title: Mechanism of factor VIIa-dependent coagulation in hemophilia blood.
abstract: The ability of factor VIIa to initiate thrombin generation and clot formation in blood from healthy donors, blood from patients with hemophilia A, and in anti-factor IX antibody-induced ("acquired") hemophilia B blood was investigated. In normal blood, both factor VIIa-tissue factor (TF) complex and factor VIIa alone initiated thrombin generation. The efficiency of factor VIIa was about 0.0001 that of the factor VIIa-TF complex. In congenital hemophilia A blood and "acquired" hemophilia B blood in vitro, addition of 10 to 50 nM factor VIIa (pharmacologic concentrations) corrected the clotting time at all TF concentrations tested (0-100 pM) but had little effect on thrombin generation. Fibrinopeptide release and insoluble clot formation were only marginally influenced by addition of factor VIIa. TF alone had a more pronounced effect on thrombin generation; an increase in TF from 0 to 100 pM increased the maximum thrombin level in "acquired" hemophilia B blood from 120 to 480 nM. Platelet activation was considerably enhanced by addition of factor VIIa to both hemophilia A blood and "acquired" hemophilia B blood. Thus, pharmacologic concentrations of factor VIIa cannot restore normal thrombin generation in hemophilia A and hemophilia B blood in vitro. The efficacy of factor VIIa (10-50 nM) in hemophilia blood is dependent on TF.
authors.affiliation: College of Medicine, University of Vermont, 89 Beaumont Ave, Burlington, VT 05405-0068, USA.
authors.forename: Saulius
authors.initials: S
authors.lastname: Butenas
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Brummel
authors.forename: Richard F
authors.initials: RF
authors.lastname: Branda
authors.forename: Sara G
authors.initials: SG
authors.lastname: Paradis
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Mann
mesh_terms: D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D015942:Factor VIIa / Q000378:metabolism / Q000494:pharmacology*; D005340:Fibrinogen / Q000187:drug effects / Q000378:metabolism; D006467:Hemophilia A / Q000097:blood*; D002836:Hemophilia B / Q000097:blood; D006801:Humans; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D013917:Thrombin / Q000096:biosynthesis; D013925:Thromboplastin / Q000378:metabolism / Q000494:pharmacology
chemical_list: D005340:Fibrinogen; D013925:Thromboplastin; D015942:Factor VIIa; D013917:Thrombin