Abstract Number: OC 24.4
Meeting: ISTH 2021 Congress
Background: One-third of severe hemophilia A (HA) patients develop factor VIII (FVIII) alloinhibitory antibodies or inhibitors, conferring the most significant treatment-related complication. Clinical trial data support plasma derived (pd)FVIII has a lower prevalence of FVIII inhibitor development than recombinant (r)FVIII in severe hemophilia A (HA) patients. One possible explanation for this observation is that non-covalent interactions with von Willebrand Factor (vWF) in plasma prevent immune recognition of FVIII. However, mechanistic studies probing the role of vWF provide conflicting lines of evidence for the role of vWF-FVIII interaction in modulating FVIII immunogenicity.
Aims: To investigate whether partitioning FVIII away from vWF alters the immune response to FVIII.
Methods: We expressed and purified two human FVIII variants with altered vWF interactions: a) FVIII-2RKR is a heterodimeric derivative lacking the entire B-domain and a3 which binds vWF; b) FVIII-R1689Q is B-domainless FVIII (BDD) variant that when bound to vWF is not readily released as thrombin and FXa cannot cleave it at position 1689. These proteins, along with wild-type FVIII-BDD, were administered weekly (0.2mg/mouse) to HA/C57Bl/6 mice by tail vein injection. Blood was collected every-other-week. Plasma samples were analyzed for anti-FVIII IgG by ELISA and functional inhibition of FVIII by Bethesda assay.
Results: Our data show that 5 of 8 mice treated with FVIII-BDD developed inhibitor titers that were higher than mice treated with FVIII-R1689Q in which only 2 of 8 mice developed inhibitors. In contrast, all mice treated with FVIII-2RKR developed inhibitor titers that were significantly higher than both FVIII-R1689Q and FVIII-BDD
(p<0.05; Figure 1).
Conclusions: FVIII inhibitor formation inversely correlated with vWF affinity. We conclude that dissociation of FVIII from vWF has a major impact on FVIII inhibitor formation. Future work aims to investigate the role of vWF in antigen presenting cell recognition of FVIII.
To cite this abstract in AMA style:Zintner SM, Davidson RJ, Wilhelm AR, Camire RM, George LA. Altered vWF-FVIII Binding Modulates the Factor VIII Immune Response [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/altered-vwf-fviii-binding-modulates-the-factor-viii-immune-response/. Accessed December 8, 2021.
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