Activation of prothrombin

The a-thrombin dissociates from the prothrombin fragment 1-2 and diffuses to its substrates platelets (the platelet thrombin receptor), factor V, factor VIII, 

Although there is an explosive increase in the reaction rate, only a small fraction ( Cl%) of the total prothrombin available ( 1.5 /zM) is converted to thrombin. The concentration of thrombin required to convert fibrinogen 

An interesting mutation in the gene for prothrombin, a G-to-A transition in the 3 untranslated region at nucleotide 20210, results in an elevated concentration of prothrombin in the circulation ( 115% of normal). It is not known if the mutation causes the elevated prothrombin levels, but the defect is associated with a twofold increase in the risk of thrombosis. 

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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... 

Activated by thrombin factor Va is a cofactor in the activation of prothrombin by factor Xa. 

The Final Common Pathway of Blood Clotting Involves Activation of Prothrombin to Thrombin... 

The activation of prothrombin, like that of factor X, occurs on the surface of activated platelets and requires the assembly of a prothrombinase complex, consisting of platelet anionic phospholipids, Ca, factor Va, factor Xa, and prothrombin. 

Figure 12.5 Proteolytic cleavage of prothrombin by factor Xa, yielding active thrombin. Although prothrombin is a single-chain glycoprotein, thrombin consists of two polypeptides linked by what was originally the prothrombin intrachain disulfide bond. The smaller thrombin polypeptide fragment consists of 49 amino acid residues, and the large polypeptide chain contains 259 amino acids. The N-terminal fragment released from prothrombin contains 274 amino acid residues. Activation of prothrombin by Xa does not occur in free solution, but at the site of vascular damage...

There is discussion on the adequacy of tests to identify the hypercoagulable states underlying susceptibility to VTED. The complexity of factors and interactions involved in the hemostatic equilibrium has favored the use of functional tests. Among the several options available the measurement of fragments 1 + 2 (F1 + 2), the amino terminus fragment split during the activation of prothrombin has been widely considered the test of choice. The sparse information available for SERMs, however, is unclear. Raloxifene did not modify... 

Blood/gout/ Oxyuranus polypept./activator of prothrombin inflamma- toxin/Sigma... 

The most obvious effect of a deficiency in vitamin K in animals is delayed blood clotting, which has been traced to a decrease in the activity of prothrombin and of clotting factors VII, IX, and X (Chapter 12, Fig. 12-17). Prothrombin formed by the liver in the absence of vitamin K lacks the ability to chelate calcium ions essential for the binding of prothrombin to phospholipids and to its activation to thrombin. The structural differences between this abnormal protein and the normal prothrombin have been pinpointed at the N terminus of the 560 residue glycoprotein.e f Tryptic peptides from the N termini differed in electrophoretic mobility. As detailed in Chapter 12, ten residues within the first 33, which were identified as glutamate residues by the sequence analysis on normal prothrombin, are actually y-carboxyglutamate (Gla). The same amino acid is present near the N termini of clotting factors VII, IX, and X. 

Ghigliotti G.Waissbluth AR, Speidel C, et al. Prolonged activation of prothrombin on the vascular wall after arterial injury. Arterioscler Thromb Vase Biol 1998 18 250-257. 

Thrombin, which catalyzes the proteolysis of fibrinogen, circulates as an inactive precursor, prothrombin, which in turn is activated by partial proteolysis to remove a peptide sequence that masks the catalytic site. There are two distinct pathways leading to the activation of prothrombin to thrombin (see Figure 5.3) ... 

The very large increases in the rates of activation of prothrombin and factor X that occur in the presence of factors Va and Villa, respectively, make the hemostatic response both rapid and localized. However, if such rates were to continue unabated, the extension of the hemostatic plug... 

CHAPTER 36, FIGURE 6 Cofactor proteins, factor V and factor VIII. Factor V and factor VIII coagulant (not the von Willebrand factor carrier of factor VIII) contain six distinct structural domains. The two A domains. A, and Aj at the N-terminal end of the polypeptide chain, are separated from the Aj domain by a highly glycosylated B domain. The two C domains are at the C-terminal end of the molecule. The A domain sequences are homologous to the A domains of ceruloplasmin. Both factor Va and factor Villa act as catalysts in the activation of prothrombin and factor X, respectively. Activation sites are indicated by green arrows inactivation sites by red arrows. In factor Va, complete inactivation requires cleavage of Arg ° . 

Activated factor X remains bound to blood - platelet membranes, which accelerates its activation of prothrombin. 

M2. Magnusson, S., Sottrup-Jensen, L., Peterson, T. E., and Claeys, H., The primary structure of prothrombin, the role of vitamin K in blood coagulation and a thrombin catalyzed negative feedback control mechanism for limiting the activation of prothrombin. In Prothrombin and Related Coagulation Factors (H. C. Hemker and J. J. Veltkamp, eds.), p. 25. Leiden Univ. Press, Leiden, 1975. 

Coagulation factor V is a glycoprotein essential for haemostasis by accelerating the activation of prothrombin. Factor V is secreted as a single-chain polypeptide of 330 kDa... 

Activation of prothrombin. The upper section shows the situation immediately before activation of the common pathway of blood clotting. Prothrombin is attached to platelets in an electrostatic linkage that can be broken by EDTA. The lower section shows the activation of the common pathway of blood clotting. Factor X has been activated to become Factor Xa, which immediately acts on adjacent prothrombin molecules and causes the release of thrombin into the plasma. 

The initial activation of prothrombin to thrombin is slow, because the activator cofactors. Factors Villa and Va, are only present in small amounts. However, once a small amount of thrombin is activated, it will accelerate its own production by cleaving Factors V and VIII to their active forms. 

Vitamin K, Unknown Activation of prothrombin deficiency causes disorders in blood clotting. 1 mg... 

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