Inhibitors - genetic and environmental factors.
It is known that a large number of both genetic and environmental factors contribute to the risk of inhibitor development, but underlying pathogenetic mechanisms are still under investigation. The clinical research on inhibitors towards factor VIII (FVIII) is challenged by the fact that this is an infrequent event occurring in a rare disease. Therefore, it is widely accepted that complementary studies involving animal models can provide important insights into the pathogenesis and treatment of this complication. In this respect, mouse models have been studied for clues to FVIII immunogenicity, natural history of immunity and for different approaches to primary and secondary tolerance induction. In the clinical setting, the type of FVIII product used and the occurrence of product switching are considered important factors which may have an influence on inhibitor development. The evaluation of data currently available in the literature does not prove unequivocally that a difference in the immunogenicity exists between particular FVIII products (e.g. recombinant vs. plasma-derived, full length vs. B-domainless). In addition, national products switches have occurred and, in this context, switching was not associated with an enhanced inhibitor risk. In contrast with severe haemophilia A, patients with moderate and mild haemophilia A receive FVIII treatment infrequently for bleeds or surgery. In this condition the inhibitor risk is low but remains present lifelong, requiring continuous vigilance, particularly after intensive FVIII exposure.
Department of Pathology and Molecular Medicine, Richardson Laboratory, Queen's University, Kingston, ON, Canada.
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Lillicrap
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Fijnvandraat
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Santagostino
D000818:Animals; D004195:Disease Models, Animal; D057915:Drug Substitution / Q000009:adverse effects; D005169:Factor VIII / Q000235:genetics* / Q000276:immunology*; D059647:Gene-Environment Interaction; D006467:Hemophilia A / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007518:Isoantibodies / Q000235:genetics* / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D012307:Risk Factors
D007518:Isoantibodies; D011994:Recombinant Proteins; D005169:Factor VIII
factor VIII; inhibitors; mild hemophilia; plasma-derived concentrates; product switch; recombinant concentrates