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Determinants of bleeding before and during immune tolerance in 222 boys with severe hemophilia A and inhibitors >5 BU.

Blood advances

Authors: Kathelijn Fischer, Gili Kenet, Karin Kurnik, Manuel Carcao, Johannes Oldenburg, Torben Stamm-Mikkelsen, Ana Rosa Cid Haro, Minna Koskenvuo, Jan Blatny, Christoph Königs

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.

© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

PMID: 38214949

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