Fibrinolysis is Misunderstood which is Responsible for an Unsuccessful Therapeutic Design

Therapeutic fibrinolysis has been synonymous with tissue plasminogen activator (tPA) for thirty years, based on the unconfirmed hypothesis that tPA alone was responsible for fibrinolysis. tPA was developed to replace streptokinase (SK), a non-specific activator, but comparative trials in acute myocardial infarction (AMI) found their benefits to be comparable except for tPA causing significantly more intracranial hemorrhage (ICH). The tPA hypothesis was contradicted by gene deletion findings in mice, which showed that fibrinolysis required both tPA and urokinase plasminogen activator (uPA)and that uPA was the dominant activator. Clot lysis studies confirmed the findings and showed tPA and uPA to have complementary effects which functioned sequentially in fibrinolysis. In combination, starting with tPA, their effects were synergistic. A sequential combination was once tested in AMI, in which 101 patients were given a mini-bolus of tPA followed by aprouPA infusion.This resulted in asix-fold lower mortality and almost two-fold higher infarct artery patency rate than that in the best of the tPA trials. Despite publication of the study in a prominent journal, the combination was never retested and fibrinolysis with tPA remained the standard. With little evidence in support of this long-standing practice, a paradigm shift is long overdue.