Overview of Inhibitors

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Inhibitory antibodies that develop in patients with hemophilia render standard therapy with factor concentrates ineffective. Several factors may influence inhibitor incidence, including genetics, the type of factor concentrate, and environment. A higher incidence of inhibitors in siblings compared to extended relatives, and in African Americans compared to Caucasians, suggests that genetics may play an important role in inhibitor development; however, genetic markers that indicate a predisposition for inhibitor development have yet to be identified. In addition, the appearance of inhibitors in immunologically challenged patients points to the role of the immune response system in the development of inhibitor antibodies, an area that warrants further study. Thus, the medical community faces the difficult task of developing new, improved therapies to combat inhibitors in patients with hemophilia, a task that will require careful consideration of the roles of environmental factors, the immune system, and genetics in inhibitor development.

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Factors Contributing to Inhibitor Development

Several factors may influence the risk of inhibitor development, such as the type of factor replacement regimen used, environmental factors, and genetics (Fig 2). The number of exposure days to factor concentrates and a patient’s age at the time of exposure may play a role. The risk for the development of new inhibitors is typically greatest shortly after the first exposure to factor concentrates. The median number of factor exposure days before development of inhibitory antibodies is

Inhibitors in Patients With Hemophilia B

The incidence of inhibitors is lower in patients with hemophilia B than in patients with hemophilia A,1 and inhibitor development is generally associated with the absence of FIX antigen due to large deletions or major derangements of the FIX gene.26 The lower incidence of inhibitors in patients with hemophilia B has been attributed to the relatively high frequency of low-risk missense or point mutations in these patients compared with patients with hemophilia A.33 In addition, the structural

Conclusions and Future Issues to Address in the Area of Inhibitor Development

Future studies will need to address some key questions regarding the relationship between genetics and inhibitor development. The patient population with hemophilia A and severe gene mutations or null mutations exhibits an inhibitor prevalence of greater than 30%.5 However, not all patients with null mutations develop inhibitors. In the case of intron 22 inversions, approximately 20% to 35% of the patients with this type of mutation develop inhibitors, while the majority of patients remain

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    This article is based in part on the proceedings from an educational symposium held at the World Federation of Hemophilia World Congress 2004 in Bangkok, Thailand. Both the symposium and this manuscript were supported by Baxter Healthcare Corporation.

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