Proteins prothrombin complex activity

In 42 patients who required immediate reversal of oral anticoagulant therapy by prothrombin complex concentrate, no laboratory and clinical evidence for coagulation activation was found (7). The authors suggested that the concentration of protein C within the prothrombin complex concentrate is an important factor for preventing thrombosis. The activated form of protein C is an important natural anticoagulant. 

Before the high-purity products were approved for use, hemophilia B patients had been treated with factor IX concentrates that also contained other vitamin K-dependent proteins (factors II, VII, and X), known as prothrombin complex concentrates (PCCs). These products contain small amounts of activated factors generated during processing, and their use has been associated with thrombotic... 

Protein C and the sixth vitamin K-dependent protein, protein S, participate in the regulation of clot formation, thus acting as anticoagulants (13). On complex formation with the vascular endothelial membrane protein, thrombomodulin, the substrate specificity of thrombin is altered from fibrinogen to protein C (90). Activation of protein C is accelerated and thrombin procoagulant activity is inhibited. Once activated, protein C interacts with phospholipid membranes and the cofactor protein S to inactivate factors Va and Villa through limited proteolysis (13). The inactivated accessory proteins lose critical interactions with their respective protease and substrate, thus effectively inhibiting the activation of prothrombin and hence the formation of the fibrin clot. 

Thrombin attacks synthetic esters, namely tosyl l-arginine methyl ester (TAMe), and when thrombin is treated with DIPT, the loss of esterase activity is proportional to the loss of clotting activity. Studies with synthetic esters have suggested that, as with trypsin, the reaction between thrombin and its substrates occurs in three steps an enzyme-substrate complex is formed the acyl portion of the ester is transferred to the enzyme, which becomes acylated while the alcoholic portion of the ester is released and the enzyme is deacylated and the peptide is transferred to water. The natural substrate of thrombin is fibrinogen. In addition to converting fibrinogen to fibrin, thrombin releases the contractile protein from platelets, activates fibrinase, and may participate in the conversion of prothrombin to thrombin. 

Initiation of the fibrin clot in response to tissue injury is carried out by the extrinsic pathway. How the intrinsic pathway is activated in vivo is unclear, but it involves a negatively charged surface. The intrinsic and extrinsic pathways converge in a final common path-vray involving the activation of prothrombin to thrombin and the thrombin-catalyzed cleavage of fibrinogen to form the fibrin clot. The intrinsic, extrinsic, and final common pathways are complex and involve many different proteins (Figure 51-1 and Table 51-1). In... 

Vitamin K status can be assessed by a functional test, called the "prothrombin time test," which involves measuring the lime required to form a blood clot. The test is performed as follows. A blood sample is withdrawn from a subject and immediately mixed with citric acid. Citric acid is a chelator, which means that it can form a tight complex with ions, such as calcium ions. The chelator prevents the interaction of calcium ions with the blood-clotting proteins and thus prevents these proteins from forming a blood clot in the sample. Calcium ions, it should be noted, are required for supporting the activity of several blood clotting proteins. The "citrated blood" is placed in a machine called a fibrometer. The fibrometer is used to detect increases in the viscosity of the blood over a period. 

FIGURE 9.30 Structures of prothrombin and thrombin. Prothrombin is a protein consisting of 581 amino acids, while thrombin consists of 308 amino acids. Prothrombin is cleaved within the bloodstream, at the indicated peptide bonds, by the factor X /factor Vg complex. The intermediary form of thrombin is called meizothrombin. The activation peptide might be considered to be a waste product of the activation scheme. Please note that thrombin consists of two separate polypeptide chains, and that these are held together by a disulfide bond. Studies by researchers have revealed that prothrombin can also be activated by factor X alone, but here the pathway of peptide bond cleavage is somewhat different than that produced by the factor XJfactor complex. 

When TF is exposed to blood, it spontaneously binds factor VII, a serine protease of the coagulation system that possesses a gla domain (Table 11.1). The TF VII complex therefore adheres to the negatively charged surface of activated platelets. About 0.4% of factor VII is activated in blood by fatty acid- or triglyceride-mediated activation of factor IX and binds similarly to TF. The TF Vila complex (Fig. 11.6a) has proteolytic activity and cleaves (converts) another gla protein that also binds to the activated platelets, factor X. Factor Xa is a serine protease that converts the remainder of the TF VII complex, generating additional Xa proteolytic activity that ultimately converts prothrombin to thrombin for... 

When blood is lost or clotting is initiated in some other way, a complex cascade of biochemical reactions is set in motion, which ends in the formation of a network or clot of insoluble protein threads enmeshing the blood cells. These threads are produced by the polymerisation of the molecules of fibrinogen (a soluble protein present in the plasma) into threads of insoluble fibrin. The penultimate step in the chain of reactions requires the presence of an enzyme, thrombin, which is produced from its precursor prothrombin, already present in the plasma. This is initiated by factor lit (tissue thromboplastin), and subsequently involves various factors including activated factor Vn, DC, X, XI and XII, and is inhibited by antithrombin in. Platelets are also involved in the coagulation process. Fibrinolysis is the mechanism of dissolution of fibrin clots, which can be promoted with thrombolytics. For further information on platelet aggregation and clot dissolution, see Antiplatelet drugs and thrombolytics , (p.697). 

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