Fibrinolytic subsystem

Pittsburgh), in which an Arg has replaced Ala at the reactive site, is a good inhibitor of thrombin. 

Several proteinase inhibitors inactivate the proteinases of the contact phase. Among the SERPINS are C-1 inactivator, O 1-proteinase inhibitor, and antithrombin. The target proteinases for these inhibitors are factor Xlla, kallikrein, and factor XIa. The molecular mechanisms are the same as those described for the procoagulant and fibrinolytic system proteinases. 

Another inhibitor is present in plasma that can inactivate thrombin, plasmin, and, to a much lesser extent, the other proteinases as well. This inhibitor, a2-macroglobulin, inhibits by a completely different mechanism from that of the SERPINS. It entraps the proteinases in a cavity that is created by the four subunits of the ai-macroglobulin molecule. The active sites of the entrapped proteinases are sterically hindered from protein substrates but are accessible to low-molecular-weight chromogenic substrates that are used in some laboratory coagulation tests for heparin and antithrombin. 

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The fibrinolytic subsystem, by proteolytic digestion of fibrin, eliminates the fibrin from the hemostatie plug. Similar to the other subsystems, the fibrinolytic subsystem... 

Because inactivation of factors Va and Villa by activated protein C promotes the dissociation of the pro-teinases, cofactor protein inactivation complements the action of the proteinase inhibitors. This eliminates the protection that the proteinases have when bound to their cofactor proteins and substrates. Inactivation of proteinases by SERPINS occurs via a common mechanism that involves a Michaelis complex between the proteinase and the inhibitor (Figure 36-16). This mechanism applies to all serine proteinases of the hemostatic system, i.e., the procoagulant, anticoagulant, and fibrinolytic subsystem proteinases. 

The fibrinolytic system removes the fibrin of the hemostatic plug and thus is responsible for the temporary existence of the fibrin clot. The proteolytic action of plasmin on fibrin and fibrinogen is extensive and more like the digestive proteolysis catalyzed by trypsin and chy-motrypsin than the proteolysis involved in proteinase precursor activation. The fibrinolytic subsystem includes the reactions of plasminogen activation, plasmin inactivation, and fibrin digestion. As is common throughout the hemostatic system, irreversible activation reactions of the fibrinolytic system are opposed by irreversible proteinase inactivation. 

It is helpful in the effort to understand activation complexes to consider complex formation, the reactions that occur in the complexes, and the demise of the complexes as proceeding in a sequence. First, a reversible, noncovalent association of proteinase, cofactor protein (strictly, activated cofactor protein), proteinase precursor, and membrane surface occurs to form the activation complex. This spontaneous association occurs as the result of complementary interaction sites on the protein molecules, e.g., the binding sites between proteinase and protein substrate, proteinase and cofactor protein, substrate and cofactor protein, and all three proteins with the membrane surface. Tissue factor normally exists as an integral membrane protein and is always associated with the membranes of cells in the vessel wall. The same processes are involved in the anticoagulant subsystem and, with a different surface, fibrin in the fibrinolytic system as well. 

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