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Prevalence and characteristics of non-neutralizing FVIII-specific antibodies in persons with hemophilia A – preliminary results

1Department of Pediatric Hematology, Emma Children’s Hospital, Amsterdam University Medical Centers, location AMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands, Amsterdam, Noord-Holland, Netherlands, 2Department of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands, Amsterdam, Noord-Holland, Netherlands, 3Institute Krems Bioanalytics, IMC University of Applied Sciences Krems, Krems, Niederosterreich, Austria, 4Department of Hematology, Maastricht University Medical Center, Maastricht University, Maastricht, the Netherlands, Maastricht, Limburg, Netherlands, 5Amsterdam University Medical Centers, Amsterdam, the Netherlands, Amsterdam, Noord-Holland, Netherlands, 6VSOP, Dutch organisation for rare and genetic disorders, Soest, Utrecht, Netherlands, 7Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands., Leiden, Zuid-Holland, Netherlands, 8Department of Clinical Epidemiology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands, Leiden, Zuid-Holland, Netherlands, 9Pediatric Hematology, Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, Groningen, Netherlands, 10Department of Hematology, Erasmus MC, University Medical Center Rotterdam, The Netherlands, Rotterdam, Zuid-Holland, Netherlands, 11Department of Clinical Epidemiology, Leiden University Medical Center, Leiden University, Leiden, the Netherlands, Leiden, Zuid-Holland, Netherlands, 12Department of Hematology, Radboud university medical center, Nijmegen, the Netherlands; Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, the Netherlands, Nijmegen, Gelderland, Netherlands, 13Institute Krems Bioanalytics, IMC University of Applied Sciences Krems, Krems, Austria, Krems, Niederosterreich, Austria, 14Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands, Leiden, Zuid-Holland, Netherlands, 15Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands, Utrecht, Utrecht, Netherlands, 16Department of Pediatric Hematology, Emma Children’s Hospital, Amsterdam University Medical Centers, location AMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden University, Leiden, the Netherlands, Amsterdam, Noord-Holland, Netherlands

Abstract Number: OC 47.2

Meeting: ISTH 2022 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical

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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