Abstract Number: OC 47.3
Meeting: ISTH 2022 Congress
Background: Acquired hemophilia A (AHA) is a bleeding disorder due to neutralizing autoantibodies against FVIII. Its clinical presentation significantly differs from that in congenital hemophilia A (CHA) with or without alloantibody inhibitors, but the underlying reason remains unknown. We have previously shown that anti-FVIII antibodies form immune complexes (IC) when FVIII protein concentration exceeds the normal range, which is expected in AHA but not CHA. These complexes incorporate von Willebrand factor (VWF) and might therefore disturb primary hemostasis.
Aims: To explore the functional impact of VWF-containing FVIII-IC on hemostasis.
Methods: IC were detected and characterized by analytical ultracentrifugation (AUC). FVIII-depleted normal plasma was supplemented with VWF, washed fluorescently-labeled platelets from healthy volunteers, and a mix of 7 monoclonal anti-FVIII IgG antibodies (Ab1-7) with or without FVIII. A Bioflux flow chamber model under high shear rates and calibrated automated thrombography were used to assess the primary and secondary hemostasis, respectively.
Results: Formation of IC by Ab1-7 was observed in the presence of FVIII, but not in its absence. VWF was incorporated into FVIII-IC as shown by AUC. VWF-dependent platelet adherence and aggregation under high shear stress was significantly impaired (by 20 to 100%), depending on platelet donor and experimental conditions, in the presence of FVIII-containing IC as compared to Ab1-7 alone. In contrast, thrombin generation capacity was not impaired by FVIII-IC.
Conclusion(s): Our data demonstrate that FVIII-IC contain vWF and disturb platelet function in an ex vivo model of primary hemostasis. We suggest that FVIII-IC occurring in AHA disturb hemostasis more severely than just the absence of FVIII in CHA with or without inhibitors. The severe impairment of primary hemostasis, combined with the suppression of FVIII activity, could contribute to the unique bleeding pattern of AHA.
The study was supported by “Early Career Research Grant 2021” from the Society of Thrombosis and Haemostasis Research (GTH e.V.).
To cite this abstract in AMA style:Oleshko O, Klingberg A, Curth U, Werwitzke S, Tiede A. Towards Explaining the Unique Bleeding Pattern of Acquired Hemophilia A: Impact of FVIII-containing Immune Complexes on Hemostasis [abstract]. https://abstracts.isth.org/abstract/towards-explaining-the-unique-bleeding-pattern-of-acquired-hemophilia-a-impact-of-fviii-containing-immune-complexes-on-hemostasis/. Accessed October 2, 2023.
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