Textbook of Hemophilia (eBook)

Christine A. Lee, MA, MD, DSc, FRCP, FRCPath, Emeritus Professor of Haemophilia, University of London; Honorary Consultant Haematologist, Oxford Haemophilia & Thrombosis Centre, Oxford, UK. Erik E. Berntorp, MD, PhD, Professor of Hemophilia, Lund University; Director, Department of Coagulation Disorders, Malmo University Hospital, Malmo, Sweden. W. Keith Hoots, MD, Professor of Pediatrics, University of Texas M.D. Anderson Cancer Center; Professor of Pediatrics and Internal Medicine, University of Texas Medical School at Houston; Medical Director, Gulf States Hemophilia and Thrombophilia Center, Houston, Texas, USA.

Cover 1
Title page 5
Copyright page 6
Contents 7
Contributors 11
Historical introduction 17
Early history 17
Treatment 17
Human immunodeficiency virus 19
Hepatitis C virus 19
New products 20
Variant Creutzfeldt–Jakob disease 21
The future 21
Notes on this edition 21
References 22
PART I: Introduction 25
CHAPTER 1: Overview of hemostasis 27
Introduction 27
Importance of complex assembly to coagulation 27
Extrinsic pathway to blood coagulation 28
Attenuation of the procoagulant response 30
Conclusion 30
Acknowledgment 31
References 31
CHAPTER 2: Cellular processing of factor VIII and factor IX 33
Factor VIII and hemophilia A 33
Factor VIII expression 33
Domain structure of factor VIII 33
Disulfide bond formation 34
Asparagine- and serine/threonine-linked glycosylation 35
Chaperone-assisted factor VIII folding 37
Tyrosine sulfation 37
Phosphorylation of serine and threonine residues 38
Proteolytic processing 38
Summary 38
Factor IX and hemophilia B 38
Domain structure of factor IX 38
Disulfide bond formation 39
Asparagine- and serine/threonine-linked glycosylation 39
?-Carboxylation of glutamic acid residues 40
?-Hydroxylation of aspartic acid and asparagine 40
Tyrosine sulfation 40
Phosphorylation of serine and threonine residues 41
Factor IX Padua 41
Proteolytic processing 41
Summary 41
Acknowledgments 41
References 41
PART II: Hemophilia A 45
CHAPTER 3: Molecular basis of hemophilia A 47
Introduction 47
Structure and function of the factor VIII gene (F8) and protein 47
F8 gene 47
Production of factor VIII protein 47
F8 gene defects found in hemophilia A 48
Gene rearrangements 48
Single-base substitutions in the F8 gene 49
Sequence insertions and deletions 53
Conclusion 54
Public database 54
Mutation nomenclature 54
Disease severity 55
References 55
CHAPTER 4: Prophylaxis 57
Rationale for prophylaxis 57
Introduction of prophylaxis 57
Prophylaxis in children 57
When to start prophylaxis 58
Prophylaxis in adults 59
Prophylaxis versus on-demand therapy: issues of cost-effectiveness 59
Optimal treatment regimen for prophylaxis 60
Future issues in prophylaxis 61
Conclusion 61
References 61
PART III: Inhibitors to factor VIII 65
CHAPTER 5: Inhibitors to factor VIII: immunology 67
Introduction 67
Homeostasis of the antifactor VIII immune response 67
Lessons from animal models 67
Clinical observations 68
Characterization of antifactor VIII antibodies 68
Factor VIII-specific T cells 69
Future perspectives 70
References 70
CHAPTER 6: Genetic and environmental risk factors for factor VIII inhibitor development 72
Introduction 72
Genetic factors 72
Type of causative mutation 72
Major histocompatibility complex 73
Immune-regulatory molecules 73
Environmental factors 74
Factor concentrate-related factors 74
Conclusion 75
References 75
CHAPTER 7: Epidemiology of inhibitors in hemophilia 77
Introduction 77
Definitions of epidemiology terms 77
Definitions relating to inhibitor terms 77
Assessing inhibitor epidemiology in hemophilia 78
Inhibitor prevalence 78
Hemophilia A 78
Hemophilia B 79
Inhibitor incidence in previously untreated patients 79
Hemophilia A 79
Hemophilia B 80
Inhibitor incidence in previously treated patients 80
Natural history of inhibitors in hemophilia A 81
References 81
CHAPTER 8: Inhibitors to factor VIII: mild and moderate hemophilia 83
Introduction 83
Incidence and prevalence 83
Clinical presentation 83
Risk factors 84
Intensive exposure to factor VIII 84
Genetic background 84
Analysis of the immune response to factor VIII in mild/moderate hemophilia A 84
Treatment 85
Bleeding episodes 85
Inhibitor eradication 85
Prevention 85
Conclusion 85
References 86
CHAPTER 9: Inhibitors to factor VIII/IX: immune tolerance 88
Introduction 88
Immune tolerance for factor VIII inhibitors 88
Role of host factors in immune tolerance induction outcome 88
Role of treatment factors in immune tolerance induction outcome 88
Past, current, and future role of immune modulation in immune tolerance induction 90
Translation into clinical practise: recommendations for immune tolerance induction in severe hemophilia A patients with high-titer inhibitors 90
Special considerations for immune tolerance induction in severe hemophilia A patients with low-titer inhibitors 92
Hemophilia B: immune tolerance induction for factor IX inhibitors 92
Immunology of factor IX inhibitor development and tolerance 92
Immune tolerance induction for FIX inhibitors 93
Translation into clinical practise: recommendations for immune tolerance induction in hemophilia B 93
Conclusion 94
References 94
CHAPTER 10: Prophylaxis in inhibitor patients 96
Introduction 96
Evidence on primary prophylaxis with bypassing agents 96
Evidence on prophylaxis with bypassing agent during immune tolerance induction 97
Evidence from retrospective and prospective cohorts on secondary prophylaxis with bypassing agents after immune tolerance induction failure 97
Evidence from randomized clinical trials on secondary prophylaxis with bypassing agents 98
Discussion 99
Disclosure 99
References 99
CHAPTER 11: Inhibitors to factor VIII: treatment of acute bleeds 102
Introduction 102
Clinical context 102
Classification between high and low responders 102
Products 102
Human factor VIII concentrates 102
Porcine factor VIII 103
Activated prothrombin complex concentrates 103
Recombinant factor VIIa 104
Antifibrinolytics 105
Immunoadsorption 105
Management of bleeding situations 105
Conclusion 106
References 106
PART IV: Acquired hemophilia 109
CHAPTER 12: Acquired inhibitors to factor VIII 111
Epidemiology 111
Pathophysiology and characteristics of autoantibodies to factor VIII 111
Associated disease states 112
Clinical manifestations of acquired hemophilia 113
Laboratory diagnosis 113
Treatment 114
Autoantibody inhibitor eradication in acquired hemophilia 116
References 117
PART V: Hemophilia B 119
CHAPTER 13: Hemophilia B: molecular basis 121
Mutation nomenclature 121
Introduction 121
Techniques for mutation detection 122
Mechanisms of mutation in the F9 gene 123
Single nucleotide changes 123
Founder effect 124
Hemophilia B Leyden 125
Small insertions or deletions 125
Gross genetic abnormalities 125
Public databases 126
References 126
CHAPTER 14: Factor IX inhibitors in hemophilia B 127
Introduction 127
Frequency of inhibitors in hemophilia B 127
Risk factors for development of factor IX inhibitors 127
Age and number of exposure days to factor IX at detection of factor IX inhibitors 128
Anaphylaxis and other allergic reactions developing in close association with factor IX inhibitor development 128
Management of patients with hemophilia B complicated by a factor IX inhibitor 128
Management of bleeding episodes in patients with factor IX inhibitors 129
References 129
CHAPTER 15: Treatment of inhibitors in hemophilia B 131
Introduction 131
Epidemiology 131
Genetic and other risk factors of inhibitor development 131
Immunology 132
Clinical features and diagnosis 132
Treatment strategies 132
Control of acute bleeding 133
Prophylaxis 135
Overview of immune tolerance 135
Immune tolerance induction in hemophilia B 135
Acquired factor IX inhibitors in nonhemophilic patients 136
Conclusion 136
References 136
PART VI: Pharmacokinetics of factors VIII and IX 139
CHAPTER 16: Pharmacokinetics 141
Why pharmacokinetics? 141
Assays and plasma levels 141
Methods, definitions, and applications of pharmacokinetics 141
Pharmacokinetics of factor VIII 143
Pharmacokinetics of factor IX 144
Application of pharmacokinetics to treatment of hemophilia 144
Conclusion 145
References 145
CHAPTER 17: Individualized dosing 147
Introduction 147
Treatment of bleeding episodes 147
Prophylaxis 147
Prophylactic regimens 148
Surgery 150
Longer acting agents 151
Conclusion 151
References 151
PART VII: Hemophilia: birth to old age 153
CHAPTER 18: Neonate with hemophilia 155
Introduction 155
Family history and genetics of hemophilia 155
Hemostatic challenges in the neonatal period 155
Investigation and management of a neonate with a positive family history of hemophilia 157
Perinatal management 157
Delivery 157
Diagnostic investigations 157
Vitamin K 158
Routine cranial scanning 158
Counseling 158
Female carriers 158
Investigation of abnormal bleeding in the absence of a positive family history 158
Hemorrhagic neonate 158
Problems with diagnosis 158
Treatment of hemophilia during the neonatal period 159
Choice of product 159
Dosing regimens 159
Prophylactic treatment 159
Conclusion 159
References 160
CHAPTER 19: Work-up of a bleeding child 162
Introduction 162
Comprehensive medical history focusing on the child’s bleeding history 162
Family history 163
Physical examination 163
Laboratory evaluation 164
Complete blood count and peripheral blood film 165
Prothrombin time and the international normalized ratio 165
Activated partial thromboplastin time 165
Combined abnormalities of the prothrombin time and activated partial thromboplastin time 165
Bleeding time 166
Platelet function analyzer 166
Von Willebrand factor testing 166
Issues in coagulation testing 166
Specific coagulation testing 167
Conclusion 167
Acknowledgments 167
References 167
CHAPTER 20: Care of the child with hemophilia 169
Introduction 169
Medical care 169
Diagnosis and risk of inhibitor development 169
Treatment 169
Monitoring treatment 170
Venous access 170
Medication 171
Psychological care 171
Social care 172
Hemophilia identification cards 172
Vaccinations 172
Day-care center attendance and school 172
Leisure activities 172
References 172
CHAPTER 21: Hemophilia in adolescence 174
Introduction 174
Issues affecting adolescents with hemophilia 175
Transitional care 175
References 176
CHAPTER 22: Old age medicine and hemophilia 178
Introduction 178
Internal diseases 178
Hypertension 178
Renal abnormalities 179
Overweight 179
Diabetes mellitus 180
Cholesterol 180
Osteoporosis 180
Cardiovascular disease 180
Management 181
Atrial fibrillation 182
Malignancy and surgical interventions 182
Prevention of deep venous thrombosis 182
Tooth extraction 182
Sexuality 182
Psychological problems 183
Fear during hospitalization 183
Quality of life 183
Pain 183
Balance dysfunctions and risk of falls 184
Conclusion 184
References 185
PART VIII: Products used to treat hemophilia 187
CHAPTER 23: Products used to treat hemophilia: recombinant products 189
Introduction 189
Recombinant factor VIII: Kogenate (Helixate), Kogenate FS (Kogenate Bayer, Helixate FS/NexGen), and Kogenate FS BIO-SET 189
Clinical trials in previously treated patients 189
Clinical trials in previously untreated patients 190
Postmarketing clinical studies 190
Recombinant factor VIII: Recombinate (Bioclate) and Advate 190
Clinical trials in previously treated patients 191
Clinical trials in previously untreated patients 191
Pharmacokinetics of rAHF-PFM 191
Effect on prophylaxis 191
Hemostatic treatment with rAHF-PFM during surgery 191
Inhibitor development using rAHF-PFM 192
Recombinant factor VIII: ReFacto and Xyntha/Refacto AF 192
Clinical trials in previously treated patients 192
Clinical trials in previously untreated patients 192
Efficacy and safety in postmarketing clinical studies 192
Efficacy for surgical treatment 193
Incidence of de-novo inhibitors using FL-rFVIII and BDD-rFVIII 193
Recombinant factor VIII concentrates with a longer half-life 193
Recombinant factor IX (BeneFIX) 193
Pharmacokinetic studies 194
Clinical trials in previously treated patients 194
Clinical trials in previously untreated patients 194
Postmarketing clinical studies 194
Longer acting recombinant factor IX products 194
Future prospects 195
Acknowledgments 195
References 195
CHAPTER 24: Products used to treat hemophilia: plasma-derived coagulation factor concentrates 198
Introduction 198
Cryoprecipitate 198
Principles of manufacture 199
Product purity 199
Methods of viral inactivation and elimination 200
Potency and labeling issues 201
Selection of products 201
Plasma-derived concentrates for rare bleeding disorders 202
References 202
CHAPTER 25: Products used to treat hemophilia: dosing 204
Introduction 204
Historical background 204
Pharmacokinetics and dosage calculations 204
Home treatment 206
Treatment guidelines for specific bleeding episodes 206
Mouth and neck region 206
Complicated joint bleeds 207
Iliopsoas hemorrhages 207
Compartment syndrome 207
Central nervous system hemorrhages 207
Hematuria 207
Other 207
Conclusion 207
References 207
CHAPTER 26: Products used to treat hemophilia: regulation 209
Introduction 209
Products of local and blood bank production 209
Products of large-scale plasma fractionation 211
Facility licensure 211
Premarket product approval 212
Postmarket surveillance 212
Considerations arising from pediatric issues 213
Issues related to hemophilia concentrates from recombinant technology 213
Conclusion 214
References 214
CHAPTER 27: New drugs in the pipeline: from concept to clinic 216
Introduction 216
Longer acting factor concentrates 216
Fragment crystallizable fusion 216
Albumin fusion 216
PEGylation 217
Polysialylation 217
Alternative mechanisms for achieving hemostasis 217
Antitissue factor pathway inhibition 217
Less immunogenic factor concentrates 217
Enhanced bypassing agents 218
PEGylated liposomes 218
Recombinant factor VIIa analogs 218
Recombinant factor VIIa variants 218
Conclusion 219
References 219
PART IX: Surgical management 221
CHAPTER 28: General surgical management of patients with hemophilia 223
Introduction 223
General considerations 223
Major surgery 223
Cardiac surgery 224
Minor surgery 224
Dental surgery 224
Liver biopsy 225
Endoscopy 225
Urologic procedures 225
Surgery in children 225
Circumcision 225
Central venous access device insertion 225
Tonsillectomy/adenoidectomy 225
Special considerations in patients with mild hemophilia 226
DDAVP 226
Antifibrinolytic therapy 226
Potential nonbleeding complications of surgery 226
Summary 226
Acknowledgments 226
References 226
CHAPTER 29: Continuous infusion of coagulation products in hemophilia 228
Introduction 228
Historical background and rationale for continuous infusion 228
Stability of concentrates and continuous infusion technique 228
Continuous infusion of new-generation recombinant products 229
Bacteriologic safety of continuous infusion 229
Prevention of thrombophlebitis 230
Modes of continuous infusion and treatment protocols 230
Adjusted-dose continuous infusion 230
Fixed-rate continuous infusion 231
Clinical indications for continuous infusion 231
Continuous infusion of factor VIII 231
Continuous infusion of factor VIII for long-term prophylaxis 232
Continuous infusion of factor IX 232
Continuous infusion in patients with inhibitor 233
Complications of continuous infusion 234
Continuous infusion and inhibitors 234
References 234
CHAPTER 30: Surgery in inhibitor patients 237
Introduction 237
Products available for surgery 237
Activated prothrombin complex concentrate and activated recombinant activated factor VII 237
Preoperative planning 237
Management of substitution therapy in the peri- and postoperative phase 238
Activated prothrombin complex concentrate–Feiba 238
Recombinant factor VIIa (NovoSeven) 239
Bypassing agents and antifibrinolytics 240
Postoperative management 240
Bypassing agents and thromboprophylaxis 240
Economic considerations 240
Conclusion 240
References 240
PART X: Musculoskeletal 243
CHAPTER 31: Joint replacement in patients with hemophilia 245
Introduction 245
Total knee replacement 245
Human immunodeficiency virus infection 246
Operative procedure 246
Elbow replacement 247
Ankle replacement 248
Total hip replacement 248
Total shoulder replacement 249
Conclusion 250
References 250
CHAPTER 32: Medical synovectomy (synoviorthesis) in hemophilia: radiosynovectomy and chemical synovectomy 252
Introduction 252
Indications for synoviorthesis 252
Types of synoviorthesis 252
Age to perform synoviorthesis 253
Technique of synoviorthesis 253
Efficacy of radiosynovectomy 253
Complications and potential risks of radiosynovectomy 253
Multiple radiosynovectomy in a single session 254
Alternatives to synoviorthesis 254
Radiosynovectomy necessary in hemophilic patients despite prophylaxis 254
Choice of type of synoviorthesis 255
Conclusion 255
References 256
CHAPTER 33: Pseudotumors in patients with hemophilia 257
Introduction 257
Pathogenesis of pseudotumors 257
Clinical presentation 257
Investigations prior to treatment 257
Additional hemostatic measure 259
Prior to surgery 259
Realistic aims 259
Complications 259
References 260
CHAPTER 34: Imaging modalities for assessment of hemophilic arthropathy 261
Introduction 261
Radiography (X-ray) 261
Magnetic resonance imaging 263
Ultrasonography 266
Funding and acknowledgments 268
References 268
CHAPTER 35: Physiotherapy in the management of hemophilia 271
Introduction 271
Rehabilitation in children and adults with hemophilia 271
Acute hemarthrosis 271
Acute hematoma 272
Chronic arthropathy 272
Physical activity and sport 273
Elective orthopedic procedures 273
Total knee replacement 274
Ankle arthrodesis 274
Synovectomy 274
Patients with inhibitors 274
The aging hemophilic individual 274
Emerging clinical assessment tools in hemophilia 274
References 275
CHAPTER 36: Outcome assessment in hemophilia 277
Introduction 277
Musculoskeletal assessment: outcome measurement 277
Musculoskeletal outcome: assessment of structure and function 277
Physical examination scores 278
Radiologic scores 279
Musculoskeletal outcome: assessment of activities and functional independence in hemophilia 281
Musculoskeletal outcome: Assessment of participation 283
Musculoskeletal outcome: quality of life 283
Conclusion 283
References 283
PART XI: Transfusion-transmitted disease 287
CHAPTER 37: Viral hepatitis and hemophilia 289
Introduction 289
Hepatitis viruses in hemophilia 289
Hepatitis A virus 289
Hepatitis B virus 289
Hepatitis C virus 289
Treatment 291
Responses in people without hemophilia 292
Early virological response 292
Responses in people with hemophilia to treatment in treatment-naive patients 292
Responses to treatment in nonresponders, partial-responders, and responder-relapsers 292
Adverse events of treatment 293
Treatment of patients with normal transaminases (ALT/AST) 293
Treatment of patients with cirrhosis 293
Treatment of HIV-coinfected patients 293
Hepatocellular carcinoma 293
Liver transplantation 294
References 294
CHAPTER 38: Transfusion-transmitted disease: emerging infections 296
Introduction 296
Lipid-enveloped viruses 296
Nonlipid-enveloped viruses 297
Future directions 298
References 299
CHAPTER 39: vCJD and hemophilia 301
Introduction 301
What are prions? 301
Prevalence of vCJD 301
Risk of vCJD transmission by blood and clotting factor concentrates 302
Reducing the risk vCJD transmission by clotting factor concentrates 303
2004 public health notification of recipients of UK plasma-derived clotting factor concentrates 303
Infection control measures in hemophilia patients considered at risk of vCJD 304
vCJD surveillance of patients with hemophilia 304
Surveillance of recipients of vCJD implicated batches 304
Surveillance of recipients of UK plasma coagulation factors not known to be implicated 304
vCJD in other countries 305
Development of a screening test for vCJD 305
References 305
PART XII: Gene therapy 307
CHAPTER 40: Hemophilia gene therapy: an overview 309
Introduction 309
Rationale for gene transfer in hemophilia 309
Basic components of a gene transfer protocol 309
Therapeutic transgene 309
Transgene cassette 309
Transgene delivery protocol 310
Transgene vehicle 310
Nonviral transgene delivery 310
Viral vector-mediated transgene delivery 311
Adenoviral vectors 311
Retroviral vectors 311
Adeno-associated viral vectors 312
Future challenges for gene therapy 313
References 313
CHAPTER 41: Gene therapy trials in hemophilia A and B 315
Introduction 315
Initial trials of gene therapy for hemophilia 315
First trial of adeno-associated virus mediated gene transfer to liver 316
Second trial successfully addresses obstacles identified in the first 316
Continuation of second trial, and additional trials now underway for hemophilia B 318
Extension of the approach to hemophilia A 319
Summary 319
References 319
CHAPTER 42: Gene therapy: molecular engineering of factor VIII and factor IX 322
Introduction 322
Factor VIII with improved functional properties 322
Improved biosynthesis and secretion 322
Improved functional activity 326
Improved plasma half-life 327
Factor IX with improved functional properties 327
Increased mRNA production 328
Reduced binding to collagen IV 328
Increased specific activity 328
Future directions 329
References 329
PART XIII: Laboratory 333
CHAPTER 43: Laboratory and quality control of assays 335
Pre-analytical variables 335
Internal quality control 335
Prothrombin time and activated partial thromboplastin time determination 336
One-stage factor assays 337
Factor VIII assay discrepancy 338
Factor VIII assays after concentrate infusion 338
Factor VIII inhibitor testing 339
References 339
CHAPTER 44: Standardization of assays in hemophilia 342
Introduction 342
Principles of biological standardization 342
Comparative bioassay 342
Standards and units 342
“Like versus like” 343
Standardization of factor VIII assays 343
Assay methods 343
Assays of concentrates 344
Comparison of methods on concentrates 344
Assays of plasma 346
Postinfusion plasma 346
Standardization of factor IX assays 347
Standardization of inhibitor assays 348
Standardization of von Willebrand factor assays 349
Assays for von Willebrand factor 349
Standards for von Willebrand factor 349
Standardization of bypassing agents 349
Activated prothrombin complex concentrates 349
Factor VIIa 349
Standardization of assays of other coagulation factors 349
Standardization of global assays 349
References 350
CHAPTER 45: Global laboratory assays in hemophilia 352
Introduction 352
Limitations of standard coagulation assays 352
The ideal global coagulation assay 353
Methodologies 353
Measurement of continuous thrombin generation 353
Recording of whole blood clot formation 355
Tissue factor activation methods 356
Contact pathway activation methods 356
Laboratory phenotyping of bleeding disorders and monitoring of hemostatic intervention 357
References 357
PART XIV: Women and bleeding disorders 359
CHAPTER 46: Obstetrics and gynecology: hemophilia 361
Introduction 361
Gynecology 361
Management of menorrhagia 362
Genetics 362
Genetic counseling and carrier detection 362
Testing the carrier status of healthy children 363
Genetic diagnosis 363
Prenatal diagnosis 363
Management of pregnancy 364
Management of labor and delivery 364
Fetus 365
Mother 365
Postpartum hemorrhage 366
Rare bleeding disorders 366
Hemostatic agents and pregnancy 367
References 367
CHAPTER 47: Women and von Willebrand disease 369
Introduction 369
Epidemiology 369
Diagnostic aspects 369
Clinical characteristics 370
Management of von Willebrand disease-related heavy menstrual bleeding 371
Hemostatic agents (antifibrinolytic therapy, desmopressin, von Willebrand factor-containing plasma concentrates) 371
Hormonal therapy 372
Obstetric aspects 372
Management of von Willebrand disease during pregnancy 372
References 373
PART XV: von Willebrand disease 377
CHAPTER 48: von Willebrand disease: molecular aspects 379
Introduction 379
Mutation spectrum in von Willebrand disease 379
Type 3 379
Type 1 381
Type 2 381
Mechanisms of mutation 382
Large deletions and duplications 382
von Willebrand factor pseudogene and gene conversion 383
5’ untranslated region 384
Timing of genetic analysis 384
Summary 384
Acknowledgments 384
References 384
CHAPTER 49: von Willebrand disease: epidemiology 386
Introduction 386
Ascertainment and validity of epidemiologic data 386
Prevalence of severe von Willebrand disease (group A) 388
Prevalence of intermediate von Willebrand disease (group B) 388
Prevalence of mild von Willebrand disease 388
Prevalence of a mutant VWF gene 389
Frequency of von Willebrand disease subtypes 390
Prevalence of von Willebrand disease in developing countries 390
Practical implications 390
Presurgical screening 390
Diagnosis based on mild bleeding symptoms 391
A clinically useful diagnosis 391
Acknowledgment 392
References 392
CHAPTER 50: von Willebrand disease: biological diagnosis 394
Introduction 394
Screening tests 394
Complete blood count 394
PTT 394
Bleeding time 394
Platelet function analyzer 395
Diagnostic tests 395
VWF:Ag 395
VWF:RCo 396
FVIII:C 396
VWF multimer distribution 396
Confirmatory tests 396
VWF:CB 396
LD-RIPA 396
VWF:PB 397
VWF:F8B 397
VWFpp 397
VWF gene sequencing 397
Diagnosis 397
References 399
CHAPTER 51: Classification and clinical aspects of von Willebrand disease 401
Introduction 401
Prevalence and classification in the von Willebrand disease registries 401
Criteria for diagnosis 402
Positive bleeding history since childhood 402
Reduced von Willebrand factor activity in plasma 403
History of bleeding in the family with autosomal dominant or recessive inheritance 405
Genetics 405
Clinical definition of severe versus mild disease 406
Conclusion and future perspectives 407
Acknowledgments 407
References 407
CHAPTER 52: Treatment of von Willebrand disease: desmopressin 410
Introduction 410
Desmopressin 410
Clinical use of desmopressin 410
Monitoring treatment 411
Side-effects of desmopressin 412
Adjuvant treatments 412
Conclusion 412
References 412
CHAPTER 53: Treatment of von Willebrand disease: therapeutic concentrates 414
Introduction 414
Concentrates 414
Clinical studies with von Willebrand factor/factor VIII concentrates 414
Prospective studies 415
Retrospective studies 416
Prophylaxis 416
Information from guidelines and reviews 417
Discussion and recommendations 417
References 417
PART XVI: Rare bleeding disorders 421
CHAPTER 54: Factor II 423
Introduction 423
Biosynthesis 423
Structure and function 423
Prothrombin deficiency 423
Laboratory diagnosis 424
Clinical manifestations 424
Therapeutic aspects 425
Conclusion 425
References 425
CHAPTER 55: Factor V and combined factor V and VIII deficiencies 427
Factor V deficiency 427
Factor V protein 427
Gene structure and mutations 428
Clinical manifestations 429
Treatment 430
Combined deficiency of factor V and factor VIII 430
LMAN1 and MCFD2 proteins 431
Genes structure and mutations 431
Clinical manifestations 432
Treatment 433
Prenatal diagnosis 433
Acknowledgments 433
References 434
CHAPTER 56: Congenital factor VII deficiency 437
Introduction 437
Factor VII protein structure and function in hemostasis 437
Gene structure and mutations 438
Factor VII deficiency 438
Clinical manifestation 439
Factor VII deficiency in women 440
Laboratory diagnosis 440
Treatment of factor VII deficiency 440
Surgery in factor VII deficiency 441
Prophylaxis 442
Acknowledgments 442
References 442
CHAPTER 57: Factor X and factor X deficiency 445
Introduction 445
The factor X gene 445
Factor X protein: Structure and function 445
Role of factor X 446
Factor X deficiency 446
Diagnosis 446
Immunologic factor X assays 446
Functional factor X assays 446
Factor X levels in pregnancy and at birth 446
Classification of factor X deficiency 447
Clinical features 447
Molecular basis of factor X deficiency 448
Acquired factor X deficiency 448
Treatment of factor X deficiency 449
Tranexamic acid 449
Fibrin glue 449
Fresh frozen plasma 449
Prothrombin complex concentrates 449
Recombinant factor VIIa 449
Factor X concentrates 449
Management of an acute bleed in patients with severe factor X deficiency 450
Management of surgery in patients with severe factor X deficiency 450
Factor X prophylaxis 450
Management of severe factor X deficiency in pregnancy 450
Management of the neonate with severe factor X deficiency 450
Management of moderate factor X deficiency (FX:C >  2 U/dL)
Liver transplantation for factor X deficiency 450
References 450
CHAPTER 58: Factor XI deficiency 452
History 452
Biochemical features and function of factor XI 452
Inheritance and functional defect 453
Mutations 453
Prevalence and ethnic distribution 454
Bleeding manifestations in patients with severe deficiency 455
Bleeding manifestations in heterozygotes 455
Thrombosis 455
Development of inhibitors 456
Diagnosis 456
Therapy 456
References 458
CHAPTER 59: Factor XIII deficiency 460
Introduction 460
Structure/function 460
Molecular genetics 462
Clinical presentation 464
Diagnosis 465
Treatment 465
Prognosis 466
References 466
CHAPTER 60: Fibrinogen deficiency 469
Introduction 469
Fibrinogen structure 469
Genetics and regulation of synthesis 469
Fibrin clot formation 470
Fibrinogen interaction with other cells 471
Measuring fibrinogen 472
Afibrinogenemia 472
Genetics and molecular biology 472
Therapy 473
Dysfibrinogenemia 473
Dysfibrinogens associated with thrombosis 473
Dysfibrinogens associated with bleeding 474
Other syndromes associated with dysfibrinogens 474
Acquired dysfibrinogenemia 474
References 474
CHAPTER 61: Miscellaneous rare bleeding disorders 476
Introduction 476
Overview of fibrinolytic system 476
Congenital plasminogen activator inhibitor 1 deficiency 476
Role of plasminogen activator inhibitor 1 in fibrinolysis 476
Clinical presentation 477
Diagnosis and management 478
?2-Plasmin inhibitor deficiency 480
Role of ?2-plasmin inhibitor in fibrinolysis 480
Clinical presentation 480
Diagnosis and management 481
Vitamin K 481
Familial deficiency of vitamin K-dependent clotting factors 481
Conclusion 482
Resources 483
References 483
PART XVII: Emergency medicine 485
CHAPTER 62: Emergency management of hemophilia 487
Introduction 487
Central nervous system bleeding 487
Intracranial hemorrhage 487
Neonatal central nervous system hemorrhage 488
Spinal hematoma 489
Clotting factor replacement: recommendations for the treatment of central nervous system bleeds 489
Neurosurgical management of acute central nervous system events in patients with high-titer inhibitors 490
Noncentral nervous system emergent events 490
Injury in proximity to the airway 490
Gastrointestinal hemorrhage 490
Bleeding from organ rupture or hematoma of an abdominal viscus 491
Symptoms of nerve compression or compartment syndrome 492
Ophthalmologic emergencies 492
Rare clinical emergencies 492
Rupture of a pseudotumor 492
Conclusion 492
References 493
PART XVIII: Evaluation of hemophilia 495
CHAPTER 63: Clinical trials and other methodologies 497
Introduction 497
Type of study designs 497
Statistical considerations 498
Conclusion 500
Acknowledgments 500
References 500
CHAPTER 64: Quality of life in hemophilia 502
Introduction 502
Quality of life 502
Definition of quality of life 502
Issues concerning quality of life 502
Instrument characteristics 503
Development of quality of life instruments 503
Measures of quality of life 503
Generic instruments 503
Disease-specific instruments 504
Choice, use, and interpretation of quality of life measures 505
Quality of life research in hemophilia 506
Results from generic instruments 506
Results from disease-specific instruments 507
Future developments 508
Conclusion 508
Disclosure 509
References 509
CHAPTER 65: The economics of hemophilia treatment 513
Introduction 513
Health economic methods and the economic perspective 513
Health economic analyses in practise 514
Health economic evaluation 514
Perspective 515
Three methods for economic evaluation 515
Study design and data 516
Conclusion 517
References 517
PART XIX: Comprehensive care and delivery of care 519
CHAPTER 66: Hemophilia databases 521
Introduction 521
Functions of a national bleeding disorder database 521
Healthcare planning 521
Research 522
Pharmacovigilance 522
Problem of funding 522
Governance issues 522
Data security 522
Data Protection Act and consent 523
Anonymous or named database? 523
Database oversight committee 523
Technical specification, design, and staffing 524
The future 525
References 525
CHAPTER 67: Comprehensive care and delivery of care: the developed world 526
Introduction 526
European principles of hemophilia care 526
Arrangements for hemophilia care in the UK 527
UKHCDO National Register of Patients 527
UKHCDO working parties develop guidelines 527
The UK Haemophilia Society 527
The Haemophilia Nurses Association 528
The Haemophilia Chartered Physiotherapists Association 528
Social work support 528
Laboratory scientists 528
The Haemophilia Alliance 528
Comprehensive hemophilia care in the UK 528
The Haemophilia Alliance Service Specification 528
Carrier detection, genetic counseling, and antenatal diagnosis 529
Outcomes of hemophilia care 529
Audit 529
European networking initiatives 530
World Federation of Haemophilia and comprehensive care training 530
Future developments in provision of hemophilia care 530
References 531
CHAPTER 68: Comprehensive care and delivery of care in hemophilia: the developing world 532
Introduction 532
Developing world and its problems with hemophilia care 532
Comprehensive care and delivery of care 533
Establishing appropriate medical facilities 533
Identification and registration of people with hemophilia 534
Selecting appropriate models of care 534
Local self-sufficiency of plasma and factor concentrates 536
Educating patients and families about hemophilia 536
Improving social awareness and advocacy 536
Developing a program for delivery of care 536
Conclusion 537
References 537
CHAPTER 69: Comprehensive care and delivery of care: the global perspective 539
Introduction 539
Role of the World Federation of Hemophilia in global development 539
Introduction of comprehensive care 539
Building justification for comprehensive care through surveillance and data collection 542
Introducing and developing national care programs 542
Future challenges 544
Acknowledgment 544
References 544
Subject Index 547
Supplemental Images 563