Blood coagulation clotting enhancement

Thrombus (clot) formation is enhanced by thrombin activation, which is mediated by the complex interaction that constitutes the blood coagulation cascade. This cascade (Fig. 45.3) consists primarily of proteins that serve as enzymes or cofactors, which function to accelerate thrombin formation and localize it at the site of injury. These proteins are listed in Table 45.2. All of these proteins are present in the plasma as proproteins (zymogens). These precursor proteins are activated by cleavage of the polypeptide chain at one or more sites. The key to successful and appropriate thrombus formation is the regulation of the proteases that activate these zymogens. 

Antithrombin III (AT3), a protein (432 aa, Mr 58 kDa) acting as inhibitor of thrombin and all active proteases of the blood clotting system ( serpins) except Factor Vila by binding to them in 1 1 complex in similar manner as BPTI binds to trypsin. The presence of heparin enhances the inhibitory activity of antithrombin by several hundredfold. In antithrombin, Arg is the reactive center residue that provides a specific cleavage site for thrombin [T. Halkier, Mechanisms in Blood Coagulation, Fibrinolysis and the Complement System, Cambridge University Press, 1991). 

Hemostasis is the process that stops bleeding in a blood vessel. Normal hemostasis involves a complex process of extrinsic and intrinsic factors. Figure 44-1 shows the coagulation pathway and factors involved. The copulation cascade is so named because as each factor is activated it acts as a catalyst that enhances the next reaction, with the net result being a large collection of fibrin that forms a plug in the vessel. Fibrin is the insoluble protein that is essential to clot formation. 

Antithrombin III (AT-III), a single-chain glycoprotein of 58 kDa and 480 amino acids, is synthesized in the liver. It is a serine protease inhibitor, and acts as the most important inhibitor in the coagulation cascade to avoid blood clot formation. AT-III inhibits a wide spectram of serine proteases induding thrombin, factors IXa, Xa and XIa, kaUikrein, plasmin, urokinase, Cl-esterase, and trypsin. AT-III interacts with heparin by binding to specific sul-fated and non-sulfated monosaccharide units on heparin. The binding of AT-III to heparin enhances the inhibition of factors IXa, Xa, and thrombin. 

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