Coagulation specific clotting factors

The concept that different structural domains on the heparin chains are principally involved for optimal activity in the foregoing interactions could not be perceived in early work on structure-activity correlations, because the activity of heparin has been most frequently evaluated only with whole-blood-clotting tests (such as the U.S.P. assay). Development of assays for specific clotting-factors (especially Factor Xa and thrombin) has permitted a better insight into the mechanism of action of heparin at different levels of the coagulation cascade. 

Clinical pharmacology Activated factor IX in combination with activated factor VIII activates factor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, and a clot can be formed. Factor IX is the specific clotting factor deficient in patients with hemophilia B and in patients with acquired factor IX deficiencies. The administration of Coagulation Factor IX (Recombinant) increases plasma levels of factor IX and can temporarily correct the coagulation defect in these patients. 

Platelets adhere to each other and to foreign surfaces and this property is referred to as platelet adhesion or aggregation or similar terms. Platelet aggregation is the initial stage of formation of a blood clot and is accompanied by release of phospholipids and specific clotting factors that trigger blood coagulation. 

Pharmacology Vitamin K promotes the hepatic synthesis of active prothrombin (factor II), proconvertin (factor VII), plasma thromboplastin component (factor IX), and Stuart factor (factor X). The mechanism by which vitamin K promotes formation of these clotting factors involves the hepatic post-translational carboxylation of specific glutamate residues to gamma-carboxylglutamate residues in proteins involved in coagulation, thus leading to their activation. 

A number of proteins of the blood clotting (coagulation) cascade (including prothrombin, and a number of other clotting factors) undergo post-translational modification in a reaction catalysed by a vitamin K-dependent carboxylase, which transforms specific Glu residues into y-carboxyglutamic acid, Gla (Fig. 4.1). In the reaction (Fig. 4.2), the dihydroquinone (reduced) form of vitamin K, KH2, is oxidised to the epoxide form, KO, by O2. The... 

Within the blood coagulation system, the six vitamin K-dependent clotting factors comprise a closely related group of plasma proteins. Factors VII, IX, X, prothrombin and protein C circulate in plasma as inactive precursors (1). Upon specific... 

The blood coagulation cascade. Each of the curved red arrows represents a proteolytic reaction, in which a protein is cleaved at one or more specific sites. With the exception of fibrinogen, the substrate in each reaction is an inactive zymogen except for fibrin, each product is an active protease that proceeds to cleave another member in the series. Many of the steps also depend on interactions of the proteins with Ca2+ ions and phospholipids. The cascade starts when factor XII and prekallikrein come into contact with materials that are released or exposed in injured tissue. (The exact nature of these materials is still not fully clear.) When thrombin cleaves fibrinogen at several points, the trimmed protein (fibrin) polymerizes to form a clot. 

Tjlood coagulation is preceded by a sequence of zymogen-to-enzyme " conversions brought about by some very specific proteases (i). In these processes the interaction between coagulation factors and phospholipids plays a crucial role (2) by accelerating some of the reaction steps leading to clot formation. 

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