Fibrinolysis and its modulation

The fibrinolytic system is a process which modulates the degradation of the clot as the organism repairs and replaces damaged vascular tissue. This process encompasses the degradation of the fibrin clot and its cellular components to soluble degradation products. Many of the constituent zymogens, activators and enzyme inhibitors are either intimately located within the clot or within the adjacent endothelial tissue associated with the clot. t-PA is a secretory product of the EC whose secretion is promoted by thrombin. Its inhibitor, PAI-1 is also observed in ECs, as well as in platelets, plasma and the EC matrix. (PA1-2 has only been seen in extracts of placental tissue in the third trimester of pregnancy.) Plasminogen, the inactive zymogen for the fibrinolytic plasmin, is readily bound by thrombo-spondin, a glycoprotein produced by platelets and expressed to the membrane surface upon activation. Thrombospondin acts to inhibit interaction of plasminogen with fibrin, as well as the activation of the plasminogen-fibrin complex. Plasminogen is entrapped in the clot and acts locally upon appropriate activation. a2-AP is a component of the a granules of platelets. Accordingly, all the components necessary for fibrinolysis and its control are strategically placed at the site of the clot. Circulating a2-AP, for example, is not believed to penetrate the clot and affect fibrinolysis, whereas a2-AP in the entrapped platelet (granules) can be released upon activation of the platelets. Likewise, fibrinolysis occurs only within the clot, and not systemically. Hence, the postulated pathway for fibrinolysis and its modulation envisions the degradation of fibrin into soluble degradation products by plasmin. (Plasmic activity may be inhibited by a2-AP.) Plasmin is activated from the inactive plasminogen by two-chain t-PA. It may also be activated by two-chain u-PA and by kal-

likrein. The two-chain t-PA and two-chain u-PA arc-both generated from their one-chain precursors by plasmin. Kallikrein transforms the one-chain u-PA into its two-chain metabolite. PAI-1 and PAI-2 inhibit the catalytic activity of one-chain t-PA, two-chain t-PA and u-PA. Only PAI-2 inhibits one-chain u-PA. The activation of plasminogen to plasmin is also inhibited by lipoprotein(a), thrombospondin and histidine-rich glycoprotein (His-rich-GP).

A summary of the active proteases associated with coagulation and fibrinolysis, together with their naturally occurring inhibitors, is given in Table 1.

See also: Erythrocytes; Fibronectin; Macrophage activation; Plasma; Platelet-activating factor (PAF); Platelets; Prostaglandins.

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