Role of coagulation-associated processes on factor VIII immunogenicity in a mouse model of severe hemophilia A

Abstract

Immune responses to therapeutic factor VIII remain a major problem, affecting 30% of patients with severe hemophilia A. The primary factors that drive immune responses in these patients remain elusive. There have been conflicting reports on a role of coagulation (or thrombin) in anti-FVIII immune responses. Objective: To assess the importance of coagulation-associated processes for the onset of the anti-FVIII immune response. Methods: Using FVIII-deficient mice, we compared the immunogenicity of recombinant FVIII or the inactive FVIIIV634M mutant. In parallel, the involvement of tissue factor (TF) activity in the anti-FVIII immune response was investigated upon injection of a neutralizing anti-TF antibody or by the use of chimeric mice that lack TF expression in myeloid cells. The development of the anti-FVIII immune response was also monitored after treatment with warfarin. Results: The kinetics of the development of antibody responses to FVIIIV634M were indistinguishable from those of wild-type FVIII. Inhibition of TF activity did not modulate immune responses to exogenous FVIII. Additionally, global inhibition of coagulation with warfarin failed to reduce the anti-FVIII immune response. Conclusions: Thrombin generation or coagulation-associated processes do not modulate the anti-FVIII antibody response in mouse model of severe hemophilia A.