Therapeutic Fibrinolysis: How Efficacy and Safety Can Be Improved

Therapeutic fibrinolysis has been dominated by the experience with tissue-type plasminogen activator (t-PA), which proved little better than streptokinase in acute myocardial infarction. In contrast, endogenous fibrinolysis, using one-thousandth of the t-PA concentration, is regularly lysing fibrin and induced Thrombolysis In Myocardial Infarction flow grade 3 patency in 15% of patients with acute myocardial infarction. This efficacy is due to the effects of t-PA and urokinase plasminogen activator (uPA). They are complementary in fibrinolysis so that in combination, their effect is synergistic. Lysis of intact fibrin is initiated by t-PA, and uPA activates the remaining plasminogens. Knockout of the uPA gene, but not the t-PA gene, inhibited fibrinolysis. In the clinic, a minibolus of t-PA followed by an infusion of uPA was administered to 101 patients with acute myocardial infarction; superior infarct artery patency, no reocclusions, and 1% mortality resulted. Endogenous fibrinolysis may provide a paradigm that is relevant for therapeutic fibrinolysis.