Blood clotting cofactors

Vitamin K (phylloquinone, K menaquinone, Kj) i Slow blood clotting Cofactor for glutamate carboxylase... 

Vitamin K A cofactor for the carboxylase of the hepatic endoplasmic reticulum, which is responsible for completing the synthesis of blood-clotting proteins. 

Factor VIII (FVIII) is an essential coagulation factor in the blood which serves as a cofactor in the complex blood-clotting cascade. A deficiency in FVIII is the... 

Every regulatory system in the body must be prevented from overactivity or activity that is unnecessarily prolonged. This can help us understand that, just as with blood clotting (Fig. 12-17), a network of regulatory factors controls the complement system. Among these are an inhibitory C4b-binding protein (C4BP),181 which acts to prevent excessive formation of the C4b C2a complex (Fig. 31-8). Complement cofactor I is a serine protease that cleaves both C3b and C4b into smaller pieces in the presence of cofactor... 

Vitamin K is essential for the activation of specific proteins involved in blood clotting and bone metabolism through its role as a cofactor for y-glutamylcarboxylase. This enzyme catalyses a... 

Much attention has focused on vitamin K 1 because of its function as an obligatory cofactor in enzymic sequences central to blood clotting. The role of molecular oxygen in the formation of vitamin K oxide 2 has been studied intensively, and the mechanism of the 1 —> 2 transformation has been the subject of much controversy. Oxidation of 1 with basic hydrogen peroxide also gives 2, and two obvious mechanisms can be postulated for this model oxidation. 180 labelling studies have been used to distinguish between these mechanisms. 

Mann KG, Jerry RJ, Krishnaswamy S. Cofactor proteins in the assembly of blood clotting enzyme complexes. Annu Rev Biochem 1988 57 915-956. 

Vitamin K is an essential cofactor for the synthesis of prothrombin and other blood-clotting factors. Vitamin K deficiency occurs due to liver disease, longterm antimicrobial therapy, and malabsorption. Vitamin K deficiency can lead to hemorrhages in newborns and development of hypoprothrombobinemia. Rapid intravenous injection of emulsified vitamin K produces flushing, breathlessness, hypotension, and may lead to death. 

The major function of the K vitamins is in the maintenance of normal levels of the blood clotting proteins, factors II, VII, IX, X and protein C and protein S, which are synthesized in the liver as inactive precursor proteins. Conversion from inactive to active clotting factor requires a post-translational modification of specific glutamate (E) residues. This modification is a carboxylation and the enzyme responsible for it requires vitamin K as a cofactor. 

Protein C is a vitamin K-dependent protein. It contains Gl-A residues. This fact raises the interesting question of whether vitamin K deficiency can prevent some degree of blood clotting (a consequence of lack of carboxylation of prothromin), but result in some abnormal prolongation in the clots that do occur (aia expected consequence of lack of carboxylation of protein C). Protein S is a protein that is a cofactor of protein C. Protein S contains GLA residues, and thus requites vitamin K for its modification, and conversion to the biologically useable protein. 

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. 

Ant ithrombin-heparin cofactor 62,000- 67,000 Thrombin, other serine proteases of blood clotting sequence 25, 2i... 

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