title: Improved hemostasis with superactive analogs of factor VIIa in a mouse model of hemophilia A.
abstract: It is currently debated whether the mechanism of action of therapeutic doses of recombinant factor VIIa (rFVIIa, Novo-Seven) relies on the tissue factor (TF)-independent activity of the enzyme. The present study was conducted to investigate the in vivo hemostatic effects of rFVIIa and 3 analogs thereof with superior intrinsic activity (FVIIaIIa, K337A-FVIIaIia, and M298Q-FVIIa) in mice with antibody-induced hemophilia A. A highly significant dose response was observed for the bleeding time and blood loss for each of the rFVIIa variants. The bleeding time and blood loss were normalized after administration of 10 mg/kg rFVIIa, 3 mg/kg K337A-FVIIaIia, and 3 mg/kg M298Q-FVIIa, indicating a potency of these FVIIa analogs 3-4 times above that of rFVIIa in FVIII-depleted mice. The different in vivo potencies of the various forms of FVIIa could not be explained by the pharmacokinetics. Histopathological evaluation of kidneys revealed no signs of treatment-related pathological changes even after treatment with the superactive variants. The fact that FVIIa analogs with enhanced intrinsic activity are more efficacious in the murine hemophilia A model strongly suggests that the TF-independent procoagulant activity of FVIIa contributes to its clinical hemostatic effect.
authors.affiliation: Pharmacology, Research and Development, A/S Novo Nordisk Park, DK-2760 Måløv Denmark. mitr@novonordisk.com
authors.forename: Mikael
authors.initials: M
authors.lastname: Tranholm
authors.forename: Kim
authors.initials: K
authors.lastname: Kristensen
authors.forename: Annemarie T
authors.initials: AT
authors.lastname: Kristensen
authors.forename: Charles
authors.initials: C
authors.lastname: Pyke
authors.forename: Rasmus
authors.initials: R
authors.lastname: Røjkjaer
authors.forename: Egon
authors.initials: E
authors.lastname: Persson
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001760:Bleeding Time; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005167:Factor VII / Q000235:genetics / Q000493:pharmacokinetics* / Q000494:pharmacology; D015942:Factor VIIa; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy*; D006487:Hemostasis / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016297:Mutagenesis, Site-Directed; D011994:Recombinant Proteins / Q000235:genetics / Q000493:pharmacokinetics* / Q000494:pharmacology; D013810:Therapeutic Equivalency
chemical_list: D011994:Recombinant Proteins; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa