Blood, amino acids coagulation

Coumarins are competitive inhibitors of vitamin K, which is required for the formation in the liver of the amino acid, gamma-carboxyglutamic acid. This is necessary for the synthesis of prothrombin and factors VII, IX and X (Figure 17.1). After starting treatment the anticoagulant effect is delayed until the concentration of normal coagulation factors falls (36-72 h). The effects can be reversed by vitamin K (slow maximum effect only after 3-6 h) or by whole blood or plasma (fast). Gut bacteria synthesise vitamin K and thus are an important source of this vitamin. Consequently, antibiotics can cause excessive prolongation of the prothrombin time in patients otherwise adequately controlled on warfarin. 

The extrinsic pathway of coagulation is activated when circulating factor VII encounters tissue factor. Tissue factor is a transmembrane glycoprotein, which is normally expressed by subendothelial fibroblast-like cells, which surround the blood vessel. An intact endothelium normally shields the circulating blood from exposure to tissue factor. The tissue factor molecule consists of a 219 amino acid hydrophilic extracellular domain, a 23 amino acid hydrophobic region that spans the membrane, and a 21 amino acid cytoplasmic tail that anchors the molecule to the cell membrane (15,16). Other sites of tissue factor expression include activated monocytes, activated endothelial cells, and atherosclerotic plaques. 

Compounds with vitamin K activity (Table 6.2) are required in our diets for y-carboxyglutamate biosynthesis (Table 4.1). This amino acid is produced from certain protein glutamyl residues by carboxylation. Proteins that contain y-carboxyglutamate are blood prothrombin and coagulation factors VII, IX, and X (see Chapter 7). Other proteins of this type are osteocalcin from bone and several kidney and muscle calcium-binding proteins. 

OC contains three specific glutamyl residues at amino acid positions 17, 21, and 24, which may be converted to y-carboxyglutamyl residues by a posttranslational, vitamin K-dependent enzymatic carboxylation. This unique car-boxylated amino acid binds calcium ions and is found in various proteins involved in blood coagulation and in calcium transport, deposition, and homeostasis. Undercar-boxylated OC, which has been reported in serum in some conditions, may be related to decreased bone density and may respond to administration of vitamin K. Although OC binds calcium and hydroxyapatite, its physiological role is unknown. 

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. 

One particularly important aspect of Ca " in mammals is its role in the blood coagulation system. Here we will meet a new type of amino acid, y-carboxyglutamic acid ( Gla )—see Figure 3.29, that seems to have been de-... 

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