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Cardiovascular Engineering and Technology

, Volume 4, Issue 4, pp 328–338 | Cite as

Fibrinolytic Mechanisms of tPA, prouPA, Mutant prouPA and Their Implications for Therapeutic Thrombolysis

  • Victor GurewichEmail author
Article

Abstract

Experience with thrombolysis for 25 years has been essentially limited to tissue plasminogen activator (tPA). Therefore, tPA has been perceived as synonymous with all thrombolysis. However, tPA has a unique mode of action different from that of urokinase plasminogen activator (uPA), whose native form is prouPA. At the pharmacological concentrations, both physiological activators induced unanticipated effects that were also different. Reperfusion with tPA is almost twice as effective as streptokinase, the former thrombolytic standard. Nevertheless, three mega-trials with a total of 94,740 patients were required to show a significant difference in acute myocardial infarction. Surprisingly, intracranial hemorrhage was also significantly more with tPA. These paradoxical findings can be explained by tPA’s rethrombosis rate undermining its efficacy, and lysis of hemostatic fibrin causing tPA bleeding. By contrast, prouPA has a low rethrombosis rate and it spares hemostatic fibrin by virtue of its different mechanism of fibrin-bound plasminogen activation. Unfortunately, these potential advantages are out of reach in practice since at high therapeutic concentrations in blood, prouPA is vulnerable to non-specific conversion to uPA, a non-specific plasminogen activator that induces a hemorrhagic diathesis. A single-site mutant, M5, was designed to correct this prouPA problem. In vitro and in vivo studies showed that M5 clot lysis was more effective than prouPA or tPA and was accompanied by a sparing of hemostatic fibrin. When M5 administration was preceded by a bolus of plasma C1-inhibitor, it further improved the plasma stability of M5 and permitted a maximum clot lysis rate to be achieved without fibrinogenolysis.

Keywords

Plasminogen activators Mode of action tPA prouPA Mutant prouPA Stroke Acute myocardial infarction 

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Copyright information

© Biomedical Engineering Society 2013

Authors and Affiliations

  1. 1.Mount Auburn HospitalHarvard Medical SchoolCambridgeUSA

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