Inhibitor development in nonsevere hemophilia: data from the European Haemophilia Safety Surveillance (EUHASS) registry

Authors: Fischer, K; Lassila, R; Peyvandi, F; Gatt, A; Gouw, SC; Hollingsworth, R; Lambert, T; Kaczmarek, R; Alvarez, DC; Makris, M.

Affiliations: Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, University Utrecht, the Netherlands. PedNet Haemophilia Research Foundation, Baarn, the Netherlands. Department of Hematology, Unit of Coagulation Disorders, Helsinki University Central Hospital, Research Program Unit in Systems Oncology, University of Helsinki, Helsinki, Finland. Angelo Bianchi Bonomi, Hemophilia and Thrombosis Centre, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico. Department of pathophysiology and Transplantation, University of Milan, Milan, Italy. Mater Dei Hospital, Tal-QRoqq, Msida, Malta. Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands. Department of Pediatric Hematology, Meibergdreef 9, Amsterdam, the Netherlands. Medical Data Solutions and Services (MDSAS), Manchester, UK. Reference Center for hemophilia and rare bleeding disorders, Hôpital Bicêtre, APHP, Université Paris Saclay. Le Kremlin Bicêtre, France. Coagulation Products Safety Supply and Access Committee, World Federation of Hemophilia, Montreal, Quebec, Canada. Wells Center for pediatric Research, Indiana University School of Medicine, Indianapolis, USA. European Association of Haemophilia and Associated Disorders, Brussels, Belgium. School of Medicine and Population Health, University of Sheffield, Sheffield, UK.

Publication: Res Pract Thromb Haemost ; 2025; 9. 102887

ABSTRACT: BACKGROUND: Information on inhibitor development in nonsevere hemophilia and its association with clotting factor concentrate type is limited. OBJECTIVES: To assess inhibitor development in patients with nonsevere hemophilia A (HA) and hemophilia B (HB) in the European Haemophilia Safety Surveillance system. METHODS: Inhibitors and total treated patients are reported annually. Any exposure to concentrate per year was considered a treatment year. Incidence rates per 1000 treatment years and 95% CIs were calculated according to type of concentrate and compared using incidence rate ratios (IRRs). RESULTS: During 2008 to 2023, 90 centers reported on 36,074 (HA) and 9238 (HB) treatment years. The inhibitor rate for nonsevere HA receiving factor (F)VIII was 4.2 per 1000 treatment years (95% CI, 3.5-4.9). Inhibitors developed at median 47.5 years (P25-P75 [IQR], 17.0-69.0), after median 40 exposure days (EDs; IQR, 17-80), with 58% occurring <50 EDs and 88% <100 EDs. Overall, 4 of 149 (2.7%) patients in the inhibitor group were female. Only one inhibitor was reported in nonsevere HB, in a female patient (FIX 7%, after 6 EDs), resulting in an inhibitor rate of 0.1 per 1000 treatment years (95% CI, 0.0-0.6). Compared with standard half-life recombinant FVIII, inhibitor rates on both plasma-derived FVIII (IRR, 0.27; 95% CI, 0.11-0.58; P < .001) and extended half-life FVIII (IRR, 0.18; 95% CI, 0.02-0.68; P = .002) were significantly reduced. CONCLUSION: Inhibitors in nonsevere hemophilia occurred at a rate of 4.2 per 1000 treatment years in HA and 0.1 per 1000 treatment years in HB. Compared with standard half-life FVIII, inhibitor development on plasma-derived and extended half-life FVIII were reduced. These data show that inhibitor monitoring is relevant with nonsevere HA in both sexes and should be continued lifelong.