Received for publication April 8, 2003.
Revised May 5, 2003.
Accepted for publication June 6, 2003.

Pharmacological Interruption of Acute Thrombus Formation with Minimal Hemorrhagic Complications by a Small Molecule Tissue Factor/Factor VIIa Inhibitor: Comparison to Factor Xa and Thrombin Inhibition in a Non-Human Primate Thrombosis Model

Abstract

This study was designed to evaluate the anti-thrombotic efficacy and bleeding propensity of a selective, small molecule inhibitor of Tissue Factor /Factor VIIa (TF/VIIa) in comparison to small molecule, selective inhibitors of Factor Xa and thrombin in a non-human primate model of thrombosis. Acute, spontaneous thrombus formation was induced by electrolytic injury to the intimal surface of a femoral blood vessel, which results in thrombus propagation at the injured site. The TF/FVIIa inhibitor, PHA-927F was fully effective in prevention of thrombosis-induced vessel occlusion at a dose of 400 µg/kg/min, i.v, in the arterial vasculature (femoral artery). Neither the effective dose nor multiples up to 4.4-fold the effective arterial plasma concentration elicited any significant effect on bleeding time or blood loss from either the bleeding time site or the surgical (femoral isolation) site. Small molecule inhibitors of Factor Xa or thrombin were effective arterial anti-thrombotic agents; however, in contrast to the TF/FVIIa inhibitor, they both elicited substantial increases in bleeding propensity at the effective dose and at multiples of the effective plasma concentration. These data indicate that TF/VIIa inhibition effectively prevented arterial thrombosis with less impact on bleeding parameters than equivalent doses of Factor Xa and thrombin inhibitors.

Key words: Animal Model, Antithrombotic, Coagulation, Factor VIIa, Thrombosis, Tissue Factor

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