Inhibition of Microarterial Thrombosis by Activated Protein C in a Rabbit Model

Abstract

Protein C is the key component in a natural anticoagulant pathway. After its activation by the thrombin-thrombomodulin complex, it degrades the activated forms of coagulation cofactors VIII and V, which leads to downregulation of the coagulation process. Due to its specific anticoagulant activity, activated protein C (APC) is potentially interesting as an antithrombotic agent. The effect of bovine activated protein C on thrombus formation and haemostasis was investigated in a rabbit model of microarterial thrombosis. Segments of both central ear arteries were prepared and blood-flow interrupted with double vascular clamps. Longitudinal arteriotomies (7 mm) and deep vessel wall trauma (5 mm) were performed, whereafter the arteriotomies were closed with running sutures. Five minutes prior to opening of the clamps (reperfusion), boluses of APC (0.8 mg/kg bodyweight) or vehicle alone were administered to two groups, each of 10 rabbits, in a blind random fashion. Vessel patency-rates were drastically improved by the administration of APC compared to vehicle. Correspondingly, thrombus weights were significantly lower in the APC group than in the control group. The activated partial thromboplastin time was prolonged to approximately twice the baseline throughout the 2 h observation interval in the APC group. Levels of circulating platelets were unaffected by the APC infusion, but the arteriotomy bleeding times were significantly longer in the APC group. In summary, activated protein C exerted powerful and long-acting antithrombotic effects in a microarterial model of thrombosis in rabbits.