnson MJ, Lail A, et al. Prompt immune tolerance
induction at inhibitor diagnosis regardless of titre may increase overall
success in haemophilia A complicated by inhibitors: experience of two
U.S. centres. Haemophilia. 2015;21(3):365-373.
56. Collins P, Chalmers E, Alamelu J, et al. First-line immune tolerance
induction for children with severe haemophilia A: a protocol from the
UK Haemophilia Centre Doctors’ Organisation Inhibitor and Paediatric
Working Parties. Haemophilia. 2017;23(5):654-659.
57. Hay CR, DiMichele DM, International Immune Tolerance Study.
e principal results of the International Immune Tolerance Study: a
randomized dose comparison. Blood. 2012;119(6):1335-1344.
58. Malec LM, Journeycake J, Ragni MV. Extended half-life factor VIII
for immune tolerance induction in haemophilia. Haemophilia.
2016;22(6):e552-e554.
59. Carcao M, Shapiro A, Staber JM, et al. Recombinant factor VIII Fc
fusion protein for immune tolerance induction in patients with severe
haemophilia A with inhibitors—a retrospective analysis. Haemophilia.
2018;24(2):245-252.
60. Ragni MV, Malec LM. Design of the INHIBIT trial: preventing
inhibitors by avoiding ‘danger’, prolonging half-life and promoting
tolerance. Expert Rev Hematol. 2014;7(6):747-755.
61. Batsuli G, Zimowski KL, Tickle K, Meeks SL, Sidonio RF Jr. Immune
tolerance induction in paediatric patients with haemophilia A
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62. Le Quellec S, Negrier C. Emicizumab should be prescribed independent
of immune tolerance induction. Blood Adv. 2018;2(20):2783-2786.
63. Carcao M, Escuriola-Ettingshausen C, Santagostino E, et al. e
changing face of immune tolerance induction in haemophilia A with
the advent of emicizumab. Haemophilia. 2019;25(4):676-684.
64. Matino D, Lillicrap D, Astermark J, et al. Switching clotting factor
concentrates: considerations in estimating the risk of immunogenicity.
Haemophilia. 2014;20(2):200-206.
65. Dube E, Bonnefoy A, Merlen C, et al. A prospective surveillance
study of inhibitor development in haemophilia A patients following a
population switch to a third-generation B-domain-deleted recombinant
factor VIII. Haemophilia. 2018;24(2):236-244.
66. Coppola A, Marrone E, Conca P, et al. Safety of switching factor VIII
products in the era of evolving concentrates: myths and facts. Semin
romb Hemost. 2016;42(5):563-576.
67. Santoro C, Quintavalle G, Castaman G, et al. Inhibitors in hemophilia
B. Semin romb Hemost. 2018;44(6):578-589.
68. Radic CP, Rossetti LC, Abelleyro MM, et al. Assessment of the F9
genotype-specic FIX inhibitor risks and characterisation of 10 novel
severe F9 defects in the rst molecular series of Argentinian patients
with haemophilia B. romb Haemost. 2013;109(1):24-33.
69. Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet.
2003;361(9371):1801-1809.
70. Male C, Andersson NG, Rafowicz A, et al. Inhibitor incidence in
an unselected cohort of previously untreated patients with severe
haemophilia B: a PedNet study. Haematologica. 2020. https://doi.
org/10.3324/haematol.2019.239160
71. Recht M, Pollmann H, Tagliaferri A, Musso R, Janco R, Neuman
WR. A retrospective study to describe the incidence of moderate to
severe allergic reactions to factor IX in subjects with haemophilia B.
Haemophilia. 2011;17(3):494-499.
72. Leissinger CA, Singleton T, Kruse-Jarres R. How I use bypassing therapy
for prophylaxis in patients with hemophilia A and inhibitors. Blood.
2015;126(2):153-159.
73. Antunes SV, Tangada S, Stasyshyn O, et al. Randomized comparison of
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of haemophilia A and B with inhibitors. Haemophilia. 2014;20(1):65-72.
74. Chowdary P, Lethagen S, Friedrich U, et al. Safety and pharmacokinetics
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with hemophilia: a randomized rst human dose trial. J romb
Haemost. 2015;13(5):743-754.
SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting
Information section.
121
9
SPECIFIC MANAGEMENT
ISSUES
Jerzy Windyga
1
| Gerard Dolan
2
| Kate Khair
3
| Johnny Mahlangu
4
| Richa Mohan
5
| Margaret V. Ragni
6
|
Abdelaziz Al Sharif
7
| Lisa Bagley
8
| R. Sathyanarayanan
9
| Glenn F. Pierce
10
| Alok Srivastava
11
1
Department of Hemostasis Disorders and Internal Medicine, Laboratory of Hemostasis and Metabolic Disease, Institute of Hematology
and Transfusion Medicine, Warsaw, Poland
2
Guy’s and St. Thomas’ Hospitals NHS Foundation Trust, London, UK
3
Centre for Outcomes and Experience Research in Child Health, Illness and Disability Research Unit (ORCHID) and Great Ormond Street
Hospital for Children, London, UK
4
Department of Molecular Medicine and Haematology, University of the Witwatersrand, National Health Laboratory Service,
Johannesburg, South Africa
5
Empowering Minds Society for Research and Development, New Delhi, India
6
Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
7
Amman, Jordan
8
London, UK
9
Chennai, India
10
World Federation of Hemophilia, Montreal, QC, Canada
11
Department of Haematology, Christian Medical College, Vellore, India
All statements identied as recommendations are consensus
based, as denoted by
.
9.1 Introduction
•
People with hemophilia and their families may experience
a number of health- or hemophilia-related conditions or
management issues over the course of their lives. ese
include bleeding and reproductive complications that
may aect carriers, specic requirements for surgery and
other invasive procedures, psychosocial matters, a range of
comorbidities due to lifestyle and aging, and other issues.
•
As the management of these conditions can sometimes
be complex, education aimed at preventing and/or
appropriately treating the issues discussed in this chapter
should be a primary and ongoing focus of collaboration
between people and family members aected by hemophilia
and their multidisciplinary healthcare team.
9.2 Carriers
•
e most severe forms of hemophilia typically aect males;
females have conventionally been designated as “carriers.”
•
Carriers oen do not show symptoms of hemophilia
because, although they have an abnormal F8 or F9 gene on
one X chromosome, their other X chromosome contains
a normal F8 or F9 gene that generally works as normal to
produce factor levels in the lower limit of the normal range.
•
A proportion of carriers have low factor VIII (FVIII) or
factor IX (FIX) activity due to lyonization (the random
suppression of one of the two X chromosomes; also called
X inactivation), which can result in mild, moderate, or
even severe hemophilia in rare instances. Symptomatic
females should be designated as having hemophilia of a
specied severity, like males with hemophilia.
Inheritance of hemophilia
•
A female who has an F8 or F9 pathogenic variant is called
an obligate carrier of hemophilia. Obligate carriers can be
identied as having a hemophilia gene based on analysis
of their family history of hemophilia.
• Obligate carriers include:
–
any biological daughter of a father with hemophilia;
–
any biological mother of a child with hemophilia
who also has at least one other family member with
hemophilia (i.e., her brother, maternal grandfather,
uncle, nephew, or male cousin) or who is a known
carrier of hemophilia (i.e., her mother, sister,
maternal grandmother, aunt, niece, or female
cousin);
–
any biological mother of two or more children with
hemophilia.
• Potential carriers include:
WFH Guidelines for the Management of Hemophilia, 3rd edition122
–
any biological daughter, sister, mother, maternal
grandmother, aunt, niece, or female cousin of a
carrier of hemophilia;
–
a biological mother of a child with hemophilia and
no known family history of hemophilia or carriers of
hemophilia.
Factor levels in carriers
•
Carriers with FVIII/FIX levels in the normal range may
never require factor replacement therapy. However, some
carriers with factor levels in the lower range of normal (i.e.,
below 50 IU/dL) experience bleeding problems similar
to males with mild hemophilia (e.g., hemorrhaging aer
dental extraction, surgery, or trauma) as well as problems
that are specic to women, such as prolonged or heavy
menstrual bleeding.
•
Carriers who exhibit a greater bleeding tendency than
would be predicted by their factor level, as in males, may
have a second coagulation defect, such as a von Willebrand
factor (VWF) gene variant or a congenital platelet defect.
RECOMMENDATION 9.2.1:
•
Carriers of hemophilia, irrespective of factor level,
should be registered at a hemophilia treatment centre.
RECOMMENDATION 9.2.2:
•
Carriers of hemophilia with low factor levels should be
treated and managed the same as males with hemophilia.
Carrier factor level testing
•
All immediate female relatives (mother, sister, or daughter)
of a person with hemophilia should have their factor levels
measured, especially prior to any invasive procedure,
childbirth, or as soon as any abnormal bleeding symptoms
occur.
•
In potential carriers, the diagnosis should be conrmed
by genetic testing, if available, as factor levels may be
above 50 IU/dL.
•
In some carriers, levels consistent with moderate or even
severe hemophilia may be found on factor level testing as
a result of lyonization. (See Chapter 2: Comprehensive
Care of Hemophilia – Table 2-1.)
RECOMMENDATION 9.2.3:
•
All potential and obligate carriers of hemophilia should
have their FVIII/FIX levels measured to establish their
baseline levels prior to major procedures, surgery, or
pregnancy.
Bleeding symptoms
•
e most common manifestations among symptomatic
carriers include:
–
menorrhagia (heavy menstrual bleeding);
–
dysmenorrhea (pain during menstrual bleeding);
–
postpartum hemorrhage;
–
perimenopausal bleeding (abnormal bleeding during
the pre-menopause transition);
–
abnormal bleeding alone, following trauma, or aer
medical interventions (e.g., dental extraction or
surgery).
•
Hormonal therapy is useful in managing heavy menstrual
bleeding. Options include:
–
oral, subcutaneous, or transdermal formulations
containing estrogen/progesterone/progestin;
–
the levonorgestrel intrauterine device (IUD).
•
Oral antibrinolytics, e.g., tranexamic acid (15-25 mg/kg
every 6-8 hours), may also be helpful in managing heavy
menstrual bleeding.
Genetic counselling
•
Genetic counselling is an essential but complex component
of comprehensive care for individuals and families with a
diagnosis of hemophilia and for those at risk.
•
While the scope and availability of services vary among
countries and individual hemophilia treatment centres,
comprehensive genetic counselling generally involves:
–
collection and analysis of family and medical
histories to assess the chance of disease occurrence;
–
education about inheritance, genetic testing,
treatment, prevention, and available resources; and
–
counselling to promote informed choices and
adaptation to the risk or condition.
•
Genetic counselling should take into account the individual’s
experiences and perceptions, as well as the social, cultural,
and religious factors and contexts that may inuence
decisions and options related to their genetic status.
•
Genetic counsellors can help both obligate and potential
carriers of hemophilia understand their bleeding and
genetic risks and adapt to the medical, psychological,
familial, and reproductive implications and consequences
of their genetic status.
•
e primary role of genetic counsellors is to educate
individuals on the natural history of hemophilia, establish
their family tree/pedigree, perform risk assessments related
to the inheritance of hemophilia, facilitate genetic testing,
help them process and integrate genetic information, and
discuss relevant reproductive options.
Chapter 9: Specific Management Issues 123
•
Where access to trained genetic counsellors is limited,
the hemophilia treatment centre and the comprehensive
care team members, specically physicians, nurses, and/
or psychosocial professionals, oen take responsibility
for delivering important genetic information.
Psychosocial support
•
Ongoing psychosocial assessment and counselling should be
integrated within case management and comprehensive care
for carriers. Carriers may require referral to psychosocial
professionals (e.g., psychologists) for further support to
address psychological or emotional issues that may arise
during the genetic counselling process or at dierent life
stages.
•
Collaboration between psychosocial professionals and
genetic counsellors can enhance overall patient care.
•
Carriers may experience a wide range of emotional
and psychosocial impacts, including feelings of guilt,
sorrow, and self-blame related to reproductive choices or
consequences such as passing on their genetic variant.
Such feelings run across generations of a family and may
also be experienced by grandmothers who were carriers
and fathers with hemophilia.
•
It is important for hemophilia treatment centres and
healthcare providers (especially genetic counsellors and
clinical geneticists), families, and patient organizations
to be aware that the experience of being a hemophilia
carrier may change with dierent life stages, and carriers
may need genetic and/or psychosocial counselling more
than once during their lifetime.
•
Comprehensive genetic counselling including a formalized
system for the education, management, follow-up, and
long-term medical and psychosocial support of carriers
should be implemented.
Genetic testing
•
Genetic testing facilitates identication of carriers and
prenatal diagnosis. Where available, formal genetic testing
should be oered to potential carriers when they are mature
enough to understand the consequences of the diagnosis
and give consent.
•
It is important to be aware of and abide by the relevant laws
governing genetic testing and prenatal diagnosis procedures
in the country where the service is being provided.
• See also Chapter 4: Genetic Assessment.
RECOMMENDATION 9.2.4:
•
Carriers of hemophilia should be oered counselling
that includes reproductive implications and choices.
Prenatal diagnosis
•
Prenatal diagnosis is usually offered to help with
reproductive planning and risk assessment. Determination
of whether a male fetus is aected by hemophilia assists
parents and healthcare providers in making decisions
regarding pregnancy management, such as caesarean
delivery of a fetus with severe disease to reduce intracranial
hemorrhage (ICH) and maternal anesthesia for childbirth.
(See Chapter 4: Genetic Assessment.)
Pregnancy and prenatal planning
Management of care for all pregnant carriers should involve
close cooperation between the hemophilia and obstetric
teams. It is important to have a clear plan for delivery that
is shared with the carrier and written in her medical le.
Factor levels during pregnancy
•
During pregnancy, FVIII levels can increase signicantly
in carriers and may completely normalize in the later
stages. Levels of FIX, however, do not usually change
signicantly.
•
Even with factor levels above 50 IU/dL in the third
trimester, carriers may experience abnormal bleeding
during childbirth; therefore, it is critical to obtain a carrier’s
bleeding history and score, family history of bleeding, and
history of bleeding with past childbirth prior to delivery
and, if possible, prior to pregnancy.
RECOMMENDATION 9.2.5:
•
Pregnant carriers of hemophilia should have their FVIII/
FIX levels assayed in the third trimester of pregnancy
to assess their bleeding risk during delivery and in the
postpartum period.
Labour and delivery
•
Regional block anesthesia (epidural) in carriers of
hemophilia is not contraindicated if the coagulation screen
is normal and the relevant factor level is above 50 IU/dL or
raised to above 50 IU/dL by prophylactic treatment. e
anesthesia should be performed by an expert anesthetist,
taking into account the carrier’s coagulation parameters
and factor levels, with arrangements for appropriate timing
of treatment, if applicable.
•
Factor replacement therapy, if required, should be
administered to maintain factor levels above 50 IU/dL
for labour and delivery and maintained in the normal
range for at least 3 days aer vaginal delivery and at least
5 days aer caesarean delivery. Route of delivery for
carriers with a fetus without hemophilia should be as per
WFH Guidelines for the Management of Hemophilia, 3rd edition124
obstetric indications. Some suggest caesarean delivery to
prevent intracranial hemorrhage in an infant expected to
be born with severe hemophilia.
•
Delivery of infants known or suspected to have hemophilia
must be atraumatic, regardless of whether it is by vaginal
or caesarean delivery, to decrease the risk of bleeding
complications.
•
Forceps and vacuum extraction vaginal delivery as well as
invasive procedures to the fetus such as fetal scalp blood
sampling and internal fetal scalp electrodes should be
avoided.
•
See Chapter 7: Treatment of Specic Hemorrhages – Table
7-2 for CFC replacement for major and minor surgery.
RECOMMENDATION 9.2.6:
•
For pregnant carriers of hemophilia, delivery should
be in a hospital with access to hemophilia specialists
where complications during labour and delivery can be
dealt with promptly to maintain the safety of mother
and child.
RECOMMENDATION 9.2.7:
•
For pregnant carriers of hemophilia, the WFH
recommends against instrumental delivery.
Postpartum care
•
Carrier FVIII and VWF levels fall o fairly rapidly aer
delivery, usually returning to baseline levels in 7-10 days,
but sometimes earlier.
•
It is important to monitor and maintain factor levels
post-delivery as carriers are at increased risk of primary
and secondary postpartum hemorrhage. If postpartum
hemorrhage occurs, factor replacement therapy,
antibrinolytics (tranexamic acid), and hormonal therapy
are the rst-line therapies for its management.
•
Prophylactic hormonal therapy may be started immediately
aer delivery and continued for one month in selected
carriers deemed to be at higher risk of bleeding.
•
Desmopressin (DDAVP) is occasionally used in the
postpartum period for hemophilia A. (See Chapter 5:
Hemostatic Agents – Other pharmacological options –
Desmopressin [DDAVP].)
•
Hemoglobin levels in carriers at risk of late postpartum
hemorrhage should be checked before discharge from
hospital.
•
Delayed bleeding up to 35 days postpartum is possible;
carriers must be informed of this risk and should be seen
2 weeks postpartum. Follow-up to monitor postpartum
bleeding for approximately 1-2 months may be appropriate.
RECOMMENDATION 9.2.8:
•
Carriers of hemophilia should be monitored for both
primary and secondary postpartum hemorrhage, which
should be treated with appropriate hemostatic measures.
Newborn testing
•
Cord blood should be collected from all male newborn
infants of carriers of hemophilia to assess clotting
factor levels for early identication and management of
hemophilia. e test results should be conveyed to the
parents by an appropriate member of the hemophilia team.
•
Normally in newborn and pre-term infants without
hemophilia, FVIII levels at birth are within the normal
adult range or mildly increased. erefore, it is possible to
diagnose most cases of hemophilia A at birth; the exception
being in mild hemophilia A, wherein a FVIII result at the
lower end of the normal range should be repeated when
the infant is around 6 months of age.
•
In contrast to FVIII, FIX levels at birth are signicantly
lower than normal in newborns without hemophilia and
even more so in preterm infants. While it is usually
possible to make a diagnosis of severe or moderate
hemophilia B in the neonatal period, infants who may
be mildly aected will require repeat screening at 3-6
months of age.
RECOMMENDATION 9.2.9:
•
Male babies born to known or potential carriers of
hemophilia should have cord blood testing of activated
partial thromboplastin time (APTT) or factor levels.
Miscarriage management
•
Miscarriage refers to a spontaneous abortion or pregnancy
loss before 20 weeks of gestation by complete or
incomplete expulsion of the products of conception from
the uterus, by failure of the embryo to develop, or by death
of the fetus in utero.
•
Once the determination has been made that the pregnancy
has ended because the embryo or fetus has died or because
a miscarriage is in progress, the obstetrician will surgically
evacuate the uterus or await spontaneous expulsion of the
products of conception.
•
Surgical management of spontaneous abortion is preferred
in patients with a pre-existing hemostatic abnormality
such as an inherited bleeding disorder. In such cases,
adequate hemostatic treatment is required in accordance
with the recommended perioperative protocols. (See 9.5
Surgery and invasive procedures, below, and Chapter 7:
Chapter 9: Specific Management Issues 125
Treatment of Specic Hemorrhages – Table 7-2 for CFC
replacement for major and minor surgery.)
•
Since bleeding in pregnancy is almost always attributed
to obstetric bleeding, adequate obstetric management is
required. In the case of bleeding in a pregnant carrier,
appropriate hemostatic management may also be required.
•
Hemostatic management consists of replacement of the
decient clotting factor or other treatment modalities in
accordance with protocols for the management of bleeding
complications in patients with hemophilia.
9.3 Circumcision
•
Circumcision is a widely practiced surgical procedure;
up to 30% of the male population in the world are
circumcised.
• Medical benets of circumcision include reduced risk of
sexually transmitted diseases, reduced risk of carcinoma
of the penis, and reduced risk of cervical cancer in sexual
partners of circumcised males.
•
e accepted medical indications include treatment of
phimosis, paraphimosis, recurrent balanitis, and recurrent
balanoposthitis. Non-medical reasons and indications
may be social, cultural, personal, or religious.
•
In hemophilia, circumcision is associated with a number
of complications including prolonged bleeding, infection,
delayed skin healing/increased morbidity, gangrene,
human immunodeciency virus (HIV) and hepatitis
infection acquired through contaminated blood products
to treat bleeding, risk of neonatal inhibitor development,
psychosocial scarring, and risk of mortality.
•
e key considerations for circumcision in patients with
hemophilia include individual patient factors such as
inhibitor development, venous access, and wound care,
as well as the expertise and resources at the hospital/
treatment centre. Patients will invariably bleed when
stitches are removed, and this should be managed with
clotting factor replacement. (See Chapter 7: Treatment of
Specic Hemorrhages – Table 7-2 for CFC replacement
for minor surgery.)
•
A risk–benet ratio assessment should be performed and
discussed with family and other caregivers.
RECOMMENDATION 9.3.1:
•
In patients with hemophilia, the circumcision procedure
should be performed electively by an experienced
surgeon and hematology team in a resourced
hematology treatment centre with access to clotting
factor concentrates.
RECOMMENDATION 9.3.2:
•
In patients with hemophilia, the plasma factor level
should be raised to 80-100 IU/dL just prior to the
procedure.
RECOMMENDATION 9.3.3:
•
In patients with hemophilia undergoing circumcision,
intraoperative care should be taken to cauterize all
bleeding vessels.
RECOMMENDATION 9.3.4:
•
For patients with hemophilia undergoing circumcision,
the WFH suggests use of topical brin sealant as an
adjunctive therapy, using a product manufactured
with robust viral reduction/inactivation processes if
available, to minimize the risk of bloodborne pathogen
transmission.
RECOMMENDATION 9.3.5:
•
For patients with hemophilia undergoing circumcision,
the WFH recommends adjusting clotting factor
replacement to the clinical course of the procedure.
If continued clotting factor replacement is required,
the goal would be to maintain factor levels above 50
IU/dL for the rst 3 days, and above 30 IU/dL for the
subsequent 4-8 days.
RECOMMENDATION 9.3.6:
•
In patients with hemophilia post-circumcision, inhibitor
measurement should be repeated if there is intractable
bleeding that is poorly responsive to replacement therapy
and local hemostatic measures.
RECOMMENDATION 9.3.7:
•
In patients with hemophilia post-circumcision, non-
dissolvable stitches (if used) should be removed 10-14
days postsurgery; the inevitable bleeding should be
managed with clotting factor replacement.
RECOMMENDATION 9.3.8:
•
In hemophilia patients with intractable bleeding post-
circumcision, all angles should be considered, including
blood vessel bleeding, clotting factor deciency, and
platelet abnormalities.
WFH Guidelines for the Management of Hemophilia, 3rd edition126
RECOMMENDATION 9.3.9:
•
In hemophilia patients with intractable bleeding post-
circumcision, adjunct and supportive therapy should
be used; this includes transfusion and local hemostatic
measures, such as the application of topical agents.
9.4 Vaccinations
•
Vaccination against communicable diseases is crucial for
disease prevention. People with hemophilia should receive
all immunizations recommended for their age group.
• Challenges associated with vaccinations include:
–
route of vaccine administration; and
–
vaccination of patients with compromised immunity
(e.g., HIV infection).
•
Live virus vaccines may be contraindicated in those with
weakened immunity.
•
ere has been no evidence that vaccinations result in
inhibitor development.
RECOMMENDATION 9.4.1:
•
Children and adults with hemophilia should be
administered the same routine vaccines as the general
population; however, they should preferably receive the
vaccines subcutaneously rather than intramuscularly or
intradermally, as it is as safe and eective as the latter
and does not require clotting factor infusion.
•
REMARK: If intramuscular injection must be the route
of administration, a dose of clotting factor concentrate
should be given, and the smallest gauge needle available
(25-27 gauge) should be used.
•
REMARK: Additionally, an ice pack should be applied
to the injection site for 5 minutes before injection of the
vaccine, and pressure should be applied to the site for
at least 10 minutes to reduce bleeding and swelling.
RECOMMENDATION 9.4.2:
•
In children and adults with hemophilia and human
immunodeciency virus (HIV) infection, the WFH
recommends standard immunizations, including
pneumococcal and inuenza vaccines and hepatitis A
and B immunization.
RECOMMENDATION 9.4.3:
•
In children and adults with hemophilia and HIV
infection, the WFH recommends that live virus vaccines
(such as chickenpox, yellow fever, rotavirus, oral polio,
and combined measles, mumps, and rubella [MMR]
vaccines) should be avoided.
9.5 Surgery and invasive procedures
•
Surgery may be required for hemophilia-related
complications or unrelated diseases. e issues discussed
here are of prime importance when performing surgery
on patients with hemophilia.
•
Surgery for patients with hemophilia requires additional
planning and interaction with the healthcare team compared
to what is required for other patients.
•
e anesthesiologist should have experience treating
patients with bleeding disorders.
•
Neuraxial anesthesia requires factor levels above 50 IU/dL
to avoid bleeding and ensuing neurological complications.
• Surgery should be scheduled early in the week and early
in the day for optimal laboratory and blood bank support,
if needed.
•
Adequate quantities of CFCs (or bypassing agents for
patients with inhibitors) should be available for the surgery
itself and to maintain adequate coverage postoperatively for
the length of time required for healing and/or rehabilitation.
(For patients with inhibitors, see Chapter 8: Inhibitors to
Clotting Factor – Surgery and invasive procedures.)
•
If CFCs or bypassing agents are not available, adequate
blood bank support for plasma components is needed.
•
e dosage and duration of CFC or other hemostatic
coverage depend on the type of surgery performed. (See
Chapter 7: Treatment of Specic Hemorrhages – Table
7-2 for CFC replacement for major and minor surgery.)
•
Eectiveness of hemostasis for surgical procedures may
be assessed as per criteria dened by the Scientic and
Standardization Committee of the International Society
on rombosis and Haemostasis (see Table 9-1).
• Treatment with CFCs or other hemostatic agents should
be considered before invasive diagnostic procedures such
as lumbar puncture, arterial blood gas determination, or
any endoscopy with biopsy.
• DDAVP may be useful hemostatic treatment for surgery
and other invasive procedures in responsive patients with
mild hemophilia A (without medical contraindications)
for minor bleeding or surgery. Limitations of DDAVP
include water retention, hyponatremia, and tachyphylaxis.
Tachyphylaxis occurs when repeated dosages of DDAVP
are given within short time intervals (12-24 hours), with
approximately 30% decrease in FVIII activity response
from the second dose onwards in the case of a 24-hour
Chapter 9: Specific Management Issues 127
interval. Due to possible tachyphylaxis, DDAVP may not
be a good option for those patients who require adequate
hemostasis for longer periods of time, e.g., following
major surgery.
•
Combined administration of DDAVP and FVIII concentrate
may be able to overcome several of the drawbacks of
these separate treatment options; however, there is a lack
of experience and knowledge with regard to the ecacy
and safety of combination treatment.
• When needed, or if CFCs are not available, DDAVP and
antibrinolytics (tranexamic acid or epsilon-aminocaproic
acid) are therapeutic options as hemostatic support to the
initial replacement treatment. More potent and better
tolerated among antibrinolytics is tranexamic acid. is
compound is particularly eective and useful in cases of
mucosal bleeds.
•
See Chapter 5: Hemostatic Agents – Other pharmacological
options – Desmopressin (DDAVP).
•
Inhibitors should be assessed prior to surgery and
when there is suboptimal response to treatment in the
postoperative period. (See Chapter 8: Inhibitors to Clotting
Factor – Surgery and invasive procedures.)
RECOMMENDATION 9.5.1:
•
Patients with hemophilia A and B should have ready
access to and be evaluated for acute and elective surgical
procedures that could enhance their well-being or
quality of life.
RECOMMENDATION 9.5.2:
•
The WFH recommends patients with hemophilia
requiring surgery should be managed at or in consultation
with a comprehensive hemophilia treatment centre.
RECOMMENDATION 9.5.3:
•
For patients with hemophilia requiring surgery, sucient
quantities of clotting factor concentrates must be available
for the surgery itself and to maintain adequate coverage
postoperatively for the duration required for recovery
and/or rehabilitation.
RECOMMENDATION 9.5.4:
•
e WFH recommends centres providing surgery for
patients with hemophilia should have adequate laboratory
support for reliable monitoring of clotting factor levels
in the perioperative period.
TABLE 9-1 Definition of adequacy of hemostasis for surgical procedures
33
Excellent Intraoperative and postoperative blood loss similar (within 10%) to that in the non-hemophilic patient.
• No extra (unplanned) doses of FVIII/FIX/bypassing agents needed and
• Blood component transfusions required are similar to those in a non-hemophilic patient
Good Intraoperative and/or postoperative blood loss slightly increased over expectation for the non-
hemophilic patient (between 10% and 25% of expected), but the difference is judged by the involved
surgeon/anesthetist to be clinically insignificant.
• No extra (unplanned) doses of FVIII/FIX/bypassing agents needed and
• Blood component transfusions required are similar to those in the non-hemophilic patient
Fair Intraoperative and/or postoperative blood loss increased over expectation (25%-50%) for the non-
hemophilic patient, and additional treatment is needed.
• Extra (unplanned) dose of FVIII/FIX/bypassing agents needed or
• Increased blood component (within 2-fold) of the anticipated transfusion requirement
Poor/None Significant intraoperative and/or postoperative blood loss that is substantially increased over expectation
(>50%) for the non-hemophilic patient, requires intervention, and is not explained by a surgical/medical
issue other than hemophilia.
• Unexpected hypotension or unexpected transfer to ICU due to bleeding or
• Substantially increased blood component (>2-fold) of the anticipated transfusion requirement
Notes: Apart from estimates of blood loss during surgery, data on pre- and postoperative hemoglobin levels and the number of packed red
blood cell units transfused may also be used, if relevant, to estimate surgical blood loss. Surgical hemostasis should be assessed by an involved
surgeon and/ or anesthetist, and records should be completed within 72 h post-surgery. Surgical procedures may be classified as major or minor.
A major surgical procedure is defined as one that requires hemostatic support for periods exceeding 5 consecutive days.
Abbreviations: FIX, factor IX; FVIII, factor VIII; ICU, intensive care unit.
WFH Guidelines for the Management of Hemophilia, 3rd edition128
RECOMMENDATION 9.5.5:
•
For patients with mild hemophilia A undergoing surgery,
the WFH recommends the use of DDAVP for hemostasis
if the patient shows good therapeutic response to DDAVP
in pre-surgery testing.
•
REMARK: DDAVP is not recommended for surgical
hemostasis in those patients with mild hemophilia A
in whom the response to DDAVP (increase of plasma
FVIII activity levels) is unsatisfactory or in whom
DDAVP is contraindicated (e.g., in those with signicant
cardiovascular disease).
•
REMARK: Due to the risk of tachyphylaxis, DDAVP
should not be given for more than 3-5 days unless
the patient can be monitored closely and switched to
clotting factor concentrate if this occurs. erefore, if the
anticipated treatment duration will be longer than 3-5
days (e.g., aer major surgery), providers may choose
to avoid the use of DDAVP from the outset.
•
REMARK: DDAVP is the rst choice for patients with
mild hemophilia A to avoid the cost of CFCs and exposure
to FVIII concentrates and the potential risk of inhibitor
development, which increases with the number of
exposures.
•
REMARK: Given the need for close monitoring, an
experienced hematology team should manage these
patients.
RECOMMENDATION 9.5.6:
•
For patients with hemophilia undergoing surgery,
antibrinolytics and topical hemostatic agents should
be considered if ancillary therapies are required beyond
factor replacement.
RECOMMENDATION 9.5.7:
• Pre- and postoperative assessment of all patients with
hemophilia A and B should include inhibitor screening
and inhibitor assay.
RECOMMENDATION 9.5.8:
• For patients with hemophilia undergoing surgery, the
WFH advises against neuraxial anesthesia. If neuraxial
anesthesia is required, it should be performed only
under adequate clotting factor coverage as the safety
of neuraxial procedures has not been established in
patients with hemophilia.
•
REMARK: It is recognized that in some centres, neuraxial
anesthesia is acceptable aer restoring hemostasis in
patients with hemophilia, whereas in other centres
this procedure is discouraged and general anesthesia
is preferred.
RECOMMENDATION 9.5.9:
• Patients with mild hemophilia A and all patients with
hemophilia receiving intensive factor replacement for the
rst time are at particular risk of inhibitor development,
and therefore should be rescreened for inhibitor presence
4-12 weeks post-operatively.
RECOMMENDATION 9.5.10:
•
In surgical patients with hemophilia B requiring intensive
replacement therapy, the WFH recommends against
use of prothrombin complex concentrate (PCC) due to
risk of accumulation of clotting factors II, VII, and X,
which can be associated with higher risk of thrombotic
complications.
RECOMMENDATION 9.5.11:
•
e WFH recommends replacement therapy for a
duration of at least 3 days for minor surgical procedures,
and at least 7-10 days for major surgical procedures.
RECOMMENDATION 9.5.12:
•
For patients with hemophilia A and B undergoing major
surgery, the WFH recommends against routine use of
pharmacologic thromboprophylaxis.
9.6 Sexuality
• People with hemophilia are able to have entirely normal
sexual lives. Although sexual health has generally been
inadequately assessed in routine care of people with
hemophilia, recent studies have shown that the prevalence
of diculty with sexual activity is signicantly higher
compared to the general population.
•
Complications of hemophilia can be accompanied by
sexual dysfunction, such as lack of libido or impotence.
Pain, fear of pain, or analgesia may aect sexual desire,
and hemophilic arthropathy may place physical limitations
on sexual intercourse.
•
Older age, joint bleeding, and joint status contribute to poor
sexual health; in addition, poor sexual health is strongly
associated with worse general health status.
•
People with hemophilia have reported experiencing joint
stiness that aected their sexual life (53%), joint pain
from sexual activity (53%), and not having adequate
information regarding sexual activity.
Chapter 9: Specific Management Issues 129
•
Muscle bleeding (e.g., iliopsoas) may sometimes arise from
sexual activity, and this may require active management or
specic counselling to reduce recurrence. (See Chapter
10: Musculoskeletal Complications.)
•
Sexuality may also be aected by viral complications such
as chronic hepatitis C virus (HCV) and HIV infection.
•
Age-related diseases such as hypertension and diabetes
mellitus may also result in sexuality issues, as well as
certain medications to treat comorbidities.
•
In some cases, oral phosphodiesterase-5 inhibitors
(sildenal, tadalal) may be helpful. Note that these
medications mildly inhibit platelet aggregation in vitro
and may cause epistaxis due to nasal congestion.
•
In addition to the physical eects on sexuality, people
with hemophilia may experience social and psychological
issues surrounding sexual health. Worries about having
a bleed due to sexual activity, lack of desire, body image
issues, fear of rejection, medication side eects, pain, and
tiredness have all been reported to aect the sexual lives
of people with hemophilia.
•
Cultural inuences may play a role in a person’s decision
about whether to discuss sexual health issues with their
healthcare provider. As some individuals may be reluctant
to have such discussions, all members of the comprehensive
care team should be procient in initiating and engaging
patients in a conversation about their sexual health and
quality of life, and this approach should be integrated
into routine care.
•
Hematospermia (dened as the macroscopic presence
of blood in the semen) is not uncommon in people with
hemophilia and may cause considerable anxiety in some
individuals and their partners.
• Hematospermia is rarely linked to serious dysfunctions;
nevertheless, a more serious pathology may be underlying,
consequently requiring further investigations.
RECOMMENDATION 9.6.1:
•
Adult patients with hemophilia should be assessed for
sexual health issues as part of routine care to address
possible impacts related to age, joint bleeding, joint
pain and stiness, and muscle bleeding (e.g., iliopsoas),
which can sometimes arise during sexual activity.
RECOMMENDATION 9.6.2:
•
For patients with hemophilia with comorbidities who may
experience complications of hemophilia accompanied
by sexual dysfunction, the WFH recommends that
healthcare providers at hemophilia treatment centres
provide a multipronged psychosocial approach that
includes communicating openly about sexual activity
and quality of life in a consistent and comprehensive
manner.
9.7 Psychosocial issues
•
Severe hemophilia is associated with major psychological
and economic burdens for people with hemophilia and
their caregivers. As hemophilia can impact many aspects
of daily living and family life, psychological and social
support are important components of comprehensive
care for hemophilia.
•
Psychosocial care is an important aspect of healthcare
services for individuals and families living with hemophilia
and related complications.
•
e hemophilia treatment centre social worker and/or
other members of the comprehensive care team typically
fulll this role. Key functions include:
–
Provide as much information as possible about all
aspects of care, including the physical, psychological,
emotional, and economic dimensions of living with
hemophilia, in terms the patient/family members
can understand.
–
Provide psychosocial support and counselling to
patients, their parents, and other family members
(including unaected siblings).
–
Interact and speak directly with children with
hemophilia about their treatment, not just with their
parents.
–
Assess and address issues related to adherence.
–
Help patients understand and deal with issues and
challenges related to school or employment.
–
Encourage patients and family members to build a
support network (e.g., by forming or joining support
groups at their hemophilia treatment centre and
patient organization).
–
Work in partnership with the patient organization
to provide education to patients, families, and
healthcare providers, and advocate for hemophilia
care.
–
Enlist the assistance of local healthcare organizations
where social workers are unavailable.
–
Encourage patients, family members and caregivers
to discuss issues or challenges with regards to mental
health such as depression or anxiety.
–
Recognize warning signs of burnout and depression,
which are common with chronic illness, and provide
suggestions and resources for coping.
WFH Guidelines for the Management of Hemophilia, 3rd edition130
–
Encourage patients to engage in productive and
fullling activities at home and in the workplace.
•
See 9.9 Medical issues with aging – Psychosocial issues
with aging, below.
RECOMMENDATION 9.7.1:
•
For patients with severe hemophilia, the WFH
recommends the provision of psychological and social
support as part of comprehensive hemophilia care,
with enlistment of assistance from local healthcare
organizations wherever psychologists or social workers
are unavailable.
RECOMMENDATION 9.7.2:
•
For patients with hemophilia, the WFH recommends
that hemophilia treatment centres assist patients and
families in forming and joining support groups or
networks, and encourage participation in their patient
organizations.
RECOMMENDATION 9.7.3:
•
For patients with hemophilia, the WFH recommends
appropriate programming at hemophilia treatment
centres and patient organizations to assist in successful
aging through assessment of their developmental
progression, assessment and prevention of comorbidities
and functional impairments, assessment of cognitive
and emotional function, identication of depression
and referral for treatment, and reinforcement of social
connectedness.
9.8 Comorbidities
•
e increase in life expectancy for people with hemophilia—
due to major advances in hemophilia care, including the
availability of safe and eective CFCs—is accompanied by
a range of new challenges. An increasing number of people
with hemophilia develop signicant comorbidities, such
as cardiovascular and metabolic diseases, renal disease,
and cancer/malignancies.
•
As a result, hemophilia treatment centres increasingly
require the expertise of specialists rarely needed before,
such as cardiologists, endocrinologists, and oncologists.
• In general, the comorbidities occurring in older patients
with hemophilia should be treated in consultation with
relevant specialists as they would in the unaffected
population of the same age, but treatment should be
adapted when the risk of bleeding is increased by the use
of invasive procedures or medications that may cause
bleeding.
Cancer/malignancy
•
e risk of developing cancer increases with age, and
the same holds true in aging patients with hemophilia.
•
It has been well documented that older patients with
hemophilia have a higher incidence of virus-related
malignancies caused by HIV (e.g., non-Hodgkin lymphoma,
basal cell carcinoma, Kaposi sarcoma) and HCV (e.g.,
hepatocellular carcinoma) infection.
•
It is unclear whether hemophilia exerts an impact on the
prevalence of other cancers among people with hemophilia,
and it is unclear whether hemophilia exerts an impact on
the clinical course of malignancy.
•
More recent analyses suggest that, with the exception of
hepatocellular carcinoma due to chronic hepatitis infection,
mortality rates from cancer are essentially the same among
people with hemophilia and the general population.
•
e risk of bleeding in people with hemophilia and cancer
is exacerbated by factors including:
–
use of invasive diagnostic and therapeutic
procedures;
–
thrombocytopenia induced by chemotherapy and/or
radiotherapy.
•
erefore, hemostatic therapy should be provided not
only episodically at the time of invasive procedures,
but also in the form of ongoing prophylaxis in cases of
severe thrombocytopenia due to chemotherapy and/or
radiotherapy.
•
It is unknown which platelet count is safe in patients
with hemophilia and malignancy. Some experts advise
considering prophylaxis with replacement of the decient
clotting factor when platelet count is less than 30 G/L
apart from management of thrombocytopenia, although
previous studies have suggested that prophylaxis should
be instituted when platelet counts fall below 50 because
of the risk of central nervous system (CNS) and other
serious bleeds. (See Chapter 7: Treatment of Specic
Hemorrhages – Table 7-2.)
•
Since thrombocytopenia is in itself not antithrombotic,
antithrombotic prophylaxis should be considered in those
types of malignancy that are associated with a high risk
of thrombosis.
•
For patients with hemophilia who are diagnosed with
cancer, which in the general population is accompanied by
an increased risk for developing venous thromboembolism
(VTE), thromboembolism prophylaxis may not be necessary
Chapter 9: Specific Management Issues 131
as patients with clotting deciencies are relatively protected
from developing VTE.
RECOMMENDATION 9.8.1:
•
In patients with hemophilia, the WFH recommends
age-appropriate cancer screening.
RECOMMENDATION 9.8.2:
•
For diagnosis and treatment of malignancy in patients
with hemophilia, the WFH recommends the provision
of adequate factor replacement as necessary to minimize
bleeding risk.
RECOMMENDATION 9.8.3:
•
In patients with hemophilia, if chemotherapy or
radiotherapy is accompanied by severe long-lasting
thrombocytopenia, the WFH recommends continuous
prophylactic replacement therapy.
RECOMMENDATION 9.8.4:
•
Antineoplastic treatments for patients with hemophilia
diagnosed with cancer should be the same as
recommended for the general population.
RECOMMENDATION 9.8.5:
•
For hemophilia patients without inhibitors
diagnosed with cancer, the WFH advises that venous
thromboembolism prophylaxis management decisions
should be based on evaluation of the individual patient’s
bleeding and thrombotic risk. If used in patients receiving
factor concentrates, it must be carefully managed to
maintain factor levels below the risk range for VTE.
•
REMARK: If pharmacologic thromboprophylaxis for
hemophilia patients without inhibitors diagnosed with
cancer is used, it should mimic what is recommended
for the general population, provided that appropriate
factor replacement therapy is administered, taking into
account that factor replacement to high factor levels
above normal is a potential risk factor for VTE.
Cerebrovascular accident/stroke
•
Patients with hemophilia are prone to hemorrhagic stroke,
the most serious type of bleeding in this population;
however, ischemic/thrombotic strokes have also been
reported. (See Chapter 7: Treatment of Specific
Hemorrhages – Table 7-2.)
Atrial fibrillation
•
Non-valvular atrial brillation (AF) is the most common
type of arrhythmia, and it is associated with a signicant
increase in the risk of embolic stroke. Its prevalence in
the general population increases with age, ranging from
<0.1% in patients less than 55 years of age to 3% in patients
between 65 and 69 years of age, and up to 9% in patients
over 80 years of age.
•
Results of recent studies indicate that the prevalence of
atrial brillation in patients with hemophilia is similar to
that reported in their peers in the general population.
•
ere is no evidence to suggest that patients with hemophilia
and atrial brillation are protected from thromboembolic
complications.
•
Management of non-valvular atrial brillation comprises
rhythm control strategies such as cardioversion or ablation;
however, these strategies do not always obviate the need
for therapeutic anticoagulation.
•
e selection of patients with hemophilia who have a
high chance of successful cardioversion should involve a
cardiologist at a hemophilia treatment centre.
•
Le atrial appendage occlusion may be an option for
patients with non-valvular atrial brillation at high risk
of bleeding and cardioembolism.
•
In patients without bleeding diathesis, treatment
decisions regarding anticoagulation in atrial brillation
are determined by weighing an individual’s stroke risk
as calculated by the CHA
2
DS
2
-VASc score against an
estimated bleeding risk occurring as a consequence of
anticoagulation therapy (the risk of bleeding associated
with anticoagulation for atrial brillation in the general
population is calculated by the HAS-BLED score).
•
ere is no evidence to support or reject the hypothesis
that the CHA
2
DS
2
-VASc and HAS-BLED scores are equally
useful in patients with hemophilia.
•
ere are no evidence-based guidelines for the management
of atrial brillation in patients with hemophilia.
RECOMMENDATION 9.8.6:
•
Patients with hemophilia and non-valvular atrial
brillation should be treated by medical teams composed
of experienced hematologists and cardiologists.
RECOMMENDATION 9.8.7:
•
For patients with severe or moderate hemophilia
and atrial brillation, the WFH recommends clinical
management based on basal FVIII/FIX levels and stroke
risk by weighing the patient’s stroke risk as calculated by
the CHA
2
DS
2
-VASc score against an estimated bleeding
WFH Guidelines for the Management of Hemophilia, 3rd edition132
risk occurring as a consequence of anticoagulation
therapy, and withholding anticoagulation if stroke risk
is deemed to be lower than bleeding risk.
RECOMMENDATION 9.8.8:
•
For patients with hemophilia and atrial brillation at
high risk of bleeding and thromboembolism, the WFH
recommends le atrial appendage occlusion, particularly
if long-term replacement therapy with decient clotting
factor is not feasible.
•
REMARK: Le atrial appendage occlusion for patients
with hemophilia and atrial brillation should be preceded
by assessments of the individual’s risk of bleeding
and thromboembolism and implemented under the
advisement of a cardiologist.
RECOMMENDATION 9.8.9:
•
For patients with hemophilia in whom the risk of non-
valvular atrial brillation-associated stroke is high
or outweighs the risk of bleeding complications, the
WFH recommends careful consideration of the use of
anticoagulants.
•
REMARK: e choice between direct oral anticoagulants
and vitamin K antagonists depends on the local protocols,
availability of antidotes for reversal of anticoagulant
activity, and feasibility of maintaining adequate trough
levels of the decient clotting factor.
•
REMARK: Despite the scarcity of evidence-based data
for this indication in patients with hemophilia, most
experts suggest maintaining trough levels of the decient
clotting factor in the individual patient at ≥15-30 IU/dL
while on anticoagulant therapy for atrial brillation.
•
REMARK: Because treatment responses to DOACs and
VKAs may vary, decisions on anticoagulant therapy
should be based on the individual patient in consultation
with a cardiologist.
RECOMMENDATION 9.8.10:
•
In hemophilia patients with inhibitors, antithrombotic
therapy is generally contraindicated.
•
More research is needed to better understand the safety
of antithrombotic therapy in patients with hemophilia
A complicated by FVIII inhibitors who are treated with
emicizumab.
Venous thromboembolism/thrombosis
•
Patients with hemophilia are considered to be protected
against venous thromboembolism (VTE) by virtue of their
coagulation factor deciency.
•
Spontaneous VTE is uncommon among patients with
hemophilia, including those with inherited thrombophilia;
however, VTE associated with surgical interventions (e.g.,
total knee or hip replacement or major abdominal surgery
for cancer) has been reported. It has been postulated that in
this clinical setting, the natural protection against VTE is
mitigated by administration of high doses of concentrates
of the decient clotting factor.
•
Intensive replacement therapy with prothrombin complex
concentrate (PCC) in patients with hemophilia B may
result in accumulation of clotting factors II, VII, and
X, which may be associated with a higher risk of VTE
development.
•
Intensive therapy with bypassing agents may also be
associated with a higher risk of VTE development.
•
Concomitant use of emicizumab and activated
prothrombin complex concentrate (aPCC) may also
result in thrombotic complications, including VTE and
thrombotic microangiopathy. (See Chapter 8: Inhibitors
to Clotting Factor.)
•
ere is currently a lack of evidence-based consensus on
how to manage VTE in patients with hemophilia. It has
been suggested that therapeutic doses of anticoagulants
may be administered when decient clotting factor levels
are maintained above 30 IU/ dL or above 15 IU/dL.
•
Hemostatic response to bypassing agents is often
unpredictable; therefore, antithrombotics should only
be used in patients with hemophilia and high-responding
inhibitors who are at the highest risk of developing
thromboses. In rare cases, the risk of untreated thrombosis
may outweigh the risk of bleeding complications and
therefore justify the use of antithrombotic agents. (For
patients with inhibitors, see Chapter 8: Inhibitors to
Clotting Factor.)
RECOMMENDATION 9.8.11:
•
In patients with hemophilia undergoing surgical
procedures who carry a high risk of developing venous
thromboembolism (e.g., in cases of major orthopedic
surgery, major abdominal surgery for cancer, or long
post-surgery immobilization), the WFH recommends
an assessment of individual risk of VTE.
Chapter 9: Specific Management Issues 133
RECOMMENDATION 9.8.12:
•
For patients with hemophilia undergoing surgery
associated with a high risk of venous thromboembolism
and bleeding complications, the WFH recommends
consideration of the use of mechanical methods for
thromboprophylaxis.
•
REMARK: In contrast to pharmacological
thromboprophylaxis, mechanical methods of
thromboprophylaxis are not associated with the risk
of bleeding complications.
RECOMMENDATION 9.8.13:
•
For patients with hemophilia in whom the balance of
the risk of bleeding compared to the risk of developing
venous thromboembolism favours pharmacological
thromboprophylaxis, the WFH recommends the same
practice as that applied in the general population,
provided that adequate replacement therapy is
administered.
•
REMARK: Decisions on anticoagulant therapy in a
patient with hemophilia should always be preceded by
assessments of the individual’s bleeding and thrombotic
risk. In some patients with hemophilia, the risk of
uncontrolled bleeding may outweigh the benet of
anticoagulation.
RECOMMENDATION 9.8.14:
•
For patients with hemophilia without inhibitors, the
WFH recommends the use of prophylactic doses of
anticoagulants only aer ensuring hemostatic control
with adequate replacement therapy.
•
REMARK: If the risk of uncontrolled bleeding outweighs
the benet of anticoagulation, anticoagulants should
not be used.
•
REMARK: is recommendation does not apply to
patients with hemophilia and inhibitors in whom
anticoagulants are generally contraindicated.
RECOMMENDATION 9.8.15:
•
In hemophilia patients without inhibitors who experience
an acute episode of venous thromboembolism, the WFH
recommends the use of high-intensity anticoagulation
for the minimal duration and under clotting factor
replacement protection and close clinical and laboratory
monitoring.
•
REMARK: This recommendation does not apply
to hemophilia patients with inhibitors in whom
anticoagulants are generally contraindicated.
•
More research is needed to better understand the safety
of antithrombotic therapy in patients with hemophilia
A complicated by FVIII inhibitors who are treated with
emicizumab.
Metabolic syndrome
•
Metabolic syndrome is associated with obesity and physical
inactivity, both of which are common in older patients
with hemophilia due to severe hemophilic arthropathy.
•
Obesity (body mass index [BMI] ≥30 kg/m) is a major
health concern in developed countries in both the general
population and in patients with hemophilia. e number
of patients with hemophilia who are overweight is also
increasing.
•
Obesity impacts physical activity in both children and
adults. Although few studies have assessed the eects
of obesity on hemophilia-specic outcomes, there is
evidence that excess weight has a signicant impact on
lower extremity joint range of motion and functional
ability, as well as on joint pain, with potentially signicant
eects on overall quality of life.
•
Overweight and obesity can aect frequency of bleeding
in dierent ways: some overweight/obese patients have
reduced bleeding rates, but this may be due to lower
levels of physical activity; conversely, obese patients with
hemophilia tend to have more joint bleeds, compared to
non-obese patients with hemophilia.
•
Venous access is more complex in obese patients with
hemophilia, which may inhibit their ability to self-infuse and
therefore result in lower compliance with their prophylaxis
regimen. Lower compliance with prophylaxis may result
in more joint bleeding and ultimately worsen hemophilic
arthropathy and osteoarthritis in obese patients with
hemophilia.
•
Factor recovery is dierent in patients with hemophilia
who are overweight or obese. A median FVIII recovery
has been observed in obese children (2.65), compared to
those with normal weight (1.94).
•
For some obese patients, lean body weight dosing may
be eective while reducing cost of treatment based on
body weight. However, each patient would have to be
assessed by pharmacokinetic studies, including trough
and peak levels, and factor levels at additional timepoints
to establish ideal dosing.
•
Weight management should be oered as part of health
promotion within hemophilia treatment centres for all
patients. is should include:
–
nutritional education for parents of children as well
as for adults with hemophilia;
WFH Guidelines for the Management of Hemophilia, 3rd edition134
–
weight management programs;
–
psychological support;
–
exercise programs (preferably monitored by the
centre’s physical therapist);
–
pharmacological therapy;
–
bariatric surgery; and
–
collaboration with or referral to obesity medical/
surgical teams.
•
Bariatric surgery is possible in morbidly obese people
with hemophilia.
RECOMMENDATION 9.8.16:
•
Patients with hemophilia should have regular height and
weight measurements to monitor body mass index.
RECOMMENDATION 9.8.17:
•
Patients with hemophilia who are overweight or obese
should be referred for dietary advice and/or weight
management.
RECOMMENDATION 9.8.18:
•
Patients with hemophilia who are obese should have
FVIII/FIX replacement therapy based on lean body
weight aer individual pharmacokinetic assessments.
Diabetes mellitus
• Little is known about the prevalence of diabetes mellitus
in people with hemophilia, but it has been found to be
higher in the hemophilia population than in the general
population.
•
If treatment with insulin is indicated, subcutaneous
injections can be administered without bleeding and
without the need for factor replacement.
•
Higher body weight/BMI is a major risk factor for not
only the development of diabetes mellitus, but also for
atherosclerosis, cardiovascular disease, and further damage
to arthropathic joints. As a result, regular physical activity
and physical therapy aimed at preventing further joint
deterioration are advisable.
RECOMMENDATION 9.8.19:
•
Patients with hemophilia should have the same screening
for diabetes as the general population.
RECOMMENDATION 9.8.20:
•
Patients with hemophilia and diabetes should have the
same management strategies to control their diabetes
as the general population; if treatment with insulin is
indicated, subcutaneous
injections can be administered without bleeding and
without the need for factor replacement.
Renal disease
•
A higher incidence of renal disease has been reported
in people with hemophilia, compared with the general
population. In addition, the likelihood of death from
renal failure is about 50 times higher among patients with
hemophilia than in the general population.
•
e increasing frequency of renal disease in older patients
with hemophilia is likely due to a number of concomitant
risk factors including:
–
older age;
–
non-white population;
–
hypertension;
–
history of renal bleeds and hematuria, potentially
resulting in structural renal damage;
–
HIV infection and combined antiretroviral therapy;
–
use of antibrinolytic amino acids.
•
erefore, the need for dialysis may be increasing in
patients with hemophilia.
•
In those patients who require renal replacement therapy,
the choice between peritoneal dialysis and hemodialysis
depends on patient-specic factors, such as the increased
risk of infection in patients with cirrhosis and/or ascites.
•
Theoretically, peritoneal dialysis is preferable to
hemodialysis because it requires factor coverage only at
the time of catheter insertion; however, the procedure
is associated with a high risk of peritoneal infections,
particularly in HCV- and HIV-infected patients. us,
hemodialysis using heparin and a single dose of CFC
before and aer each procedure is oen preferred.
•
If hemodialysis is selected, central venous access is
mandatory. Before placement of the device, factor levels
should be 80-100 IU/ dL and then maintained between 50
and 70 IU/dL for 3 days aer the procedure.
Osteoporosis
•
Bone mineral density (BMD) has been shown to be lower
in people with hemophilia. An increased number of
arthropathic joints, loss of joint movement, and muscle
atrophy leading to inactivity are associated with a lower
BMD.
•
It is not clear whether patients with hemophilia require
routine monitoring of bone mass; it may be advisable in
patients with high risk or multiple risk factors.
•
Weight-bearing activities and suitable sports that promote
development and maintenance of good bone density
should be encouraged for younger patients, if their joint
Chapter 9: Specific Management Issues 135
health permits, to build bone mass and reduce the risk
of later osteoporosis.
•
Calcium and vitamin D supplements or bisphosphonates
should be considered for patients with demonstrated
osteopenia, and a dental evaluation should be carried out
before initiating long-term bisphosphonate therapy.
Degenerative joint disease
•
Joint damage progresses with increasing age in a near-linear
fashion not only in patients with severe hemophilia but
also in moderate cases.
•
Contributing factors include osteoporosis and osteopenia,
a sedentary lifestyle, overweight, and obesity.
•
Due to the increased rate of joint morbidity, preventive
strategies are necessary. While secondary prophylaxis
reduces the incidence of bleeding, its ecacy in improving
orthopedic function has not been clearly established.
• See also Chapter 10: Musculoskeletal Complications.
RECOMMENDATION 9.8.21:
• All patients with hemophilia should be encouraged to
engage in regular physical activity and to have adequate
calcium and vitamin D intake.
• REMARK: Hemophilia patients with musculoskeletal
conditions and injuries should have physical therapy
and rehabilitation supervised by a physical therapist
with hemophilia experience.
RECOMMENDATION 9.8.22:
•
Hemophilia patients with osteoporosis, fragility fractures,
or who are at increased fracture risk should be treated
with individually adjusted anti-osteoporotic medications.
9.9 Medical issues with aging
•
See also 9.8 Comorbidities, above, for discussion of
cancer/malignancy, cerebrovascular accident/stroke,
atrial brillation, venous thromboembolism/thrombosis,
metabolic syndrome, diabetes mellitus, renal disease, and
degenerative joint disease.
•
It is important to provide older patients with regular
education and counselling on the importance of informing
the hemophilia team of their health issues to ensure
appropriate treatment.
•
Aging patients with hemophilia require the same access
as patients without hemophilia to health education and
preventive strategies to reduce the risk or impact of age-
related morbidity.
•
The hemophilia team should be closely involved in
managing aspects and complications of care related to
aging, and ensure close consultation and agreement on
treatment plans.
•
Patients with mild hemophilia may require specific
education and attention to highlight potential issues
associated with hemophilia and other illnesses.
RECOMMENDATION 9.9.1:
•
The WFH recommends that aging patients with
hemophilia be granted the same access to health
education and preventive strategies to reduce the risks
or impacts of age-related morbidities as the general
population.
RECOMMENDATION 9.9.2:
•
e WFH recommends the hemophilia team should be
closely involved in managing aspects and complications
of care related to aging and ensure close consultation
and agreement on treatment plans.
Hypertension
•
Studies have shown that people with hemophilia have
higher mean blood pressure, are twice as likely to have
hypertension, and use more antihypertensive medications
compared to the general population.
•
Hypertension is associated with the usual risk factors, such
as older age, diabetes mellitus, dyslipidemia, or higher
BMI and obesity; however, the causes of the increased
prevalence of hypertension in patients with hemophilia
remain unclear.
•
Hypertension is a well-established risk factor for
cardiovascular diseases, renal diseases, and intracranial
hemorrhage, all of which may pose signicant challenges
in the management of care for patients with hemophilia.
•
In view of the increased risk of bleeding, hypertensive
patients with hemophilia should receive appropriate
treatment and have their blood pressure checked regularly.
•
In the absence of other cardiovascular risk factors, a
systolic blood pressure ≤130 mm Hg and a diastolic blood
pressure ≤80 mm Hg should be maintained.
RECOMMENDATION 9.9.3:
•
For all patients with hemophilia, the WFH recommends
regular blood pressure measurements as part of their
standard care.
WFH Guidelines for the Management of Hemophilia, 3rd edition136
•
REMARK: is recommendation is based on data
indicating a higher prevalence of arterial hypertension
among patients with hemophilia irrespective of age as
compared with males in the general population.
RECOMMENDATION 9.9.4:
•
For patients with hemophilia, the WFH recommends
the same management of arterial hypertension as that
applied in the general population.
•
REMARK: Patients with hemophilia diagnosed with
hypertension may be treated in a hemophilia treatment
centre or referred to primary care providers depending
on the local healthcare system and practices.
Coronary artery disease
•
ere is evidence that people with hemophilia develop
atherosclerosis at similar rates to those in the general
population.
•
By contrast, patients with hemophilia have lower
cardiovascular mortality rates compared with the general
population (most likely because of lower thrombin
generation at the point of plaque rupture).
•
It is not known whether the increasing use of prophylaxis
in aging patients with hemophilia will result in an increase
in cardiovascular mortality.
• Individuals with severe, moderate, and mild hemophilia
may develop overt ischemic heart disease. e management
of such cases should be individualized and requires close
cooperation between the hemophilia and cardiology teams.
•
Making a decision on antithrombotic therapy in a patient
with innate bleeding tendency is particularly dicult; a
recent study found that antiplatelet and anticoagulant
medications increased severe bleeding in patients with
hemophilia (odds ratio [OR] = 3.5).
•
When considering antithrombotic therapy in patients with
hemophilia, the following aspects should be evaluated:
–
patient bleeding phenotype;
–
intensity of the antithrombotic therapy;
–
duration of the planned therapy; and
–
characteristics of the antithrombotic agent.
•
Healthcare providers working with patients with hemophilia
should educate them on cardiovascular risk and encourage
risk reduction (smoking, obesity, exercise) or optimization
(hypertension, hyperlipidemia).
RECOMMENDATION 9.9.5:
•
Patients with hemophilia should receive the same
screening and management for individual cardiovascular
disease risk factors as the general population.
RECOMMENDATION 9.9.6:
•
Patients with hemophilia and cardiovascular disease
should receive routine care adapted to their individual
situation in consultation with a cardiologist.
RECOMMENDATION 9.9.7:
•
For patients with hemophilia without inhibitors who
have been diagnosed with cardiovascular disease, the
WFH recommends similar management as that applied
to the general population, except for the necessary
additional correction of impaired hemostasis with
clotting factor concentrates.
•
REMARK: Decisions on cardiovascular treatment
strategy for patients with hemophilia should always be
preceded by assessments of the individual’s bleeding
and thrombotic risks and cardiac disease severity and
implemented under the advisement of a cardiologist.
RECOMMENDATION 9.9.8:
•
Among patients with hemophilia and high-responding
inhibitors, the WFH recommends limiting the use of
antithrombotics to those patients in whom the risk of
untreated thrombosis outweighs the risk of bleeding
complications.
•
REMARK: This recommendation is based on the
observation that hemostatic response to bypassing
agents is oen unpredictable.
•
REMARK: More research is needed to better understand
the safety of antithrombotic therapy in patients treated
with emicizumab.
RECOMMENDATION 9.9.9:
•
Given the scarcity of published data on antiplatelet
therapy in patients with hemophilia, the WFH
recommends careful evaluation of an individual’s
bleeding and thrombotic risk.
•
REMARK: It has been suggested that the trough level
of the decient clotting factor be maintained at ≥15-30
IU/dL during dual antiplatelet therapy and at ≥1-5 IU/
dL during single-agent antiplatelet therapy; however,
treatment strategy should be tailored to the individual.
• REMARK: e decision on use of antiplatelet therapy
in a patient with hemophilia should always be made in
consultation with a cardiologist.
RECOMMENDATION 9.9.10:
•
Given the scarcity of published data on patients
with hemophilia undergoing percutaneous coronary
Chapter 9: Specific Management Issues 137
intervention, the WFH recommends careful evaluation
of an individual’s bleeding and thrombotic risk.
•
REMARK: It has been suggested that in patients with
hemophilia without inhibitors who are undergoing PCI,
the decient clotting factor be maintained at the peak
level of 80-100 IU/dL for as long as therapeutic doses of
antithrombotics are used; however, treatment strategy
should be tailored to the individual.
•
REMARK: e decision on use of antithrombotic therapy
for this indication should always be made in consultation
with a cardiologist.
RECOMMENDATION 9.9.11:
•
Given the scarcity of published data on patients
with hemophilia undergoing coronary artery bypass
graing, the WFH recommends careful evaluation of
an individual’s bleeding and thrombotic risk.
•
REMARK: It has been suggested that in patients with
hemophilia without inhibitors who are undergoing
CABG, similarly to other major surgical procedures,
the decient clotting factor be maintained at the peak
level of 80-100 IU/dL before, during, and aer CABG
until sucient wound healing has taken place; however,
treatment strategy should be tailored to the individual.
•
REMARK: e decision on use of antithrombotic therapy
for this indication should always be made in consultation
with a cardiologist.
RECOMMENDATION 9.9.12:
•
Given the scarcity of published data on patients with
hemophilia and ST-elevation myocardial infarction in
whom early percutaneous coronary intervention is not
available, the WFH recommends careful evaluation of
an individual’s bleeding risk and cardiac disease severity.
•
REMARK: Use of brinolytic therapy may only be
considered aer complete correction of hemostasis
with decient clotting factor replacement.
•
REMARK: e decision on use of brinolytic therapy for
this indication should always be made in consultation
with a cardiologist.
RECOMMENDATION 9.9.13:
• When heart valve replacement is indicated in patients
with hemophilia, a bioprosthetic valve should be the rst
choice to avoid the need for indenite anticoagulation.
Hypercholesterolemia
•
Mean cholesterol levels in patients with hemophilia have
been reported to be lower than in the general population.
Cholesterol levels (total cholesterol, HDL, and LDL fraction)
should be measured in aging patients with hemophilia at
risk of cardiovascular disease.
• Treatment is indicated if cholesterol levels are high. As a
general rule, the total cholesterol/HDL ratio should not
be higher than 8.
RECOMMENDATION 9.9.14:
•
In patients with hemophilia, the management of
hypercholesterolemia should be the same as for the
general population.
Psychosocial issues with aging
•
For aging patients with hemophilia, crippling, painful
arthropathy can aect quality of life and may lead to loss
of independence.
•
Aging patients may be confronted with unexpected
emotional problems due to memories of negative
experiences related to hemophilia (e.g., hospitalization)
during their youth.
• Adaptations at home or at work and an appropriate pain
management regimen are indicated to improve quality of
life and preserve independence.
•
Active psychosocial support should be provided by a social
worker, hemophilia nurse, physician, and/or psychologist.
•
e patient’s annual checkup at the hemophilia treatment
centre is a good time to assess and address changing
needs with age. Refer patients to appropriate services and
resources as needed and as mutually agreed upon.
RECOMMENDATION 9.9.15:
•
As adults with hemophilia experience many personal
and social changes with aging, the WFH recommends
active psychosocial assessments and support for their
changing needs.
Quality of life assessment
•
People with hemophilia may face a variety of psychosocial
issues which may impact their well-being. Quality of life
assessments can help to:
–
identify patient perceptions of their health status and
needs;
–
gather evidence on clinical ndings that can lead to
improved quality of care;
–
serve as a rapid screening to identify individual
patients or populations who might require more
detailed assessment of their health and quality of life
needs; and
WFH Guidelines for the Management of Hemophilia, 3rd edition138
–
identify individual and overall patient needs in terms
of gaps in knowledge and/or education to facilitate
better self-management.
• See also Chapter 11: Outcome Assessment.
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60. Schutgens RE, Klamroth R, Pabinger I, Malerba M, Dolan G,
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61. Schutgens RE, Tuinenburg A, Roosendaal G, Guyomi SH, Mauser-
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62. Hermans C. Venous thromboembolic disease in patients with
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63. Dargaud Y, Meunier S, Negrier C. Haemophilia and thrombophilia: an
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66. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in
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87. Biere-Ra S, Zwiers M, Peters M, et al. e eect of haemophilia and
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SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting
Information section.
141
MUSCULOSKELETAL
COMPLICATIONS
10
Adolfo Llinás
1
| Pradeep M. Poonnoose
2
| Nicholas J. Goddard
3
| Greig Blamey
4
| Abdelaziz Al Sharif
5
|
Piet de Kleijn
6
| Gaetan Duport
7
| Richa Mohan
8
| Gianluigi Pasta
9
| Glenn F. Pierce
10
| Alok Srivastava
11
1
Fundacion Santa Fe de Bogota and Universidad de los Andes, Bogota, Columbia
2
Department of Orthopaedics, Christian Medical College, Vellore, India
3
Department of Trauma and Orthopaedics, Royal Free Hospital, London, UK
4
Adult Bleeding Disorders Clinic, Winnipeg Health Sciences Centre, Winnipeg, Canada
5
Amman, Jordan
6
Van Creveldkliniek, University Medical Center Utrecht, Utrecht, the Netherlands
7
Lyon, France
8
Empowering Minds Society for Research and Development, New Delhi, India
9
Orthopedic and Traumatology Department, Fondazione IRCCS Policlinico San Matteo di Pavia, Pavia, Italy
10
World Federation of Hemophilia, Montreal, QC, Canada
11
Department of Haematology, Christian Medical College, Vellore, India
All statements identied as recommendations are consensus
based, as denoted by
.
10.1 Introduction
•
Hemophilia is characterized by acute bleeds, over 80%
of which occur in specic joints (most commonly the
ankle, knee, and elbow joints, and frequently the hip,
shoulder, and wrist joints) and in particular muscles
(iliopsoas and gastrocnemius). Spontaneous bleeding
may occur depending on the severity of the disease (see
Chapter 2: Comprehensive Care of Hemophilia – Table
2-1), or breakthrough bleeding may occur depending on
the prophylactic treatment approach.
•
In children with severe hemophilia, the rst joint and
muscle bleeds typically occur when they begin to crawl and
walk, usually between 1 and 2 years of age, but sometimes
in later toddler years.
•
Recurrent joint bleeds cause progressive joint damage as a
result of blood accumulation in the joint cavity and synovial
inammation. is leads to complications such as chronic
synovitis and hemophilic arthropathy. For discussion
and recommendations on joint bleeds, see Chapter 7:
Treatment of Specic Hemorrhages and Table 7-2.
•
Inadequate treatment of intramuscular bleeds can lead
to muscle contractures, especially in bi-articular muscles
(e.g., calf and psoas muscles), oen within the rst decades
of life. Other more serious complications such as
compartment syndrome and pseudotumours may also
develop. (See “Clotting factor replacement therapy” and
10.5 Pseudotumours, below.)
•
Prophylaxis to prevent bleeding episodes is considered
the standard of care to the extent that resources permit.
•
Successful treatment to achieve complete functional
recovery generally requires a combination of clotting
factor concentrate (CFC) replacement therapy or other
hemostatic coverage (e.g., bypassing agents for patients
with inhibitors) and physical therapy.
Patient/caregiver education
•
Patient education on musculoskeletal issues in hemophilia
is critical and should encompass joint and muscle health,
recognition and treatment of musculoskeletal bleeds,
pain management, musculoskeletal complications, and
the importance of physical therapy and rehabilitation. A
multidisciplinary approach to addressing the bleed and its
consequences is essential. (See Chapter 2: Comprehensive
Care of Hemophilia.)
10.2 Synovitis
•
Following acute hemarthrosis, the synovium becomes
inamed, hyperemic, and friable. is acute synovitis can
take several weeks to resolve.
•
Failure to manage acute synovitis results in recurrent
hemarthroses and subclinical bleeds; the synovium
becomes chronically inamed and hypertrophic, and the
joint becomes prone to further bleeding. A vicious cycle
WFH Guidelines for the Management of Hemophilia, 3rd edition142
of bleeding, loss of joint motion, and inammation can
ensue which ultimately leads to irreversible cartilage
and bone damage and impaired joint function.
•
If this process exceeds 3 months, it is dened as chronic
synovitis.
•
Regular assessments are required until the joint and synovial
condition are fully rehabilitated, and there is no evidence
of residual blood and/or associated synovitis. Physical
examination for joint changes (e.g., in joint circumference,
muscle strength, joint eusion, joint angle, pain according
to a visual analogue scale) should be conducted at all
routine follow-ups. (See Chapter 11: Outcome Assessment.).
However, in many cases, the synovium never returns to
its original state.
•
Given that clinical signs do not always adequately represent
the actual situation, ultrasound evaluation is advised.
Magnetic resonance imaging (MRI), while currently the
gold standard for imaging, is expensive technology, time-
consuming, and is not feasible for very young children.
RECOMMENDATION 10.2.1:
•
For people with hemophilia, the WFH recommends
regular physical assessment of the synovial condition
aer every bleed, preferably using suitable imaging
techniques such as ultrasound (when feasible) until the
situation is controlled, as clinical assessment alone is
inadequate to detect early synovitis.
Treatment of chronic synovitis
•
e goal of chronic synovitis treatment is to suppress
synovial activation and reduce inammation to preserve
joint integrity and function.
• Nonoperative options include prophylaxis for 6-8 weeks
(for those not on regular prophylaxis), physical therapy,
and selective COX-2 inhibitors to reduce inammation.
RECOMMENDATION 10.2.2:
•
For patients with hemophilia who have chronic
synovitis and no access to regular prophylaxis, the
WFH recommends nonsurgical treatment, including
short-term prophylaxis for 6-8 weeks to control bleeding;
physical therapy to improve muscle strength and joint
function; and selective COX-2 inhibitors to reduce pain
and inammation.
• REMARK: Physical therapy with individualized goals
and exercises based on the patient’s functional level
should start slowly with increasing progression of
weight-bearing activities.
• REMARK: For patients with acute pain and recurrent
bleeding, bracing may stabilize the aected joint and
limit motion, but caution is advised as prolonged
immobilization leads to muscle weakness, so isometric
exercises even within bracing are advised.
•
REMARK: If unresponsive to nonsurgical interventions,
treatment should be escalated to treat the synovitis
directly, by the treatment intervention of the local
expert.
RECOMMENDATION 10.2.3:
•
For patients with hemophilia who have chronic synovitis
(characterized only by minimal pain and loss of range
of motion) the WFH recommends consultation with an
experienced musculoskeletal specialist in a hemophilia
treatment centre.
Physical therapy for synovitis
•
Physical therapy under the direction of a hemophilia
treatment centre is advised throughout the entire
rehabilitation trajectory, with progressive exercises to
build up to full weight bearing and complete functional
recovery. is may include daily exercises to improve
muscle strength and restore joint range of motion.
•
Functional training may commence based on practical
goals for each individual.
•
Bracing may be appropriate to stabilize the aected joint
and limit movement in order to prevent recurrent bleeding
and synovial impingement during movement. (See
Chapter 7: Treatment of Specic Hemorrhages – Joint
hemorrhage – Physical therapy and rehabilitation.)
• In chronic cases that no longer respond to nonoperative
measures, synovectomy/synoviorthesis may be indicated.
Synovectomy/synoviorthesis
•
Synovectomy should be considered if chronic synovitis
persists with frequent recurrent bleeding not controlled
by other means.
•
The procedure can be performed in several ways:
chemical or radioisotope intra-articular injection
(synoviorthesis); arthroscopic synovectomy; or open
surgical synovectomy.
•
Nonsurgical synovectomy should always be the rst
procedure of choice for all patients.
• Radiosynovectomy is indicated for synovitis (conrmed
clinically or by point-of-care ultrasound) causing 2 or
more bleeds in a particular joint over the last 6 months
despite adequate treatment.
Chapter 10: Musculoskeletal Complications 143
•
Radioisotope synovectomy using a pure beta emitter
(phosphorus-32, yttrium-90, rhenium-186, or rhenium-188)
is highly effective, has few side effects, and can be
accomplished in a single outpatient procedure.
•
Choice and dose of radioisotope depend on the joint to
be injected, the condition of its synovium, and available
radioisotopes.
•
Prophylaxis should be administered prior to
radiosynovectomy; one dose of CFC is usually sucient
for a single injection of the radioisotope.
•
Where possible, simultaneous administration of intra-
articular steroids is recommended.
•
e joint should then be rested for at least 24-48 hours
in a splint or other immobilization device, aer which
rehabilitation can commence.
•
Rehabilitation aer radiosynovectomy is less intensive than
aer surgical synovectomy, but it is still required to help
patients regain strength, proprioception, and functional use
of the joint. An individualized rehabilitation program for
at least 3 weeks may be appropriate. Intensive exercise and
weight bearing should be avoided immediately following
radiosynovectomy.
•
The aim of treatment is to reduce synovitis and the
frequency of bleeds, thereby indirectly reducing pain. It has
no eect on articular degeneration. With the improvement
in pain and the reduction of bleeds, the patient may regain
function through appropriate rehabilitation. Pain reduction
typically occurs 1-3 weeks postinjection.
•
e minimum interval between repeated treatments in
the same joint is 6 months.
•
If radioisotopes are not available, chemical synoviorthesis
with either rifampicin or oxytetracycline chlorhydrate may
be considered. Chemical synoviorthesis may be painful, and
the sclerosant injection should be combined with an intra-
articular local anesthetic to minimize pain, supplemented
by oral analgesics (a combination of acetaminophen/
paracetamol and an opioid) as required.
•
Frequent injections may be required; typically, 5-6 weekly
injections are needed until the synovitis is controlled.
RECOMMENDATION 10.2.4:
•
For patients with hemophilia who have unresolved
chronic synovitis, the WFH recommends nonsurgical
synovectomy as a rst-line treatment option using
radioisotope synovectomy with a pure beta emitter
(phosphorus-32, yttrium-90, rhenium-186, or
rhenium-188). One dose of CFC per dose of isotope
should be used.
•
REMARK: Choice of isotope depends on the joint being
injected and isotope availability.
•
REMARK: e joint should be immobilized for at least
24 hours, followed by progressive rehabilitation for
restoration of strength and function.
•
REMARK: When radioisotopes are not available,
chemical synoviorthesis with either rifampicin or
oxytetracycline chlorhydrate (once weekly injection
for 5-6 weeks) is an alternative, accompanied by one
dose of CFC per treatment, a local anesthetic, and oral
analgesics.
•
In cases where chronic synovitis is resistant to treatment
with radiosynovectomy, selective embolization of the blood
vessels that supply the synovium may be performed. is
procedure is to be performed only in specialized medical
imaging centres.
•
Surgical synovectomy may be considered when other less
invasive procedures have failed or when an additional
procedure is required that must be performed through
arthroscopy such as removal of a tibial anterior osteophyte
of the ankle.
•
Arthroscopic synovectomy is suggested over open
synovectomy.
•
If surgical synovectomy (either open or arthroscopic) is
necessary, ensure longer prophylaxis coverage with CFCs
or other appropriate hemostatic agents sucient for the
procedure and postoperative rehabilitation. e procedure
must be performed by an experienced team at a dedicated
hemophilia treatment centre.
RECOMMENDATION 10.2.5:
•
For patients with hemophilia who have chronic synovitis
that no longer responds to nonoperative interventions,
the WFH recommends surgical synovectomy (preferably
arthroscopic, not open) only by an experienced team
in a hemophilia treatment centre.
•
See also Chapter 7: Treatment of Specic Hemorrhages
– Table 7-2; Chapter 8: Inhibitors to Clotting Factor –
Hemophilia A/Hemophilia B – Surgery and invasive
procedures; and Chapter 9: Specic Management Issues
– Surgery and invasive procedures.
10.3 Hemophilic arthropathy
•
Hemophilic arthropathy can result from a single bleed
or recurrent bleeds. It generally evolves gradually from
WFH Guidelines for the Management of Hemophilia, 3rd edition144
hemarthrosis to chronic synovitis and extended erosions of
the articular surface, culminating in the nal stage of joint
destruction, chronic hemophilic arthropathy, which oen
manifests during the second decade of life, particularly if
prophylactic therapy is unavailable or inadequate.
•
Muscle bleeds can result in joint deformity and contracture,
particularly with bleeds within the psoas muscle or
gastrocnemius. Fixed exion contractures result in loss
of motion and signicant functional impairment and thus
need to be prevented.
•
As the arthropathy worsens, range of motion and swelling
of the joint oen subside due to progressive brosis of the
synovium and capsule. As the joint becomes ankylosed
(stiened), pain may diminish or disappear.
•
e appropriate radiographic technique for assessing
chronic hemophilic arthropathy depends on the stage of
progression.
•
MRI is useful to assess early arthropathy and will show
early so tissue and osteochondral changes.
•
Ultrasound imaging is useful for assessing so tissue
and peripheral cartilage pathology in early hemophilic
arthropathy.
• Plain radiographs are insensitive to early change and are
used to assess late arthropathic changes.
• See Chapter 11: Outcome Assessment.
Treatment of chronic hemophilic arthropathy
•
e goals of treatment are to reduce the incidence of
hemarthroses, improve joint function, relieve pain, and
help the patient continue or resume normal activities of
daily living.
•
Treatment options for chronic hemophilic arthropathy
depend on many factors including:
–
the stage of the condition;
–
the patient’s symptoms;
–
the patient’s age;
–
the impacts on the patient’s lifestyle and functional
abilities;
–
the resources available.
• Pain should be controlled with appropriate analgesics.
•
See Chapter 2: Comprehensive Care of Hemophilia – Pain
management.
Physical therapy for hemophilic arthropathy
•
Physical therapy aimed at preserving muscle strength and
functional ability is an essential component of treatment
of chronic hemophilic arthropathy.
•
e intensity of physical therapy should be increased
gradually and adapted according to prophylaxis coverage;
physical therapy should be less intense in patients with
limited access to CFC replacement.
• In settings with limited resources and factor availability,
physical therapy without factor coverage may be performed
if the treatment is coordinated by an experienced
multidisciplinary team with musculoskeletal expertise.
•
Intermittent prophylaxis coverage may be necessary
if breakthrough bleeding occurs as a result of physical
therapy. Other modes of therapy such as exercise therapy,
manual therapy, electrotherapy, and hydrotherapy have
been used to complement physical therapy.
RECOMMENDATION 10.3.1:
•
For the prevention and treatment of chronic hemophilic
arthropathy in people with hemophilia, the WFH
recommends a combination of regular replacement
therapy to reduce frequency of bleeding and physical
therapy aimed at preserving muscle strength and
functional ability. Physical therapy may be done with
or without factor coverage, depending on availability
and the patient’s response to therapy.
• Other conservative management techniques include:
–
serial casting to correct deformities;
–
traction devices;
–
bracing and orthotics to support painful and
unstable joints;
–
walking aids or mobility aids to decrease stress on
weight-bearing joints;
–
adaptations to the home, school, or work
environment to allow participation in community
activities and employment, and to facilitate activities
of daily living.
RECOMMENDATION 10.3.2:
•
For the prevention and treatment of the sequelae of
joint arthropathy in people with hemophilia, the WFH
recommends nonsurgical measures such as bracing,
orthotics, mobility aids, and serial casting and traction
devices to aid in the correction of exion contractures.
is may be done with or without factor coverage.
Surgical interventions
•
If nonsurgical measures fail to provide satisfactory pain
relief and improved function, surgical intervention may
be necessary.
•
Surgical procedures, depending on the specic condition,
may include:
–
synovectomy and joint debridement, if required;
Chapter 10: Musculoskeletal Complications 145
–
arthroscopy to release intra-articular adhesions
and correct impingement, especially in the ankle or
elbow joint;
–
extra-articular so tissue release to treat
contractures;
–
osteotomy to correct angular deformity;
–
external xators to assist in deformity correction;
–
prosthetic joint replacement (knee, hip, shoulder,
elbow, or ankle);
–
radial head excision for select patients with
radiocapitellar arthropathy;
–
arthrodesis for painful ankle joint arthropathy.
•
Adequate resources, including prophylaxis (e.g., sucient
supply of CFCs) and postoperative rehabilitation, must be
available to support and increase the likelihood of success
of any surgical procedure.
RECOMMENDATION 10.3.3:
•
For patients with hemophilia with chronic hemophilic
arthropathy for whom nonsurgical measures have
failed to provide satisfactory pain relief and improved
function, the WFH recommends consultation with an
orthopedic specialist on surgical intervention options
which may include:
–
synovectomy and joint debridement;
–
arthroscopy to release intra-articular adhesions
and correct impingement;
–
extra-articular so tissue release to treat
contractures;
–
osteotomy to correct angular deformity;
–
arthrodesis (of the ankle);
–
joint replacement in end-stage arthritis.
•
REMARK: Adequate resources including a sucient
supply of CFCs or other appropriate hemostatic agents
(e.g., bypassing agents for patients with inhibitors) and
postoperative rehabilitation services must be available
to increase the likelihood of success for any surgical
procedure.
•
See also Chapter 7: Treatment of Specic Hemorrhages
– Joint hemorrhage and Table 7-2; Chapter 8: Inhibitors
to Clotting Factor – Hemophilia A/Hemophilia B –
Surgery and invasive procedures; and Chapter 9: Specic
Management Issues – Surgery and invasive procedures.
10.4 Muscle hemorrhage
•
Bleeds may occur in any muscle of the body, oen as a
result of injury or a sudden stretch.
•
A muscle bleed is dened as an episode of bleeding into a
muscle, determined clinically and/or by imaging studies.
It is generally associated with pain and/or swelling and
functional impairment, e.g., a limp associated with a calf
bleed.
•
Early identication and proper management of muscle
bleeds are important to prevent permanent contracture, re-
bleeding, and possible later formation of pseudotumours.
• Symptoms of a muscle bleed include:
–
discomfort in the muscle and maintenance of the
limb in a position of comfort;
–
severe pain if the muscle is actively contracted or
stretched;
–
tension and tenderness upon palpation; and
–
swelling.
•
Sites of muscle bleeding that are associated with
neurovascular compromise, such as the deep exor muscle
groups of the limbs, require immediate management to
prevent permanent damage and loss of function. ese
groups include:
–
the iliopsoas muscle (risk of femoral nerve palsy);
–
the supercial and deep posterior compartments
of the lower leg (risk of posterior tibial and deep
peroneal nerve injury); and
–
the exor group of forearm muscles (risk of
Volkmann’s ischemic contracture).
•
Bleeding can also occur in more supercial muscles such
as the biceps, hamstrings, quadriceps, and gluteal muscles.
•
ere is emerging evidence that suggests musculoskeletal
ultrasound (MSKUS) may be useful in dierentiating
between muscle bleeds and other regional pain
syndromes. Nonetheless, if a patient or clinician
suspects a muscle bleed or has diculty assessing whether
a bleed is in progress, hemostatic treatment is advised
immediately before performing conrmatory investigations
or awaiting such results.
Clotting factor replacement therapy
•
An untreated muscle bleed can result in compartment
syndrome (a deep muscle bleed within a closed space)
with secondary neurovascular and tendon damage and
muscle contracture and necrosis. In addition, an injured
muscle that is not properly rehabilitated can exert secondary
eects on the adjacent joints.
WFH Guidelines for the Management of Hemophilia, 3rd edition146
• e best practice to achieve the best outcomes is to treat
muscle bleeds with CFC immediately, ideally when the
patient recognizes the rst signs of discomfort or right
aer trauma, to raise the patient’s factor level to stop the
bleed. Factor replacement therapy should continue until
bleeding symptoms and signs resolve, generally for 5-7
days or longer, if symptoms indicate recurrent bleeding
or worsening neurovascular symptoms. (See Chapter
7: Treatment of Specic Hemorrhages – Table 7-2.)
•
Repeat infusions are oen required, particularly if there
is a potential risk of compartment syndrome and/or if
extensive rehabilitation is required.
•
See Chapter 8: Inhibitors to Clotting Factor for the
management of bleeds in patients with inhibitors.
RECOMMENDATION 10.4.1:
•
All hemophilia patients with muscle bleeds should be
given clotting factor replacement therapy immediately
and, where applicable, be observed for neurovascular
complications associated with the bleed.
Clinical monitoring and management
•
It is important to monitor the patient continuously for
possible compartment syndrome. Symptoms of possible
compartment syndrome include increasing pain, loss of
sensation, loss of function, and poor blood supply in the
distal area. If in doubt, measure the compartment pressure.
•
Pain should be assessed frequently and regularly, as it is
an indirect measure of compartment pressure.
•
Acute muscle bleeds may require escalating the analgesia
protocol to obtain relief. (See Chapter 2: Comprehensive
Care of Hemophilia – Pain management.)
•
In addition to factor replacement therapy or other
appropriate hemostatic therapy, clinicians may apply the
following measures as adjunctive management of acute
muscle bleeds:
–
Rest the injured muscle.
–
Where possible, elevate the aected area; this may
help to reduce the associated swelling.
–
If appropriate, splint the aected limb in a position
of comfort and adjust to a position of function as
pain subsides.
–
Apply ice/cold packs around the muscle for 15-20
minutes every 4-6 hours for pain relief. Do not apply
the ice directly on the skin.
•
See also “Physical therapy and rehabilitation for muscle
bleeds” below.
RECOMMENDATION 10.4.2:
•
For all hemophilia patients with muscle bleeds, the WFH
recommends detailed clinical assessment, grading, and
monitoring of pain according to the WHO pain scale, as
muscle bleed pain may be an early indicator of reversible
neurovascular and tissue damage.
•
REMARK: While many pain assessment scales exist, use
of the WHO pain scale is preferred because it is a simple
and universal tool that permits uniform measurement of
pain in people with hemophilia and generates comparable
population-level outcome data important to advancing
hemophilia treatment and research.
Compartment syndrome
•
Neurovascular compromise is a musculoskeletal
emergency and requires direct, continuous observation
and monitoring of the need for fasciotomy. Prophylaxis
should be administered to raise and maintain factor levels
for 5-7 days or longer as symptoms indicate, along with
physical therapy and rehabilitation to restore baseline
muscle function. (See Chapter 7: Treatment of Specic
Hemorrhages – Table 7-2.)
•
If compartment syndrome is suspected on clinical
grounds, measure the compartment pressure. If conrmed,
fasciotomy should be performed within 12 hours of onset of
the compartment syndrome. Late fasciotomy has a very
high incidence of complications and is contraindicated.
•
Earlier fasciotomy is associated with improved patient
outcomes, including decreased muscle and nerve injury.
Once a motor nerve decit has occurred, patients rarely
recover fully aer fasciotomy.
•
In patients with hemophilia, if there is uncertainty
regarding the adequacy of hemostatic response, as may
occur in patients with high-responding inhibitors, a longer
observation period may be warranted to possibly avoid
fasciotomy and the risk of uncontrolled bleeding aer the
procedure. However, any delay in performing fasciotomy
once compartment syndrome is established may lead to
suboptimal outcomes in muscle recovery and subsequent
loss of function.
RECOMMENDATION 10.4.3:
•
In hemophilia patients with muscle bleeds with
evidence of compartment syndrome and neurovascular
compromise, a fasciotomy is required within 12 hours
from the time of onset of symptoms before irreversible
damage sets in due to tissue necrosis.
Chapter 10: Musculoskeletal Complications 147
Physical therapy and rehabilitation for muscle
bleeds
•
Physical therapy should begin as soon as pain subsides
and should be progressed gradually to restore full muscle
length, strength, and function. Supervised physical
therapy and rehabilitation directed by a physical therapist
experienced in hemophilia management should be initiated:
–
Ensure appropriate prophylaxis coverage during
physical therapy and rehabilitation. In settings with
limited resources and factor availability, physical
therapy without factor coverage may be performed
during the rehabilitation period if the treatment is
coordinated by an experienced multidisciplinary
team with musculoskeletal expertise.
–
Use serial casting or splinting as required to correct
any contracture.
–
Use supportive bracing if there has been nerve
damage.
–
Regularly evaluate the patient for pain during
physical therapy, which may suggest re-bleeding.
Iliopsoas hemorrhage
•
Iliopsoas hemorrhages can potentially lead to
musculoskeletal damage; therefore, early and eective
factor replacement therapy or other appropriate hemostatic
therapies are essential to minimize and prevent the related
complications.
•
An iliopsoas hemorrhage has a particular presentation that
can sometimes be misleading. Signs may include pain in
the lower abdomen, groin, and/or lower back, with inability
to straighten or stand up from a seated position; and pain
on extension, but not on rotation, of the hip joint. e
symptoms of iliopsoas hemorrhage may mimic those of
acute appendicitis, including a positive Blumberg’s sign
(rebound tenderness). It can also be mistaken for a hip
joint bleed.
•
ere may be paresthesia in the medial aspect of the thigh
or other signs of femoral nerve compression, such as loss
of the patellar tendon reex, quadriceps weakness, and
ultimately muscle wasting.
•
Patients with an iliopsoas bleed may need to be hospitalized
for observation and pain control.
•
Strict bed rest may be indicated. Ambulation with crutches
should be avoided as muscle contractions may exacerbate
pain and bleeding.
• It is useful to conrm the diagnosis and monitor patient
recovery using imaging studies (ultrasound, CT scan,
or MRI).
•
Physical activity should be restricted until pain resolves and
hip extension improves. A carefully supervised program
of physical therapy is essential to restore complete hip
extension and full activity and function, and prevent
re-bleeding.
•
If residual neuromuscular decits persist, further orthotic
support may be necessary, particularly to prevent exion
of the knee due to quadriceps weakness.
•
See also Chapter 7: Treatment of Specic Hemorrhages
– Table 7-2, and Chapter 8: Inhibitors to Clotting Factor.
10.5 Pseudotumours
•
A pseudotumour is a potentially limband life-threatening
condition unique to hemophilia.
•
It develops as a result of inadequately treated so tissue
bleeds, usually in muscle adjacent to bone, which can be
secondarily involved.
•
If untreated, a pseudotumour can become massive, causing
pressure on the adjacent neurovascular structures and
possibly resulting in pathologic fractures.
• A stula can develop through the overlying skin.
•
Pseudotumours may be assessed and serially followed up
using ultrasound imaging.
•
A more detailed and accurate evaluation of a pseudotumour
can be obtained with a CT scan and MRI.
RECOMMENDATION 10.5.1:
•
For hemophilia patients with so tissue bleeding and
signs of a possible pseudotumour, the WFH recommends
clinical assessment and radiological conrmation using
X-ray, ultrasound, and magnetic resonance imaging,
as appropriate.
•
REMARK: While ultrasound is useful for serial
assessment of a so tissue pseudotumour, MRI provides
more detailed information prior to surgical intervention.
•
REMARK: A CT scan or CT angiogram may be indicated,
especially for a large pseudotumour and/or pre-operative
planning.
•
Management of a pseudotumour depends on its site, size,
growth rate, and eect on adjoining structures. Options
include factor replacement therapy and monitoring,
aspiration, radiation, surgical excision, and surgical ablation.
•
For small early pseudotumours, a short course (6-8 weeks)
of factor replacement therapy can be attempted, and the
pseudotumour can be monitored using serial ultrasound
screening. If the pseudotumour is shown to be shrinking,
WFH Guidelines for the Management of Hemophilia, 3rd edition148
continue factor replacement therapy in combination with
repeat ultrasound evaluation for 4-6 months. (See
Chapter 7: Treatment of Specic Hemorrhages – Table 7-2.)
RECOMMENDATION 10.5.2:
•
For patients with hemophilia who have developed small
early pseudotumours (prior to acquiring a pseudocapsule)
and have no access to regular prophylaxis, the WFH
recommends a short course (6-8 weeks) of clotting
factor replacement therapy with possible continuation
of therapy if serial ultrasound evaluations indicate that
the pseudotumour is shrinking, with repeat evaluation
aer 4-6 months.
•
e management of pseudotumours is complex and
associated with a high rate of potential complications.
erapeutic alternatives include embolization, radiation,
percutaneous management, surgical removal, and lling
of the dead cavity.
•
Aspiration of the pseudotumour followed by injections of
brin sealant, arterial embolization, or radiotherapy may
heal some smaller lesions.
•
Surgical excision may be necessary for large pseudotumours.
Removal of the pseudotumour with the pseudocapsule—
rather than evacuation of the hematoma—is required.
•
Surgical resection of large abdominal/pelvic pseudotumours,
which present a special challenge in the surgical
management of hemophilia, must only be performed by
a surgical team with experience in hemophilia. Preoperative
embolization has been found to be useful in excision of
these large tumours.
RECOMMENDATION 10.5.3:
•
For patients with hemophilia who have developed
large pseudotumours, the WFH recommends surgical
excision of the pseudotumour with the pseudocapsule,
performed only by a surgical team with experience in
hemophilia, in a hemophilia treatment centre wherever
possible, followed by close monitoring and long-term
prophylaxis to prevent recurrence of bleeding.
•
REMARK: Fluctuations in factor levels during the
rst postoperative year may increase the likelihood
of bleed recurrence. erefore, close monitoring and
optimal correction of factor levels are of paramount
importance.
•
See also Chapter 7: Treatment of Specic Hemorrhages
– Table 7-2; Chapter 8: Inhibitors to Clotting Factor –
Hemophilia A/ Hemophilia B – Surgery and invasive
procedures; and Chapter 9: Specic Management Issues
– Surgery and invasive procedures.
10.6 Fractures
•
Fractures are not frequent in patients with hemophilia
despite a high incidence of osteopenia and osteoporosis,
possibly due to lower levels of ambulation and intensity
of activities.
• However, a patient with hemophilic arthropathy may be
at risk for fractures around a joint with signicant loss of
motion and in bones that are osteoporotic.
•
Treatment of a fracture requires immediate factor
replacement therapy. Ideally, patients should be on
continuous prophylaxis (e.g., high doses of CFC) and
factor levels of at least 50 IU/ dL should be maintained
for at least a week. Subsequently, lower levels may
be maintained for 10-14 days while the fracture becomes
stabilized and to prevent so tissue bleeding. (See Chapter
7: Treatment of Specic Hemorrhages – Table 7-2.)
RECOMMENDATION 10.6.1:
•
For people with hemophilia who incur fractures, the WFH
recommends immediate treatment with clotting factor
concentrates or other hemostatic agents, and continued
treatment to maintain suciently high factor levels for
bleed control for a week or longer, depending on the
likelihood of bleeding due to fracture site or stability.
Subsequently, lower factor levels may be maintained
for 10-14 days to prevent so tissue bleeding while the
fracture becomes stabilized. Clinical monitoring is
paramount due to the risk of compartment syndrome.
• e management plan should be devised for the specic
fracture and include appropriate prophylaxis coverage if
surgical procedures are necessary.
•
Avoid full circumferential plaster and split casts if possible,
especially in the early stages; splints are preferred.
Monitoring, especially of forearm fractures, is mandatory
in order to avoid complications such as compartment
syndrome.
• Consider external xators for open/infected fractures.
•
Avoid prolonged immobilization if possible as it can lead
to signicant limitation of range of motion in the adjacent
joints.
•
Arrange for physical therapy as soon as the fracture is
stabilized to restore range of motion, muscle strength,
and function.
Chapter 10: Musculoskeletal Complications 149
RECOMMENDATION 10.6.2:
•
For people with hemophilia who incur fractures, the WFH
recommends splints over full casts to avoid compartment
syndrome (especially in the early stages), and external
xators for open or infected fractures.
RECOMMENDATION 10.6.3:
•
For people with hemophilia who incur fractures, the WFH
recommends avoiding prolonged immobilization and
advises supervised physical therapy and rehabilitation
as soon as the fracture is stabilized to restore range of
motion, muscle strength, and function.
•
See also Chapter 7: Treatment of Specic Hemorrhages
– Table 7-2; Chapter 8: Inhibitors to Clotting Factor –
Hemophilia A/ Hemophilia B – Surgery and invasive
procedures; and Chapter 9: Specic Management Issues
– Surgery and invasive procedures.
10.7 Orthopedic surgery in hemophilia
•
For patients with hemophilia undergoing orthopedic
surgery, best results are achieved in dedicated hemophilia
centres where skillful multidisciplinary teams are prepared
to manage these patients using tailored approaches.
•
Multiple-site elective surgery with simultaneous or staggered
procedures may simultaneously allow for a more expedient
recovery of gait and overall function, as well as for judicious
use of factor replacement therapy or other hemostatic
agents. (See Chapter 7: Treatment of Specic Hemorrhages
– Table 7-2.)
•
Use of local coagulation enhancers may be appropriate.
Wound inltration with local anesthetic agents (lignocaine/
lidocaine and/or bupivacaine) with an adrenaline and brin
sealant/spray is useful to control oozing when operating
in extensive surgical elds.
•
Postoperative care in patients with hemophilia requires, in
addition to factor replacement therapy (continuous infusion
preferred) or other prophylaxis, close monitoring of pain,
and oen higher doses of analgesics in the immediate
postoperative period.
•
Good communication with the postoperative rehabilitation
team is essential. Knowledge of the details of the surgery
performed and intra-operative joint status will facilitate
planning of an appropriate rehabilitation program.
•
As part of comprehensive care, both pre- and postoperative
physical therapy is needed to achieve optimal functional
outcome.
RECOMMENDATION 10.7.1:
•
For patients with hemophilia requiring orthopedic
surgery, especially in cases where oozing is present at
closure as well as dead space or cavities, the WFH suggests
the use of local coagulation enhancers and wound
inltration with local anesthetic agents (lignocaine/
lidocaine and/or bupivacaine) with an adrenaline and
brin sealant or spray to control blood oozing when
operating in extensive surgical elds.
RECOMMENDATION 10.7.2
•
For patients with hemophilia requiring orthopedic
surgery, the WFH recommends factor replacement
therapy and close pain control and monitoring, with
higher doses of analgesics in the immediate postoperative
period.
RECOMMENDATION 10.7.3:
•
For patients with hemophilia in the postoperative period
following orthopedic surgery, the WFH recommends
gradual rehabilitation by a physical therapist experienced
in hemophilia management.
•
See also Chapter 7: Treatment of Specic Hemorrhages
– Table 7-2; Chapter 8: Inhibitors to Clotting Factor –
Hemophilia A/ Hemophilia B – Surgery and invasive
procedures; and Chapter 9: Specic Management Issues
– Surgery and invasive procedures.
10.8 Joint replacement
•
Joint replacement is indicated in cases of established
hemophilic arthropathy with associated pain and functional
impairment not responsive to nonsurgical or other surgical
treatments.
•
Joint replacement should be performed only in recognized
hemophilia treatment centres with experienced orthopedic
surgeons and appropriate hematological and laboratory
support.
•
Such centres will have a multidisciplinary team including
a nurse, social worker, and physical therapist familiar
with the requirements of hemophilia patients undergoing
arthroplasty.
Hemostasis during the perioperative period
•
Meticulous hemostasis is critical for the success of the
surgical procedure. e specic plasma factor levels needed
during dierent phases of surgery are described in Chapter
WFH Guidelines for the Management of Hemophilia, 3rd edition150
7: Treatment of Specic Hemorrhages – Table 7-2. Some
centres use continuous infusion of factor replacement
therapy, particularly during the rst 72 hours, which more
consistently maintains a protective factor trough level.
•
e use of perioperative antibrinolytics and brin sealants
has been shown to reduce blood loss. However, there is no
consensus on the duration of postoperative treatment.
•
There is usually no need for deep vein thrombosis
prophylaxis in those undergoing arthroplasty under
factor coverage unless very high plasma levels are
maintained during the postoperative period. (For venous
thromboembolism and thromboprophylaxis considerations
for surgery, see Chapter 9: Specic Management Issues –
Surgery and invasive procedures.)
Surgical considerations
•
In the knee, there is oen an anteroposterior/medio-lateral
mismatch, which should be anticipated. Occasionally,
a custom implant may be required. Signicant angular
deformity, patellar subluxation, and posterior subluxation
of the tibia are oen encountered, all of which may require
extensive so tissue release.
•
Bilateral simultaneous knee replacement has been
recommended in some instances, and consideration
should be given to undertaking additional procedures if
indicated.
•
e principles of knee replacement are the same as in the
general population. Most oen, posterior-stabilized implants
or implants with stems and augments for associated bony
defects are used.
•
Antibiotic-loaded cement should be used in all cases where
cement xation is performed.
• Wound closure should be meticulous.
• ere is no consensus on the use of drains.
•
ere is no consensus on the best type of xation for hip
replacement.
Postoperative physical therapy
•
Physical therapy should be started as soon as possible,
ideally on the day of the surgery. erapy sessions need
to focus on regaining body functions such as range of
motion and muscle strength before increasing functional
training and endurance.
•
To prevent the formation of joint adhesions, early
mobilization and dedicated work on regaining motion
are critical. During this phase, attention to delayed
wound and tissue healing and risks for re-bleeds is also
required. Functional rehabilitation should be the goal,
but only when all possible body functions are restored.
•
Physical therapists at the hemophilia treatment centre
are generally the best resource for devising a safe and
comprehensive outpatient program. Alternatively, the
hemophilia physical therapist can contact a physical
therapist in the patient’s community to arrange for
postoperative care.
RECOMMENDATION 10.8.1:
•
For patients with hemophilia, the WFH recommends
joint replacement only in cases of established hemophilic
arthropathy that is not responsive to nonsurgical or
other surgical treatments, and that is accompanied by
associated pain, functional impairment, and loss of
participation in activities of daily living.
•
REMARK: Perioperatively, tranexamic acid and brin
sealants may be used to reduce blood loss.
•
REMARK: Physical therapy should ideally start on the
day of surgery with early mobilization and appropriately
progressive exercises to regain motion and muscle
strength.
Complications and long-term considerations
•
Patients with hemophilia tend to have less favourable knee
functional scores and more postoperative complications
following knee replacement, compared to the general
population. is is mainly due to complicating factors
and multijoint involvement.
•
Knee surgery should not be delayed for too long, as
preoperative exion deformity has a signicant eect on
postoperative outcome. Knees with exion deformity of
more than 25 degrees have a higher risk of a poor outcome
and of developing postoperative exion deformities.
•
Historically, infection rates following arthroplasty in
hemophilia patients were higher than those seen in the
general population. However, these infection rates have
decreased over the past decade. Today, they are reported
to be almost the same as in the general population.
•
Patients with hemophilia are at a higher risk of contracting
a delayed secondary infection.
•
Patients with HIV or HCV infection may have a higher
risk for prosthetic joint infection.
•
e long-term survival of joint replacement implants may
be the same as in the general population, depending on
the level of expertise of the hemophilia care team, the
type of implant used, and the severity of musculoskeletal
disease of the joint.
•
See also Chapter 8: Inhibitors to Clotting Factor –
Hemophilia A/ Hemophilia B – Surgery and invasive
procedures, and Chapter 9: Specic Management Issues
– Surgery and invasive procedures.
Chapter 10: Musculoskeletal Complications 151
10.9 Psychosocial impacts of
musculoskeletal complications
•
Despite great strides in hemophilia care in recent years,
people with hemophilia continue to face psychosocial
challenges with hemophilia-related musculoskeletal
complications. In particular, this aects those who grew
up prior to prophylaxis and those who do not have access
to prophylaxis.
• A study of people with moderate and severe hemophilia
found that those with more significant arthropathy
experienced a lower quality of life, especially in the physical
domain.
•
Psychosocial limitations from hemophilic arthropathy
may be compounded by:
–
gait changes;
–
multiple joints being aected;
–
chronic pain.
• e psychosocial impacts of these compounding factors
may result in:
–
lost time from school or work;
–
limitations in sports participation;
–
decreased socialization and/or increased isolation;
–
negative self-perceptions related to body image,
masculinity, and/or self-esteem;
–
lack of a sense of normalcy;
–
limited physical exibility with sexual positioning;
–
challenges in personal relationships;
–
role loss and/or role changes;
–
increase in fatigue;
–
negative coping behaviours.
•
In people with hemophilia, disability from joint disease
frequently occurs at an earlier age than in the general
population and may impair their ability to perform reliably
in the workplace. is may cause individuals to retire
earlier than planned, result in unwanted role loss or shis
in all aspects of life, and negatively impact nances.
•
Psychosocial interventions should be tailored to meet
the specic circumstances and needs of each individual,
including their physical, emotional, social, educational,
and cultural needs.
•
Individual psychosocial intervention strategies may be
aimed at helping individuals adapt to pain and functional
impairment and develop coping strategies such as:
–
identifying/recognizing stressors and strengths;
–
partializing concerns (i.e., setting goals and priorities
and developing strategies to address issues one by
one);
–
examining options;
–
seeking information;
–
strengthening support systems;
–
communicating eectively;
–
reframing the situation;
–
using distraction techniques;
–
using coping self-statements.
•
Psychosocial intervention strengthens patient resilience
by fostering self- and health ecacy, cognitive exibility,
hardiness, optimism, and self-advocacy.
•
Peer mentoring and group learning opportunities help
foster support, reduce isolation, enhance receptivity to
information, and strengthen resilience.
RECOMMENDATION 10.9.1:
•
For patients with hemophilia who have chronic
musculoskeletal pain or functional limitations, the
WFH recommends psychosocial interventions tailored
to meet the specic needs of each individual based
on their physical, emotional, social, educational, and
cultural circumstances.
RECOMMENDATION 10.9.2:
•
For patients with hemophilia who have chronic
musculoskeletal pain or functional limitations, the
WFH recommends specic individualized psychosocial
assessments and intervention strategies aimed at
achieving better quality of life, including psychosocial
counselling, educational and employment counselling,
and nancial planning.
RECOMMENDATION 10.9.3:
•
For patients with hemophilia who have chronic
musculoskeletal pain or functional limitations, the
WFH recommends the promotion of support networks,
peer mentoring, and group educational opportunities
to support their ability to cope with musculoskeletal
complications, reduce social isolation, and strengthen
resilience.
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60. Caviglia HA, Landro ME, Salgado P, Douglas Price AL, Daunchio
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61. Ceponis A, Wong-Sedan I, Glass CS, von Drygalski A. Rapid
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62. Kidder W, Nguyen S, Larios J, Bergstrom J, Ceponis A, von Drygalski
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63. Stephensen D, Drechsler WI, Scott OM. Inuence of ankle
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64. Ashrani AA, Osip J, Christie B, Key NS. Iliopsoas haemorrhage
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65. Balkan C, Kavakli K, Karapinar D. Iliopsoas haemorrhage in
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66. Fernandez-Palazzi F, Hernandez SR, De Bosch NB, De Saez AR.
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67. Singleton T, Kruse-Jarres R, Leissinger C. Emergency department care
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68. Lobet S, Hermans C, Lambert C. Optimal management of hemophilic
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70. Beyer R, Ingerslev J, Sorensen B. Current practice in the management of
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71. Railton GT, Aronstam A. Early bleeding into upper limb muscles in
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75. Sheridan GW, Matsen FA 3rd. Fasciotomy in the treatment of the acute
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77. Beeton KE, Rodríguez-Merchan C, Alltree J, Cornwall J. Rehabilitation
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80. Rodriguez-Merchan EC. e haemophilic pseudotumour. Int Orthop.
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81. Alcalay M, Deplas A. Rheumatological management of patients with
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83. Rodriguez-Merchan EC. Bone fractures in the haemophilic patient.
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85. Mortazavi SM, Heidari P. Retrograde intramedullary nailing of
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97. Bae DK, Yoon KH, Kim HS, Song SJ. Total knee arthroplasty in
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SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting
Information section.
155
OUTCOME
ASSESSMENT
11
Pradeep M. Poonnoose
1
| Brian M. Feldman
2
| Piet de Kleijn
3
| Manuel A. Baarslag
4
|
Radoslaw Kaczmarek
5
| Johnny Mahlangu
6
| Margaret V. Ragni
7
| Glenn F. Pierce
8
| Alok Srivastava
9
1
Department of Orthopaedics, Christian Medical College, Vellore, India
2
Department of Paediatrics, University of Toronto, Division of Rheumatology, Hospital for Sick Children, Toronto, ON, Canada
3
Van Creveldkliniek, University Medical Center Utrecht, Utrecht, the Netherlands
4
Bemmel, the Netherlands
5
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
6
Department of Molecular Medicine and Haematology, University of the Witwatersrand, National Health Laboratory Service,
Johannesburg, South Africa
7
Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
8
World Federation of Hemophilia, Montreal, QC, Canada
9
Department of Haematology, Christian Medical College, Vellore, India
All statements identied as recommendations are consensus
based, as denoted by
.
11.1 Introduction
•
In order to optimize treatment and make economically
sound clinical decisions, objective evidence of both short-
and long-term outcomes of treatment regimens is required.
•
Outcome refers to the condition of a patient that results
from a disease or medical intervention. It is assessed by
clinical evaluation including the use of generic and disease-
specic health-related quality of life (HRQoL) assessment
instruments, measures of patient-reported outcomes
(PROs), and laboratory tests including imaging studies.
ese instruments measure a variety of parameters including
activities and participation, body structure and function,
burden of disease, and subjective health status, as described
later in this chapter.
•
Both generic and hemophilia-specific assessment
instruments make it possible to evaluate the nature of
the physical impairments and functional limitations and
their impacts on the lives of people with hemophilia and
their families.
• e increasing use of these instruments will standardize
assessment and permit comparison of data between
individuals and cohorts.
Purposes of outcome assessment
•
Outcome assessment may be used to follow an individual’s
disease course, obtain information to guide routine clinical
care, measure response to therapy, and determine whether
there is a need to modify therapy. Outcome assessment may
also be used to quantify the health of a group of patients,
measure quality of care, and advocate for resources.
•
In addition, outcome assessment may be used for research
purposes such as to document the natural history of the
disease, test new therapies, or compare dierent therapies.
•
Health outcome research may be used to inform decisions
regarding expenditures on treatment.
11.2 Outcome assessment in hemophilia
•
Outcome assessment in hemophilia should cover two
aspects: disease-related and therapy-related outcomes.
•
Disease-related outcomes pertain to the eectiveness of
hemostatic therapy and are reected in outcomes such as:
–
frequency of bleeding; and
–
impact of bleeding on the musculoskeletal system
and other systems in the short and long term,
including the psychosocial impact of hemophilia.
•
erapy-related outcomes need to be monitored using
a prospective and systematic plan and should include
screening and testing of people with hemophilia treated
with clotting factor concentrates (CFCs) for inhibitor
development. (See Chapter 8: Inhibitors to Clotting Factor.)
•
Other less common complications of CFC replacement
therapy include thrombosis and allergic/anaphylactic
reactions. (See Chapter 9: Specic Management Issues.)
WFH Guidelines for the Management of Hemophilia, 3rd edition156
Frequency of bleeding
•
Frequency of bleeding (particularly joint and muscle
bleeds) and response to treatment have been the most
important indicators of the eectiveness of hemostatic
therapy and the best surrogate predictors of long-term
musculoskeletal outcomes.
•
All bleeds must be documented by patients/caregivers in
real time as they occur using manual or electronic diaries
or other reporting systems, and analyzed periodically
(at least once a year) by their hemophilia treater using a
standard protocol. (See Chapter 2: Comprehensive Care
of Hemophilia – Home therapy – Self-management.)
•
In particular, bleeding into the central nervous system
(CNS) requires documentation because of its potential
impact on neurological and musculoskeletal functions.
•
Given the potential diculties in clinical determination
of joint and muscle bleeding and to bring consistency into
documenting this important parameter, criteria dened
by the Scientic and Standardization Committee of the
International Society on rombosis and Haemostasis
should be followed.
•
A joint bleed is dened as an unusual sensation “aura”
in the joint, in combination with any of the following:
–
increasing swelling or warmth of the skin over the
joint;
–
increasing pain; or
–
progressive loss of range of motion or diculty in
using the limb as compared with baseline.
•
A muscle bleed is dened as an episode of bleeding into a
muscle, determined clinically and/or by imaging studies,
generally associated with pain and/or swelling and loss of
movement over baseline.
•
In infants and young children, reluctance to use the limb
alone may be indicative of a joint or muscle bleed.
•
Denitions for eectiveness of hemostatic therapy for joint
and muscle bleeds have been developed and should be used
when documenting treatment outcomes. (See Chapter 7:
Treatment of Specic Hemorrhages – Table 7-1.)
RECOMMENDATION 11.2.1:
•
For providers of care for people with hemophilia,
the WFH recommends ensuring that the frequency
of all bleeds is documented in real time by patients/
caregivers and reviewed together at least annually, with
particular reference to intra-articular, intramuscular, and
central nervous system bleeds, including their recovery
status. Standard criteria dened by the Scientic and
Standardization Committee of the International Society
on rombosis and Haemostasis should be used.
Pain assessment in hemophilia
•
Pain in hemophilia can be either acute (as in an acute
bleed) or chronic (as a result of arthropathy), or both may
occur concurrently.
•
Hemophilia-related pain can be assessed using single-
dimensional numerical or visual rating scales such as the
Wong-Baker FACES Scale, or multi-dimensional pain
questionnaires like the generic McGill Pain Questionnaire
or the Brief Pain Inventory (BPI), or disease-specic
instruments like the Multidimensional Haemophilia Pain
Questionnaire (MHPQ).
•
Pain can also be scored through subscales within quality-
of-life questionnaires—both generic and disease-specic
questionnaires—and also within specic joint assessment
instruments such as the Gilbert Score and the Hemophilia
Joint Health Score (HJHS).
•
Pain is best assessed and addressed in the context of a
comprehensive care setting.
Domains to assess the impact of bleeding on
the musculoskeletal and other systems
•
In conditions like hemophilia, it is recommended that
outcomes be assessed according to the domains in the
International Classication of Functioning, Disability and
Health (ICF) model of the World Health Organization
(WHO).
•
According to the ICF, evaluation of disability and health
should focus on the impact of the disease on body structures
and functions, activities, and participation.
•
ese domains can be aected by individual contextual
factors, which represent a person’s circumstances and
background, and include both environmental and personal
factors.
•
Environmental factors comprise the physical, social, and
attitudinal environments in which an individual lives and
conducts day-to-day activities.
•
Personal factors include aspects that are not necessarily
part of an individual’s health condition or health status,
such as age, sex, and indigenous status.
•
See Figure 11-1 for an overview of the ICF model and
outcome assessment instruments by domain.
•
e concept of quality of life (QoL) is complex and
encompasses many characteristics of an individual’s social,
cultural, economic, and physical environments as well as
physical and mental health state.
•
Health-related quality of life (HRQoL) is a synonym
for self-reported health state; HRQoL measurements
generally include several aspects of the ICF model. To be
Chapter 11: Outcome Assessment 157
meaningful, this is best not used in isolation but in addition
to assessment of body structure, function, and activities.
• While most outcome assessment instruments have been
validated for older children, there is a paucity of validated
disease-specic instruments to assess outcomes in very
young children with severe hemophilia (i.e., younger than
4 years of age) during the period when they are typically
started on long-term prophylaxis and the chances of
inhibitor development are at their highest.
•
e ability of the instruments to detect subtle changes
following treatment interventions in children with good
joint status and low bleeding frequency is limited and
needs further attention.
11.3 Body structure and function
•
Body structure refers to anatomical structures and bodily
parts, such as organs, limbs, and their components.
•
Body function refers to the physiologic functions of these
systems, such as range of motion, strength, and joint
stability.
•
In hemophilia, this refers to, for example, the status of
joints and specic muscle groups, assessed both clinically
and radiologically.
Recommended measures of body structure
and function in hemophilia
•
e Hemophilia Joint Health Score (HJHS) is the best
studied of the physical examination instruments in both
children and adults. (See Figure 11-2.)
FIGURE 11-1 International Classification of Functioning and Health (ICF) model, with domain-related
outcome assessment instruments. COPM, Canadian Occupational Performance Measure; FISH, Functional
Independence Score in Hemophilia; HAEMO-QoL-A, hemophilia-specific quality-of-life questionnaire for
adults; HAL, Haemophilia Activities List; HJHS, Hemophilia Joint Health Score; MRI, magnetic resonance
imaging; PaedHAL, Haemophilia Activities List for children; PROBE, Patient-Reported Outcomes, Burdens
and Experiences; SF-36, 36-Item Short Form Survey Instrument; US, ultrasound
Chapter 11: Outcome Assessment 159
•
e radiological Pettersson score is the most widely
used imaging measure of joint structure. is score is
not sensitive to early changes; therefore, more sensitive
instruments have been developed to assess arthropathy.
(See Table 11-1.)
•
Magnetic resonance imaging (MRI) is likely the most
sensitive measure of joint structure. ere are a number of
scales that can be used to quantify arthropathy on MRI;
however, this modality is expensive, time consuming, and
dicult to perform in small children. (See Table 11-2.)
•
Ultrasound (US) scoring systems to assess hemophilic
arthropathy are now available and can detect joint
eusion, early joint disease, and subclinical joint
disease, and promote medication adherence. (See
Table 11-3.)
•
US scoring algorithms can be relatively subjective, but their
reliability can be improved if the assessment is performed
by a hemophilia provider trained in musculoskeletal US.
•
ere is emerging evidence that suggests musculoskeletal
ultrasound (MSKUS) may be useful in the clinical
assessment and management of painful hemophilic
arthropathy as it can dierentiate between joint bleeds
and joint inammation and between muscle bleeds and
other regional pain syndromes. Nonetheless, in any
circumstance, if a patient or clinician suspects an acute
joint or muscle bleed or has diculty assessing whether
a bleed is in progress, hemostatic treatment is advised
immediately before performing conrmatory investigations
or awaiting such results.
11.4 Activities and participation
•
Activity refers to the execution of a task or action by an
individual. In the context of hemophilia, activity generally
refers to instrumental activities of daily living (e.g., walking,
climbing steps, brushing teeth, toileting).
•
Participation refers to involvement in life situations in the
context of social interactions.
•
It is oen dicult to distinctly categorize items and outcome
assessment instruments as belonging to only one of these
two domains; therefore, the two domains are oen combined
in outcome assessment.
• In hemophilia, measurements of activities are dened as
either self-reported or performance-based (i.e., observed).
Recommended instruments for measuring
activities and participation
•
e Haemophilia Activities List (HAL) is a disease-
specic measurement instrument. It is the best-studied
measure of self-reported activities for adults and has
been translated into many languages. e three subscores
(upper extremity, basic lower extremity, and complex
lower extremity) have been proven useful in the United
States and the United Kingdom. (See Table 11-4.)
•
e Paediatric Haemophilia Activities List (PedHAL) is
derived from the HAL. It is a self-reported measure for
children with hemophilia. (See Table 11-5.)
•
Both the HAL and PedHAL were developed by hemophilia
treaters in the Netherlands; thus, they may not apply as
well when used in other cultural settings.
TABLE 11-1 Radiological Pettersson score
29
Radiologic change Finding
Score
a
(points)
Osteoporosis Absent 0
Present 1
Enlargement of epiphysis Absent 0
Present 1
Irregularity of subchondral
surface
Absent 0
Slight 1
Pronounced 2
Narrowing of joint space Absent 0
<50% 1
>50% 2
Subchondral cyst formation Absent 0
1 cyst 1
>1 cyst 2
Erosions at joint margin Absent 0
Present 1
Incongruence between joint
surfaces
Absent 0
Slight 1
Pronounced 2
Deformity (angulation and/or
displacement of articulating
bones)
Absent 0
Slight 1
Pronounced 2
ª Possible joint score: 0- 13 points for each joint (total possible score,
6 × 13 = 78).
WFH Guidelines for the Management of Hemophilia, 3rd edition160
•
e Functional Independence Score in Hemophilia
(FISH) is the best-studied observed performance
measure for people with hemophilia, with many reports
of its use in dierent countries and age groups. (See Table
11-6.)
•
e Patient-Reported Outcomes, Burdens and Experiences
(PROBE) questionnaire also includes metrics that assess
activities and participation, such as school/education,
employment, family life, and impact on activities of daily
living. (See 11.8 Patient reported outcomes, below.)
•
The Canadian Occupational Performance Measure
(COPM) and the McMaster Toronto Patient Disability
Questionnaire (MACTAR) are generic instruments that
have been used for day-to-day assessment of a person’s
perception of changes in the domains of activities and
participation. ey can be used for goal attainment scaling.
11.5 Environmental and personal factors
Environmental factors
•
While environmental factors are part of the ICF model,
they are not oen considered “outcomes” per se but can
be the major intervention in the rehabilitation process.
TABLE 11-2 IPSG MRI Scale to Assess Hemophilic Arthropathy
43
Soft tissue
changes
Effusion/hemarthrosis Small (1)
Moderate (2)
Large (3)
Synovial hypertrophy Small (1)
Moderate (2)
Large (3)
Hemosiderin Small (1)
Moderate (2)
Large (3)
Soft tissue changes subscore Maximum 9 points (1)
Osteochondral
changes
Surface erosions involving
subchondral cortex or joint
margins
Any surface erosion (1)
Half or more of the articular surface eroded in at least
one bone
(1)
Subchondral cysts
At least one subchondral cyst (1)
Subchondral cysts in at least two bones, or cystic
changes involving a third or more of the articular surface
in at least one bone
(1)
Cartilage degradation Any loss of joint cartilage height (1)
Loss of half or more of the total volume of joint cartilage
in at least one bone
(1)
Full-thickness loss of joint cartilage in at least some area
in at least one bone
(1)
Full-thickness loss of joint cartilage including at least
one half of the joint surface in at least one bone
(1)
Osteochondral changes subscore Maximum 8 points (1)
Abbreviations: IPSG, International Prophylaxis Study Group; MRI, magnetic resonance imaging.
Chapter 11: Outcome Assessment 161
TABLE 11-3 HEAD-US Scoring Method
32
Disease activity (synovitis) Scale
Hypertrophic synovium
0. Absent/minimal 0
1. Mild/moderate 1
2. Severe 2
Disease damage (articular surfaces)
Cartilage
0. Normal 0
1. Echotexture abnormalities, focal partial-/full-thickness loss of the articular cartilage involving <25% of the
target surface
a
1
2. Partial-/full-thickness loss of the articular cartilage involving ≤50% of the target surface
a
2
3. Partial-/full-thickness loss of the articular cartilage involving >50% of the target surface
a
3
4. Complete cartilage destruction or absent visualization of the articular cartilage on the target bony surface
a
4
Bone
1. Normal 0
2. Mild irregularities of the subchondral bone with/without initial osteophytes around the joint 1
3. Deranged subchondral bone with/without erosions and presence of prominent osteophytes around the joint 2
Abbreviations: HEAD-US, Haemophilia Early Arthropathy Detection with Ultrasound.
a
Elbow, anterior aspect of the distal humeral epiphysis; knee, femoral trochlea; ankle, anterior aspect of the talar dome.
TABLE 11-4 Haemophilia Activities List (HAL)
2005
15
Items (n)
HAL overall 42
HAL domains
Lying/sitting/kneeling/standing 8
Functions of the legs 9
Functions of the arms 4
Use of transportation 3
Self-care 5
Household tasks 6
Leisure activities and sports 7
HAL components
Upper extremity (HAL
upper
) 9
Basic lower extremity (HAL
lowbas
) 6
Complex lower extremity (HAL
lowcom
) 9
Note : Available in multiple languages at: http://elearning.wfh.org/
resource/hemophilia-activities-list-hal/
TABLE 11-5 Haemophilia Activities List
—Pediatric (PedHAL) v.11
47
Items (n)
PedHAL overall 53
PedHAL domains
Lying/sitting/kneeling/standing 10
Functions of the legs 11
Functions of the arms 6
Use of transportation 3
Self-care 9
Household tasks 3
Leisure activities and sports 11
Note : Available at: http://elearning.wfh.org/resource/haemophilia-
activities-list-pediatric-pedhal/
WFH Guidelines for the Management of Hemophilia, 3rd edition162
•
Environmental factors that inuence outcome include
facilitators and barriers to treatment. ese might include
access to a comprehensive hemophilia care centre,
availability of CFCs, medical understanding, medical
insurance coverage, and travel distance to a hemophilia
treatment centre.
•
For children with hemophilia, family support and, if
needed, additional psychosocial support and assessment
provided by the hemophilia care team, may be an important
facilitating factor.
Personal factors
•
An individual’s personal strengths and deciencies may
signicantly inuence treatment outcomes.
•
Assessment of factors, such as the locus of control, and
psychological characteristics, such as anger, depression,
and optimism, can be used to guide and inform individual
care or research.
•
Another important and measurable inuence on treatment
outcomes is patient/family treatment adherence.
11.6 Economic factors
•
e costs and associated benets of medical care can be
quantied and used in research, program development,
and advocacy.
Direct costs
•
Direct costs include the cost of medical treatments, health
services, and surgical and medical supplies.
•
CFCs for patients with severe hemophilia usually account
for more than 90% of treatment-related costs.
Indirect costs
•
Indirect costs arise from loss of work productivity of adult
patients and of parents of pediatric patients due to the
time they spend managing their child’s hemophilia care.
•
e costs that result from illness or seeking medical care
are sometimes similar but oen vary by country.
11.7 Health-related quality of life
• Health-related quality of life is a synonym for subjective
(self- or family-reported) health status.
•
HRQoL measurements are usually questionnaires that aim
to quantify a patient’s health in a global way.
•
Given their global nature, HRQoL measures are oen
more supercial in their scope than individual measures
of the dierent domains listed above; therefore, they are
best applied in combination with specic assessments of
the ICF domains rather than in isolation.
• An additional challenge in their use is that they must be
validated in the language and social and cultural contexts
of their application.
Instruments most used for measurement of
health-related quality of life
•
e EQ-5D and SF-36 are widely used generic
instruments for assessing QoL in hemophilia. (See Tables
11-7 and 11-8.)
•
e PROBE questionnaire assesses QoL in addition to
burden of disease in people with hemophilia.
•
For children with hemophilia, the Canadian Hemophilia
Outcomes-Kids Life Assessment Tool (CHO-KLAT) has
been extensively used.
•
For adults with hemophilia, the Hemophilia Well-Being
Index and the hemophilia-specic QoL questionnaire
for adults (HAEMO-QoL-A) have been widely used.
TABLE 11-6 Functional Independence Score in
Hemophilia (FISH)
48
List of activities tested
Self-care Transfers Locomotion
Eating Chair transferring Walking
Grooming Walking Climbing stairs
Bathing Running
Dressing
Notes : Scores range from 1 to 4 for each activity depending on the
degree of independence: 1, unable to perform; 2, requires the help of
an assistant/aid; 3, able to perform the activity without an aid but not
like a healthy subject; 4, able to perform the activity like other healthy
subjects. Available at: https://elearning.wfh.org/resource/functional-
independence-score-in-hemophilia-fish/
TABLE 11-7 Q-5D Instrument
68
EQ-5D
description
systemª EQ-VAS
Mobility
Self-care
Usual activities
Pain/discomfort
Anxiety/depression
Records the respondent’s self-rated
health on a vertical, visual analogue
scale ranging from 0 (worst
imaginable health state) to 100
(best imaginable health state)
Abbreviations: EQ, EuroQoL; VAS, visual analogue scale.
ª Three- item, five- item, and youth versions are available.
Chapter 11: Outcome Assessment 163
RECOMMENDATION 11.7.1:
•
e WFH recommends assessing and documenting
the musculoskeletal and overall health of each patient
at least annually. is should include an assessment of
body structure and function, activity levels, participation
and health-related quality of life as per the World
Health Organization’s International Classication of
Functioning, Disability and Health (WHO ICF), as
much as possible, in the right clinical context.
•
REMARK: Standard denitions and validated tools
should be used as much as possible, including the
following:
–
For body structure and function, clinical
assessment of joints is (most) commonly done
using the Hemophilia Joint Health Score (HJHS)
in both children and adolescents.
–
Under the same domain, early structural changes
in joints are best assessed using ultrasound (US)
or magnetic resonance imaging (MRI). Late
osteochondral changes may be assessed on plain
radiographs.
–
Functional activity levels should be assessed
using the most appropriate option available
for that individual, including the Haemophilia
Activities List (HAL), the Haemophilia Activities
List for children (PedHAL), or the Functional
Independence Score in Hemophilia (FISH).
–
HRQoL is an important aspect of outcome
measurement that may be assessed using either
generic or disease-specic tools, but only in
combination with the other domains of the WHO
ICF.
11.8 Patient-reported outcomes
•
Patient-reported outcomes (PROs) provide a report of the
status of a patient’s health condition that comes directly
from the patient, without interpretation of the patient’s
response by a clinician or anyone else.
•
It encompasses both single-dimensional and multi-
dimensional measures of symptoms, HRQoL, health
status, adherence to treatment, satisfaction with treatment,
and other measures.
•
PROs include generic instruments such as EQ-5D-5L, Brief
Pain Inventory v2 (BPI), International Physical Activity
Questionnaire (IPAQ), Short Form 36 Health Survey v2
(SF-36v2), Patient-Reported Outcomes Measurement
Information System (PROMIS), and disease-specic
instruments such as the HAL, HRQoL measures such as
CHO-KLAT, HAEMO-QoL-A, and burden of disease
questionnaires such as PROBE.
•
While data generated by a PRO instrument can provide
evidence of a treatment benet from the patient perspective,
the choice of instrument should be tailored to the study
design or clinical need for specic outcome assessment,
rather than just psychometric properties of the instrument.
11.9 Core set of measures for use in the
clinic or research setting
•
In health care, the focus is increasingly shiing from
the volume of services delivered to the value created for
patients. In this context, value is dened as outcomes
achieved relative to costs.
•
While many outcome assessment options have been
described here, in practice, hemophilia treatment centres
and clinicians may select the instruments most appropriate
for their patients. Outcome assessment instruments may
be classied as mandatory, recommended, and optional.
•
To extract the potential of value-based health care,
standardized outcome measures must be encouraged.
•
is will mean committing to measuring a minimum
sucient set of outcomes for every major medical condition,
with well-dened methods for their collection, which will
then need to be applied universally.
TABLE 11-8 36-Item Short Form Survey
Instrument (SF-36)
69
Items (n)
SF-36 overall 36
SF-36 domains
Physical functioning 10
Role limitations due to physical health
problems
4
Role limitations due to personal or
emotional problems
3
Energy/fatigue 4
Emotional well- being 5
Social functioning 2
Pain 2
General health 5
WFH Guidelines for the Management of Hemophilia, 3rd edition164
•
e WFH World Bleeding Disorders Registry (WBDR)
provides a platform for hemophilia treatment centres to
collect uniform and standardized patient data and outcomes
globally to guide clinical practice (http://www.w.org/
en/our-work-research-data/world-bleeding-disorders-
registry).
•
Dening a standardized core set of outcome measures
for specic clinical settings within which hemophilia is
managed worldwide is key to advancing the clinical care
of people with hemophilia and conducting further studies
on treatment options. A selection of outcome assessment
instruments can be accessed at the WFH Compendium
of Assessment Tools webpage (http://elearning.w.org/
resource/compendium-of-assessment-tools/).
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with hemophilia B: the Bridging Hemophilia B Experiences, Results
and Opportunities into Solutions (B-HERO-S) study. Eur J Haematol.
2017;98(Suppl 86):18-24.
60. vanden Berg HM, Feldman BM, Fischer K, Blanchette V, Poonnoose
P, Srivastava A. Assessments of outcome in haemophilia—what is the
added value of QoL tools? Haemophilia. 2015;21(4):430-435.
61. Ware JE. e SF36 Health Survey. In: Spilker B, ed. Quality of Life and
Pharmacoeconomics in Clinical Trials. Philadelphia, PA: Lippincott-
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62. Brazier J, Usherwood T, Harper R, omas K. Deriving a preference-
based single index from the UK SF-36 Health Survey. J Clin Epidemiol.
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63. Chai-Adisaksopha C, Skinner MW, Curtis R, et al. Exploring regional
variations in the cross-cultural, international implementation of the
Patient Reported Outcomes Burdens and Experience (PROBE) study.
Haemophilia. 2019;25(3):365-372.
64. Chai-Adisaksopha C, Skinner MW, Curtis R, et al. Test-retest properties
of the Patient Reported Outcomes, Burdens and Experiences (PROBE)
questionnaire and its constituent domains. Haemophilia. 2019;25(1):75-
83.
65. Chai-Adisaksopha C, Skinner MW, Curtis R, et al. Psychometric
properties of the Patient Reported Outcomes, Burdens and Experiences
(PROBE) questionnaire. BMJ Open. 2018;8(8):e021900.
66. Young NL, Bradley CS, Blanchette V, et al. Development of a health-
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67. Remor E. Development and psychometric testing of the Hemophilia
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November 7, 2019.
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SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting
Information section.
167
METHODOLOGY
12
Sandra Zelman Lewis
1
| Donna Coffin
2
| Lucy T. Henry
3
| Sonia O’Hara
4
| Thomas J. Schofield
5
|
Maura Sostack
6
| Debbie Hum
2
| Melanie Golob
7
| Fiona Robinson
2
| Mark Brooker
8
| Vincent Dumez
9
|
Glenn F. Pierce
2
| Alok Srivastava
10
1
EBQ Consulting, LLC, Northbrook, Illinois, USA
2
World Federation of Hemophilia, Montreal, QC, Canada
3
Ottawa, ON, Canada
4
HCD Economics, Chester, UK
5
EBQ Consulting, LLC, Santa Monica, California, USA
6
EBQ Consulting, LLC, Philadelphia, Pennsylvania, USA
7
EBQ Consulting, LLC, Olympia, Washington, USA
8
Formerly World Federation of Hemophilia, Montreal, QC, Canada
9
Centre of Excellence on Partnership with Patients and the Public, Université de Montréal, Montreal, QC, Canada
10
Department of Haematology, Christian Medical College, Vellore, India
12.1 Background
e World Federation of Hemophilia (WFH) developed
the rst edition of the Guidelines for the Management of
Hemophilia in 2005. ese guidelines were updated in 2012
and have since seen global print and online distribution
of more than one million (including downloads from
the Haemophilia journal and WFH websites, WFH print
distributions, and WFH and National Member Organization
translations). For this third edition, the WFH decided to adopt
a dierent method for development, incorporating evidence-
based and Trustworthy Consensus-Based Statement (TCBS)
approaches in conformance with established international
standards for clinical practice guidelines.
In rare diseases such as hemophilia, there are limitations
in developing evidence-based guidelines due to gaps in
the evidence base related to small sample sizes and the
paucity of methodologically rigorous data stemming from
randomized controlled trials. e wide range of hemophilia
treatments and practices used globally also contributes to
the disparate research foci in the current state of hemophilia
science. Quantitative analyses of the data for several aspects
of management (e.g., direct meta-analyses or network meta-
analyses) are not feasible under these circumstances.
When the evidence is not suciently evolved to support
quantitative analyses for evidence-based recommendations,
it is important to provide physicians and other healthcare
providers, people with hemophilia, and advocates with advice
they can trust. e TCBS approach produces unbiased,
scientically valid, and trustworthy recommendations through
a transparent process that incorporates both the available
evidence, identied using a systematic approach to reduce
biases, and expert clinical advice.
is chapter describes the methodology used to develop
the third edition of the WFH Guidelines for the Management
of Hemophilia.
12.2 Methodology
The TCBS process produces evidence-informed
recommendations supported by a comprehensive and
systematic search for relevant scientic literature, which is
rst screened based on predetermined inclusion/exclusion
criteria, then followed by data extraction of the available and
relevant evidence. e Delphi technique is a widely used and
well-accepted process for soliciting feedback and achieving
consensus. ere are several variations, but the modied
Delphi approach for guideline recommendations allows
consideration of the evidence base as well as expert opinion
while suppressing the introduction of group interaction
bias. e WFH adopted the TCBS approach, already in use
by several medical professional societies, as this type
of guideline brings thoroughness and transparency to the
guideline development process for the expert panel’s evidence-
informed and consensus-based recommendations. As with
fully evidence-based guidelines, the TCBS approach includes
a rigorous review of both methods and content by internal
WFH Guidelines for the Management of Hemophilia, 3rd edition168
and external stakeholders of all types. is approach is based
on ve important pillars:
• condence in the panel composition and screening;
• systematic and comprehensive evidence searches;
• formal consensus achievement;
• transparency of data and methods throughout; and
• rigorous review process.
Composition of the panels: structure and
review
e WFH appointed an overall content lead (AS) and an
assistant content lead (GP), both highly experienced in the
eld of hemophilia, and a methodology consultant (SZL) with
extensive experience in developing guidelines and expertise
in the TCBS approach. A WFH Guidelines Process Task Force
(GPTF) was established to provide objective oversight of the
process. e GPTF was composed of members of the WFH
Education Committee, including patients and a hematologist
not involved in the development of the guidelines.
e content lead and the previous WFH Vice President,
Medical, offered initial invitations to the expert and
representative panel to meet the criteria described below.
An important goal, not always achieved by guideline and
research organizations, was to ensure that no serious
topic-related conicts of interest existed for the leads and to
minimize the percentage of the panel with relevant conicts.
is third edition of the WFH guidelines comprises an
extensive revision of the existing seven chapters of the 2012
edition, as well as several new chapters. Each chapter was
assigned to a panel composed of 7-10 members, including a
chapter lead, healthcare professionals with clinical expertise,
and patients/caregivers, with the latter making up at least 25%
of each chapter panel. A total of 50 panelists were assigned
to the 11 content chapters, with some panelists serving on
more than one panel. e WFH drew upon its international
volunteers and wide stakeholder network to recruit experts
from diverse healthcare disciplines (hematologists, orthopedic
surgeons and other musculoskeletal specialists, physical and
occupational therapists, laboratory scientists, nurses, dentists,
and psychosocial professionals). e panel also included
a broad representation of people living with hemophilia
including those with related complications such as inhibitors,
musculoskeletal complications, and diverse comorbidities,
as well as parents of children living with these conditions.
Panelists were recruited from diverse demographic, geographic,
and socioeconomic contexts to ensure the global relevance
of these guidelines.
Process for panel workflow and oversight
e content and chapter leads guided the panels through
the chapter development process and provided content
expertise. e responsibilities of the chapter leads, with
help from other healthcare professionals on their panels,
included developing a comprehensive set of important
subtopics per chapter, advising the medical librarians on
relevant search terms, draing initial recommendations, and
developing the manuscripts including citation of important
research. e responsibilities of the chapter leads also included
ensuring that the patient/ caregiver panelists’ perspectives
were solicited and addressed. Even though the vast majority
of recommendations address the care and management of
patients, rather than treatments, content and chapter leads
also ensured that no specic products or brand names were
mentioned; with the exception of the Laboratory Diagnosis
and Monitoring chapter, wherein the therapeutic products
may not be recognized by their international nonproprietary
names (INN) by the community and brand names were
included for all products, without which medical errors
could inadvertently be made. For the diagnostic reagents, the
specic brand names for which published evidence of assay
validation is available were included within each category
of the reagents.
All panelists were involved throughout topic organi-
zation, evidence generation, consensus achievement of
recommendations, and manuscript draing and reviews.
Meetings, communications, and trainings were conducted via
videoconferences, emails, and electronic surveys. Recordings
and slides of training sessions and calls were made available
to all members aerward. All panelists were aorded the
opportunity to review all of the chapters before nalization
and external reviews.
e equal status of all panelists (whether healthcare
professional or patient/caregiver), the importance of each
individual’s expertise, and the imperative for all panelists to
work together to solicit and validate all perspectives were
emphasized in the trainings. Under the direction of the
GPTF, a patient partner facilitator was hired to contribute
training on the value that this approach adds to guideline
development and the practicalities of its application, and
assist with the implementation of this philosophy. e patient
partner facilitator supported the patient/caregiver panelists
throughout the guideline development process with monthly
calls and guidance and non-nancial support as needed.
Chapter 12: Methodology 169
Funding
e sole source of funding for these guidelines was the World
Federation of Hemophilia.
12.3 Evidence generation
A team of qualied and experienced medical librarians,
screeners, methodologists, and data extractors was assembled
to update the evidence base. Separate systematic reviews of the
published literature were conducted on 10 of the 11 content
chapters. A review of the literature was deemed not relevant for
one chapter, Principles of Care, which focuses on ideal goals
and aspirations given the current understanding of hemophilia
and available science and technologies. Additional searches
were developed specically to target dental procedures,
planned and emergent surgical and invasive procedures,
and the emerging area of genetic assessment, resulting in a
total of 11 reviews conducted. Details of the search strategies,
the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA), and the extracted evidence are
provided in the online supplemental materials.
Study eligibility criteria
Population, interventions, comparisons, and
outcomes
For all chapters, studies that included patients with hemophilia
A or B were retained. Additional population criteria were
established for each chapter. ere were no exclusions based
on sex or age. Eligibility of included studies was not restricted
by interventions, comparisons, or outcomes for any content
area.
Search strategies and information sources
All search strategies were developed by a medical librarian
in collaboration with content experts involved in each of
the chapters and the overall content lead. All searches were
restricted to English language and human-only studies. No
exclusions based on geography or type of care setting were
implemented. Searches were run in PubMed, the Cochrane
Database of Systematic Reviews (CDSR), the Cochrane
Central Register of Controlled Trials (CENTRAL), and
EMBASE, covering the period from January 1, 2000, to
the date of the search between May and November 2019.
e complete search strategies can be found in the online
supplemental materials.
No crawling or searching of reference lists of identied
systematic reviews was conducted. One exception was made
for the new review on Outcome Assessment, for which the
reference list of one generally well-respected landmark paper
was crawled. Chapter leads and panelists were invited to
propose any directly relevant literature that was not identied
through formal searching to be reviewed for inclusion.
Setting and study designs
Due to the volume of literature identied, post hoc restrictions
on included studies (e.g., by publication year and study
design) were applied without knowledge of the literature
identied. Most studies selected for extractions were limited to
publication dates aer January 1, 2010 (preceding the search
date limit for the previous edition of the guidelines), with the
exception of the new chapter on Outcome Assessment, for
which the inclusion date extended back to January 1, 2005.
Additional papers and qualitative reviews were referenced
when relevant, but data extraction was not performed. Study
designs retained were randomized controlled trials, quasi-
randomized controlled trials, and prospective comparative
studies. In some cases, retrospective studies were included at
the request of individual chapter leads. Some included studies
were later conrmed as retrospective during extraction.
ese were retained in the evidence tables and marked as
retrospective in the study design column. Cross-sectional
studies were included in the evidence base for the Laboratory
Diagnosis and Monitoring chapter. Systematic reviews were
included for reference only.
Study selection
For each of the 11 search strategies, screening criteria were
developed based on pre-specied criteria as dened during
the chapter’s search development calls and in collaboration
with the chapter leads. Identied references were screened for
chapter-specic eligibility using the reference management
soware Distiller SR®.
A team of seven trained reviewers screened titles and
abstracts. Pilot testing was conducted prior to screening
of each chapter, with all reviewers screening the same 50
references, followed by discussions and modications to
the screening forms when required for clarication. e
remainder of title and abstract screening was completed
by single review for all chapters. Dual screenings were not
performed. For 8 of the 11 chapters, a secondary round of title
and abstract screening of those studies deemed potentially
eligible was conducted for two reasons. First, as the screening
team became more familiar with the literature identied
by the searches and through further discussions with the
chapter and content leads, additional screening criteria
were applied for subsequent rounds of review. Screening
WFH Guidelines for the Management of Hemophilia, 3rd edition170
decisions were made without the panelists’ knowledge of
the identied literature to avoid biasing the results. Second,
a secondary title and abstract screening allowed the team to
eciently eliminate irrelevant references, providing time-
and cost-saving measures. References not eliminated during
title and abstract screening were reviewed for eligibility at
full-text screening.
For further details related to the ow of references in
PRISMA diagrams, please see the online supplemental
materials.
Data extraction and development of evidence
tables
Evidence tables were created for each chapter. Relevant
outcomes were determined with the help of the chapter leads.
A senior methodologist (TS) provided oversight
and organization of the evidence tables. A team of 15
methodologists and data analysts extracted the relevant
data from all included studies. Dual extractions were
not performed. e evidence tables and the underlying
research articles for each chapter were shared with the entire
chapter panel and used by the chapter leads and healthcare
professionals to inform the recommendations. e evidence
tables are available in the online supplemental materials.
Risk of bias in individual studies
No formal quantitative analyses were conducted, and no
critical assessments were made of individual study quality. It
should be noted that hemophilia is classied as a rare disease
which results in inherent limitations of primary research
studies; thus, most assessments would have resulted in low
or very low levels of evidence. Other than the study design
limitations placed on the literature search and screenings, no
additional exclusions were made based on methodological
quality of the research studies.
By design, no recommendations were graded as the vast
majority of the evidence base in the eld, given the barriers
to clinical research and data collection in rare diseases, is
insucient to support meta-analyses. Grading is based
on two components, the quality of the evidence and the
balance of benets to harms and/or risks. e former is an
assessment of the quality of the evidence supporting the
recommendations specic to each outcome. When low-level
evidence is partitioned by outcomes, the remaining data are
not feasible to support quantitative analyses. Attempting to
grade such recommendations can be misleading to the target
audience of healthcare providers. e second component is
not explicit in the absence of the quality assessments, so we
did not assign a level of strength to the recommendations.
erefore, in the interest of transparency, the WFH guideline
recommendations were not graded but were clearly marked
“CB” for consensus-based.
12.4 Formal consensus achievement
through Delphi techniques
A priori rules and processes
Following the draing of the recommendations by the assigned
healthcare professionals, each set of recommendations went
through the modied Delphi consensus process.
Several a priori decisions guiding the modied Delphi
process were determined by the GPTF:
• Up to three rounds of Delphi surveys were
permitted to achieve consensus.
• e minimum response rate for each survey round
was set at 75% of eligible voting panelists.
• e threshold for achieving consensus was 80% of
the respondents indicating agreement or strong
agreement.
• Statements achieving consensus in the rst or
second round were not subjected to subsequent
rounds.
• No minority reports were permitted.
Draed recommendations that did not achieve consensus
aer three rounds do not appear as recommendations in
the nal guidelines. However, the underlying topics may
be included in the relevant chapter text, oen with a call
for additional research in these areas to help resolve some
of the controversies.
Delphi surveys
The modified Delphi surveys were conducted using
SurveyMonkey, with all responses remaining anonymous
except to the independent administrator (MG) who created
and managed the process. All panelists received two trainings
on the TCBS approach, written reminders of the Delphi process
and rules, and instructions on the rst page of the surveys.
The initial recommendations were drafted by the
healthcare professionals, as assigned by the chapter leads.
Recommendations were based on the evidence provided in
the evidence tables and articles, as well as on the experience
and expertise of the panelists. Panelists were trained in writing
recommendations. e consultant and editors provided
advice and edited the recommendations to make them
specic and actionable.
Chapter 12: Methodology 171
Before the modied Delphi process began, the entire
chapter panel, including the patients/caregivers, convened
via teleconference to discuss the evidence as a group and
receive instructions on the Delphi process. ey were not
permitted to discuss the draed recommendations so as to
avoid the occurrence or even perception of group interaction
bias. Panelists were permitted to suggest topics for additional
recommendations that did not appear in the list. When new
topics were suggested, the assigned healthcare professionals
for that chapter’s section were tasked with draing new
recommendations to address the identied gaps.
Panelists were encouraged to respond completely to
all recommendations in every round of the surveys. e
healthcare professionals were advised to base their level
of agreement or disagreement on the evidence and their
experience treating patients with hemophilia. e patient/
caregiver panelists were asked to make similar judgments based
on the evidence and their experience as hemophilia patients/
family caregivers in the healthcare system. ese guidelines
benetted from the experiences of patient/caregiver panelists.
However, some expressed hesitation about being asked to
vote on recommendations for which they did not have any
expertise or experience. erefore, if the recommendation
addressed an area in which the patient/caregiver panelists
were not familiar, they could opt out of the denominator by
voting neutral and adding the phrase “No experience in this
area” in the comments eld. is signaled that their neutral
vote should not be added to the denominator when the votes
were tallied. Across all chapters, 53 of 344 recommendations
(15%) achieved consensus with at least one patient/caregiver
panelist selecting this option. ese choices were made
selectively by individual patient/caregiver panelists on a
recommendation-by-recommendation basis and did not
impact the votes of others.
For recommendations that did not achieve consensus in
the rst or second round, the chapter leads draed revisions
based on the comments provided by the respondents. e
revised recommendations were submitted for the next
round of voting. e topics of any recommendations that
did not achieve consensus by the end of the third round
could be noted in the manuscripts along with calls for future
research in the respective areas. Aer all Delphi rounds were
completed, consensus was not achieved for 13 (<4%) of the
recommendations. Research funding agencies are encouraged
to prioritize these areas to address knowledge gaps.
Survey tallies with the degree of consensus for
each recommendation are available upon request
(research@w.org).
Diversions from the process
ere were a few diversions from the described process
requiring additional surveys aer the third round. One
recommendation in the muscle hemorrhage section of the
Treatment of Specic Hemorrhages chapter was resubmitted
for voting because new evidence (albeit low level) was brought
forth that raised doubts about the timeframe specied in the
recommendation. Due to inadvertent group discussion of this
recommendation, this section with all three recommendations
was then moved to the Musculoskeletal Complications
chapter, which was composed of dierent panelists, to avoid
the introduction of group interaction bias. e panelists
were informed of the full set of evidence, provided with the
relevant papers and extracted data, and voting on the updated
recommendation took place. During reviews for consistency
and gaps, three additional recommendations (one from the
Treatment of Specic Hemorrhages chapter and two from
the Inhibitors to Clotting Factor chapter) required additional
revisions or the addition of remarks. One recommendation
was inadvertently excluded from the original surveys for
the Prophylaxis in Hemophilia chapter. All were rectied
through additional survey rounds.
12.5 Finalization of the
recommendations and manuscript
development
At the conclusion of the nal round of the modied Delphi
surveys, the chapter leads nalized the manuscripts for
their assigned chapters. All recommendations that achieved
consensus were incorporated within the relevant section of the
manuscript, bolded, and numbered accordingly. All remarks
are considered integral to the recommendations themselves
and therefore included as part of the recommendations. e
WFH advises that as recommendations are uploaded into
digital platforms, incorporated into separate lists, or otherwise
removed from this full guideline publication, the remarks
should always be kept with the rest of the recommendation
as a single unit.
ese guidelines have an intrinsic navigation system for
the chapters, sections, recommendations, and supplemental
materials. e numbering system uses the chapter number
as the initial number, followed by the section numbers.
Recommendations are numbered according to the chapter
and section in which they appear. is will help readers locate
the background information that builds the case for the
recommendations themselves. For example, a recommendation
WFH Guidelines for the Management of Hemophilia, 3rd edition172
numbered 4.2.3 represents the third recommendation in
Chapter 4, section 2.
Review and finalization
Each chapter manuscript underwent extensive review. Final
manuscripts were reviewed by the chapter lead and panelists;
the content lead and co-lead; the GPTF; key members of the
WFH senior management team; followed by an external
team of highly experienced healthcare professionals with
expertise in the care of people with hemophilia, and well-
informed expert people with hemophilia from around the
world, ensuring a global perspective. Finally, the entirety of
the guidelines was submitted to several organizations for
their review and consideration for endorsement. Comments
at each stage of review were considered by the chapter leads,
and modications were made when relevant. No editing or
changes to the recommendations or remarks were permitted.
A nal independent peer review was also done through
the Haemophilia journal and the extensive comments were
addressed.
12.6 Methodology limitations
As is common in guideline development, methodological
processes have to be pragmatically adjusted to accommodate
challenges with the available evidence, organizational matters,
and other constraints. Similarly, with these guidelines,
compromises were required in order to provide the best
guidance possible in a clinical area with limitations in the
evidence base.
e panels were organized by invitation and without a
declared review of conicts of interest (although current
disclosures accompany this publication). All panelists were
invited to participate in the scope of the chapter searches,
which was accepted as a proxy for a priori established PICO
(Population/Intervention/Comparators/ Outcomes paradigm)
questions.
Search strategies were then developed by highly
experienced medical librarians based on the scope discussions
and early dras, although they were not peer-reviewed. Since
the last guidelines were published in 2012, the searches were
restricted to the years 2010-2019 for the chapters which are
revisions from the previous edition. However, since that
edition did not include a formal systematic review, future
searches may have to be extended further back in time.
Studies identied as retrospective by the screeners were
excluded, except where specied above. For a rare disease,
especially for the more subjective topics, a more comprehensive
and reliable evidence base would have included these reviews.
Due to the high yield of references from the searches
for the Prophylaxis in Hemophilia chapter, references were
limited to studies with a minimum sample size of 40. Sample
size is not a proxy for quality, but alternative options to limit
the number of studies to meet the timeframe did not exist.
Both single screening, rather than dual screening with
adjudication, and single data extractions, rather than dual
extractions with adjudication, were necessary compromises.
ere were no critical appraisals of the quality of the
evidence or assessments of the feasibility of quantitative
analyses as these had been ruled out in advance due to previous
eorts to conduct systematic reviews in this rare disease.
Considerable support was provided to reduce the burden
on the volunteer panelists in the literature searches, screenings,
data extractions, and draing of the manuscripts. Like all
multi-chapter guidelines, the level of consistency of writing
varied across chapters, but the medical editors strove to
reduce duplication and ensure standardization. is helped to
ensure a nal consistent format in these important guidelines
for all users.
12.7 Future plans for updates
With this third edition, the WFH Guidelines for the
Management of Hemophilia have advanced considerably and
comply with current standards for guideline development using
the TCBS approach. As additional research is conducted in the
eld of hemophilia, as methods standardize, and knowledge
grows, published data should become more homogeneous
and quantiable, permitting more evidence-based guideline
updates by the WFH in many of the content areas. is
will also increase the methodological rigor and allow the
evolving science to guide future recommendations, especially
in areas where the research is growing, such as diagnostic
methods, hemostatic agents, regular replacement strategies,
and management of inhibitors apart from curative treatments.
Additional eorts will follow the advancing work of several
international initiatives to provide recommendations for digital
platforms and repositories and to increase implementation,
especially at the point of care.
12.8 Conclusion
Even though this third edition of the WFH Guidelines for
the Management of Hemophilia is primarily intended for
Chapter 12: Methodology 173
use by healthcare professionals, it will also be useful for
people living with hemophilia and healthcare agencies and
advocates around the world. ese are trustworthy, reliable,
evidence-informed, and expert-driven recommendations that
should inform and empower medical professionals, patients
and their caregivers so that they can be better informed
and active participants in shared decision-making guiding
hemophilia treatment and management plans.
e WFH, guideline panelists, sta, and consultants did
not receive any external funding for these guidelines.
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SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting
Information section.
How to cite this article: Srivastava A, Santagostino E, Dougall A, et al. WFH Guidelines for the Management of
Hemophilia, 3rd edition. Haemophilia. 2020:26(Suppl 6):1-158. https://doi.org/10.1111/hae.14046
174
ACKNOWLEDGEMENTS
AUTHOR CONTRIBUTIONS
Panelists
Alok Srivastava served as the Content Lead for the overall
guidelines project. He made substantial contributions to
the design and conception, organization of the panel, and
methodology decisions, and was the primary author of the
Introduction and the Principles of Care chapter.
Glenn F. Pierce served as the Co-Content Lead for the
overall guidelines project, panelist on three chapters, and
performed extensive reviews of all chapters at multiple times
in the process. He also contributed to the methodology
decisions. H. Marijke van den Berg, as initial Co-Content
Lead, helped design the project and panel, in addition to
serving as a panelist on three chapters.
Chapter Leads served as the primary authors of their assigned
chapters and most were also panelists on other chapters. All
panelists voted in the Delphi rounds.
Manuel Carcao
Steve Kitchen
Adolfo Llinás
Johnny Mahlangu
Steven W. Pipe
Pradeep M. Poonnoose
Margaret V. Ragni
Elena Santagostino
Megan Sutherland
Alok Srivastava
Jerzy Windyga
Health Care Provider Panelists other than Chapter Leads
primarily reviewed and provided comments on various
iterations of the chapters to which they were assigned but
some also provided extensive draing of sections of the
chapters. All panelists voted in the Delphi rounds and were
invited to review and comment on all chapters.
Erik Berntorp
Greig Blamey
Carlos D. De Brasi
Piet de Kleijn
Silmara A. de Lima
Montalvão
Gerard Dolan
Alison Dougall
Carmen Escuriola
Ettingshausen
Brian M. Feldman
Nicholas J. Goddard
Emna Gouider
Kate Khair
Barbara A. Konkle
Rolf C. R. Ljung
Richa Mohan
Margareth C. Ozelo
Gianluigi Pasta
Shrimati Shetty
Alison Street
Claude Tayou Tagny
Pierre Toulon
People with Hemophilia (PWH) and Parents of PWH
Panelists participated as reviewers of chapter manuscripts,
voters in all relevant Delphi rounds, and were invited to
review and comment on all chapters.
Abdelaziz Khaled
Al Sharif
Manuel A. Baarslag
Lisa Bagley
Francisco de Paula
Careta
Kim Chew
Gaetan Duport
Mathieu Jackson
Radoslaw Kaczmarek
Augustas Nedzinskas
Enrique David Preza
Hernández
Bradley Rayner
R. Sathyanarayanan
Andrew Selvaggi
Ekawat Suwantaroj
Other
e following individuals served as consultants or sta and
did not vote in any Delphis:
•
Sandra Zelman Lewis contributed the first draft of
the Methodology chapter and consulted on guideline
development, TCBS process, and methods. She helped
review chapters and provided overall guidance on
development and publication steps.
•
Donna Con provided overall management of the guideline
development and was responsible for specic sections of
the Methodology chapter.
•
Lucy T. Henry oversaw the library work and contributed
to draing sections of the Methodology chapter.
•
Sonia O’Hara served as lead reviewer, advised on search,
screening, and review strategies, and contributed to the
Methodology chapter.
•
omas J. Schoeld served as lead methodologist for
data extractions, advised on several library activities, and
contributed to the Methodology chapter.
•
Maura Sostack served as lead librarian developing and
conducting all searches, and contributed to the Methodology
chapter.
•
Debbie Hum, lead medical editor and co-author of
the Principles of Care chapter, led the review, editing,
formatting, and reference implementation by the
editorial team for all manuscripts, and contributed to
the Methodology chapter.
175Acknowledgements
•
Melanie M. Golob served as the project manager, controlling
and organizing all aspects of the project, including serving
as the independent administrator of the Delphi process.
She also assisted with reviewing the Methodology chapter
and other chapters.
•
Fiona Robinson was the rst manager of this process,
coordinating the panel, processes, and chapter development,
and contributed to the methods selection and the
Methodology chapter.
•
Mark Brooker assisted with panel composition and
management, as well as methods selection and chapter
development.
•
Vincent Dumez served as the Guidelines Process Task
Force chair, managing all taskforce activities, decisions,
and content reviews.
All authors and contributors were involved in nal approval
of the submitted version.
GUIDELINES PROJECT TEAM
e authors would like to acknowledge the work of the WFH sta and team of professionals led by Donna Con, WFH
Director of Research and Public Policy, towards the development and completion of these guidelines.
Project director
Donna Con
Methodology consultant
Sandra Zelman Lewis
Project manager
Melanie M. Golob
Literature manager
Lucy T. Henry
Patient partner facilitator
Mathieu Jackson
Medical librarians
Maura Sostack
Heidi Tibollo
Aleksandra Florek
Literature screeners
Sonia O’Hara
Rebecca Bungay
Chantelle Garritty
Bianca Lallitto
Denisse Mendoza
Ellia Tootoonchian
S op h i e Yo on
Methodologists and data analysts
omas J. Schoeld
Oluwaseun Akinyede
Zuleika Aponte
Saranya Chandurdu
Rodin El-Hachache
Michael Friend
Brandon Kerr
Sharath Krishna
Jane Lam
Denisse Mendoza
Erin Murray
Sheena Patel
Amy Shim
Ambrish Singh
Tracy Slanger
S op h i e Yo on
Medical editors
Debbie Hum
Ellen Klaschka Espiau
Georghia Michael
David Page
GUIDELINES PROCESS TASK FORCE
Vincent Dumez, Chair
Magdy El Ekiaby
Kate Meier
Glenn F. Pierce
omas Sannié
Deon York
WFH Guidelines for the Management of Hemophilia, 3rd edition176
REVIEWERS
WFH Executive Reviewers
Alain Baumann
Glenn F. Pierce
Alok Srivastava
Alain Weill
External Reviewers
Victor S. Blanchette
(reviewed full
document)
Jan Astermark
Miguel A. Escobar
Gili Kenet
Michael Makris
Pier M. Mannucci
Ingrid Pabinger-
Fasching
Kathelijne Peerlinck
Rajiv K. Pruthi
Doris V. Quon
Leonard A. Valentino
Christopher E. Walsh
DISCLOSURES
• Alok Srivastava – AS has research support from
Sano, Roche-Genentech, Novo Nordisk and Bayer
Healthcare and has served on advisory board / grants
review committee of Takeda, Novo Nordisk, Roche-
Genentech, Pzer and Bayer Healthcare.
• Elena Santagostino – ES acted as a member of speaker
bureau and/or advisory board sponsored by Shire/
Takeda, Bayer, Pzer, CSL Behring, Novo Nordisk,
Grifols, Bioverativ, Sobi, Octapharma, Kedrion, Spark,
uniQure and Roche.
• Alison Dougall – No competing interests to declare.
• Steve Kitchen – SK has received consultancy/speaker
fees from Sobi, Novo Nordisk, Werfen, Roche, Bayer,
Pzer in the last 2 years.
• Megan Sutherland – No competing interests to declare.
• Steven W. Pipe – Consulting Fees: Apcintex, Bayer,
BioMarin, Catalyst Biosciences, CSL Behring, HEMA
Biologics, Freeline, Novo Nordisk, Pzer, Roche/
Genentech, Sangamo erapeutics, Sano, Takeda,
Spark erapeutics, uniQure.
• Manuel Carcao – MC reports having received research
support from Bayer, Bioverativ/Sano, CSL-Behring,
Novo Nordisk, Octapharma, Pzer and Shire/
Takeda. He has also received honoraria for speaking/
participating in advisory boards from Bayer/Sano,
Biotest, CSL-Behring, Grifols, LFB, Novo Nordisk,
Octapharma, Pzer, Roche and Shire/Takeda.
• Margaret V. Ragni – MR has had institutional support
for research from Alnylam, BioMarin, Bioverativ,
Sangamo, and Spark; and has served on Advisory
Boards for Alnylam, BioMarin, Bioverativ, and Spark.
• Johnny Mahlangu – JM reports receiving research
grants from BioMarin, Baxalta, Catalyst Biosciences,
CSL, Novartis, Novo Nordisk, Pzer, Roche, Sano,
Spark, Roche, uniQure, advisory board from BioMarin,
Baxalta, Catalyst Biosciences, CSL, Novartis, Novo
Nordisk, Pzer, Roche, Sano, Spark, Roche, uniQure
and speaker bureau for ISTH, Novo Nordisk, Pzer,
Roche, Sano, Takeda, and WFH.
• Jerzy Windyga – JW reports receiving grant support
from Alnylam Pharmaceuticals Baxalta, Novo Nordisk,
Octapharma, Rigel Pharmaceuticals, Roche, Shire/
Takeda, Sobi; sponsored lectures: Alexion, Baxalta,
CSL Behring, Ferring Pharmaceuticals, Novo Nordisk,
Octapharma, Roche, Sano/Genzyme, Shire/ Takeda,
Siemens, Sobi, Werfen.
• Adolfo Llinás – AL has acted as paid consultant for
Bayer and Novo Nordisk over the last 12 months.
• Nicholas J. Goddard – No competing interests to
declare.
• Richa Mohan – No competing interests to declare.
• Pradeep M. Poonnoose – No competing interests to
declare.
• Brian M. Feldman – BF has received research grant
funding from Novo Nordisk, and is one of the inventors
of the Haemophilia Joint Health Score.
• Sandra Zelman Lewis – SZL was contracted by the
WFH to serve as the Guidelines Consultant on this
project.
• H. Marijke van den Berg – No competing interests to
declare.
• Glenn F. Pierce – Consultant: BioMarin, Geneception,
Generation Bio, St. Jude; Advisory Boards: Takeda,
Pzer; Boards: World Federation of Hemophilia VP
Medical, NHF MASAC.
177
AAV adeno-associated virus
ABR annualized bleeding rate
AJBR annualized joint bleeding rate
ACMG American College of Medical
Genetics and Genomics
AF atrial fibrillation
aPCC activated prothrombin complex
concentrate
APTT activated partial thromboplastin time
ASA acetylsalicylic acid
AVF arteriovenous fistula
BDD B-domain–deleted
BMD bone mineral density
BMI body mass index
BPI Brief Pain Inventory
BT bleeding time
BU Bethesda unit
CABG coronary artery bypass grafting
CDC Centers for Disease Control (U.S.)
CDSR Cochrane Database of Systematic
Reviews
CENTRAL Cochrane Central Register of
Controlled Trials
CFC clotting factor concentrate
CHAMP CDC Hemophilia A Mutation Project
CHBMP CDC Hemophilia B Mutation Project
CHO-KLAT Canadian Hemophilia Outcomes-
Kids Life Assessment Tool
CNS central nervous system
CNV copy number variation
COPM Canadian Occupational Performance
Measure
COX-2 cyclooxygenase-2
CSGE conformation sensitive gel
electrophoresis
CT computed tomography
CV coefficient of variation
CVAD central venous access device
DDAVP 1-deamino-8-D-arginine vasopressin,
also known as desmopressin
DNA deoxyribonucleic acid
DOAC direct oral anticoagulant
EACA epsilon aminocaproic acid
EAHAD European Association for
Haemophilia and Allied Disorders
EHL extended half-life
EMA European Medicines Agency
EQ EuroQoL
EQA external quality assessment
EQAS external quality assessment scheme
EQ-VAS EuroQoL Visual Analogue Scale
EQ-5D EuroQoL 5 Dimensions
FDA Food and Drug Administration (U.S.)
FFP fresh frozen plasma
FII, FIIa factor II, activated factor II
FISH Functional Independence Score in
Hemophilia
FIX, FIXa factor IX, activated factor IX
FIX:C factor IX activity
FV factor V
FVII, FVIIa factor VII, activated FVII
FVIII factor VIII
FVIII:C factor VIII activity
FX, FXa factor X, activated factor X
FXI factor XI
FXIII factor XIII
GenQA Genomics Quality Assessment
GI gastrointestinal
GMP Good Manufacturing Practices
GPTF Guidelines Process Task Force
HAL Haemophilia Activities List
HAV hepatitis A virus
ACRONYMS AND ABBREVIATIONS
WFH Guidelines for the Management of Hemophilia, 3rd edition178
HAEMO-QoL-A Hemophilia-specific quality of life
questionnaire for adults
HBsAg surface antigen of the hepatitis B
virus
HBV hepatitis B virus
HCCC Hemophilia comprehensive care
centre
HCV hepatitis C virus
HDL high density lipoprotein
HEAD-US Haemophilia Early Arthropathy
Detection with Ultrasound
HGVS Human Genome Variation Society
HIV human immunodeficiency virus
HJHS Hemophilia Joint Health Score
HMWK high-molecular-weight kininogen
HRQoL health-related quality of life
HTC hemophilia treatment centre
ICF International Classification of
Functioning, Disability and Health
(WHO)
ICH intracranial hemorrhage;
intracerebral hemorrhage
ICU intensive care unit
IDB inferior alveolar dental block, inferior
alveolar nerve block
IEQAS International External Quality
Assessment Scheme
IgG immunoglobulin G (IgG1, IgG2,
IgG3, IgG4)
Inv1 intron 1 inversion
IPAQ International Physical Activity
Questionnaire
IPSG International Prophylaxis Study
Group
IQC internal quality control
ISTH International Society on Thrombosis
and Haemostasis
ITI immune tolerance induction
IU international unit
IUD intrauterine device
IV intravenous
LA lupus anticoagulant
LDL low density lipoprotein
MACTAR McMaster Toronto Patient Disability
Questionnaire
MLPA multiplex ligation-dependent probe
amplification
MMR measles, mumps, rubella
MPS massively parallel sequencing
MRI magnetic resonance imaging
MSK musculoskeletal
MSKUS musculoskeletal ultrasound
NAT nucleic acid testing
NGC National Guideline Clearinghouse
NGS next generation sequencing
NMO national member organization
NSAIDs nonsteroidal anti-inflammatory drugs
OR odds ratio
PCC prothrombin complex concentrate
PCI percutaneous coronary intervention
PCR polymerase chain reaction
PedHAL Paediatric Haemophilia Activities List
PEG polyethylene glycol
PGD pre-implantation genetic assessment
PICO Population/Intervention/
Comparators/ Outcomes
PK pharmacokinetics
PND prenatal diagnosis
PNP pooled normal plasma
POLICE protection, optimum loading, ice,
compression, elevation
PPP platelet-poor plasma
PRICE protection, rest, ice, compression,
elevation
PRISMA Preferred Reporting Items for
Systematic Reviews and Meta-
Analyses
PRO patient-reported outcome
PROBE Patient-Reported Outcomes,
Burdens and Experiences
PT prothrombin time
179Acronyms and Abbreviations
PUPs previously untreated patients
QA quality assurance
QoL quality of life
rFIX recombinant factor IX
rFIXFc recombinant FIX-Fc
rFVIIa recombinant activated factor VII
rFVIII recombinant factor VIII
rFIX-FP recombinant FIX fusion protein
rFVIIIFc recombinant FVIII–Fc
rVIII-SingleChain single-chain recombinant FVIII
RICE rest, compression, ice, elevation
RNA ribonucleic acid
SF-36 36-Item Short Form Survey
Instrument
SHL standard half-life
siRNA-AT small interfering RNA agent
targeting antithrombin
SNV single nucleotide variant
SSC Scientific and Standardization
Committee of the ISTH
STEMI ST segment elevation myocardial
infarction
STR short tandem repeat
SV structural variant
t½ half-life
TCBS Trustworthy Consensus-Based
Statement
TFPI tissue factor pathway inhibitor
UK NEQAS U.K. National External Quality
Assessment Service
US ultrasonography, ultrasound
VAS visual analogue scale
vCJD variant Creutzfeldt-Jakob disease
VKA vitamin K antagonist
VTE venous thromboembolism
VWD von Willebrand disease
VWF von Willebrand factor
WBDR World Bleeding Disorders Registry
WFH World Federation of Hemophilia
WGS whole genome sequencing
WHO World Health Organization
XCI X chromosome inactivation
WFH Guidelines for the Management of Hemophilia, 3rd edition180
SYMBOLS AND MEASUREMENTS
μg microgram (mcg)
°C Celsius degrees
> greater than
< less than
= equal to
≥ greater than or equal to
≤ less than or equal to
± plus or minus
× multiplied by (times)
BU Bethesda Unit
cm centimetre
dL decilitre
g gram
IU international unit
kDa kilodalton
kg kilogram
m metres
mcg microgram, also known as μg
mg milligram
mL millilitre
ORCID
Alok Srivastava https://orcid.org/0000-0001-5032-5020
Elena Santagostino https://orcid.org/0000-0001-9639-6422
Alison Dougall https://orcid.org/0000-0003-0543-3940
Steve Kitchen https://orcid.org/0000-0002-6826-8519
Steven W. Pipe https://orcid.org/0000-0003-2558-2089
Manuel Carcao https://orcid.org/0000-0001-5350-1763
Margaret V. Ragni https://orcid.org/0000-0002-7830-5379
Johnny Mahlangu https://orcid.org/0000-0001-5781-7669
Jerzy Windyga https://orcid.org/0000-0001-7877-4784
Adolfo Llinás https://orcid.org/0000-0001-9573-8902
Pradeep M. Poonnoose https://orcid.org/0000-0001-7715-9982
Brian M. Feldman https://orcid.org/0000-0002-7813-9665
Sandra Zelman Lewis https://orcid.org/0000-0003-3934-4452
H. Marijke van den Berg https://orcid. org/0000-0002-2553-2324
Glenn F. Pierce https://orcid.org/0000-0002-3310-328X
Gerard Dolan https://orcid.org/0000-0003-3270-6932
Margareth C. Ozelo https://orcid.org/0000-0001-5938-0675
Emna Gouider https://orcid.org/0000-0001-7315-3479
Kate Khair https://orcid.org/0000-0003-2001-5958
Francisco de Paula Careta https://orcid. org/0000-0001-8590-3089
Silmara A. de Lima Montalvão https://orcid. org/0000-0002-8920-3765
Radoslaw Kaczmarek https://orcid.org/0000-0001-8084-1958
Claude T. Tagny https://orcid.org/0000-0002-2179-3105
Barbara A. Konkle https://orcid.org/0000-0002-3959-8797
Rolf C. R. Ljung https://orcid.org/0000-0003-3999-8747
Erik Berntorp https://orcid.org/0000-0002-2888-4931
Gianluigi Pasta https://orcid.org/0000-0002-1919-5130
Donna Con https://orcid.org/0000-0001-8372-4474
Melanie Golob https://orcid.org/0000-0002-5800-3672
