The fibrinolytic system (Fig. 22.2) is involved in restricting clot propagation in the blood and in the removal of fibrin as wounds heal. Treatment of patients with fibrinolytic (thrombolytic) drugs that activate the fibri-nolytic system is not a substitute for the anticoagulant drugs. The purpose of thrombolytic therapy is rapid lysis of already formed clots.
Fibrinolysis is initiated by the activation of the proenzyme plasminogen (present in clots and in plasma) into plasmin, a protease enzyme not normally present in blood. Plasmin catalyzes the degradation of fibrin. The conversion of plasminogen to plasmin is initiated normally by the plasminogen activators, tissue-type plas-minogen activator (t-PA) and single-chain urokinase-type plasminogen activator (scu-PA). t-PA and scu-PA are serine protease enzymes synthesized by the endothe-lium and released into the circulation. The endothelium also releases plasminogen activator inhibitor-1 (PAI-1), which complexes with and inactivates t-PA in the plasma.
t-PA and scu-PA bind with high affinity to fibrin on the clot surface. Circulating plasminogen binds to the plasminogen activator-fibrin complex to form a ternary complex consisting of fibrin, activator, and plasmino-gen. Therefore, the specificity of t-PA and scu-PA binding to fibrin normally localizes plasmin protease activity to thrombi.
Circulating plasmin is rapidly neutralized by a2-an-tiplasmin, a physiological serine protease inhibitor that forms an inert complex with plasmin. In contrast, fibrin-bound plasmin is resistant to inactivation by a2-an-tiplasmin. Under normal circumstances plasma t-PA is inactive because it is inhibited by PAI-1, while t-PA that is bound to fibrin is unaffected by PAI-1. In addition, plasma t-PA has a very rapid turnover in blood (half-life 5 to 8 minutes). For these reasons, fibrinolysis is normally restricted to the thrombus.
Activation of the fibrinolytic system with throm-bolytic drugs can disturb the balance of these regulatory mechanisms and elevate circulating plasmin activity. Plasmin has low substrate specificity and degrades fibrinogen (fibrinogenolysis), plasminogen, and coagulation factors. The systemic unphysiological activation of the fibrinolytic system with thrombolytic drugs causes consumption of the coagulation factors, a lytic state, and bleeding.
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