Antithrombotic and hemostatic capacity of factor Xa versus thrombin inhibitors in models of venous and arteriovenous thrombosis

Thrombin plays a central role in venous and arterial thrombosis. We utilize d two different rabbit models of in vivo thrombosis to investigate the effe ct of inhibitors of thrombin generation and thrombin activity. The agents t ested were specific inhibitors of factor Xa (fXa) [N2-[(phenylmethyl)sulfon yl]-D-arginyl-N-[(1S)-4-[(aminoiminomethyl)amino]-1-(2-thiazolylcarbonyl)bu tyl]-glycinamide (C921-78)] and thrombin [D-phenylalanyl-N-[4-[(aminoiminom ethyl (PPACK)], as well as drugs that affect both thrombin and fXa, unfract ionated and low molecular weight (enoxaparin) heparin. The agents administe red as constant intravenous infusion were evaluated for antithrombotic effi cacy in anesthetized rabbits. All four agents were capable of dose dependen t inhibition of thrombosis in venous and arteriovenous thrombosis models. H owever, due to the more aggressive nature of thrombotic stimulation in the arteriovenous shunt model, complete cessation of thrombus growth was not ac hieved for any of the agents at the doses tested. Comparison between the ag ents focused on the differences in extension of coagulation parameters (act ivated partial thromboplastin time, prothrombin time, thrombin clotting tim e), changes in hematological parameters, and extension of rabbit cuticle bl eeding time at doses required to produce maximum inhibition in the thrombos is models. In the venous thrombosis model at the maximally effective dose, C921-78 had minimal extension of ex vivo clotting parameters, while enoxapa rin and unfractionated heparin demonstrated a two to sevenfold increase in activated partial thromboplastin times, and PPACK had a threefold extension of thrombin clotting times: In addition, unlike the other three agents, wh ich exhibited no significant changes in hematological parameters, PPACK dem onstrated dose dependent thrombocytopenia. A standardized cuticle bleeding time was used as a measure of perturbation of hemostasis. The agents were e valuated for significant increases in bleeding time at doses up to eight ri mes that needed to completely inhibit venous thrombus formation. Unfraction ated heparin displayed a significant bleeding time effect at the dose requi red to inhibit venous thrombosis (100 u/kg + 2 u/kg/min). Enoxaparin and PP ACK caused significant bleeding time extensions at four times the fully eff icacious venous dose (800 u/kg + 8 u/kg/min and 30 mu g/kg/min). By contras t, C921-78 did not significantly increase bleeding time even at eight times the maximally effective dose (240 mu g/kg + 7.2 mu g/kg/min). Our results demonstrate that specific inhibition of fXa can be utilized to derive poten t antithrombotic activity without disrupting extravascular hemostasis. (C) 2000 Elsevier Science B.V. All rights reserved.