A FRESH LOOK AT THE MOLECULAR PHARMACOLOGY OF PLASMINOGEN ACTIVATORS - FROM THEORY TO TEST-TUBE TO CLINICAL OUTCOMES

The molecular pharmacology of plasminogen activators and its implicati ons for thrombolytic therapy are discussed. The benefits of coronary t hrombolysis were first demonstrated with intracoronary and i.v. strept okinase. Tissue plasminogen activator (t-PA) or recombinant t-PA (alte plase) proved to be superior to streptokinase with respect to speed of reperfusion and reperfusion efficacy. Since alteplase neither lessene d the risk of bleeding found with streptokinase nor generated Thrombol ysis in Myocardial Infarction (TIMI) grade 3 flow rates above about 50 %, the quest for faster-acting, safer, and more effective thrombolytic agents has continued. The ideal agent would be highly efficient at co nverting plasminogen to plasmin, have an intermediate half-life, have a low affinity for fibrin, and be of reasonable cost. Genetic engineer ing of the wild-type t-PA molecule resulted in reteplase, which has a longer half-life than alteplase and may be superior in terms of lytic activity, myocardial salvage, and survival. Also under investigation a re TNK-t-PA and n-PA, which have longer half-lives and, in animal mode ls, seem to produce more rapid and complete thrombolysis, at less risk of intracranial bleeding, than alteplase. The risk of intracranial bl eeding remains a problem with all thrombolytics; the risk versus the b enefit will have to be assessed in large randomized trials. An underst anding of the functions of various regions of the t-PA molecule has le d to genetic engineering of new and promising plasminogen activators.