Best Practice & Research Clinical Haematology
Volume 19, Issue 1 , Pages 51-66 , March 2006

Management of factor VIII inhibitors

  • Suchitra S. Acharya, MD (Assistant Professor of Pediatrics)

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +1 212 746 4942; Fax: +1 212 746 8986.
    • ,
  • Donna M. DiMichele, MD (Associate Professor of Pediatrics)

References 

  1. DiMichele DM, Neufeld EJ. Haemophilia. A new approach to an old disease. Hematol Oncol Clin North Am. 1998;12(6):1315–1344
  2. Oldenburg J, Brackmann HH, Schwaab R. Risk factors for inhibitor development in haemophilia A. Haematologica. 2000;85:7–13
  3. Peerlinck K, Jacquemin M. Characterization of inhibitors in congenital haemophilia. In:  Rodriguez-Merchan EC,  Lee CA editor. Inhibitors in Patients with Haemophilia. Oxford: Blackwell Science; 2002;p. 9–13[26]
  4. Lacroix-Desmazes S, Sooryanarayana , Moreau A, et al. Factor VIII inhibitor with catalytic activity towards factor VIII. Haematologica. 2000;85(10 supplement):89–92
  5. 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;83:1978–1984
  6. Shima M, Scandella D, Yoshioka A, et al. A factor VIII neutralizing monoclonal antibody and a human inhibitor alloantibody recognizing epitopes in the C2 domain inhibit factor VIII binding to von Willebrand factor and to phosphatidylserine. Thromb Haemost. 1993;69:240–246
  7. Kazatchkine MD, Sultan Y, Burton-Kee EJ, Mowbray JF. Circulating immune complexes containing anti-FVIII antibodies in multitransfused patients with haemophilia A. Clin Exp Immunol. 1980;39:315–320
  8. Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet. 1992;339:594–598
  9. Brown DL, Bray GL, Scharrer I. Transient inhibitors in patients with haemophilia A. Thromb Haemost. 1999;573:1804;[Abstract]
  10. Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor VIII (Recombinate): safety, efficacy and inhibitor risk in previously untreated individuals with haemophilia A. The Recombinate Study Group. Blood. 1994;83:2428–2435
  11. Lusher JM, Spira J, Rodriguez D. A four-year update of safety and efficacy of an albumin-free formulated B-domain deleted factor VIII (BBD rFVIII, rVIIIISQ) in previously untreated severe haemophilia A patients. Thromb Haemost. 1999;82:1493
  12. Giles AR, Rivard GE, Teitel J, Walker I. Surveillance for factor VIII inhibitor development in the Canadian haemophilia A population following the widespread introduction of recombinant factor VIII replacement therapy. Transfus Sci. 1998;19(2):139–148
  13. Kreuz W, Ettingshausen CE, Auerswald G, et al. GTH PUP Study Group. Epidemiology of inhibitors and current treatment strategies. Haematologica. 2003;88(6):EREP04
  14. Kasper CK, Aledort L, Aronson D, et al. Proceedings: a more uniform measurement of factor VIII inhibitors [Letter]. Thromb Diath Haemorrh. 1975;34:612
  15. 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;73:247–251
  16. Paisley S, Wight J, Currie E, Knight C. The management of inhibitors in haemophilia A: introduction and systematic review of current practice. Haemophilia. 2003;9:405–417
  17. White GC, Rosendaal F, Aledort L, et al. Factor VIII and factor IX subcommittee. Definitions in haemophilia. 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(3):560
  18. Fulcher CA. Immunochemistry of factor VIII:C inhibitors antibodies. Am J Med. 1991;91:6S–8S
  19. Gilles JGG, Arnout J, Vermylen J, et al. Anti-factor VIII antibodies of hemophiliac patients are frequently directed towards non-functional determinants and do not exhibit isotypic restriction. Blood. 1993;82:2452–2461
  20. Saenko EL, Ananyeva NM, Kouiavskaia DV, et al. Haemophilia A: effects of inhibitory antibodies on factor VIII functional interactions and approaches to prevent their action. Haemophilia. 2002;8(1):1–11
  21. Fulcher CA, De Graaf Mahoney S, et al. Localization of human factor VIII epitopes to two polypeptide fragments. Proc Natl Acad Sci USA. 1985;82:7728–7732
  22. Bretscher PA. A two-step, two signal model for the primary activation of precursor helper T cells. Proc Natl Acad Sci. 1999;96:185–190
  23. Coyle AJ, Gutierrez-Ramos J-C. The expanding B7 superfamily: increasing complexity in co-stimulatory signals regulating T cell function. Nat Immunol. 2001;2:203–209
  24. Kreuz W, Ettingshausen CE, Zyschka A, et al. Inhibitor development in previously untreated patients with haemophilia A: a prospective long-term follow-up comparing plasma-derived and recombinant products. Semin Thromb Hemost. 2002;28:285–290
  25. Oldenberg J, Tuddenham E. Genetic basis of inhibitor development in severe haemophilia A and B. In:  Rodriguez-Merchan EC,  Lee CA editor. Inhibitors in Patients with Haemophilia. Oxford: Blackwell Publishing; 2002;p. 21–26
  26. Astermark J, Berntorp E, White GC, Kroner BL. The Malmo International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in haemophilia patients. Haemophilia. 2001;7:267–272
  27. Addiego JR, Kasper C, Abildgaard C, et al. Increased frequency of inhibitors in African American haemophilia A patients. Blood. 1994;1(supplement):239a
  28. Lorenzo JI, Lopez A, Altisent C, Aznar JA. Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age. Br J Haematol. 2001;113(3):600–603
  29. Sharathkumar A, Lillicrap D, Blanchette VS, et al. Intensive exposure to factor VIII is a risk factor for inhibitor development in mild haemophilia A. J Thromb Haemost. 2003;1:1228–1236
  30. Knobe KE, Sjorin E, Tengborn LI, et al. Inhibitors in the Swedish population with severe haemophilia A and B. A 20 year surgey. Acta Pediatr. 2002;910–914
  31. Rothschild C, Goudemand J, Demiguel V, et al. Effect of type of treatment (recombinant vs plasmatic) on FVIII inhibitor incidence according to known risk cofactors in previously untreated severe haemophilia A patients (PUPs). J Thromb Haemost. 2003;1(supplement):[Abstract OC 215]
  32. Behrmann M, Pasi J, Saint-Remy JM, et al. Von Willebrand factor modulates factor VIII immunogenicity: comparative study of different factor VIII concentrates in a haemophilia A mouse model. Thromb Haemost. 2002;88:221–229
  33. Morfini M, Lee M, Messori A. The design and analysis of half-life and recovery studies for factor VIII and factor IX. Factor VIII/Factor IX Scientific and Standardization Committee of the International Society for Thrombosis and Haemostasis. Thromb Haemost. 1991;66(3):384–386
  34. Batorova A, Martinowitz U. Intermittent injections vs. continuous infusion of factor VIII in haemophilia patients undergoing major surgery. Br J Haematol. 2000;110(3):715–720
  35. Lusher JM, Blatt PM, Penner JA, et al. Autoplex versus proplex: a controlled, double-blind study of effectiveness in acute hemarthroses in haemophiliacs with inhibitors to factor VIII. Blood. 1983;62:1135–1138
  36. Turecek PL, Varadi K, Gritsch H, Schwarz HP. FEIBA: mode of action. Haemophilia. 2004;10(supplement 2):3–9
  37. 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;77:1113–1119
  38. Hilgartner MW, Makipernaa A, DiMichele DM. Long-term FEIBA prophylaxis does not prevent progression of existing joint disease. Haemophilia. 2003;9:261–268
  39. Brackmann HH, Oldenberg J, Schwaab R. Immune tolerance for the treatment of of FVIII inhibitors-twenty years of the Bonn protocol. Vox Sang. 1996;70(supplement):30–35
  40. Hoffman M, Monroe DM. The action of high-dose factor VIIa (FVIIa) in a cell-based model of hemostasis. Semin Hematol. 2001;38:6–9
  41. Lisman T, Mosnier LO, Lambert T, et al. Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe haemophilia A. Blood. 2002;99:175–179
  42. Bech RM. Recombinant factor VIIa in joint and muscle bleeding episodes. Haemostasis. 1996;26:135–138
  43. 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;4:790–798
  44. 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(6):912–918
  45. Lusher JM. Acute hemarthroses: the benefits of early versus late treatment with recombinant activated factor VII. Blood Coagul Fibrinolysis. 2000;11(supplement 1):S45–S49
  46. 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;80:773–778
  47. Ingerslev J, Freidman D, Gastineau D, et al. Major surgery in haemophilic patients with inhibitors using recombinant factor VIIa. Haemostasis. 1996;26:118–123
  48. Schulman S, d'Oiron R, Martinowitz U, et al. Experiences with continuous infusion of recombinant activated factor VII. Blood Coagul Fibrinolysis. 1998;9(supplement 1):S97–S101
  49. Shapiro A. Inhibitor treatment: state of the art. Semin Hematol. 2001;38:26–34
  50. Kenet G, Lubetsky A, Luboshitz J, Martinowitz U. A new approach to treatment of bleeding episodes in young haemophilia patients: a single bolus megadose of recombinant activated factor VII (NovoSeven). J Thromb Haemost. 2003;1:450–455
  51. Hoffman M, Monroe DM. The action of high-dose factor VIIa (FVIIa) in a cell-based model of hemostasis. Semin Hematol. 2001;38(4 supplement 12):6–9
  52. Ehrlich HJ, Henzl MJ, Gomperts ED. Safety of factor VIII inhibitor bypass activity (FEIBA): 10-year compilation of thrombotic adverse events. Haemophilia. 2002;8(2):83–90
  53. Ludlam CA. The evidence behind inhibitor treatment with recombinant factor VIIa. Pathophysiol Haemost Thromb. 2002;32(supplement 1):13–18
  54. Antovic J, Schulman S, Eelde A, Blomback M. Total thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and pro-TAFI in patients with haemophilia A. Haemophilia. 2001;7:557–560
  55. Mariani G, Kroner B. Immune tolerance in haemophilia with factor VIII inhibitors: predictors of success. Haematologica. 2001;86:1186–1193
  56. Jansen M, Schmaldienst S, Banyai S, et al. Treatment of coagulation inhibitors with extracorporeal immunoadsorption (Ig-Therasorb). Br J Haematol. 2001;112(1):91–97
  57. Brackmann HH, Gormsen J. Massive factor-VIII infusion in haemophiliac with factor-VIII inhibitor, high responder. Lancet. 1977;29(2(8044)):933
  58. Mariani G, Siragusa S, Kroner BL. Immune tolerance induction in hemophilia A: a review. Semin Thromb Hemost. 2003;29(1):69–76
  59. Mariani G, Scheibel E, Nogao T, et al. Immunetolerance as treatment of alloantibodies to factor VIII in haemophilia. The International Registry of Immunetolerance Protocols. Semin Hematol. 1994;31:62–64
  60. Lenk H, ITT Study Group . The German Registry of immune tolerance treatment in hemophilia-1999 update. Haematologica. 2000;85(10 supplement):45–47
  61. DiMichele DM, Kroner B, the North American Immune Tolerance Study Group . The North American Immune Tolerance Registry: practices, outcomes, outcome predictors. Thromb Haemost. 2002;87:52–57
  62. DiMichele DM. Immune tolerance: a synopsis of the international experience. Haemophilia. 1998;4:568–573
  63. Kroner BL. Comparison of the International Immune Tolerance Registry and the North American Immune Tokerance Registry. Vox Sang. 1999;77(supplment 1):33–37
  64. Ljung R. Central venous lines in haemophilia. Haemophilia. 2003;(supplment 1):88–92[discussion 93]
  65. DiMichele D, Kroner B, Factor VIII/IX Subcommittee of the International Society for Thrombosis and Hemostasis . The maintenance of tolerance after successful immune tolerance induction in haemophilia A and B: the North American Registry. Factor VIII/IX Subcommittee of the International Society for Thrombosis and Hemostasis. Haematologica. 2000;85(10):40–44
  66. Hay CRM, Ludlam CA, Colvin BT, et al. FVIII inhibitors mild moderate severity haemophilia A. Thromb Haemost. 1998;79:762–766
  67. Freiburghaus C, Berntorp E, Ekman M, et al. Tolerance induction using the Malmo treatment model 1982–1995. Haemophilia. 1999;(1):32–39
  68. Stasi R, Brunetti M, Stipa E, Amadori S. Selective B-cell depletion with rituximab for the treatment of patients with acquired hemophilia. Blood. 2004;103(12):4424–4428
  69. Mathias M, Khair K, Hann I, Liesner R. Rituximab in the treatment of alloimmune factor VIII and IX antibodies in two children with severe haemophilia. Br J Haematol. 2004;125(3):366–368
  70. Barrow RT, Healey JF, Gailani D, et al. Reduction of the antigenicity of factor VIII toward complex inhibitory antibody plasmas using multiply-substituted hybrid human/porcine factor VIII molecules. Blood. 2000;95:564–568
  71. Villard S, Lacroix-Desmazes S, Kieber-Emmons T, et al. Peptide decoys selected by phage display block in vitro and in vivo activity of a human anti-FVIII inhibitor. Blood. 2003;102(3):949–952
  72. Evans GL, Morgan RA. Genetic induction of immune tolerance to human clotting factor VIII in a mouse model for haemophilia A. Proc Natl Acad Sci USA. 1998;95:5734–5739
  73. Reding MT, Okita DK, Diethelm-Okita BM, et al. Human CD4+ T-cell epitope repertoire on the C2 domain of coagulation factor VIII. J Thromb Haemost. 2003;1:1777–1784
  74. Berntorp E, Astermark J, Carlborg E. Immune tolerance induction and the treatment of hemophilia. Malmo protocol update. Haematologica. 2000;85(10 supplement):48–50[discussion 50–1]
  75. Smith MP, Spence KJ, Waters EL, et al. Immune tolerance therapy for haemophilia A patients with acquired factor VIII alloantibodies: comprehensive analysis of experience at a single institution. Thromb Haemost. 1999;81(1):35–38
  76. Rocino A, Papa ML, Salerno E, et al. Immune tolerance induction in haemophilia A patients with high-responding inhibitors to factor VIII: experience at a single institution. Haemophilia. 2001;7(1):33–38
  77. Mauser-Bunschoten EP, Rosendaal FR, Nieuwenhuis HK, et al. Clinical course of factor VIII inhibitors developed after exposure to a pasteurised Dutch concentrate compared to classic inhibitors in hemophilia A. Thromb Haemost. 1994;71(6):703–706
  78. Gruppo RA, Valdez LP, Stout RD. Induction of immune tolerance in patients with hemophilia A and inhibitors. Am J Pediatr Hematol Oncol. 1992;14(1):82–87

PII: S1521-6926(05)00069-1

doi: 10.1016/j.beha.2005.03.002

Best Practice & Research Clinical Haematology
Volume 19, Issue 1 , Pages 51-66 , March 2006

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