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Thromb Haemost 1999; 82(02): 974-982
DOI: 10.1055/s-0037-1615941
Research Article
Schattauer GmbH

Mechanism of Action of Plasminogen Activators

Jeffrey I. Weitz
1   From the Department of Medicine, McMaster University and Hamilton Civic Hospitals Research Centre Hamilton, Ontario, CANADA
,
Ronald J. Stewart
1   From the Department of Medicine, McMaster University and Hamilton Civic Hospitals Research Centre Hamilton, Ontario, CANADA
,
James C. Fredenburgh
1   From the Department of Medicine, McMaster University and Hamilton Civic Hospitals Research Centre Hamilton, Ontario, CANADA
› Author Affiliations
Further Information

Publication History

Publication Date:
09 December 2017 (online)

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Introduction

Acute coronary ischemic syndromes and stroke are usually caused by thrombosis in arteries where obstruction leads to ischemia of the heart or brain, respectively. Likewise, venous thrombosis predisposes to pulmonary emboli that cause infarction of lung tissue by blocking pulmonary arteries. Although antithrombotic drugs form the cornerstone of treatment of established thrombosis, pharmacologic lysis of fibrin thrombi, using plasminogen activators, is a widely used approach for treatment of acute myocardial infarction and selected cases of stroke or venous thromboembolism.

Plasminogen activators cause thrombus dissolution by initiating fibrinolysis (Fig. 1). The fibrinolytic system is comprised of inactive plasminogen, which is converted to plasmin by plasminogen activators.1 Plasmin, a trypsin-like serine protease, degrades fibrin into soluble fibrin degradation products. The fibrinolytic system is regulated to provide efficient localized activation of plasminogen on the fibrin surface, yet prevent systemic plasminogen activation. To localize plasminogen activation to the fibrin surface, both plasminogen and tissue-type plasminogen activator (t-PA), the major initiator of intravascular fibrinolysis, bind to fibrin. Plasminogen activator inhibitors,2 the most important of which is type-1 plasminogen activator inhibitor (PAI-1), prevent excessive plasminogen activation by t-PA and urokinase-type plasminogen activator (u-PA). Systemic plasmin is rapidly inhibited by α2-antiplasmin, whereas plasmin generated on the fibrin surface is relatively protected from inactivation by α2-antiplasmin.3

The beneficial effect of thrombolytic therapy reflects dissolution of fibrin within occlusive thrombi and subsequent restoration of antegrade blood flow. Bleeding, the major side effect of thrombolytic therapy, occurs because plasmin is a relatively nonspecific enzyme that does not distinguish between fibrin in occlusive thrombi and fibrin in hemostatic plugs. In addition, circulating plasmin also degrades fibrinogen and other clotting factors, a phenomenon known as the systemic lytic state. Although the contribution of the systemic lytic state to bleeding remains controversial, much attention has focussed on the development of plasminogen activators that produce thrombolysis without depleting circulating fibrinogen in the hope that agents with greater fibrin-specificity will produce less bleeding.

In addition to causing bleeding, currently available plasminogen activators have other limitations. Despite aggressive dosing regimens and adjunctive antithrombotic drugs, up to 25% of coronary thrombi are resistant to thrombolysis at 60 to 90 minutes. Early thrombotic reocclusion of previously opened coronary arteries further reduces the benefits of thrombolytic therapy.4-6 These problems have triggered the quest for more potent thrombolytic agents that have the potential to overcome factors that render some thrombi resistant to lysis. Furthermore, to simplify administration, plasminogen activators with longer half-lives have been developed so that bolus dosing is possible.

This chapter reviews the mechanism of action of currently available plasminogen activators, including agents with greater fibrin-specificity, longer half-lives, and a potential for increased thrombolytic potency.

 

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