ASSESSMENT OF THROMBIN INHIBITOR EFFICACY IN A NOVEL RABBIT MODEL OF SIMULTANEOUS ARTERIAL AND VENOUS THROMBOSIS

The importance of thrombin in arterial and venous thrombosis renders t hrombin inhibition an important therapeutic target. Identification of novel inhibitors requires an appropriate animal model. We modified a p reviously reported rat arterial thrombosis model to allow simultaneous assessment of the arterial and venous antithrombotic efficacies of he parin, hirudin, hirulog, a novel thrombin inhibitor e)-Pro-L-trans-4-a minocyclohexyl-Gly-[CO-CO]-NHCH3 (L-370,518) and the factor X-a inhibi tor tick anticoagulant peptide in rabbits. Thrombosis was induced thro ugh application of 70% ferric chloride to the femoral artery and jugul ar vein. Incidence of occlusion, thrombus weight, aPTT and plasma inhi bitor concentrations were determined. Heparin was efficacious in preve nting arterial and venous occlusive thrombosis but at a dose that prof oundly elevated aPTT. On a molar dosing basis, the approximate order o f potency of the thrombin and factor X-a inhibitors was similar in art ery and vein: hirudin>tick anticoagulant peptide>hirulog greater than or equal to L-370,518. Data suggest ed that compounds tended to be mor e potent in preventing venous thrombosis than arterial. This thrombin- dependent model is an economical and efficient approach to arterial an d venous antithrombotic efficacy screening that eliminates variabiliti es encountered when multiple model/multiple animal strategies are empl oyed.