Blood clotting cross-linking

The success of thrombus lysis depends mainly on how large the thrombus is and whether any blood flow stiU remains. The outcome is better the larger the surface of the entire thrombus exposed to the thrombolytic agent. As the clot ages, the polymerization of fibria cross-linking and other blood materials iacreases and it becomes more resistant to lysis. Therefore, the eadier the thrombolysis therapy starts, the higher the frequency of clot dissolution. Thrombolytic agents available are Hsted ia Table 7 (261—276). 

FIGURE 15.5 The cascade of activation steps leading to blood clotting. The intrinsic and extrinsic pathways converge at Factor X, and the final common pathway involves the activation of thrombin and its conversion of fibrinogen into fibrin, which aggregates into ordered filamentous arrays that become cross-linked to form the clot. 

Figure 12.4 Terminal steps of a blood clot (haemostatic plug) cross-linked fibrin molecules bind together platelets and red blood cells congregated at the site of damage, thus preventing loss of any more blood...

Simultaneously, activation of the extrinsic coagulation cascade occurs as a result of exposure of blood to the thrombogenic lipid core and endothelium, which are rich in tissue factor. This pathway ultimately leads to the formation of a fibrin clot composed of fibrin strands, cross-linked platelets, and trapped red blood cells. 

The most important reaction in blood clotting is the conversion, catalyzed by thrombin, of the soluble plasma protein fibrinogen (factor 1) into polymeric fibrin, which is deposited as a fibrous network in the primary thrombus. Thrombin (factor 11a) is a serine proteinase (see p. 176) that cleaves small peptides from fibrinogen. This exposes binding sites that spontaneously allow the fibrin molecules to aggregate into polymers. Subsequent covalent cross-linking of fibrin by a transglutaminase (factor Xlll) further stabilizes the thrombus. 

In some proteins, the linear polypeptide chain is cross-linked. The most common cross-links are disulfide bonds, formed by the oxidation of a pair of cysteine residues (Figure 3.21). The resulting unit of linked cysteines is called cystine. Extracellular proteins often have several disulfide bonds, whereas intracellular proteins usually lack them. Rarely, nondisulfide cross-links derived from other side chains are present in some proteins. For example, collagen fibers in connective tissue are strengthened in this way, as are fibrin blood clots. 

The relationship between vitamin K and blood clotting is as follows. Generation of the blood clot, which is composed of cross-linked platelets and cross-linked fibrin, is dependent on the activity of a number of proteins. Some of these proteins are vitamin K-dependent proteins. This means that a vitamin K-dependent reac-... 

Plasmin is soluble but it remains active in the location of a clot. As it diffuses into the blood with clot fragments, the plasmin binds to a2-antiplasmin, a serine protease inhibitor (see next section). In addition to inhibiting plasmin in the blood (Fig. 11.10b), a2-antiplas-min inhibits various other serine proteases, especially activated protein C (APC) (next section) and elastase (Sect. 6.2.1). Plasmin action is inhibited where fibrin is cross-linked to fibronectin, but the large fibrin fragments tend to promote healing. The fragments of fibrin are named as shown in Fig. 11.10c and d. Factors that activate or inhibit fibrinolysis are summarized in Table 11.2. 

The overwhelming majority of peptide bonds in proteins occur between a-amino and a-carboxylate groups, giving a single linear unbranched chain. In rare, but important, cases, side-chain amino and carboxylate groups can be joined by an isopeptide bond to create a branch (as in joining the C-terminus of the small protein ubiquitin to another protein) or to provide cross links (as in fibrin polymers in a blood clot). 

A blood clot is formed mainly from a network of crosslinked fibrin molecules that traps platelets, erythrocytes, and other materials to form a solid clot. The aggregation and cross-linking of fibrin is the final stage of a proteolytic cascade or pathway which is triggered by one or both of two mechanisms the intrinsic pathway and the extrinsic pathway. 

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