Premium
Role of coagulation‐associated processes on factor VIII immunogenicity in a mouse model of severe hemophilia A
Author(s) -
Gangadharan B.,
Delignat S.,
Ollivier V.,
Gupta N.,
Mackman N.,
Kaveri S. V.,
LacroixDesmazes S.
Publication year - 2014
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12740
Subject(s) - immunogenicity , coagulation , immune system , immunology , tissue factor , antibody , factor ix , medicine , thromboplastin , thrombin , platelet
Summary Background 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 FVIII V 634M 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 FVIII V 634M 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.