Factor VIII gene (F8) mutation and inhibitor development in non-severe hemophilia A

Background: The development of neutralizing antibodies (inhibitors) towards factor VIII is a major complication in non-severe hemophilia A, profoundly aggravating the bleeding pattern. Identification of high risk patients is hampered by lack of data on the association between factor VIII gene (F8) mutations and the development of inhibitors that take exposure days to therapeutic factor VIII concentrates into account. Aims: To determine the risk of inhibitor development in patients with non-severe hemophilia A and to analyze the association with F8 mutation, taking exposure days to therapeutic factor VIII concentrates into account. Methods: The study population was derived from a source population of 2711 non-severe hemophilia A patients (factor VIII 2-40%), treated in 34 hemophilia treatment centers in Europe and Australia (the INSIGHT consortium). The association between F8 mutation and inhibitor development was assessed in 1112 patients, only recruited from centers that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as time variable. Thus, risk was calculated as the proportion of patients that developed an inhibitor after a certain number of exposure days (e.g. 20 or 50) to therapeutic factor VIII concentrates. Results: During 44,800 exposure days (median 24 exposure days per patient; Inter Quartile Range (IQR), 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval (CI), 4.0-6.6) after a median of 28 exposure days (IQR, 12- 71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5- 8.9) and at 100 exposure days this risk was further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 221 different F8 point mutations 19 were associated with inhibitor development. The inhibitor risk was highest for R593C, D2074G, R2159C and W2229C, reaching 19%, 21%, 39% and 42%, respectively, at 50 exposure days. Conclusion: Among a total of 221 different point mutations, 19 mutations were associated with inhibitor development. Longitudinal analysis revealed that the inhibitor incidence in non-severe hemophilia A patients with certain F8 mutations approaches the incidence observed in patients with severe hemophilia. These results emphasize the importance of F8 genotyping in non-severe hemophilia A. New preventive and therapeutic approaches in this patient group are urgently needed