Fibrin-specific thrombolytic agents.

Abstract

Human plasma contains two physiologic activators of the fibrinolytic system: prourokinase, also called single chain urokinase-type plasminogen activator (scu-PA), and tissue-type plasminogen activator (t-PA). Both activators can catalyze the proenzyme plasminogen to plasmin. Plasmin transforms fibrin into soluble fibrin breakdown products. t-PA is an inefficient plasminogen activator in the absence of fibrin. In the presence of fibrin, t-PA and plasminogen bind to fibrin; the resultant ternary complex increases the efficiency of the transformation of plasminogen to plasmin two to five hundred times. The activity of the fibrinolytic system is modulated by inhibitors. alpha 2-antiplasmin forms 1:1 stochiometric complexes with plasmin and thus neutralizes circulating plasmin with exceptional rapidity. A specific plasminogen activator-inhibitor has recently been described which rapidly inactivates t-PA and urokinase. The fibrin-specific thrombolytic t-PA has undergone intensive clinical trials, particularly in acute myocardial infarction. It has been found that t-PA is better tolerated (bleeding) while being at least as effective, or more so, than streptokinase. Several research groups are attempting through gene manipulation to produce t-PA with even better therapeutic effect (e.g. even better binding to fibrin, longer half life). Clinical trials of prourokinase and combined prourokinase/t-PA are under way and have also provided favourable therapeutic results so far.