A COMPARATIVE-STUDY OF PROTHROMBINASE AND THROMBIN INHIBITORS IN A NOVEL RABBIT MODEL OF NONOCCLUSIVE DEEP-VEIN THROMBOSIS

A quantitative and non-occlusive deep vein thrombosis model was develo ped in rabbits. We used this model to test the antithrombotic activity of the prothrombinase complex inhibitors factor rXai and its chemical analog glutamyl-glycyl-arginyl chloromethyl ketone inactivated human factor Xa (EGR-Xai), along with the thrombin inhibitors D-phenylalanyl -prolyl-arginyl chloromethyl ketone (PPACK) and heparin. Dose dependen t effects of the inhibitors during constant infusion were monitored. M easurements included thrombus weights, hemostatic parameters and both cuticle and ear bleeding times. In this model, factor rXai and EGR-Xai had comparable in-vivo efficacy, and showed 80%-93% inhibition at pla sma levels of 6.5 nM (rXai) and 8 nM (EGR-Xai). Effects on ex-vivo clo tting times varied among the inhibitors. At 80-100% thrombus inhibitio n, factor rXai and EGR-Xai had no statistically significant effect, wh ile PPACK extended thrombin clotting time (TCT) times 2.3-fold, and he parin prolonged both activated partial thromboplastin time (APTT), pro thrombin time (PT) and TCT ex-vivo clotting times 6.9-, 1.2-, and 7-fo ld respectively. At these dosages, cuticle and ear bleeding times were prolonged for all inhibitors and showed increases of 177%-389% (cutic le) and 45%-129% (ear). Our results demonstrate that direct inhibition of prothrombinase complex assembly is effective in arresting venous t hrombosis.