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)	450
	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