Abstract Number: OC 47.2
Meeting: ISTH 2022 Congress
Background: Development of neutralizing antibodies (inhibitors) is a major complication of hemophilia A treatment, which renders replacement therapy ineffective and increases susceptibility to major bleeding. Non-neutralizing FVIII-specific antibodies (NNA) that appear to increase clearance of exogenous clotting factors and limit its hemostatic efficacy have been identified recently. We hypothesize that FVIII-binding antibodies form a spectrum from low titer, low affinity NNA and high affinity antibodies with or without neutralizing potential, to inhibitors detectable with the widely used Bethesda assay, depicted in Figure 1. We further hypothesize that a subset of NNA are in fact low-titer inhibitors with titers below the lowest detection limit of the Bethesda assay.
Aims: To assess the prevalence and characteristics of NNA among persons with hemophilia A (PwHA), and to investigate whether these NNA have neutralizing potential.
Methods: PwHA with an available plasma sample were included from the cross-sectional unselected nationwide ‘Hemophilia in the Netherlands’ (HIN) cohort. The NNA prevalence and isotype characteristics (IgA, IgM and IgG subclasses) are assessed in the overall population using a highly sensitive and fully validated ELISA. Samples with confirmed specificity for FVIII will be assessed for apparent affinity with a competition-based ELISA approach. The presence of inhibitors will be assessed using the Nijmegen Bethesda assay and the novel Nijmegen low-titer inhibitor assay.
Results: In total, 801 PwHA were included. 71 patients (8.9%) had a positive Nijmegen low-titer inhibitor assay, of whom 15 (21.1%) had also a positive Nijmegen Bethesda Assay (Figure 2). Results of NNA prevalence and characteristics will be available at the time of the ISTH 2022.
Conclusion(s): This study is the first to describe the full spectrum of anti-FVIII antibodies in an unselected population of PwHA. Improved knowledge of the prevalence and characteristics of NNA will eventually contribute to understanding of differences in pharmacokinetics and potentially identify patients at risk for inhibitor development.
To cite this abstract in AMA style:Oomen I, Miranda M, Allacher P, Beckers E, Coppens M, Driessens M, Eikenboom J, Fijnvandraat K, Hassan S, Hooimeijer L, Kaijen P, Leebeek F, Rosendaal F, Schols S, Schweiger H, Smit C, van Vulpen L, van der Bom J, Voorberg J, Gouw S. Prevalence and characteristics of non-neutralizing FVIII-specific antibodies in persons with hemophilia A – preliminary results [abstract]. https://abstracts.isth.org/abstract/prevalence-and-characteristics-of-non-neutralizing-fviii-specific-antibodies-in-persons-with-hemophilia-a-preliminary-results/. Accessed September 24, 2023.
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