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Factor VIII and factor IX inhibitors in patients with hemophilia

W Keith Hoots, MD
Amy D Shapiro, MD
Section Editors
Lawrence LK Leung, MD
Donald H Mahoney, Jr, MD
Deputy Editor
Jennifer S Tirnauer, MD


The hemophilias are a group of related bleeding disorders that most commonly are inherited. Inherited bleeding disorders include abnormalities of coagulation factors and platelet function; the most common of these disorders is von Willebrand disease. However, when the term "hemophilia" is used, it most often refers to the following two disorders:

Factor VIII deficiency (hemophilia A)

Factor IX deficiency (hemophilia B, also called Christmas disease)

Patients with hemophilia, particularly those with severe disease, develop bleeding episodes that are treated with replacement of the missing factor (ie, factor VIII or factor IX concentrates). A complication of hemophilia treatment is the development of an inhibitor, which usually occurs shortly after replacement therapy has been initiated. The inhibitors are antibodies (primarily IgG) directed against the specific deficient factor.

Development of inhibitors is typically assessed in relationship to the number of exposure days (ie, days on which the patient has received one or more doses of replacement factor).


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Literature review current through: Oct 2015. | This topic last updated: Jul 28, 2015.
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  1. Kempton CL, White GC 2nd. How we treat a hemophilia A patient with a factor VIII inhibitor. Blood 2009; 113:11.
  2. White GC 2nd, Rosendaal F, Aledort LM, et al. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 2001; 85:560.
  3. Allain JP, Frommel D. Antibodies to factor VIII. V. Patterns of immune response to factor VIII in hemophilia A. Blood 1976; 47:973.
  4. Feinstein DI. Inhibitors in hemophilia. In: : Basic Principles and Practice, 3rd ed, Hoffman R, Benz EJ Jr, Shattil SJ, et al. (Eds), Churchill Livingstone, New York 2000. p.1504.
  5. Caram C, de Souza RG, de Sousa JC, et al. The long-term course of factor VIII inhibitors in patients with congenital haemophilia A without immune tolerance induction. Thromb Haemost 2011; 105:59.
  6. Hoyer LW, Scandella D. Factor VIII inhibitors: structure and function in autoantibody and hemophilia A patients. Semin Hematol 1994; 31:1.
  7. Lusher JM, Arkin S, Abildgaard CF, Schwartz RS. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. Kogenate Previously Untreated Patient Study Group. N Engl J Med 1993; 328:453.
  8. Rasi V, Ikkala E. Haemophiliacs with factor VIII inhibitors in Finland: prevalence, incidence and outcome. Br J Haematol 1990; 76:369.
  9. Hay CR, Ludlam CA, Colvin BT, et al. Factor VIII inhibitors in mild and moderate-severity haemophilia A. UK Haemophilia Centre Directors Organisation. Thromb Haemost 1998; 79:762.
  10. Fijnvandraat K, Turenhout EA, van den Brink EN, et al. The missense mutation Arg593 --> Cys is related to antibody formation in a patient with mild hemophilia A. Blood 1997; 89:4371.
  11. Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate Study Group. Blood 1994; 83:2428.
  12. McMillan CW, Shapiro SS, Whitehurst D, et al. The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors. Blood 1988; 71:344.
  13. Sultan Y. Prevalence of inhibitors in a population of 3435 hemophilia patients in France. French Hemophilia Study Group. Thromb Haemost 1992; 67:600.
  14. Xi M, Makris M, Marcucci M, et al. Inhibitor development in previously treated hemophilia A patients: a systematic review, meta-analysis, and meta-regression. J Thromb Haemost 2013; 11:1655.
  15. Hay CR, Palmer B, Chalmers E, et al. Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom. Blood 2011; 117:6367.
  16. Prescott R, Nakai H, Saenko EL, et al. The inhibitor antibody response is more complex in hemophilia A patients than in most nonhemophiliacs with factor VIII autoantibodies. Recombinate and Kogenate Study Groups. Blood 1997; 89:3663.
  17. Healey JF, Barrow RT, Tamim HM, et al. Residues Glu2181-Val2243 contain a major determinant of the inhibitory epitope in the C2 domain of human factor VIII. Blood 1998; 92:3701.
  18. Healey JF, Lubin IM, Nakai H, et al. Residues 484-508 contain a major determinant of the inhibitory epitope in the A2 domain of human factor VIII. J Biol Chem 1995; 270:14505.
  19. Scandella D, Mattingly M, Prescott R. A recombinant factor VIII A2 domain polypeptide quantitatively neutralizes human inhibitor antibodies that bind to A2. Blood 1993; 82:1767.
  20. Zhong D, Saenko EL, Shima M, et al. Some human inhibitor antibodies interfere with factor VIII binding to factor IX. Blood 1998; 92:136.
  21. Arai M, Scandella D, Hoyer LW. Molecular basis of factor VIII inhibition by human antibodies. Antibodies that bind to the factor VIII light chain prevent the interaction of factor VIII with phospholipid. J Clin Invest 1989; 83:1978.
  22. Scandella D, Gilbert GE, Shima M, et al. Some factor VIII inhibitor antibodies recognize a common epitope corresponding to C2 domain amino acids 2248 through 2312, which overlap a phospholipid-binding site. Blood 1995; 86:1811.
  23. Jacquemin MG, Desqueper BG, Benhida A, et al. Mechanism and kinetics of factor VIII inactivation: study with an IgG4 monoclonal antibody derived from a hemophilia A patient with inhibitor. Blood 1998; 92:496.
  24. Saenko EL, Shima M, Rajalakshmi KJ, Scandella D. A role for the C2 domain of factor VIII in binding to von Willebrand factor. J Biol Chem 1994; 269:11601.
  25. Lollar P, Parker ET, Curtis JE, et al. Inhibition of human factor VIIIa by anti-A2 subunit antibodies. J Clin Invest 1994; 93:2497.
  26. Lamphear BJ, Fay PJ. Factor IXa enhances reconstitution of factor VIIIa from isolated A2 subunit and A1/A3-C1-C2 dimer. J Biol Chem 1992; 267:3725.
  27. O'Brien LM, Medved LV, Fay PJ. Localization of factor IXa and factor VIIIa interactive sites. J Biol Chem 1995; 270:27087.
  28. Lacroix-Desmazes S, Moreau A, Bonnemain C, et al. Catalytic activity of antibodies against factor VIII in patients with hemophilia A. Nat Med 1999; 5:1044.
  29. Lacroix-Desmazes S, Bayry J, Misra N, et al. The prevalence of proteolytic antibodies against factor VIII in hemophilia A. N Engl J Med 2002; 346:662.
  30. Schwaab R, Brackmann HH, Meyer C, et al. Haemophilia A: mutation type determines risk of inhibitor formation. Thromb Haemost 1995; 74:1402.
  31. Santagostino E, Mancuso ME, Rocino A, et al. Environmental risk factors for inhibitor development in children with haemophilia A: a case-control study. Br J Haematol 2005; 130:422.
  32. Gouw SC, van der Bom JG, Marijke van den Berg H. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood 2007; 109:4648.
  33. Antonarakis SE, Rossiter JP, Young M, et al. Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. Blood 1995; 86:2206.
  34. Kemball-Cook G, Tuddenham EG, Wacey AI. The factor VIII Structure and Mutation Resource Site: HAMSTeRS version 4. Nucleic Acids Res 1998; 26:216.
  35. Goodeve AC, Williams I, Bray GL, Peake IR. Relationship between factor VIII mutation type and inhibitor development in a cohort of previously untreated patients treated with recombinant factor VIII (Recombinate). Recombinate PUP Study Group. Thromb Haemost 2000; 83:844.
  36. Gouw SC, van den Berg HM, Oldenburg J, et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood 2012; 119:2922.
  37. Green PM, Bagnall RD, Waseem NH, Giannelli F. Haemophilia A mutations in the UK: results of screening one-third of the population. Br J Haematol 2008; 143:115.
  38. Jacquemin M, Vantomme V, Buhot C, et al. CD4+ T-cell clones specific for wild-type factor VIII: a molecular mechanism responsible for a higher incidence of inhibitor formation in mild/moderate hemophilia A. Blood 2003; 101:1351.
  39. Gill JC. The role of genetics in inhibitor formation. Thromb Haemost 1999; 82:500.
  40. 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 Thromb Haemost 2009; 7:930.
  41. Lorenzo JI, López A, Altisent C, Aznar JA. Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age. Br J Haematol 2001; 113:600.
  42. van der Bom JG, Mauser-Bunschoten EP, Fischer K, van den Berg HM. Age at first treatment and immune tolerance to factor VIII in severe hemophilia. Thromb Haemost 2003; 89:475.
  43. Rivard GE, Lillicrap D, Poon MC, et al. Can activated recombinant factor VII be used to postpone the exposure of infants to factor VIII until after 2 years of age? Haemophilia 2005; 11:335.
  44. Kempton CL, Soucie JM, Miller CH, et al. In non-severe hemophilia A the risk of inhibitor after intensive factor treatment is greater in older patients: a case-control study. J Thromb Haemost 2010; 8:2224.
  45. Astermark J, Berntorp E, White GC, et al. The Malmö International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients. Haemophilia 2001; 7:267.
  46. Carpenter SL, Michael Soucie J, Sterner S, et al. Increased prevalence of inhibitors in Hispanic patients with severe haemophilia A enrolled in the Universal Data Collection database. Haemophilia 2012; 18:e260.
  47. Viel KR, Ameri A, Abshire TC, et al. Inhibitors of factor VIII in black patients with hemophilia. N Engl J Med 2009; 360:1618.
  48. Iorio A, Halimeh S, Holzhauer S, et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010; 8:1256.
  49. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 9:418.
  50. Franchini M, Tagliaferri A, Mengoli C, Cruciani M. Cumulative inhibitor incidence in previously untreated patients with severe hemophilia A treated with plasma-derived versus recombinant factor VIII concentrates: a critical systematic review. Crit Rev Oncol Hematol 2012; 81:82.
  51. Gouw SC, van der Bom JG, Ljung R, et al. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 368:231.
  52. Mancuso ME, Mannucci PM, Rocino A, et al. Source and purity of factor VIII products as risk factors for inhibitor development in patients with hemophilia A. J Thromb Haemost 2012; 10:781.
  53. Giles AR, Rivard GE, Teitel J, Walker I. Surveillance for factor VIII inhibitor development in the Canadian Hemophilia A population following the widespread introduction of recombinant factor VIII replacement therapy. Transfus Sci 1998; 19:139.
  54. Bacon CL, Singleton E, Brady B, et al. Low risk of inhibitor formation in haemophilia A patients following en masse switch in treatment to a third generation full length plasma and albumin-free recombinant factor VIII product (ADVATE®). Haemophilia 2011; 17:407.
  55. Gouw SC, van der Bom JG, Auerswald G, et al. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood 2007; 109:4693.
  56. http://www.clinicaltrials.gov/ct2/show/record/NCT01064284 (Accessed on January 25, 2013).
  57. Kessler CM, Iorio A. The Rodin (Research Of Determinants of INhibitor Development among PUPs with haemophilia) study: the clinical conundrum from the perspective of haemophilia treaters. Haemophilia 2013; 19:351.
  58. Peerlinck K, Arnout J, Di Giambattista M, et al. Factor VIII inhibitors in previously treated haemophilia A patients with a double virus-inactivated plasma derived factor VIII concentrate. Thromb Haemost 1997; 77:80.
  59. Spiegel PC Jr, Stoddard BL. Optimization of factor VIII replacement therapy: can structural studies help in evading antibody inhibitors? Br J Haematol 2002; 119:310.
  60. Iorio A, Puccetti P, Makris M. Clotting factor concentrate switching and inhibitor development in hemophilia A. Blood 2012; 120:720.
  61. 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; 122:1954.
  62. Astermark J, Donfield SM, Gomperts ED, et al. The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort. Blood 2013; 121:1446.
  63. 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; 121:4046.
  64. Hay CR, Ollier W, Pepper L, et al. HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. UKHCDO Inhibitor Working Party. Thromb Haemost 1997; 77:234.
  65. Pavlova A, Delev D, Lacroix-Desmazes S, et al. Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-alpha and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia A. J Thromb Haemost 2009; 7:2006.
  66. Astermark J, Oldenburg J, Pavlova A, et al. Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with hemophilia A. Blood 2006; 107:3167.
  67. Astermark J, Wang X, Oldenburg J, et al. Polymorphisms in the CTLA-4 gene and inhibitor development in patients with severe hemophilia A. J Thromb Haemost 2007; 5:263.
  68. Lu Y, Ding Q, Dai J, et al. Impact of polymorphisms in genes involved in autoimmune disease on inhibitor development in Chinese patients with haemophilia A. Thromb Haemost 2012; 107:30.
  69. Astermark J, Oldenburg J, Carlson J, et al. Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A. Blood 2006; 108:3739.
  70. ter Avest PC, Fischer K, Mancuso ME, et al. Risk stratification for inhibitor development at first treatment for severe hemophilia A: a tool for clinical practice. J Thromb Haemost 2008; 6:2048.
  71. Morfini M, Haya S, Tagariello G, et al. European study on orthopaedic status of haemophilia patients with inhibitors. Haemophilia 2007; 13:606.
  72. Kasper CK, Aledort L, Aronson D, et al. Proceedings: A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975; 34:612.
  73. Verbruggen B, Novakova I, Wessels H, et al. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73:247.
  74. Krudysz-Amblo J, Parhami-Seren B, Butenas S, et al. Quantitation of anti-factor VIII antibodies in human plasma. Blood 2009; 113:2587.
  75. Soucie JM, Miller CH, Kelly FM, et al. National surveillance for hemophilia inhibitors in the United States: Summary report of an expert meeting. Am J Hematol 2014; 89:621.
  76. Kulkarni R, Aledort LM, Berntorp E, et al. Therapeutic choices for patients with hemophilia and high-titer inhibitors. Am J Hematol 2001; 67:240.
  77. Hay CR, Baglin TP, Collins PW, et al. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the UK Haemophilia Centre Doctors' Organization (UKHCDO). Br J Haematol 2000; 111:78.
  78. Hay CR, Brown S, Collins PW, et al. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the United Kingdom Haemophilia Centre Doctors Organisation. Br J Haematol 2006; 133:591.
  79. Gringeri A, Mantovani LG, Scalone L, et al. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood 2003; 102:2358.
  80. Lusher JM. Use of prothrombin complex concentrates in management of bleeding in hemophiliacs with inhibitors--benefits and limitations. Semin Hematol 1994; 31:49.
  81. Astermark J, Donfield 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; 109:546.
  82. Uehlinger J, Button GR, McCarthy J, et al. Immunoadsorption for coagulation factor inhibitors. Transfusion 1991; 31:265.
  83. Hay C, Lozier JN. Porcine factor VIII therapy in patients with factor VIII inhibitors. Adv Exp Med Biol 1995; 386:143.
  84. Hay CR, Lozier JN, Lee CA, et al. Safety profile of porcine factor VIII and its use as hospital and home-therapy for patients with haemophilia-A and inhibitors: the results of an international survey. Thromb Haemost 1996; 75:25.
  85. Brettler DB, Forsberg AD, Levine PH, et al. The use of porcine factor VIII concentrate (Hyate:C) in the treatment of patients with inhibitor antibodies to factor VIII. A multicenter US experience. Arch Intern Med 1989; 149:1381.
  86. Negrier C, Goudemand J, Sultan Y, et al. Multicenter retrospective study on the utilization of FEIBA in France in patients with factor VIII and factor IX inhibitors. French FEIBA Study Group. Factor Eight Bypassing Activity. Thromb Haemost 1997; 77:1113.
  87. Sjamsoedin LJ, Heijnen L, Mauser-Bunschoten EP, et al. The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII. A double-blind clinical trial. N Engl J Med 1981; 305:717.
  88. Lusher JM, Blatt PM, Penner JA, et al. Autoplex versus proplex: a controlled, double-blind study of effectiveness in acute hemarthroses in hemophiliacs with inhibitors to factor VIII. Blood 1983; 62:1135.
  89. Hough RE, Hampton KK, Preston FE, et al. Recombinant VIIa concentrate in the management of bleeding following prothrombin complex concentrate-related myocardial infarction in patients with haemophilia and inhibitors. Br J Haematol 2000; 111:974.
  90. Dargaud Y, Lienhart A, Negrier C. Prospective assessment of thrombin generation test for dose monitoring of bypassing therapy in hemophilia patients with inhibitors undergoing elective surgery. Blood 2010; 116:5734.
  91. Leissinger C, Gringeri A, Antmen B, et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med 2011; 365:1684.
  92. Antunes SV, Tangada S, Stasyshyn O, et al. Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia 2014; 20:65.
  93. Hedner U. Treatment of patients with factor VIII and factor IX inhibitors with special focus on the use of recombinant factor VIIa. Thromb Haemost 1999; 82:531.
  94. Key NS, Aledort LM, Beardsley D, et al. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. Thromb Haemost 1998; 80:912.
  95. Shapiro AD, Gilchrist GS, Hoots WK, et al. Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery. Thromb Haemost 1998; 80:773.
  96. Hedner U, Erhardtsen E. Potential role for rFVIIa in transfusion medicine. Transfusion 2002; 42:114.
  97. O'Connell N, Mc Mahon C, Smith J, et al. Recombinant factor VIIa in the management of surgery and acute bleeding episodes in children with haemophilia and high responding inhibitors. Br J Haematol 2002; 116:632.
  98. Santagostino E, Morfini M, Rocino A, et al. Relationship between factor VII activity and clinical efficacy of recombinant factor VIIa given by continuous infusion to patients with factor VIII inhibitors. Thromb Haemost 2001; 86:954.
  99. Ludlam CA, Smith MP, Morfini M, et al. A prospective study of recombinant activated factor VII administered by continuous infusion to inhibitor patients undergoing elective major orthopaedic surgery: a pharmacokinetic and efficacy evaluation. Br J Haematol 2003; 120:808.
  100. Smith MP, Ludlam CA, Collins PW, et al. Elective surgery on factor VIII inhibitor patients using continuous infusion of recombinant activated factor VII: plasma factor VII activity of 10 IU/ml is associated with an increased incidence of bleeding. Thromb Haemost 2001; 86:949.
  101. Ewenstein BM. Continuous infusion of recombinant factor VIIa: continue or not? Thromb Haemost 2001; 86:942.
  102. Pruthi RK, Mathew P, Valentino LA, et al. Haemostatic efficacy and safety of bolus and continuous infusion of recombinant factor VIIa are comparable in haemophilia patients with inhibitors undergoing major surgery. Results from an open-label, randomized, multicenter trial. Thromb Haemost 2007; 98:726.
  103. Santagostino E, Mancuso ME, Rocino A, et al. A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors. J Thromb Haemost 2006; 4:367.
  104. Kavakli K, Makris M, Zulfikar B, et al. Home treatment of haemarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. A multi-centre, randomised, double-blind, cross-over trial. Thromb Haemost 2006; 95:600.
  105. Young G, Shafer FE, Rojas P, Seremetis S. Single 270 microg kg(-1)-dose rFVIIa vs. standard 90 microg kg(-1)-dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: a randomized comparison. Haemophilia 2008; 14:287.
  106. Shapiro AD. Single-dose recombinant activated factor VII for the treatment of joint bleeds in hemophilia patients with inhibitors. Clin Adv Hematol Oncol 2008; 6:579.
  107. Konkle BA, Ebbesen LS, Erhardtsen E, et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J Thromb Haemost 2007; 5:1904.
  108. Hoots WK, Ebbesen LS, Konkle BA, et al. Secondary prophylaxis with recombinant activated factor VII improves health-related quality of life of haemophilia patients with inhibitors. Haemophilia 2008; 14:466.
  109. Huth-Kühne A, Baudo F, Collins P, et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica 2009; 94:566.
  110. Ingerslev J, Sørensen B. Parallel use of by-passing agents in haemophilia with inhibitors: a critical review. Br J Haematol 2011; 155:256.
  111. 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; 13:256.
  112. Hay CR, DiMichele DM, International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012; 119:1335.
  113. Kurth M, Puetz J, Kouides P, et al. The use of a single von Willebrand factor-containing, plasma-derived FVIII product in hemophilia A immune tolerance induction: the US experience. J Thromb Haemost 2011; 9:2229.
  114. Colowick AB, Bohn RL, Avorn J, Ewenstein BM. Immune tolerance induction in hemophilia patients with inhibitors: costly can be cheaper. Blood 2000; 96:1698.
  115. Ewing NP, Sanders NL, Dietrich SL, Kasper CK. Induction of immune tolerance to factor VIII in hemophiliacs with inhibitors. JAMA 1988; 259:65.
  116. Reipert BM, van Helden PM, Schwarz HP, Hausl C. Mechanisms of action of immune tolerance induction against factor VIII in patients with congenital haemophilia A and factor VIII inhibitors. Br J Haematol 2007; 136:12.
  117. Waters B, Lillicrap D. The molecular mechanisms of immunomodulation and tolerance induction to factor VIII. J Thromb Haemost 2009; 7:1446.
  118. Nilsson IM, Berntorp E, Zettervall O, Dahlbäck B. Noncoagulation inhibitory factor VIII antibodies after induction of tolerance to factor VIII in hemophilia A patients. Blood 1990; 75:378.
  119. Mariani G, Ghirardini A, Bellocco R. Immune tolerance in hemophilia-principal results from the International Registry. Report of the factor VIII and IX Subcommittee. Thromb Haemost 1994; 72:155.
  120. Mauser-Bunschoten EP, Nieuwenhuis HK, Roosendaal G, van den Berg HM. Low-dose immune tolerance induction in hemophilia A patients with inhibitors. Blood 1995; 86:983.
  121. DiMichele DM, Kroner BL, North American Immune Tolerance Study Group. The North American Immune Tolerance Registry: practices, outcomes, outcome predictors. Thromb Haemost 2002; 87:52.
  122. 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; 150:515.
  123. Coppola A, Margaglione M, Santagostino E, et al. Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance induction of hemophilia A patients with high-responding inhibitors. J Thromb Haemost 2009; 7:1809.
  124. Dunkley S, Kershaw G, Young G, et al. Rituximab treatment of mild haemophilia A with inhibitors: a proposed treatment protocol. Haemophilia 2006; 12:663.
  125. Chuansumrit A, Husapadol S, Wongwerawattanakoon P, et al. Rituximab as an adjuvant therapy to immune tolerance in a haemophilia A boy with high inhibitor titre. Haemophilia 2007; 13:108.
  126. Alexander S, Hopewell S, Hunter S, Chouksey A. Rituximab and desensitization for a patient with severe factor IX deficiency, inhibitors, and history of anaphylaxis. J Pediatr Hematol Oncol 2008; 30:93.
  127. Collins PW, Mathias M, Hanley J, et al. Rituximab and immune tolerance in severe hemophilia A: a consecutive national cohort. J Thromb Haemost 2009; 7:787.
  128. Kempton CL, Allen G, Hord J, et al. Eradication of factor VIII inhibitors in patients with mild and moderate hemophilia A. Am J Hematol 2012; 87:933.
  129. Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339:594.
  130. Shapiro AD, Ragni MV, Lusher JM, et al. Safety and efficacy of monoclonal antibody purified factor IX concentrate in previously untreated patients with hemophilia B. Thromb Haemost 1996; 75:30.
  131. Giannelli F, Choo KH, Rees DJ, et al. Gene deletions in patients with haemophilia B and anti-factor IX antibodies. Nature 1983; 303:181.
  132. Warrier I, Ewenstein BM, Koerper MA, et al. Factor IX inhibitors and anaphylaxis in hemophilia B. J Pediatr Hematol Oncol 1997; 19:23.
  133. Ljung RC. Gene mutations and inhibitor formation in patients with hemophilia B. Acta Haematol 1995; 94 Suppl 1:49.
  134. Parquet A, Laurian Y, Rothschild C, et al. Incidence of factor IX inhibitor development in severe haemophilia B patients treated with only one brand of high purity plasma derived factor IX concentrate. Thromb Haemost 1999; 82:1247.
  135. DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention. Br J Haematol 2007; 138:305.
  136. Green P. A database of point mutations and short additions and deletions in the Factor IX gene. Version 13, 2004. Available at: www.kcl.ac.uk/ip/petergreen/haemBdatabase.html (Accessed on August 06, 2007).
  137. Barthels M. Clinical efficacy of prothrombin complex concentrates and recombinant factor VIIa in the treatment of bleeding episodes in patients with factor VII and IX inhibitors. Thromb Res 1999; 95:S31.
  138. Mizon P, Goudemand J, Jude B, Marey A. Myocardial infarction after FEIBA therapy in a hemophilia-B patient with a factor IX inhibitor. Ann Hematol 1992; 64:309.
  139. Lusher JM, Roberts HR, Davignon G, et al. A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with haemophilia A and B, with and without inhibitors. rFVIIa Study Group. Haemophilia 1998; 4:790.
  140. Dharnidharka VR, Takemoto C, Ewenstein BM, et al. Membranous glomerulonephritis and nephrosis post factor IX infusions in hemophilia B. Pediatr Nephrol 1998; 12:654.
  141. Klarmann D, Martinez Saguer I, Funk MB, et al. Immune tolerance induction with mycophenolate-mofetil in two children with haemophilia B and inhibitor. Haemophilia 2008; 14:44.
  142. Thorland EC, Drost JB, Lusher JM, et al. Anaphylactic response to factor IX replacement therapy in haemophilia B patients: complete gene deletions confer the highest risk. Haemophilia 1999; 5:101.
  143. Chitlur M, Warrier I, Rajpurkar M, Lusher JM. Inhibitors in factor IX deficiency a report of the ISTH-SSC international FIX inhibitor registry (1997-2006). Haemophilia 2009; 15:1027.
  144. Tengborn L, Hansson S, Fasth A, et al. Anaphylactoid reactions and nephrotic syndrome--a considerable risk during factor IX treatment in patients with haemophilia B and inhibitors: a report on the outcome in two brothers. Haemophilia 1998; 4:854.