LABORATORY INVESTIGATION CORONARY THROMBOLYSIS Coronary thrombolysis in dogs with intravenously administered human pro-urokinase

Coronary thrombolysis was induced by infusion of highly purified human pro-urokinase isolated from a transformed kidney cell line (ACHN) or by infusion of urokinase of urinary origin in anesthetized dogs with 1-hr-old clots in the left anterior descending coronary artery. The clots were induced with a copper coil and thrombolysis was detected by repeat coronary angiography. Intravenous infusion of pro-urokinase at a rate of 1 0 ,ug/kg/min for 30 min in two dogs did not induce thrombolysis, which was only obtained after 8 and 15 min of its subsequent intracoronary administration. Intravenous infusion of pro-urokinase at a rate of 20 gg/kg/min for 30 min in four dogs induced coronary thrombolysis within 23 + 2 min (mean + SEM). This was not associated with systemic fibrinolytic activation because the a2,-antiplasmin and fibrinogen levels did not decrease. Intravenous infusion of urokinase at a rate of 10 gg/kg/min for 30 min elicited thrombolysis in four of seven dogs within an average of 19 ± 2 min. In the other three dogs thrombolysis was only obtained within 1 1 -'3 min of its subsequent intracoronary infusion. Administration of urokinase was associated with systemic fibrinolytic activation as evidenced by a decrease of a2-antiplasmin to about 10% and of fibrinogen to 43 13% of the preinfusion value. It is concluded that intravenous infusion of pro-urokinase at a sufficiently high rate produces coronary thrombolysis without systemic fibrinolysis in dogs. Circulation 72, No. 2, 384-388, 1985. CORONARY THROMBOLYSIS has been widely investigated as a means to abort the evolution of acute transmural myocardial infarction. Several attempts have also been made to develop fibrin-specific thrombolytic agents that would be more effective than streptokinase and would induce less systemic fibrinolysis. Thrombolytic agents with anticipated fibrin selectivity now include human tissue-type plasminogen activator (t-PA),' acylated plasminogen-streptokinase complex) and pro-urokinase. Pro-urokinase is a precursor of urokinase, first identified in tissue-culture media4 5 and later purified from urine,6 plasma,' conditioned cell culture media,'' and transformed bacteria. 1f Although the mechanism of action of pro-urokinase remains to be established, recent From the Center for Thrombosis and Vascular Research. Department of Medical Research. and Laboratory of Experimental Cardiologxv Department of Pathophysiology. University of Leuven. Belgium. Supported by the Geconcerteerde Onderzoeksactie (project 80-85-3) and grants from the University of Leuven. Belgium. D. Stump is the recipient of NHLBI Clinical Investigator Award HL 01176. Address for correspondence: D. Collen. M.D._ Center for Thrombosis and Vascular Research, Department of Medical Research. Campus Gasthuisberg-University of Leuven. Herestraat 49. B-3000 Leuven. Belgium. Received Jan. 30. 1985; revision accepted April 18, 1985. *Permanent address: Mochida Pharmaceutical Co.. Research Laboratory of Cell Science. Tokyo. 115 Japan. 384 reports have provided evidence that it can indeed induce more clot-selective thrombolysis in animal preparations than urokinase. "'' In this study we used a well-characterized preparation for the study of thrombolysis after coronary occlusion in dogs4 to evaluate the relative fibrinolytic effects of pro-urokinase as compared with urokinase.