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  • Title: Fibrin-specific thrombolytic agents.
    Author: Collen D.
    Journal: Klin Wochenschr; 1988; 66 Suppl 12():15-23. PubMed ID: 3126344.
    Abstract:
    The fibrinolytic system comprises a proenzyme, plasminogen, which can be converted to the active enzyme plasmin, which will degrade fibrin. Plasminogen activation is mediated by plasminogen activators which are classified as either tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). Inhibition of the fibrinolytic system may occur at the level of the activators or at the level of generated plasmin. Plasmin has a low substrate specificity and when circulating freely in the blood will degrade several proteins including fibrinogen, Factor V and Factor VIII. Plasma does, however, contain a fast-acting plasmin inhibitor, alpha 2-antiplasmin, which will inhibit free plasmin extremely rapidly (t1/2: 0.1 s) but which reacts much slower (10(3)-fold) with plasmin bound to fibrin. A "systemic fibrinolytic state" may, however, occur by extensive activation of plasminogen (conc. in plasma 2 microM) and depletion of alpha 2-antiplasmin (conc. in plasma 1 microM). Clot-specific thrombolysis therefore requires plasminogen activation restricted to the vicinity of the fibrin. Two physiological plasminogen activators, t-PA and single-chain u-PA (scu-PA) induce clot-specific thrombolysis, however via entirely different mechanisms. t-PA is relatively inactive in the absence of fibrin, but fibrin strikingly enhances the activation rate of plasminogen by t-PA. This is explained by an increased affinity of fibrin-bound t-PA for plasminogen and not by alteration of the catalytic rate constant of the enzyme. The high affinity of t-PA for plasminogen in the presence of fibrin thus allows efficient activation on the fibrin clot while no significant plasminogen activation by t-PA occurs in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
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