Coronary thrombolysis with K1K2PU, a chimeric tissue-type and urokinase-type plasminogen activator

Abstract

K1K2Pu is a recombinant chimeric tissue-type and urokinase-type plasminogen activator consisting of the two kringle domains (K1 and K2) of human tissue-type plasminogen activator (t-PA) and the serine proteinase domain (Pu) of single-chain urokinase-type plasminogen activator (scu-PA). In experimental animal models of thrombosis, its thrombolytic potency has been shown to be five- to 10-fold greater than that of its parent molecules. The effect of a bolus injection of K1K2Pu on coronary thrombolysis over 30 min was evaluated in six patients with acute myocardial infarction of less than 5 h duration in whom total occlusion of the infarct-related artery was confirmed using angiography. In two patients given an intravenous bolus of 10 mg over 5 min, persistent coronary artery recanalization was not observed within 30 min. In two out of four patients given a second bolus of 10 mg K1K2Pu, 15 min after the first, persistent coronary recanalization occurred within 30 min. The four patients without recanalization within 30 min were immediately given 100 mg t-PA over 90 min. In all patients the infarct-related artery was patent after 24 h, and the hospital course was uneventful. The bolus injections did not produce significant fibrinogen breakdown or alpha 2-antiplasmin consumption within 30 min. The plasma K1K2Pu level increased to 2-3 micrograms/ml after the first bolus injection and to 4-5 micrograms/ml after the second. K1K2Pu disappeared from the plasma with an initial half-life of 9 min and a clearance of approximately 50 ml/min. A bolus injection of 20 mg K1K2Pu is well tolerated and can induce clot-selective coronary thrombolysis in patients with acute myocardial infarction.