The Function of tPA in Fibrinolysis is Analogous to the Starter of An Automobile

Therapeutic fibrinolysis has used tissue plasminogen activator (tPA) as the fibrinolytic of choice ever since tPA was given FDA approval for the treatment of acute myocardial infarction (AMI) in 1987. This was followed in few years by its approval for ischemic stroke and tPA re-mains the treatment today based on an assumption that tPA is responsible for biological fibrinolysis. However, the evidence for this was never strong but has remained unchallenged for the past 33 years. When tPA became the fibrinolytic of choice it was on the results of three clinical trials in almost 100,000 patients with AMI in whom treatment with tPA was compared with streptokinase (SK), the fibrinolytic at the time. However, SK is an indirect activator that has first to form a complex with plasminogen or plasmin before it becomes an activator, which means that SK consumes its own substrate and the fibrinolytic itself, an inefficient mechanism of action. By contrast, tPA is a direct plasminogen activator. Nevertheless, in the first two trials the mortalities with tPA and SK were identical. Finally, in a third trial, which was divided into four groups, a significantly lower mortality was found but only in one of the four groups [1-3]. In addition, there were significantly more hemorrhagic side effects with tPA than SK.