Prevention of bleeding and its consequences is the main goal of hemophilia treatment and determines treatment choices for patients who develop inhibitors. To assess bleeding before and during immune tolerance induction (ITI) and its association with ITI regimen and inhibitor titer, we selected and analyzed data on patients receiving high-titer inhibitors from the international prospective PedNet cohort study. In total, 222 patients with severe hemophilia A and inhibitor titers of >5 Bethesda units (BU) were followed from the first positive to the first negative inhibitor result (median overall follow-up, 1.7 years). Mean annual (joint) bleeding rates (AJBR) and 95% confidence intervals (CIs) were compared according to treatment and inhibitor titer using multivariable negative binomial regression. Before ITI, 115 patients showed an ABR of 6.1 (5.0-7.4) and an AJBR 2.6 (2.1-3.2). Bleeding was independent of inhibitor titer. During ITI, 202 patients had an ABR of 4.4 (3.9-5.1) and an AJBR of 1.7 (1.5-2.0). AJBR during ITI increased with inhibitor titer (hazard ratio [HR] for ≥200 BU vs 5 to 39 BU [4.9; CI, 3.2-7.4]) and decreased with daily ITI infusions (HR, 0.4; CI, 0.3-0.6) or activated prothrombin complex concentrate prophylaxis (HR, 0.4; CI, 0.2-0.8), whereas ITI dose and recombinant activated factor VII prophylaxis did not independently affect bleeding. These data provide evidence for a protective effect of repeated FVIII infusions (ITI) on bleeding in patients who have developed inhibitors; these data should be used to plan ITI and/or serve as a comparator for prophylaxis with nonreplacement therapy.

Aarhus University Hospital Department of Pediatrics and Adolescent Medicine Aarhus Denmark

Center for Benign Haematology Thrombosis and Haemostasis Van Creveldkliniek University Medical Center Utrecht Utrecht The Netherlands

Department of Paediatric Haematology and Biochemistry University Hospital and Masaryk University Brno Brno Czech Republic

Department of Paediatric Haemostasis University Children's Hospital Munich Germany

Division of Haematology Oncology Hospital for Sick Children Toronto Canada

Division of Hematology Oncology and Stem Cell Transplantation New Children's Hospital University of Helsinki and Helsinki University Hospital Helsinki Finland

Haemostasia and Thrombosis Unit Hospital Universitario y Politécnico La Fe Valencia Spain

Institute of Experimental Hematology and Transfusion Medicine University Hospital Bonn Medical Faculty University of Bonn Bonn Germany

The Israel National Hemophilia Center and Thrombosis Institute Sheba Medical Center and The Amalia Biron Thrombosis Research Institute Tel Aviv University Tel Aviv Yafo Israel

University Hospital Frankfurt Goethe University Department of Pediatrics and Adolescent Medicine Frankfurt Germany

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