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.

• Contributors ixHistorical introduction xvChristine A. LeePart I: Introduction1 Overview of hemostasis 3Kathleen Brummel Ziedins and Kenneth G. Mann2 Cellular processing of factor VIII and factor IX 9Michael U. Callaghan and Randal J. KaufmanPart II: Hemophilia A3 Molecular basis of hemophilia A 23Geoffrey Kemball-Cook and Keith Gomez4 Prophylaxis 33Kathelijn Fischer and H. Marijke van den BergPart III: Inhibitors to Factor VIII5 Inhibitors to factor VIII: immunology 43Jean-Marie R. Saint-Remy and Marc G. Jacquemin6 Genetic and Environmental Risk Factors for Factor VIII inhibitor development 48Jan Astermark7 Epidemiology of inhibitors in hemophilia 53Alfonso Iorio8 Inhibitors to factor VIII: mild and moderate hemophilia 59Kathelijne Peerlinck and Marc Jacquemin9 Inhibitors to factor VIII/IX: immune tolerance 64Donna M. DiMichele10 Prophylaxis in inhibitor patients 72Alessandro Gringeri11 Inhibitors to factor VIII: treatment of acute bleeds 78Claude NegrierPart IV: Acquired Hemophilia12 Acquired inhibitors to factor VIII 87Craig M. KesslerPart V: Hemophilia B13 Hemophilia B: molecular basis 97Keith Gomez and Pratima Chowdary14 Factor IX inhibitors in hemophilia B 103Meera B. Chitlur and Jeanne M. Lusher15 Treatment of inhibitors in hemophilia B 107Anand Tandra and Amy D. ShapiroPart VI: Pharmacokinetics of Factors VIII and IX16 Pharmacokinetics 117Sven Björkman17 Individualized dosing 123Peter W. CollinsPart VII: Hemophilia: Birth to Old Age18 Neonate with hemophilia 131Angela E. Thomas and Elizabeth A. Chalmers19 Work-up of a bleeding child 138Manuel D. Carcao and Victor S. Blanchette20 Care of the child with hemophilia 145Rolf C.R. Ljung21 Hemophilia in adolescence 150Pia Petrini22 Old age medicine and hemophilia 154Evelien P. Mauser-Bunschoten and Roger E.G. SchutgensPart VIII: Products Used to Treat Hemophilia23 Products used to treat hemophilia: recombinant products 165Midori Shima and Akira Yoshioka24 Products used to treat hemophilia: plasma-derived coagulation factor concentrates 174Paul L.F. Giangrande25 Products used to treat hemophilia: dosing 180Miguel A. Escobar26 Products used to treat hemophilia: regulation 185Albert Farrugia27 New drugs in the pipeline: from concept to clinic 192Leonard A. ValentinoPart IX: Surgical management28 General surgical management of patients with hemophilia 199Cindy Leissinger and Rebecca Kruse-Jarres29 Continuous infusion of coagulation products in hemophilia 204Angelika Batorova and Uri Martinowitz30 Surgery in inhibitor patients 213Pål Andrè HolmePart X: Musculoskeletal31 Joint replacement in patients with hemophilia 221Nicholas Goddard32 Medical synovectomy (synoviorthesis) in hemophilia: radiosynovectomy and chemical synovectomy 228E. Carlos Rodriguez-Merchan33 Pseudotumors in patients with hemophilia 233Michael Heim and Uri Martinowitz34 Imaging modalities for assessment of hemophilic arthropathy 237Andrea S. Doria and Björn Lundin35 Physiotherapy in the management of hemophilia 247Sébastien Lobet and David Stephensen36 Outcome assessment in hemophilia 253Pradeep M. Poonnoose and Alok SrivastavaPart XI: Transfusion-transmitted Disease37 Viral hepatitis and hemophilia 265Michael Makris and Geoffrey Dusheiko38 Transfusion-transmitted disease: emerging infections 272Thomas R. Kreil39 vCJD and hemophilia 277Carolyn M. MillarPart XII: Gene Therapy40 Hemophilia gene therapy: an overview 285David Lillicrap41 Gene therapy trials in hemophilia A and B 291Katherine A. High42 Gene therapy: molecular engineering of factor VIII and factor IX 298Sundar R. Selvaraj and Steven W. PipePart XIII: Laboratory43 Laboratory and quality control of assays 311Steve Kitchen44 Standardization of assays in hemophilia 318Sanj Raut and Trevor W. Barrowcliffe45 Global laboratory assays in hemophilia 328Benny Sørensen and Guy YoungPart XIV: Women and Bleeding Disorders46 Obstetrics and gynecology: hemophilia 337Rezan A. Kadir and Christine A. Lee47 Women and von Willebrand disease 345Peter A. KouidesPart XV: von Willebrand Disease48 von Willebrand disease: molecular aspects 355Daniel Hampshire and Anne Goodeve49 von Willebrand disease: epidemiology 362Francesco Rodeghiero and Giancarlo Castaman50 von Willebrand disease: biological diagnosis 370Veronica H. Flood and Robert R. Montgomery51 Classification and clinical aspects of von Willebrand disease 377Augusto B. Federici52 Treatment of von Willebrand disease: desmopressin 386Pier M. Mannucci53 Treatment of von Willebrand disease: therapeutic concentrates 390Erik E. BerntorpPart XVI: Rare Bleeding Disorders54 Factor II 399Jan Astermark55 Factor V and combined factor V and VIII deficiencies 403Flora Peyvandi and Marzia Menegatti56 Congenital factor VII deficiency 413Angelika Batorova57 Factor X and factor X deficiency 421David J. Perry58 Factor XI deficiency 428Paula H.B. Bolton-Maggs and Uri Seligsohn59 Factor XIII deficiency 436Diane Nugent and Loan Hsieh60 Fibrinogen deficiency 445Michael Laffan61 Miscellaneous rare bleeding disorders 452Frederico Xavier and Amy D. ShapiroPart XVII: Emergency Medicine62 Emergency management of hemophilia 463W. Keith HootsPart XVIII: Evaluation of Hemophilia63 Clinical trials and other methodologies 473Sharyne M. Donfield and Alice E. Lail64 Quality of life in hemophilia 478Sylvia von Mackensen and Alessandro Gringeri65 The economics of hemophilia treatment 489Katarina Steen Carlsson and Erik E. BerntorpPart XIX: Comprehensive Care and Delivery of Care66 Hemophilia databases 497Charles R.M. Hay67 Comprehensive care and delivery of care: the developed world 502Christopher A. Ludlam and Cedric R.J.R. Hermans68 Comprehensive care and delivery of care in hemophilia: the developing world 508Alok Srivastava and Auro Viswabandya69 Comprehensive care and delivery of care: the global perspective 515Mark W. Skinner and Alison M. StreetIndex 523Color plate section can be found facing page 202

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.

• Contributors ixHistorical introduction xvChristine A. LeePart I: Introduction1 Overview of hemostasis 3Kathleen Brummel Ziedins and Kenneth G. Mann2 Cellular processing of factor VIII and factor IX 9Michael U. Callaghan and Randal J. KaufmanPart II: Hemophilia A3 Molecular basis of hemophilia A 23Geoffrey Kemball-Cook and Keith Gomez4 Prophylaxis 33Kathelijn Fischer and H. Marijke van den BergPart III: Inhibitors to Factor VIII5 Inhibitors to factor VIII: immunology 43Jean-Marie R. Saint-Remy and Marc G. Jacquemin6 Genetic and Environmental Risk Factors for Factor VIII inhibitor development 48Jan Astermark7 Epidemiology of inhibitors in hemophilia 53Alfonso Iorio8 Inhibitors to factor VIII: mild and moderate hemophilia 59Kathelijne Peerlinck and Marc Jacquemin9 Inhibitors to factor VIII/IX: immune tolerance 64Donna M. DiMichele10 Prophylaxis in inhibitor patients 72Alessandro Gringeri11 Inhibitors to factor VIII: treatment of acute bleeds 78Claude NegrierPart IV: Acquired Hemophilia12 Acquired inhibitors to factor VIII 87Craig M. KesslerPart V: Hemophilia B13 Hemophilia B: molecular basis 97Keith Gomez and Pratima Chowdary14 Factor IX inhibitors in hemophilia B 103Meera B. Chitlur and Jeanne M. Lusher15 Treatment of inhibitors in hemophilia B 107Anand Tandra and Amy D. ShapiroPart VI: Pharmacokinetics of Factors VIII and IX16 Pharmacokinetics 117Sven Björkman17 Individualized dosing 123Peter W. CollinsPart VII: Hemophilia: Birth to Old Age18 Neonate with hemophilia 131Angela E. Thomas and Elizabeth A. Chalmers19 Work-up of a bleeding child 138Manuel D. Carcao and Victor S. Blanchette20 Care of the child with hemophilia 145Rolf C.R. Ljung21 Hemophilia in adolescence 150Pia Petrini22 Old age medicine and hemophilia 154Evelien P. Mauser-Bunschoten and Roger E.G. SchutgensPart VIII: Products Used to Treat Hemophilia23 Products used to treat hemophilia: recombinant products 165Midori Shima and Akira Yoshioka24 Products used to treat hemophilia: plasma-derived coagulation factor concentrates 174Paul L.F. Giangrande25 Products used to treat hemophilia: dosing 180Miguel A. Escobar26 Products used to treat hemophilia: regulation 185Albert Farrugia27 New drugs in the pipeline: from concept to clinic 192Leonard A. ValentinoPart IX: Surgical management28 General surgical management of patients with hemophilia 199Cindy Leissinger and Rebecca Kruse-Jarres29 Continuous infusion of coagulation products in hemophilia 204Angelika Batorova and Uri Martinowitz30 Surgery in inhibitor patients 213Pål Andrè HolmePart X: Musculoskeletal31 Joint replacement in patients with hemophilia 221Nicholas Goddard32 Medical synovectomy (synoviorthesis) in hemophilia: radiosynovectomy and chemical synovectomy 228E. Carlos Rodriguez-Merchan33 Pseudotumors in patients with hemophilia 233Michael Heim and Uri Martinowitz34 Imaging modalities for assessment of hemophilic arthropathy 237Andrea S. Doria and Björn Lundin35 Physiotherapy in the management of hemophilia 247Sébastien Lobet and David Stephensen36 Outcome assessment in hemophilia 253Pradeep M. Poonnoose and Alok SrivastavaPart XI: Transfusion-transmitted Disease37 Viral hepatitis and hemophilia 265Michael Makris and Geoffrey Dusheiko38 Transfusion-transmitted disease: emerging infections 272Thomas R. Kreil39 vCJD and hemophilia 277Carolyn M. MillarPart XII: Gene Therapy40 Hemophilia gene therapy: an overview 285David Lillicrap41 Gene therapy trials in hemophilia A and B 291Katherine A. High42 Gene therapy: molecular engineering of factor VIII and factor IX 298Sundar R. Selvaraj and Steven W. PipePart XIII: Laboratory43 Laboratory and quality control of assays 311Steve Kitchen44 Standardization of assays in hemophilia 318Sanj Raut and Trevor W. Barrowcliffe45 Global laboratory assays in hemophilia 328Benny Sørensen and Guy YoungPart XIV: Women and Bleeding Disorders46 Obstetrics and gynecology: hemophilia 337Rezan A. Kadir and Christine A. Lee47 Women and von Willebrand disease 345Peter A. KouidesPart XV: von Willebrand Disease48 von Willebrand disease: molecular aspects 355Daniel Hampshire and Anne Goodeve49 von Willebrand disease: epidemiology 362Francesco Rodeghiero and Giancarlo Castaman50 von Willebrand disease: biological diagnosis 370Veronica H. Flood and Robert R. Montgomery51 Classification and clinical aspects of von Willebrand disease 377Augusto B. Federici52 Treatment of von Willebrand disease: desmopressin 386Pier M. Mannucci53 Treatment of von Willebrand disease: therapeutic concentrates 390Erik E. BerntorpPart XVI: Rare Bleeding Disorders54 Factor II 399Jan Astermark55 Factor V and combined factor V and VIII deficiencies 403Flora Peyvandi and Marzia Menegatti56 Congenital factor VII deficiency 413Angelika Batorova57 Factor X and factor X deficiency 421David J. Perry58 Factor XI deficiency 428Paula H.B. Bolton-Maggs and Uri Seligsohn59 Factor XIII deficiency 436Diane Nugent and Loan Hsieh60 Fibrinogen deficiency 445Michael Laffan61 Miscellaneous rare bleeding disorders 452Frederico Xavier and Amy D. ShapiroPart XVII: Emergency Medicine62 Emergency management of hemophilia 463W. Keith HootsPart XVIII: Evaluation of Hemophilia63 Clinical trials and other methodologies 473Sharyne M. Donfield and Alice E. Lail64 Quality of life in hemophilia 478Sylvia von Mackensen and Alessandro Gringeri65 The economics of hemophilia treatment 489Katarina Steen Carlsson and Erik E. BerntorpPart XIX: Comprehensive Care and Delivery of Care66 Hemophilia databases 497Charles R.M. Hay67 Comprehensive care and delivery of care: the developed world 502Christopher A. Ludlam and Cedric R.J.R. Hermans68 Comprehensive care and delivery of care in hemophilia: the developing world 508Alok Srivastava and Auro Viswabandya69 Comprehensive care and delivery of care: the global perspective 515Mark W. Skinner and Alison M. StreetIndex 523Color plate section can be found facing page 202

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.

• Contributors ixHistorical introduction xvChristine A. LeePart I: Introduction1 Overview of hemostasis 3Kathleen Brummel Ziedins and Kenneth G. Mann2 Cellular processing of factor VIII and factor IX 9Michael U. Callaghan and Randal J. KaufmanPart II: Hemophilia A3 Molecular basis of hemophilia A 23Geoffrey Kemball-Cook and Keith Gomez4 Prophylaxis 33Kathelijn Fischer and H. Marijke van den BergPart III: Inhibitors to Factor VIII5 Inhibitors to factor VIII: immunology 43Jean-Marie R. Saint-Remy and Marc G. Jacquemin6 Genetic and Environmental Risk Factors for Factor VIII inhibitor development 48Jan Astermark7 Epidemiology of inhibitors in hemophilia 53Alfonso Iorio8 Inhibitors to factor VIII: mild and moderate hemophilia 59Kathelijne Peerlinck and Marc Jacquemin9 Inhibitors to factor VIII/IX: immune tolerance 64Donna M. DiMichele10 Prophylaxis in inhibitor patients 72Alessandro Gringeri11 Inhibitors to factor VIII: treatment of acute bleeds 78Claude NegrierPart IV: Acquired Hemophilia12 Acquired inhibitors to factor VIII 87Craig M. KesslerPart V: Hemophilia B13 Hemophilia B: molecular basis 97Keith Gomez and Pratima Chowdary14 Factor IX inhibitors in hemophilia B 103Meera B. Chitlur and Jeanne M. Lusher15 Treatment of inhibitors in hemophilia B 107Anand Tandra and Amy D. ShapiroPart VI: Pharmacokinetics of Factors VIII and IX16 Pharmacokinetics 117Sven Björkman17 Individualized dosing 123Peter W. CollinsPart VII: Hemophilia: Birth to Old Age18 Neonate with hemophilia 131Angela E. Thomas and Elizabeth A. Chalmers19 Work-up of a bleeding child 138Manuel D. Carcao and Victor S. Blanchette20 Care of the child with hemophilia 145Rolf C.R. Ljung21 Hemophilia in adolescence 150Pia Petrini22 Old age medicine and hemophilia 154Evelien P. Mauser-Bunschoten and Roger E.G. SchutgensPart VIII: Products Used to Treat Hemophilia23 Products used to treat hemophilia: recombinant products 165Midori Shima and Akira Yoshioka24 Products used to treat hemophilia: plasma-derived coagulation factor concentrates 174Paul L.F. Giangrande25 Products used to treat hemophilia: dosing 180Miguel A. Escobar26 Products used to treat hemophilia: regulation 185Albert Farrugia27 New drugs in the pipeline: from concept to clinic 192Leonard A. ValentinoPart IX: Surgical management28 General surgical management of patients with hemophilia 199Cindy Leissinger and Rebecca Kruse-Jarres29 Continuous infusion of coagulation products in hemophilia 204Angelika Batorova and Uri Martinowitz30 Surgery in inhibitor patients 213Pål Andrè HolmePart X: Musculoskeletal31 Joint replacement in patients with hemophilia 221Nicholas Goddard32 Medical synovectomy (synoviorthesis) in hemophilia: radiosynovectomy and chemical synovectomy 228E. Carlos Rodriguez-Merchan33 Pseudotumors in patients with hemophilia 233Michael Heim and Uri Martinowitz34 Imaging modalities for assessment of hemophilic arthropathy 237Andrea S. Doria and Björn Lundin35 Physiotherapy in the management of hemophilia 247Sébastien Lobet and David Stephensen36 Outcome assessment in hemophilia 253Pradeep M. Poonnoose and Alok SrivastavaPart XI: Transfusion-transmitted Disease37 Viral hepatitis and hemophilia 265Michael Makris and Geoffrey Dusheiko38 Transfusion-transmitted disease: emerging infections 272Thomas R. Kreil39 vCJD and hemophilia 277Carolyn M. MillarPart XII: Gene Therapy40 Hemophilia gene therapy: an overview 285David Lillicrap41 Gene therapy trials in hemophilia A and B 291Katherine A. High42 Gene therapy: molecular engineering of factor VIII and factor IX 298Sundar R. Selvaraj and Steven W. PipePart XIII: Laboratory43 Laboratory and quality control of assays 311Steve Kitchen44 Standardization of assays in hemophilia 318Sanj Raut and Trevor W. Barrowcliffe45 Global laboratory assays in hemophilia 328Benny Sørensen and Guy YoungPart XIV: Women and Bleeding Disorders46 Obstetrics and gynecology: hemophilia 337Rezan A. Kadir and Christine A. Lee47 Women and von Willebrand disease 345Peter A. KouidesPart XV: von Willebrand Disease48 von Willebrand disease: molecular aspects 355Daniel Hampshire and Anne Goodeve49 von Willebrand disease: epidemiology 362Francesco Rodeghiero and Giancarlo Castaman50 von Willebrand disease: biological diagnosis 370Veronica H. Flood and Robert R. Montgomery51 Classification and clinical aspects of von Willebrand disease 377Augusto B. Federici52 Treatment of von Willebrand disease: desmopressin 386Pier M. Mannucci53 Treatment of von Willebrand disease: therapeutic concentrates 390Erik E. BerntorpPart XVI: Rare Bleeding Disorders54 Factor II 399Jan Astermark55 Factor V and combined factor V and VIII deficiencies 403Flora Peyvandi and Marzia Menegatti56 Congenital factor VII deficiency 413Angelika Batorova57 Factor X and factor X deficiency 421David J. Perry58 Factor XI deficiency 428Paula H.B. Bolton-Maggs and Uri Seligsohn59 Factor XIII deficiency 436Diane Nugent and Loan Hsieh60 Fibrinogen deficiency 445Michael Laffan61 Miscellaneous rare bleeding disorders 452Frederico Xavier and Amy D. ShapiroPart XVII: Emergency Medicine62 Emergency management of hemophilia 463W. Keith HootsPart XVIII: Evaluation of Hemophilia63 Clinical trials and other methodologies 473Sharyne M. Donfield and Alice E. Lail64 Quality of life in hemophilia 478Sylvia von Mackensen and Alessandro Gringeri65 The economics of hemophilia treatment 489Katarina Steen Carlsson and Erik E. BerntorpPart XIX: Comprehensive Care and Delivery of Care66 Hemophilia databases 497Charles R.M. Hay67 Comprehensive care and delivery of care: the developed world 502Christopher A. Ludlam and Cedric R.J.R. Hermans68 Comprehensive care and delivery of care in hemophilia: the developing world 508Alok Srivastava and Auro Viswabandya69 Comprehensive care and delivery of care: the global perspective 515Mark W. Skinner and Alison M. StreetIndex 523Color plate section can be found facing page 202