Recombinant single-chain urokinase-type plasminogen activator (rscu-pa) induces thrombolysis and systemic fibrinolysis in a canine model of coronary artery thrombosis

Abstract

The thrombolytic efficacy of recombinant single-chain urokinase-type plasminogen activator (rscu-PA) was studied in an open-chest canine model of coronary artery thrombosis. Dogs (n=16) were anesthetized, a left thoracotomy performed, and a two cm segment of the left circumflex coronary artery was isolated and instrumented with an electromagnetic flow probe, an intracoronary stimulation electrode, and an adjustable mechanical occluder. Anodal direct current (100 [mu]A) was applied to the stimulation electrode until thrombosis occurred (n=14). After 30 min of thrombotic occlusion, rscu-PA was administered intravenously. Dogs were sacrificed either 6 h after thrombolysis or 6.5 h after initiation of rscu-PA when thrombolysis did not occur. In group A (30-50 [mu]g/kg bolus rscu-PA + 20-40 [mu]g/kg/min infusion rscu-PA for 30 min, N=5) thrombolysis occurred in one case (20%) and this artery reoccluded. In group B (250 [mu]g/kg bolus rscu-PA + 25 [mu]g/kg/min infusion rscu-PA for 30 min, N=6) all reperfused and only one reoccluded (16.6%). In group C (200 [mu]g/kg bolus rscu-PA + 100 [mu]g/kg/min rscu-PA infusion for 30 min, N=2) both reperfused and neither reoccluded. Infarct size, determined as a percentage of left ventricle, was smaller when thrombolysis was followed by persistent reperfusion (n=7), than when reperfusion did not occur (n=4): 16.9 +/- 3.7% vs 31.3 +/- 2.2%, respectively (mean +/-SEM, p<0.02). If thrombolysis was followed by reocclusion, infarct size was 27.0 +/- 10.0%. In this study thrombolysis occurred when changes in prothrombin time, partial thromboplastin time, fibrinogen and fibrin split products were suggestive of systemic finbrinogenolysis. In conclusion, effective thrombolysis with rscu-PA appears to limit infarct size and to be accompanied by evidence of systemic fibrinolysis.