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Fibrinolysis: an unfinished agenda
1Vascular Research Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. vgurewic@caregroup.harvard.edu
Insights
Interest in fibrinolysis has waned, but cardiovascular disease remains a major health issue. Further research into fibrinolysis mechanisms is crucial for improving thrombolytic therapies and defining physiological roles.
Area of Science:
- Biochemistry
- Cardiovascular Medicine
- Pharmacology
Background:
- Declining research interest in fibrinolysis contrasts with the persistent global burden of cardiovascular disease.
- Existing understanding of fibrinolysis and thrombolytic therapy may be incomplete, hindering therapeutic advancements.
- The 't-PA paradox,' a discrepancy between tissue plasminogen activator (t-PA) efficacy and clinical benefit, remains unexplained.
Purpose of the Study:
- To review inconsistencies in fibrinolysis research and highlight the need for a deeper understanding of its physiological basis.
- To re-evaluate the established roles of tissue plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) in fibrinolysis.
- To address the limited understanding of pro-urokinase (pro-u-PA) and its implications for therapeutic thrombolysis.
Main Methods:
- Review of clinical trials and experimental animal data concerning t-PA and u-PA.
- Analysis of dose-finding studies for t-PA to assess plasminogen activation.
- Examination of clinical data and plasma stability of pro-u-PA at pharmacological concentrations.
Main Results:
- Clinical trials of t-PA show a significant unexplained discrepancy between its fibrinolytic efficacy and clinical benefit (the 't-PA paradox').
- t-PA's fibrinolytic efficacy necessitates substantial nonspecific plasminogen activation, challenging its proposed specific role.
- Experimental data contradicts the traditional view of t-PA and u-PA roles, with u-PA's mechanisms receiving limited attention.
Conclusions:
- Physiological fibrinolysis requires further definition, as current understanding is insufficient.
- The mechanisms of the u-PA paradigm in fibrinolysis warrant greater investigation.
- It is premature to conclude that therapeutic thrombolysis is inherently limited by side effects; improved understanding may lead to better therapies.
Abstract:
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.