Coronary thrombolysis with intravenously administered human tissue-type plasminogen activator produced by recombinant DNA technology.

Abstract

Coronary thrombolysis was induced by intravenous infusion of human tissue-type plasminogen activator (recombinant human t-PA or rt-PA) obtained by expression of the cloned gene in a mammalian cell system. Thrombolysis was detected by the appearance of reperfusion arrhythmia and confirmed by repeat angiography in anesthetized dogs with 1-hr-old thrombi of the left anterior descending coronary artery that were induced with a copper coil. Infusion of 1000 IU (10 ,ug)/kg/min intravenous rt-PA (n = 9) elicited reperfusion within 13.7 1.9 min (mean + SE) without producing systemic fibrinolysis or distal coronary embolization. Infusion of urokinase at the same rate elicited thrombolysis in seven of 10 dogs within an average of 19.3 + 2.2 min. However, distal coronary embolization occurred in two dogs and systemic fibrinolysis was observed in all. In three dogs treated with urokinase thrombolysis was obtained only with subsequent intracoronary infusion. Restoration of myocardial perfusion and metabolism assessed with positron-emission tomography was consistently noted in dogs treated with rt-PA. Thus, rt-PA, a clot-selective thrombolytic agent that does not activate the fibrinolytic system systemically and that is potentially available in large quantities, in view of its synthesis by recombinant DNA technology, offers a promising practical approach for coronary thrombolysis in patients with acute myocardial infarction. Circulation 69, No. 3, 605-610, 1984. THROMBOSIS in an atherosclerotic coronary artery occurs in most patients with transmural myocardial infarction at the time of the acute episode.' Whether or not the clot initiates the infarction or is an early secondary event, it appears increasingly likely that early thrombolysis may be beneficial. Intracoronary infusion of streptokinase results in recanalization in as many as 80% of patients in this category.2, 3 Based on the assumption that timely recanalization may result in the salvage of jeopardized myocardial tissue, decreased mortality, and improved quality of life, several large-scale studies of the early treatment of myocardial

Reduction in infarct size and enhanced recovery of systolic function after coronary thrombolysis with tissue-type plasminogen activator combined with beta-adrenergic blockade with metoprolol.

“…The infusion of rt-PA was not associated with systemic activation of the fibrinolytic system or with clinically evident bleeding. In the 24 dogs that received rt-PA and completed the study, fibrinogen levels before and after infusion were nearly identical ( figure 1. The infarct size in reperfused dogs (groups I to IV) was significantly smaller than in the dogs with persistent coronary artery occlusion (groups V and VI).…”

Prourokinase Mutant That Induces Highly Effective Clot Lysis Without Interfering With Hemostasis

“…26 The infusion rates of proUK and tPA used in the present study were previously shown in a coronary thrombosis model to be both effective and fibrin specific in dogs. 23,24 Because the lysis properties of M5 in vitro and in vivo were comparable and reflect the catalytic changes induced by the mutation, it seems likely that these properties will also be seen in other clot lysis models.…”

“…Then an intravenous infusion of saline or activator was started. Infusion rates of proUK (20 g/kg per minute) or tPA (10 g/kg per minute), which have been reported in the literature to be both effective and fibrin-specific in dogs, 23,24 were used. The tPA infusion was limited to 60 minutes because of its high cost.…”

Prevention of coronary thrombosis with subthrombolytic doses of tissue-type plasminogen activator.

“…With addition of t-PA after thrombin-coagulation in euglobulin fractions and in whole plasma samples, the response to a given concentration of exogenous t-PA was diminished (figure 2) Results are for t-PA antigen activity (n 316 analyses).…”