Understanding Fibrinolysis Misconceptions: Developing Effective Therapeutic Strategies

The present study highlights the understanding of Fibrinolysis Misconceptions. Tissue plasminogen activator (tPA) has been associated with therapeutic fibrinolysis for thirty years due to the unproven theory that fibrinolysis was caused by tPA alone. Streptokinase (SK), a non-specific activator, was replaced with tPA during development; nonetheless, comparative trials in acute myocardial infarction (AMI) revealed similar benefits for both drugs, with the exception that tPA dramatically increased 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 that 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 a pro-UK infusion. This resulted in a six-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, which is against standard practice which invariably repeats an unusually successful treatment result to see whether or not it was a fluke, and fibrinolysis with tPA remained the standard. With little evidence in support of this long-standing practice, a paradigm shift is long overdue. By using the biological complementary and synergistic properties of tPA and uPA in a sequential combination, fibrinolytic therapy can be made more effective and safer. This was already tested and validated in a clinical trial of AMI but its recognition and utilization awaits the paradigm shift referred to by Thomas Kuhn.