title: Role of coagulation-associated processes on factor VIII immunogenicity in a mouse model of severe hemophilia A.
abstract: 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.
authors.affiliation: Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR S) 1138, Paris, France; Centre de Recherche des Cordeliers, UMR S 1138, Université Pierre et Marie Curie-Paris 6, Paris, France; Centre de Recherche des Cordeliers, Université Paris Descartes, UMR S 1138, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Gangadharan
authors.forename: S
authors.initials: S
authors.lastname: Delignat
authors.forename: V
authors.initials: V
authors.lastname: Ollivier
authors.forename: N
authors.initials: N
authors.lastname: Gupta
authors.forename: N
authors.initials: N
authors.lastname: Mackman
authors.forename: S V
authors.initials: SV
authors.lastname: Kaveri
authors.forename: S
authors.initials: S
authors.lastname: Lacroix-Desmazes
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D001777:Blood Coagulation; D004195:Disease Models, Animal; D005169:Factor VIII / Q000276:immunology*; D006467:Hemophilia A / Q000097:blood* / Q000235:genetics; D056724:Immunity, Humoral; D007249:Inflammation; D051379:Mice; D009154:Mutation; D010957:Plasmids; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000276:immunology; D013917:Thrombin / Q000737:chemistry; D013925:Thromboplastin / Q000737:chemistry; D014859:Warfarin / Q000494:pharmacology
chemical_list: D057134:Antibodies, Neutralizing; D011994:Recombinant Proteins; D014859:Warfarin; D005169:Factor VIII; D013925:Thromboplastin; D013917:Thrombin
keywords: blood coagulation; coagulation factor VIII; hemophilia A; humoral immune response; thrombin; tissue factor