Intensive peri-operative use of factor VIII and the missense mutation Arg593Cys are risk factors for factor VIII inhibitors in mild and moderate hemophilia A

Background: A severe and challenging complication in the treatment of hemophilia A is the development of factor VIII (FVIII) inhibiting antibodies. Inhibitors aggravate bleeding complications, disabilities and costs. The etiology of inhibitor development is incompletely understood. In a large cohort study in patients with mild or moderate hemophilia A (MHA), we evaluated the role of genotype and intensive FVIII exposure in inhibitor development. Methods: Longitudinal clinical data from 138 MHA patients were retrospectively collected from 1980 to 2008 and analyzed by multivar- iate analysis. Results: Genotyping demonstrated the Arg593Cys missense mutation in 52 (38%) patients, while the remaining 86 patients had 26 other missense mutations. Sixty-three (46%) patients underwent a period of intensive FVIII exposure, in 41 of them for surgery. Ten patients (7%) developed inhibitors, eight of them carrying the Arg593Cys mutation. The Arg593Cys mutation resulted in a threefold increased risk of developing inhibitors (RR 3.1, 95%CI 1.05-9.3).The other two inhibitor patients had newly detected mutations Pro1761Gln and Glu2228Asp. In seven patients the inhibitor occurred within three months after intensive peri-operative use of FVIII concentrates (RR124, 95%CI 66-232). Conclusion: This is the first cohort study in patients with MHA demonstrating that both Arg593Cys genotype and intensive peri-operative use of FVIII concentrates are associated with a high risk for inhibitor development. Limitation of intensive FVIII exposure or use of des- mopressin should be considered in MHA whenever possible.