Semin Thromb Hemost 2000; Volume 26(Number 02): 167-172
DOI: 10.1055/s-2000-9819
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 760-0888

Correlation between Factor VIII Genotype and Inhibitor Development in Hemophilia A

Steven S. Fakharzadeh, Haig H. Kazazian, Jr.
  • Departments of Genetics and Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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Publication History

Publication Date:
31 December 2000 (online)

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ABSTRACT

The development of neutralizing antibodies, or inhibitors, against infused factor VIII represents a significant complication of treatment for hemophilia A. Although it is likely that both genetic and environmental factors influence whether patients form inhibitors, correlations between types of factor VIII mutations and inhibitor development are becoming apparent. Approximately 20% of all patients with severe hemophilia A generate inhibitors. Of these inhibitor patients, 90% have inversions, large deletions or nonsense mutations of the factor VIII gene that would be predicted to eliminate production of factor VIII antigen. In contrast to patients with severe disease, inhibitor formation in patients with mild/moderate hemophilia A is rare. Inhibitor patients with mild/moderate disease typically have missense mutations that may cause local conformational changes within immunogenic domains of factor VIII and lead to production of dysfunctional antigen. Taken together, hemophilia A patients are predisposed to inhibitor development with mutations causing infused factor VIII to be perceived as either 1) a completely novel antigen or 2) an immunologically altered antigen.