A Novel Role for Tissue-Type Plasminogen Activator

Abstract

Activation of plasminogen by agents such as tissue-type plasminogen activator (tPA), yields plasmin, lyses fibrin, and thereby restores flow to blood vessels occluded by thrombi. Because tPA binds to fibrin, as does plasminogen, at low doses, tPA-mediated generation of plasmin is localized, rendering tPA clot selective. This result, plus its short half-life (4.5 minutes), led to the hope that its use would not only enhance coronary and cerebral thrombolysis but also reduce the risk of bleeding, including intracranial hemorrhage.1 At high conventionally used doses, clot selectivity is incomplete. Perhaps that is why treatment with tPA compared with a non–clot-selective agent, streptokinase, reduced mortality in patients with ST-elevation myocardial infarction but did not diminish the incidence of intracranial hemorrhage.2 Article p 1442 In this issue of Circulation , Danielyan and colleagues describe a novel use of tPA, prevention rather than treatment of thrombi-occluding vessels resulting from emboli.3 Linkage of tPA to red blood cells (RBCs) prohibited its penetration into protective established thrombi, facilitated lysis of nascent thrombi induced by embolization of fibrin, and markedly prolonged the half-life of tPA in the circulation. Compared with soluble tPA, RBC-coupled tPA (RBC/tPA) more effectively lysed nascent cerebral thromboemboli and diminished hemorrhagic complications. Nascent thrombi are lysed with particular efficacy by very low concentrations of tPA probably because cross-linking of fibrin is limited in such thrombi. …