Inhibitors in mild/moderate haemophilia A: An update

Summary

The development of inhibitors in patients with mild/moderate hemophilia A is an increasingly recognized occurrence and is manifested by the patients’ bleeding pattern becoming more severe. Inherited (hemophilia genetic mutations) and acquired (type and delivery of factor VIII replacement therapy) factors have been associated with an increased likelihood of developing factor VIII inhibitors. Although the use of bypassing agents (i.e. activated prothrombin complex concentrates and recombinant factor VII activated) has been demonstrated to be effective in controlling bleeding episodes in patients who develop factor VIII inhibitors, the limited data available in the literature are insufficient to determine the optimal approach to the eradication of inhibitors (i.e. immune tolerance induction, immunosuppression or both) for this group. Particular attention should be directed to the prevention of this complication in those patients with mild/moderate hemophilia recognized to be at increased risk of developing a factor VIII inhibitor. In conclusion, large prospective trials are warranted in order to elucidate the many still unclear pathogenic and therapeutic aspects of the development of inhibitors in patients with mild/moderate hemophilia A.

Keywords

Inhibitors - bleeding - mild hemophilia A

• References

• 1 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 09: 418-35.
• 2 Hay CRM. Factor VIII inhibitors in mild and moderate-severity haemophilia A. Haemophilia 1998; 04: 558-63.
• 3 Rizza CR, Spooner RJ. Treatment of haemophilia and related disorders in Britain and Northern Ireland during 1976–80: report on behalf of the directors of haemophilia centres in the United Kingdom. Br Med J (Clin Res Ed) 1983; 286: 929-33.
• 4 Ehrenforth S, Kreuz W, Scharrer I. et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-8.
• 5 Addiego J, Kasper C, Abildgaard C. et al. Frequency of inhibitor development in haemophiliacs treated with low-purity factor VIII. Lancet 1993; 342: 462-4.
• 6 Sultan Y. Prevalence of inhibitors in a population of 3435 hemophilia patients in France. French Hemophilia Study Group. Thromb Haemost 1992; 67: 600-2.
• 7 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: 344-8.
• 8 Hay CRM, 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: 762-6.
• 9 Sharathkumar A, Lillicrap D, Blanchette VS. et al. Intensive exposure to factor VIII is a risk factor for inhibitor development in mild hemophilia A. J Thromb Haemost 2003; 01: 1228-36.
• 10 Oldenburg J, Schroder J. Hermann, et al. Environmental and genetic factors influencing inhibitor development. Semin Hematol 2004; 41 (Suppl. 01) 82-8.
• 11 Santagostino E, Gringeri A, Tagliavacca L. et al. Inhibitors to factor VIII in a family with mild hemophilia: molecular characterization and response to factor VIII and desmopressin. Thromb Haemost 1995; 74: 619-21.
• 12 Knobe KE, Villoutreix BO, Tengborn LI. et al. Factor VIII inhibitors in two families with mild haemophilia A: structural analysis of the mutations. Haemostasis 2000; 30: 268-79.
• 13 Jacquemin M, De Maeyer M, D’Oiron R. et al. Molecular mechanisms of mild and moderate hemophilia A. J Thromb Haemost 2003; 01: 456-63.
• 14 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: 1811-9.
• 15 Schwaab R, Oldenburg J, Tuddenham EG. et al. Mutations in hemophilia A. Br J Haematol 1993; 83: 450-8.
• 16 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: 1351-8.
• 17 Schwaab R, Oldenburg J, Schwaab U. et al. Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs. Br J Haematol 1995; 90: 458-64.
• 18 Fijnvandraat K, Turenhout EA, van den Brink EN. et al. The missense mutation Arg593 à Cys is related to antibody formation in a patient with mild hemophilia A. Blood 1997; 89: 4371-7.
• 19 Thompson AR, Murphy ME, Liu M. et al. Loss of tolerance to exogenous and endogenous factor VIII in a mild hemophilia A patient with an Arg593 to Cys mutation. Blood 1997; 90: 1902-10.
• 20 Suzuki H, Shima M, Arai M. et al. Factor VIII Ise (R2159C) in a patient with mild hemophilia A, an abnormal factor VIII with retention of function but modification of C2 epitopes. Thromb Haemost 1997; 77: 862-7.
• 21 Peerlinck K, Jacquemin MG, Arnout J. et al. Antifactor VIII antibody inhibiting allogeneic but not autologous factor VIII in patients with mild hemophilia A. Blood 1999; 93: 2267-73.
• 22 Liu ML, Shen BW, Nakaya S. et al. Hemophilic factor VIII C1- and C2-domain missense mutations and their modeling to the 1.5-angstrom human C2-domain crystal structure. Blood 2000; 96: 979-87.
• 23 Jacquemin M, Lavend’homme R, Benhida A. et al. A novel cause of mild/moderate hemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Willebrand factor. Blood 2000; 96: 958-65.
• 24 Ivaskevicius V, Jurgutis R, Rost S. et al. Lithuanian haemophilia A and B registry comprising phenotypic and genotypic data. Br J Haematol 2001; 112: 1062-70.
• 25 d’Oiron R, Lavergne JM, Lavend’homme R. et al. Deletion of alanine 2201 in the FVIII C2 domain results in mild hemophilia A by impairing FVIII binding to VWF and phospholipids and destroys a major FVIII antigenic determinant involved in inhibitor development. Blood 2004; 103: 155-7.
• 26 Fernandez-Lopez O, Garcia-Lozano JR, Nunez-Vazquez R. et al. The spectrum of mutations in Southern Spanish patients with hemophilia A and identification of 28 novel mutations. Haematologica 2005; 90: 707-10.
• 27 Roelse JC, De Laaf RT, Timmermans SM. et al. Intracellular accumulation of factor VIII induced by missense mutations Arg593-->Cys and Asn618-->Ser explains cross-reacting material-reduced haemophilia A. Br J Haematol 2000; 108: 241-6.
• 28 Van den Brink EN, Timmermans SM, Turenhout EA. et al. Longitudinal analysis of factor VIII inhibitors in a previously untreated mild haemophilia A patient with an Arg593-->Cys substitution. Thromb Haemost 1999; 81: 723-6.
• 29 Jacquemin M, Benhida A, Peerlinck K. et al. A human antibody directed to the factor VIII C1 domain inhibits factor VIII cofactor activity and binding to von Willebrand factor. Blood 2000; 95: 156-63.
• 30 Bril WS, MacLean PE, Kaijen PH. et al. HLA class II genotype and factor VIII inhibitors in mild haemophilia A patients with an Arg593 to Cys mutation. Haemophilia 2004; 10: 509-14.
• 31 Naylor JA, Green PM, Rizza CR. et al. Analysis of factor VIII mRNA reveals defects in everyone of 28 haemophilia A patients. Hum Mol Genet 1993; 02: 11-7.
• 32 Cutler JA, Mitchell MJ, Smith MP. et al. The identification and classification of 41 novel mutations in the factor VIII gene (F8C). Hum Mutat 2002; 19: 274-8.
• 33 Hay CRM, Lee CA. Inhibitors in mild and moderate haemophilia A. In: Inhibitors in patients with haemophilia. Blackwell Publishing; 2002: 92-7.
• 34 Baglin T, Beacham E. Is a change of factor VIII product a risk factor for the development of a factor VIII inhibitor?. Thromb Haemost 1998; 80: 1036-7.
• 35 Yee TT, Lee CA. Is a change of factor VIII product a risk factor for the development of a factor VIII inhibitor?. Thromb Haemost 1999; 81: 852.
• 36 White B, Cotter M, Byrne M. et al. High responding factor VIII inhibitors in mild haemophilia - is there a link with recent changes in clinical practice?. Haemophilia 2000; 06: 113-5.
• 37 Batorova A, Martinowitz U. Continuous infusion of coagulation factors. Haemophilia 2002; 08: 170-7.
• 38 Von Auer CH, Oldenburg J, von Depka M. et al. Inhibitor development in patients with hemophilia A after continuous infusion of FVIII concentrates. Ann N Y Acad Sci 2005; 1051: 498-505.
• 39 Grzelak I, Olszewski WL, Zaleska M. et al. Blood cytokine levels rise even after minor surgical trauma. J Clin Immunol 1996; 16: 159-64.
• 40 Lechner K, Ludwig E, Niessner H. et al. Factor VIII inhibitor ina patient with mild hemophilia A. Haemostasis 1972; 73 01: 261-70.
• 41 Bovill EG, Burns SL, Golden EA. Factor VIII antibody in a patient with mild haemophilia. BrJ Haematol 1985; 61: 323-8.
• 42 Puetz JJ, Bouhasin JD. High-titre factor VIII inhibitor in two children with mild haemophilia A. Haemophilia 2001; 07: 215-9.
• 43 Robbins D, Kulkarni R, Gera R. et al. Successful treatment of high titer inhibitors in mild hemophilia A with avoidance of factor VIII and immunosuppressive therapy. Am J Hematol 2001; 68: 184-8.
• 44 Leebeek FW, Kappers-Klunne MC, Jie KS. Effective and safe use of recombinant factor VIIa (Novo-Seven) in elderly mild haemophilia A patients with high-titre antibodies against factor VIII. Haemophilia 2004; 10: 250-3.
• 45 Ketseven PJ, Holland LJ, Lawrie AS. et al. Inhibitor to factor VIII in mild haemophilia. Thromb Haemost 1984; 52: 50-2.
• 46 Lowes GDO, Forbes CD. Inhibitor to factor VIII in mild haemophilia. Thromb Haemost 1985; 53: 159.
• 47 Vlot AJ, Wittebol S, Strengers PF. et al. Factor VIII inhibitor in a patient with mild haemophilia A and an Asn618-->Ser mutation responsive to immune tolerance induction and cyclophosphamide. Br J Haematol 2002; 117: 136-40.
• 48 Wiestner A, Cho HJ, Asch AS. et al. Rituximab in the treatment of acquired factor VIII inhibitors. Blood 2002; 100: 3426-8.
• 49 d’Orion R, Volot F, Reynaud J. et al. Impact of choice of treatment for bleeding episodes on inhibitors outcome in patients with mild/moderate hemophilia A and inhibitors. Semin Hematol 2006; 43 (Suppl. 01) S3-S9.
• 50 Aledort LM. Can we prevent inhibitors in mild and moderate factor VIII-deficient patients?. J Thromb Haemost 2006; 04: 914.