A Higher than Expected Incidence of Factor VIII Inhibitors in Multitransfused Haemophilia A Patients Treated with an Intermediate Purity Pasteurized Factor VIII Concentrate

Summary

In May 1990, 218 patients with haemophilia A regularly attending the Leuven Haemophilia Center were randomly assigned to a group receiving either of two newly introduced factor VIII concentrates: factor VIII-P, an intermediate purity pasteurized concentrate, or factor VIII-SD, a high purity concentrate treated with solvent-detergent for viral inactivation.

Patients were followed from May 1990 until October 1991. Between August 1991 and October 1991 a clinically important factor VIII inhibitor was detected in five out of the 109 patients receiving factor VIII-P while none of the 109 patients receiving factor VIII-SD developed such antibodies. All patients acquiring an inhibitor had previously been clinically tolerant to transfused factor VIII with 200 to more than 1,000 days of exposure to factor VIII prior to May 1990. Patients with inhibitors were transfused daily with 30 U factor VIII-SD per kg body weight, which was associated with a gradual decline of the inhibitor level. In all patients the antibodies were relatively slow-acting and predominantly directed towards the light chain of factor VIII.

This study demonstrates a higher than expected incidence of factor VIII inhibitors associated with the use of a specific factor VIII concentrate in multitransfused haemophilia A patients. It indicates the usefulness of evaluating newly introduced concentrates in prospective, randomized trials.

• References

• 1 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: 344-348
• 2 Rasi V, Ikkala E. Haemophiliacs with factor VIII inhibitors in Finland: prevalence, incidence and outcome. Br J Haematol 1990; 76: 369-371
• 3 Schwarzinger I, Pabinger I, Korninger C. et al. Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates. Am J Hematol 1987; 24: 241-245
• 4 Ehrenforth S, Kreuz W, Scharrer I. et al. Incidence of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-598
• 5 White GC, Shoemaker CB. Factor VIII gene and hemophilia A. Blood 1989; 73: 1-12
• 6 Frommel D, Allain JP. Genetic predisposition to develop factor VIII antibody in classic hemophilia. Clin Immunol Immunopathol 1977; 8: 34-38
• 7 Hiemstra H, Nieuweboer CEF, Idoe MA. et al. Evaluation of a wet pasteurization of a factor VIII concentrate produced by controlled-pore silica adsorption. Folia Haematol (Leipzig) 1990; 117: 557-563
• 8 Burnouf T, Burnouf-Radosevich M, Huart JJ, Goudemand M. A highly purified factor VIII:c concentrate prepared from cryoprecipitate by ion-exchange chromatography. Vox Sang 1991; 60: 8-15
• 9 Peerlinck K, Arnout J, Tamise M, Vanherle A, Fondu P, Vermylen J. In vitro and in vivo evaluation of two factor VIII concentrates virally inactivated by solvent-detergent or by pasteurization. Acta Clin Belg 1991; 46: 298-304
• 10 Kasper CK, Aledort LM, Counts RB. et al. A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975; 34: 869-872
• 11 Langdell RD, Wagner RH, Brinkhous KM. Effect of antihemophilic factor on one-stage clotting tests: a presumptive test for hemophilia and a simple one-stage antihemophilic factor assay procedure. J Lab Clin Med 1953; 41: 637-647
• 12 Biggs R, Austen DEG, Denson KWE, Rizza CR, Borrett R. The mode of action of antibodies which destroy factor VIII. I. Antibodies which have second-order concentration graphs. Br J Haematol 1972; 23: 125-135
• 13 Fulcher CA, de Graaf MahoneyS, Roberts JR, Kasper CK, Zimmerman TS. Localization of human factor FVIII inhibitor epitopes to two polypeptide fragments. Proc Natl Acad Sci USA 1985; 82: 7728-7732
• 14 Vermylen J, Peerlinck K. Epidemic of factor VIII inhibitors linked to factor VIII-P. Acta Clin Belg 1991; 46: 419-420 (Letter)
• 15 Schwartz RS, Abildgaard CF, Aledort LM. et al. Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med 1990; 323: 1800-1805
• 16 Rosendaal FR, Nieuwenhuis HK, van den Berg HM. et al. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in the Netherlands. Blood. 1993 in press.