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Immune Complex Formation of Factor VIII (FVIII) with Inhibitors is Modulated by von Willebrand Factor (vWF)

O. Oleshko1, U. Curth2, A. Tiede1, S. Werwitzke1

1Department of Haematology, Haemostaseology, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany, 2Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany

Abstract Number: PB0455

Meeting: ISTH 2021 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Basic

Background: Formation of neutralizing anti-FVIII antibodies (inhibitors) due to FVIII replacement in hemophilia A patients leads to therapy failure. Moreover, immune reaction could be potentially augmented by FVIII-containing immune complexes (FVIII-IC) binding to low affinity Fc gamma receptor IIB (CD32) and/or C1q initiating thereby FVIII internalization by antigen-presenting cells. VWF is considered a possible immuno-protective factor in inhibitors formation, but there is little information on the vWF influence on potentially harmful FVIII-IC characteristics.

Aims: The aim of this study is to analyze the effect of vWF on FVIII-IC characteristics concerning their size and CD32 and C1q binding.

Methods: For FVIII-IC generation, two types of inhibitors were used: anti-FVIII murine sera and a mix of 7 purchasable monoclonal anti-FVIII IgG antibodies. Plasma-derived vWF was incubated with recombinant human FVIII followed by inhibitors addition and examination by in-house ELISA and analytical ultracentrifugation with fluorescence detection. Data analysis was performed using SEDFIT (a diffusion-deconvoluted differential sedimentation coefficient distribution model, c(s)) and GraphPadPrism software.

Results: FVIII-IC but not monomeric IgG were bound by CD32 and C1q. As demonstrated in both assays, vWF suppressed binding in a dose-related manner independently on used inhibitors type. Under conditions of 60-fold FVIII excess, vWF reduced binding by 70%, while application of vWF at physiologically relevant ratios almost fully prevented FVIII-IC CD32 and C1q binding. In the presence of vWF, we observed incorporation of fewer inhibitors into FVIII-IC, as indicated by increased amounts of free IgG, but also increased size of FVIII-IC as indicated by faster sedimenting complexes.

Conclusions: vWF impedes FVIII-IC binding to effector molecules as Fc gamma receptor and C1q possibly via concealment of the IgG Fc-fragments. The ability of vWF to alter the FVIII-IC characteristics is indicative of its potential role for the regulation of anti-FVIII immune response and for achieving immune tolerance.

To cite this abstract in AMA style:

Oleshko O, Curth U, Tiede A, Werwitzke S. Immune Complex Formation of Factor VIII (FVIII) with Inhibitors is Modulated by von Willebrand Factor (vWF) [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/immune-complex-formation-of-factor-viii-fviii-with-inhibitors-is-modulated-by-von-willebrand-factor-vwf/. Accessed September 27, 2023.

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