Thrombolysis: A Critical First-Line Therapy with an Unfulfilled Potential

A blood clot or thrombus triggers the onset of most vascular diseases, like stroke or heart attack. Thrombolysis is the only treatment that can restore blood flow rapidly and easily. Unfortunately, the standard thrombolytic, tissue plasminogen activator (tPA), has proven inadequate and is being replaced by invasive endovascular procedures, which are time consuming and limited in their availability in relation to the scope of the problem. Historically, when tPA clinical trials began, it was not recognized sufficiently that without the other natural plasminogen activator, prourokinase (proUK), thrombolysis by tPA was seriously compromised. The reason is that the 2 activators have complementary mechanisms of action in fibrinolysis, making their combination a requirement for optimal efficacy and synergy. Biological fibrinolysis also uses both activators, explaining why such low endogenous concentrations are sufficient. A low-dose sequential combination of tPA and proUK was tested in acute myocardial infarction, where it was exceptionally effective and safe. Because native proUK at pharmacological doses was vulnerable to spontaneous conversion to urokinase, jeopardizing safety, a site-directed mutant was developed that improved proUK's plasma stability fivefold without interfering with its mode of action. Mini-bolus tPA followed by low-dose proUK infusion is a simple, safe, effective, and promising first-line treatment of acute thrombotic disorders.