The development of an inhibitor is a serious complication for patients with hemophilia (PwH). Previous international studies have reported some therapeutic and genetic factors associated with inhibitor development. However, actual situations, such as genetic-background, treatment, and inhibitor development, have remained unclear in PwH in Japan. The Japan Hemophilia Inhibitor Study 2 (J-HIS2) was organized in 2008 to establish a nation-wide registry system for PwH in Japan and prospectively investigate the risk factors for inhibitor development. Patients who were newly diagnosed after 2007 without inhibitor and whose treatment was traceable from 0 to 75 exposure days were enrolled in J-HIS2. Of the 386 patients (hemophilia A [HA]: 315, hemophilia B [HB]: 71) from 46 facilities, inhibitor development was observed in 77 (HA: 71, HB: 6) by November 2018. Inhibitor development was observed in 31.6% of patients with severe hemophilia A, 6.5% with moderate hemophilia A, and 1.8% with mild hemophilia A. However, it was observed in 15.4% of those with severe hemophilia B. The relative-risk of the F8 null genotype for inhibitor development was higher than that of the non-null one (p<0.01). In patients with severe hemophilia A with 25 exposure days of infusions or inhibitor development, prophylaxis was more protective for inhibitor development than non-prophylaxis (p<0.01). A simultaneous infusion of FVIII-concentrates and vaccination seemed to exert a limited effect on inhibitor development. History of intracranial hemorrhage appears to be associated with inhibitor development.
Keywords: Hemophilia; Inhibitor; Prospective study.