Coronary Thrombolytic Properties of a Novel Recombinant Plasminogen Activator (BM 06.022) in a Canine Model

Abstract

We studied the thrombolytic dose-response relationship of a recombinant plasminogen activator (rPA) (BM 06.022) compared with alteplase in a canine model of coronary artery thrombosis. BM 06.022 consists of the kringle 2 and protease domains of human tissue PA (tPA) and lacks oligosaccharide side chains because of its expression in Escherichia coli. Thrombus formation in anesthetized, open-chest dogs was induced by electrical injury to the intimal surface of the left circumflex coronary artery in the presence of a critical stenosis. Intravenous bolus injection of BM 06.022 (50, 100, 140, and 200 kU/kg) or of alteplase (200, 800, 1,130, and 1,600 kU/kg) 30 min after coronary occlusion to six heparinized dogs per group achieved a dose-dependent increase in reperfusion rate and decrease in residual thrombus wet weight. Vehicle-treated dogs did not reperfuse. Semilogarithmic regression analysis showed that the effective dose that produced 50% reperfusion of BM 06.022 (83 kU/kg) was 11.6-fold lower than that of alteplase (951 kU/kg). Comparison with infusion experiments showed that intravenous bolus injection of 140 kU/kg of BM 06.022 was equieffective to a 90-min infusion of 800 kU/kg (= 1 mg/kg) of alteplase as a standard treatment regarding reperfusion rate (66%) and time to reperfusion (15 ± 6 vs. 18 ± 8 min). Pharmacokinetic analysis for functionally active BM 06.022 or alteplase in plasma revealed a total plasma clearance of 4.1–6.6 ml/min/kg for BM 06.022 and of 12.6–42.3 ml/min/kg for alteplase. At equieffective treatment regimens, residual fibrinogen was not different between BM 06.022 (93 ± 1%) and alteplase (97 ± 5%) and effects of BM 06.022 and alteplase on bleeding time and platelet count were not significantly different. We conclude that, due to its slower plasma clearance, BM 06.022 has a higher thrombolytic potency than alteplase after i.v. bolus injection, but has the same degree of fibrin selectivity as alteplase in a canine model of coronary thrombosis.