ANTITHROMBOTIC ACTIVITY OF RECOMBINANT TICK ANTICOAGULANT PEPTIDE ANDHEPARIN IN A RABBIT MODEL OF VENOUS THROMBOSIS

An in vivo rabbit model of venous thrombosis which includes physiologi cal blood flow was used to compare the efficacy of the potent and spec ific factor Xa inhibitor recombinant tick anticoagulant peptide (rTAP) with standard heparin in the prevention of venous thrombus formation. In anesthetized rabbits, an autologous thrombus was induced with thro mbin in a jugular vein and the increase in thrombus size was determine d by measuring the accretion of intravenously injected [I-125]fibrin(o gen) onto the developing thrombus. The effects of rTAP on hemostasis w ere monitored by changes in APTT values and template bleeding times. I nhibition of thrombus formation by an intravenous bolus followed by in fusion of either rTAP or heparin exhibited a dose-response relationshi p with an IC50 of 0.9 mug/kg/min and 0.12 units/kg/min, respectively. At the IC50 doses, both rTAP and heparin inhibited fibrin(ogen) deposi tion without any significant effect on APTT or bleeding times. Bleedin g times were modestly elevated at the fully efficacious doses of rTAP and heparin. Significant changes in APFT (1.9 +/- 0.3 fold over baseli ne) were only evident at the highest dose of rTAP while heparin caused a significant dose-dependent increase froin 1.3 +/- 0.2 to greater th an 4.2 +/- 0.6 fold over baseline. Therefore, in this rabbit model of venous thrombosis, specific inhibition of factor Xa by rTAP is an effe ctive antithrombotic mechanism that does not require changes in system ic hemostatic parameters.