Hemophilia A

Epidemiology

  • Hemophilias are inherited bleeding disorders due to a deficiency of specific clotting factors
  • Hemophilia A (classic hemophilia): caused by a deficiency of factor VIII
  • Hemophilia B (Christmas disease): caused by a deficiency of factor IX
  • Hemophilia A occurs in all races and is prevalent worldwide
  • Factor VIII is a large plasma glycoprotein with a half-life of 12 hours in adults and is critical for secondary hemostasis, the stabilization of a platelet plug by fibrin, a process mediated by thrombin
  • Mild hemophilia A is associated with factor VIII clotting activity (FVIIIC) that is 5 to 40% of normal and is manifested by bleeding after surgery, but not spontaneous bleeding
  • Moderate hemophilia A is associated with FVIIIC that is 1 to 5% of normal and is manifested by bleeding into joints and muscles after injury, and excessive bleeding after surgery
  • Severe hemophilia A is associated with FVIIIC <1% of normal and is manifested by spontaneous bleeding into joints and muscles, with the risk of limb loss from compression of nerves and blood vessels
  • Multiple mutations in factor VIII gene have been described, but the most common is a large inversion and translocation of exons 1 to 22 on the long arm of the X chromosome occurring in the male germline
    • This mutation affects almost half of those with severe hemophilia A

Clinical

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Treatment

  • Mild hemophilia A can have factor VIIIC effectively raised by desmopressin

  • However, more severe cases require prophylactic or on-demand treatment with FVIII concentrate

    • Since 1992 recombinant FVIII has been available to reduce the risk of virus transmission
  • Nevertheless, a serious complication of therapy with FVIII concentrate remains: the development of inhibitors, polyclonal immunoglobulin G antibodies to the factor

    • Inhibitors develop in 20 to 30% of patients with hemophilia A and are more likely to occur in those with severe disease who have large gene mutations
    • The risk of inhibitor formation is greatest in previously untreated patients when starting factor replacement therapy
    • With low levels of inhibitor (<5 to 10 Bethesda units) larger doses of FVIII may be effective in attaining hemostasis
    • However, patients with high levels of inhibitor, or severe or persistant bleeding, should be treated with activated prothrombin complex concentrate (aPCC) or activated factor VII
  • FENOC trial: some patients may respond better to one agent than another, and so a consensus conference of hemophilia experts could not recommend one approach over another
  • Treatment should continue until there is objective evidence of adequate hemostasis
  • Patients who do not have an adequate hemostatic response should have treatment changed

  • Rescue therapy with the addition of platelet transfusion, immunoabsorption, or plasmapheresis may be necessary if both aPCC and factor VIIa fail to achieve hemostasis

  • For much of the developing world, treatment of hemophilia patients with inhibitors relies on plasma or cryoprecipitate

  • However, despite the availability of testing for hepatitis C and HIV in blood products, exposure to multiple donors with the risk that some could be in the window between exposure and antibody formation increases the cumulative risk of infection above that associated with recombinant or viral-inactivated products

  • Factor VIII: indicated for treatment of bleeding

  • Factor VIIa: indicated for bleeding in patients with known Factor VIII inhibitors

References

  • Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systemic review. Crit Care Med 2005; 33:883
  • Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet. 2003;361:1801-1809.
  • Berntorp E, Shapiro A, Astermark J, et al. Inhibitor treatment in haemophilias A and B: summary statement for the 2006 international consensus conference. Haemophilia. 2006;12(suppl 6):1-7.
  • Goudemand J, Laurian Y, Calvez T. Risk of inhibitors in haemophilia and the type of factor replacement. [Review] [42 refs]. Curr Opin Hematol. 2006;13:316-322.
  • 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;13:256-263.
  • 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;109:546-551.
  • Evatt BL, Austin H, Leon G, et al. Haemophilia therapy: assessing the cumulative risk of HIV exposure by cryoprecipitate. Haemophilia. 1999;5:295-300.