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.
