Therefore, on initiation of the cascade TF-FVIIa complexes are formed and small amounts of Factor Xa and thrombin are generated. The limited quantities of Factor Xa will result in feedback inhibition of its own synthesis via TFPI. Of importance, heparin increases action of TFPI 2-4 fold. Two mechanisms are involved. The first involves heparin binding TFPI and TF-FVIIa complex, bring them closer together and hence increasing their interaction. Heparin also causes the release of endothelial stores of TFPI.
Antithrombin III (AT): This is a protein synthesized by liver and endothelial cells which binds and directly inactivates thrombin and the other serine proteases (Factors IXa, Xa., and XIa). The uncatalyzed reaction between the serine proteases and AT is relatively slow. The serine proteases still have time to generate thrombin and fibrin before becoming inactivated. However, in the presence of heparin or similar sulfated glycosaminoglycans, the reaction between AT and the serine proteases is virtually instantaneous resulting in the immediate blockage of fibrin formation. Normal endothelial cells express heparan sulfate (a sulfated glycosaminoglycan). AT binds to this and then is able to inactivate any nearby serine proteases, thus preventing the formation of fibrin clot in undamaged areas. Note, In the presence of heparin, the primary target of AT is thrombin.
Activated Protein C and Protein S: Proteins C and S are both Vitamin K dependent inhibitors of the procoagulant system. Together, they inactivate Factors Va and VIIIa. Protein C circulates in the blood as a zymogen and is activated to a serine protease by the binding of thrombin to thrombomodulin (see below). Protein S markedly enhances the activity of Protein C. By inactivating Factors Va and VIIa, Proteins C and S significantly decrease the tempo of thrombin generation, thereby significantly dampening the cascade.
Thrombomodulin: This is an endothelial cell receptor which binds thrombin. When thrombodulin and thrombin form a complex, the conformation of the thrombin molecule is changed. This altered thrombin molecule now readily activates Protein C and loses is platelet activating and protease activities. Therefore, the binding of thrombomodulin to thrombin converts thrombin from a tremdendously potent procoagulant into an anticoagulant. This is important in the normal physiological state because normal endothelial cells produce thrombomodulin which binds any circulating thrombin, thus preventing clot formation in undamaged vessels.
The Fibrinolytic System: The continuous generation of cross-linked fibrin would create a clot capable of obstructing normal blood flow. The Fibrinolytic system is present to keep clot formation in check by actually degrading the fibrin strands. Plasminogen is an inactive protein made in endothelial cells, liver cells, and eosinophils. It is activated to plasmin by an enzyme called plasminogen activator. Plasmin has this ability to degrade fibrin strands, preventing the build-up of excess clot.
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