Abstract Number: PB0455
Meeting: ISTH 2021 Congress
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 1). https://abstracts.isth.org/abstract/immune-complex-formation-of-factor-viii-fviii-with-inhibitors-is-modulated-by-von-willebrand-factor-vwf/. Accessed September 16, 2021.
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