title: Pharmacological concentrations of recombinant factor VIIa restore hemostasis independent of tissue factor in antibody-induced hemophilia mice.
abstract: ESSENTIALS: The role of tissue factor (TF) in recombinant factor VIIa (rFVIIa) therapy in hemophilia is unclear. An acquired mouse hemophilia model with very low or normal levels of human TF was used in the study. rFVIIa is equally effective in correcting the bleeding in mice expressing low or normal levels of TF. Pharmacological doses of rFVIIa restore hemostasis in hemophilia independent of TF.
  
  
  CONCLUSIONS
  
  
  
  BACKGROUND
  Recombinant factor VIIa (rFVIIa) has been used widely for treating hemophilia patients with inhibitory autoantibodies against factor VIII or IX. Its mechanism of action is not entirely known. A majority of in vitro studies suggested that pharmacological concentrations of rFVIIa restore hemostasis in hemophilia in a phospholipid-dependent manner, independent of tissue factor (TF). However, a few studies suggested that a TF-dependent mechanism has a primary role in correction of bleeding by rFVIIa in hemophilia patients. Here, we investigated the potential contribution of TF in rFVIIa-induced hemostasis in hemophilia employing a model system of FVIII antibody-induced hemophilia in TF transgenic mice.
  
  
  METHODS
  Mice expressing low levels of human TF (LTF mice), mice expressing relatively high levels of human TF (HTF mice) and wild-type mice (WT mice) had neutralizing anti-FVIII antibodies administered in order to induce hemophilia in these mice. The mice were then treated with varying concentrations of rFVIIa. rFVIIa-induced hemostasis was evaluated with the saphenous vein bleeding model.
  
  
  RESULTS
  Administration of FVIII inhibitory antibodies induced the hemophilic bleeding phenotype in all three genotypes. rFVIIa administration rescued the bleeding phenotype in all three genotypes. No significant differences were observed in rFVIIa-induced correction of bleeding between LTF and HTF mice that had FVIII antibodies administered.
  
  
  CONCLUSIONS
  Our results provide strong evidence supporting the suggestion that the hemostatic effect of pharmacological doses of rFVIIa stems from a TF-independent mechanism.
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Keshava
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Sundaram
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Rajulapati
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX, USA.
authors.forename: U R
authors.initials: UR
authors.lastname: Pendurthi
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX, USA.
authors.forename: L V M
authors.initials: LV
authors.lastname: Rao
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003029:Coagulants / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII / Q000037:antagonists & inhibitors / Q000276:immunology; D015942:Factor VIIa / Q000494:pharmacology*; D005838:Genotype; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D011994:Recombinant Proteins / Q000494:pharmacology; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003029:Coagulants; C528643:F8 monoclonal antibody; D011994:Recombinant Proteins; D005169:Factor VIII; D013925:Thromboplastin; D015942:Factor VIIa
keywords: factor VIIa; hemophilia A, acquired; hemorrhage; hemostasis; thromboplastin