Fibrinolysis: an unfinished agenda.

There has been a recent decline in interest in fibrinolysis, suggesting that its physiological basis is sufficiently understood and that therapeutic thrombolysis has reached its limit. The importance of the subject has not diminished since cardiovascular disease is now a leading health problem even in developing countries. Certain highlights and inconsistencies are reviewed. The clinical trials of tissue plasminogen activator (t-PA) revealed a major discrepancy between its fibrinolytic efficacy and its clinical benefit (the 't-PA paradox') that is unexplained. Dose-finding studies also showed that the fibrinolytic efficacy of t-PA required significant nonspecific plasminogen activation. Furthermore, the longstanding belief that t-PA is responsible for physiological fibrinolysis and urokinase-type PA (u-PA) for pericellular plasminogen activation is belied by extensive experimental animal data, but these findings have had little impact on traditional thinking. As a result, the mechanisms responsible for the u-PA paradigm of fibrinolysis have received little attention. Clinical experience with pro-u-PA remains limited and most clinical trials have used infusion rates at which pro-u-PA is largely converted systemically to urokinase. This is due to the unanticipated instability of pro-u-PA in plasma at pharmacological concentrations. Insufficient understanding of basic mechanisms of fibrinolysis has handicapped the design of chimeric or mutant activators. It is submitted that physiological fibrinolysis remains to be better defined, and that it is premature to conclude that therapeutic thrombolysis will be inevitably accompanied by side effects that undermine this method of inducing reperfusion.