BACKGROUND: Reocclusion of recanalized coronary arteries often limits the efficacy of coronary thrombolytic therapy in patients with acute myocardial infarction. Activated protein C (APC) is an important regulatory enzyme in hemostasis. In view of the potential of human APC as an anticoagulant and profibrinolytic agent, the effect of APC on thrombolysis with recombinant tissue-type plasminogen activator (rTPA) was studied in a canine model of coronary artery thrombosis. METHODS AND RESULTS: Continuous artery flow monitoring in the left anterior descending coronary artery of 30 anesthetized adult beagles was performed by a magnetic flowmeter. Localized thrombosis was produced in the left anterior 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 adjunctive therapy was started simultaneously with rTPA and lasted for 60 minutes. Coronary recanalization occurred in all dogs of each adjunctive treatment group in 19.1 +/- 1.9 minutes (mean +/- SEM). In a 120-minute observation 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 in the APC group (P < .002 versus control and heparin). Time from recanalization 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 thromboplastin time was prolonged similarly in each group after thrombolytic therapy. On the other hand, bleeding time was prolonged in only the heparin group after the treatment. Serious hemorrhagic side effects were not observed in all three groups. CONCLUSIONS: APC prevents coronary artery reocclusion after recanalization with rTPA in a canine model of coronary artery thrombosis. This finding suggests that APC may be useful as an adjunctive treatment to enhance the effects of thrombolytic therapy in patients with acute myocardial infarction.
BACKGROUND: Reocclusion of recanalized coronary arteries often limits the efficacy of coronary thrombolytic therapy in patients with acute myocardial infarction. Activated protein C (APC) is an important regulatory enzyme in hemostasis. In view of the potential of humanAPC as an anticoagulant and profibrinolytic agent, the effect of APC on thrombolysis with recombinant tissue-type plasminogen activator (rTPA) was studied in a canine model of coronary artery thrombosis. METHODS AND RESULTS: Continuous artery flow monitoring in the left anterior descending coronary artery of 30 anesthetized adult beagles was performed by a magnetic flowmeter. Localized thrombosis was produced in the left anterior 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 adjunctive therapy was started simultaneously with rTPA and lasted for 60 minutes. Coronary recanalization occurred in all dogs of each adjunctive treatment group in 19.1 +/- 1.9 minutes (mean +/- SEM). In a 120-minute observation 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 in the APC group (P < .002 versus control and heparin). Time from recanalization 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 thromboplastin time was prolonged similarly in each group after thrombolytic therapy. On the other hand, bleeding time was prolonged in only the heparin group after the treatment. Serious hemorrhagic side effects were not observed in all three groups. CONCLUSIONS:APC prevents coronary artery reocclusion after recanalization with rTPA in a canine model of coronary artery thrombosis. This finding suggests that APC may be useful as an adjunctive treatment to enhance the effects of thrombolytic therapy in patients with acute myocardial infarction.