Abstracts

Abstract

Introduction: Inhibitor development is a major complication of the treatment with factor VIII (FVIII) concentrates in patients with non-severe hemophilia A. Current hypothesis suggest that the mutation in the FVIII gene (F8) is an important predictor of inhibitor risk in these patients, however identification of high-risk patients is limited by the absence of absolute inhibitor risk of individual F8 mutations. The aim of this study was to assess inhibitor risk of F8 mutations in a large unselected cohort of non-severe hemophilia A patients. Methods: The INSIGHT cohort included 2,711 non-severe hemophilia A patients (FVIII 2-40%) who were treated with FVIII concentrates between 1980 and 2011 in 34 centres in Europe and Australia. Absolute inhibitor risk of F8 mutations was assessed in 1,112 patients located in 14 centres in which genotyping was universally performed; these were calculated as cumulative Kaplan-Meier incidences with inhibitor as the event and cumulative number of exposure days (ED) as time variable. Results: During 117,700 ED, 109 patients developed an inhibitor (absolute risk, 8.9%, 95% CI 7.1-10.6) after a median of 28 ED (IQR 14-68). F8 genotype was available in 898 patients (81%) among whom 236 different F8 mutations were identified. Eighteen mutations (L412F, R531C, R593C, P1761Q, F1775V, R1781G, P1854L, R1997W, D2074G, F2101C, Y2105C, R2150H, R2159C, E2228D, W2229C, V2232A, H2309D, Stop2333C) were classified as high risk mutation (n=274 patients; 50 inhibitors) with absolute inhibitor risks between 7 and 100%, the other 218 mutations were classified as low-risk mutation (absolute risk