Coronary thrombolysis by intravenous infusion of recombinant single chain urokinase-type plasminogen activator or recombinant urokinase in baboons: Effect of regional blood flow, infarct size and hemostasis

Abstract

An occlusive thrombus was produced by thrombin-induced coagulation in the left anterior descending coronary artery of 18 open chest baboons. In six control animals, occlusive thrombosis persisting for 4 hours resulted in a large transmural infarct (66 ± 4% of the perfusion area, mean ± SEM). In six animals, single chain urokinase-type plasminogen activator, obtained by recombinant deoxyribonucleic acid (DNA) technology, was infused intravenously at a rate of 20 μg/kg per min for 60 minutes after approximately 45 minutes of coronary thrombosis. Persistent reperfusion occurred within 21 ± 4 minutes (mean ± SD). The mean duration of occlusion before reperfusion was 72 ± 6 minutes. Recanalization resulted in a reduction of infarct size (42 ± 4%, p < 0.01 versus control animals). Myocardial blood flow in the perfusion area of the left anterior descending coronary artery was 107% of normal 2.5 hours after recanalization. The infusion of recombinant single chain urokinase-type plasminogen activator was not associated with systemic activation of the fibrinolytic system, fibrinogen breakdown or evident bleeding. In six baboons recombinant low molecular weight urokinase (molecular weight 33,000) was infused intravenously at a rate of 20 μg/kg per min for 60 minutes after approximately 45 minutes of coronary thrombosis. Persistent reperfusion occurred within 14 ± 5 minutes (p < 0.05 versus recombinant single chain urokinase-type plasminogen activator). The mean duration of occlusion was 69 ± 14 minutes. Recanalization resulted in a reduction of infarct size (45 ± 8%, p < 0.05 versus control animals), and myocardial blood flow in the perfusion area of the left anterior descending coronary artery was 97% of normal 2.5 hours after recanalization. Infusion of recombinant low molecular weight urokinase was associated with complete fibrinogen breakdown, a decrease of alpha2-antiplasmin to less than 20% and profuse bleeding from the surgical wounds. It is concluded that intravenous infusion of recombinant single chain urokinase-type plasminogen activator may recanalize thrombosed coronary vessels without inducing systemic lysis. Recombinant low molecular weight urokinase appears to have a comparable or somewhat higher thrombolytic effect but is associated with extensive systemic fibrinolytic activation.