CVS-1123, A DIRECT THROMBIN INHIBITOR, PREVENTS OCCLUSIVE ARTERIAL AND VENOUS THROMBOSIS IN A CANINE MODEL OF VASCULAR INJURY

CVS-1123, low-molecular-weight, direct thrombin inhibitor was studied in an anesthetized canine model of arterial and venous thrombosis to d etermine whether thrombin inhibition could reduce the incidence of occ lusive thrombosis in response to vessel-wall injury. The left carotid artery (LCA) and right jugular vein (RJV) were instrumented with a flo w probe, intraluminal electrode, and critical stenosis. Either saline (n = 9), or CVS-1123 (n = 12) was administered in a loading dose of 2 mg/kg i.v., followed by an infusion (2.46 mg/kg/h for 180 min). Vessel -wall injury was initiated by applying a 300-mu A anodal current to th e intimal surface of the LCA and RJV; Platelet aggregation in response to gamma-thrombin remained inhibited by CVS-1123 for 8 h. The activat ed partial thromboplastin time (aPTT) was increased and remained eleva ted for the duration of the protocol. The prothrombin time (PT) showed an initial increase and then a rapid decrease after the infusion was discontinued. There was a twofold increase in the bleeding time (BT) a t 2 h. The time to occlusion of the LCA was prolonged (380 +/- 22 min in the CVS-1123 group vs. 152 +/- 18 min in the saline group) with sev en of 12 patent arteries at 8 h. Similarly, the time to occlusion for RJV was prolonged (415 +/- 16 min in the CVS-1123 group vs. 99 +/- 8 m in in the saline group) with eight of 12 veins remaining patent at 8 h . CVS-1123 administration was associated with a decrease in the thromb us weights in both the LCA and RJV as compared with the saline-treated animals. In summary, CVS-1123 modifies the thrombogenic response to d eep vessel-wall injury in both the arterial and venous circulations. T he results suggest that CVS-1123 is an effective antithrombin and may offer a therapeutic alternative to current antithrombins in the manage ment of arterial and venous thrombosis.