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Prepublished online as a Blood First Edition Paper on July 17, 2003; DOI 10.1182/blood-2003-05-1369.
Submitted May 1, 2003
Accepted July 8, 2003
Improved hemostasis with superactive analogues of factor VIIa in a mouse model of hemophilia A
Mikael Tranholm*, Kim Kristensen, Annemarie T Kristensen, Charles Pyke, Rasmus Roejkjaer, and Egon Persson
Novo Nordisk A/S, Maaloev, Denmark
The Royal Veterinary and Agricultural University, Copenhagen, Denmark
* Corresponding author; email: mitr{at}novonordisk.com.
It is currently debated whether the mechanism of action of therapeutic doses of recombinant factor VIIa (rFVIIa, NovoSeven®) 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 three analogues 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 on 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 analogues 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 analogues 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.
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