Summary
A quantitative and non-occlusive deep vein thrombosis model was developed 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 dependent effects of the inhibitors
during constant infusion were monitored. Measurements 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 plasma levels
of 6.5 nM (rXai) and 8 nM (EGR-Xai). Effects on ex-vivo clotting times varied among
the inhibitors. At 80-100% thrombus inhibition, factor rXai and EGR-Xai had no statistically
significant effect, while PPACK extended thrombin clotting time (TCT) times 2.3-fold,
and heparin prolonged both activated partial thromboplastin time (APTT), prothrombin
time (PT) and TCT ex-vivo clotting times 6.9-, 1.2-, and 7-fold respectively. At these
dosages, cuticle and ear bleeding times were prolonged for all inhibitors and showed
increases of 177%-389% (cuticle) and 45%-129% (ear). Our results demonstrate that
direct inhibition of prothrombinase complex assembly is effective in arresting venous
thrombosis.
