PREVENTION OF ARTERIAL REOCCLUSION AFTER THROMBOLYSIS WITH ACTIVATED PROTEIN-C - COMPARISON WITH HEPARIN IN A CANINE MODEL OF CORONARY-ARTERY THROMBOSIS

Background Reocclusion of recanalized coronary arteries often limits t he efficacy of coronary thrombolytic therapy in patients with acute my ocardial infarction. Activated protein C (APC) is an important regulat ory enzyme in hemostasis. In view of the potential of human APC as an anticoagulant and profibrinolytic agent, the effect of APC on thrombol ysis with recombinant tissue-type plasminogen activator (rTPA) was stu died in a canine model of coronary artery thrombosis. Methods and Resu lts Continuous artery flow monitoring in the left anterior descending coronary artery of 30 anesthetized adult beagles was performed by a ma gnetic flowmeter. Localized thrombosis was produced in the left anteri or descending coronary artery and administration of rTPA (alteplase, 0 .45 mg/kg IV) was done for 30 minutes. The dogs were randomly assigned to receive one of the following intravenous adjunctive therapies: (1) control group (n=10): human albumin at a rate of 0.83 mL/min; (2) APC group (n=10): human plasma-derived APC (0.6 mg/kg) with human albumin as a vehicle at a rate of 0.83 mL/min; and (3) heparin group (n=10): heparin (200 U/kg) with saline at a rate of 0.83 mL/min. Each adjuncti ve therapy was started simultaneously with rTPA and lasted for 60 minu tes. Coronary recanalization occurred in all dogs of each adjunctive t reatment group in 19.1r1.9 minutes (mean+/-SEM). In a 120-minute obser vation after the termination of rTPA, reocclusion developed in all the dogs in the control and heparin groups but in only 3 of the 10 dogs i n the APC group (P<.002 versus control and heparin). Time from recanal ization to reocclusion (minutes, mean+/-SEM) was prolonged in the APC group (103.2+/-14.2) as compared with the control (10.2+/-2.3, P<.001) and heparin (30.3+/-11.8, P<.002) groups. Activated partial thrombopl astin time was prolonged similarly in each group after thrombolytic th erapy. On the other hand, breeding time was prolonged in only the hepa rin group after the treatment. Serious hemorrhagic side effects were n ot observed in all three groups. Conclusions APC prevents coronary art ery reocclusion after recanalization with rTPA in a canine model of co ronary artery thrombosis. This finding suggests that APC may be useful as an adjunctive treatment to enhance the effects of thrombolytic the rapy in patients with acute myocardial infarction.