CVS-1123, low-molecular-weight,
direct thrombin inhibitor was studied in an anesthetized canine model of arterial and
venous thrombosis to determine whether
thrombin inhibition could reduce the incidence of occlusive
thrombosis in response to vessel-wall injury. The left carotid artery (LCA) and right jugular vein (RJV) were instrumented with a flow 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-microA anodal current to the intimal surface of the LCA and RJV. Platelet aggregation in response to
gamma-thrombin remained inhibited by
CVS-1123 for 8 h. The activated partial thromboplastin time (aPTT) was increased and remained elevated 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) at 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 seven 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 min in the saline group) with eight of 12 veins remaining patent at 8 h.
CVS-1123 administration was associated with a decrease in the
thrombus weights in both the LCA and RJV as compared with the saline-treated animals. In summary,
CVS-1123 modifies the thrombogenic response to deep vessel-wall injury in both the arterial and venous circulations. The results suggest that
CVS-1123 is an effective
antithrombin and may offer a therapeutic alternative to current
antithrombins in the management of arterial and
venous thrombosis.