Blood clot coagulation factor inhibitors

Considerably more is known about anticoagulants from the blood-feeding hookworm, Ancylostoma caninum. Several families of small, anti-clotting peptides have been described in A. caninum. AcAP, an 8.7 kDa peptide secreted by adult worms that does not exhibit homology to other anticoagulants, but is a potent inhibitor of Factor Xa, was described by Cappello et at. (1995). A family of related peptides, one of which uniquely inhibited a complex of blood coagulation factor VIIA and tissue factor, was also reported (Stanssens et al., 1996). 

If thrombin and factor Xa, the major activated blood coagulation factors (Fig. 11.6), escape into healthy blood vessels, blood clots will develop and occlude capillaries throughout the body. Direct inhibition of these activated enzymes in the blood flow utilizes serine protease inhibitors, of which there are two common types a Kunitz inhibitor and a serpin. The former possess a Kunitz domain, a convex antiparallel (1-sheet that exactly fits into the concave active site of a serine protease, directly blocking it (lock and key mechanism). By contrast, serpins undergo complex interactions with other proteins to cause conformational changes that bait and block the catalytic action (Fig. 11.12 shows the bait). Table 11.3 fists the major coagulation inhibitors and cofactors, their targets and mechanisms of action. 

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. 

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). 

Mectianism of Action A factorXa inhibitor and pentasaccharide that selectively binds to antithrombin, and increases its affinity for factor Xa, thereby inhibiting factor Xa and stopping the blood coagulation cascade. Therapeutic Effect Indirectly prevents formation of thrombin and subsequently the fibrin clot. 

Heparin acts by binding to anti thrombin III, which serves as a major inhibitor of serine protease clotting enzymes. Abruptly ending heparin treatment can be hazardous because of reduced levels of antithrombin III. Coumarins, typified by warfarin, are structurally similar to vitamin K, which plays an important role in blood coagulation. By interfering with the function of vitamin K, vitamin K-dependent proteins such as clotting factors VII, IX, X and prothrombin are reduced. 

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