Fibrinogen conversion

Blood coagulation might well be the chemical transformation in the blood known to physicians for the longest time. Still, little is known of the process except for some steps in fibrinogen conversion to fibrin. Therefore, blood coagulation continues to be described in mysterious terms, reminiscent more of a secret code than of chemical nomenclature. 

Thrombin finally catalyzes the only reaction in the cycle that is partially understood—fibrinogen conversion to fibrin. Obviously, these coagulation theories have many variations concerned mainly with the number and specific role of the factors involved. It seems futile to describe these theories in detail since the nature of most of the molecules involved in the reaction is not known. 

Thrombin, the two-chain derivative of the prothrombin molecule, has a molecular weight of approximately 37,000 daltons. Its proteolytic properties induce the conversion of fibrinogen to fibrin to produce the initial visible manifestation of coagulation, the soluble fibrin clot. In addition, thrombin influences the activity of Factors V, VIII, and XIII and plasmin. Thrombin affects platelet function by inducing viscous metamorphosis and the release reaction with subsequent aggregation. 

Factor II. Prothrombin is a vitamin K-dependent compound synthesized by the Hver. When prothrombin is activated it is cleaved at two sites, resulting in a two-chain molecule linked by a disulfide bond that has a molecular weight of 37,000 daltons. Thrombin is the serine protease that initiates the conversion of soluble fibrinogen into fibrin. 

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. 

Fibrin is formed from fibrinogen synthesized by the liver and secreted into the circulation. The conversion of fibrinogen to fibrin is initiated by a serine protease, thrombin. Thrombin, at the same time, can activate a transglutaminase enzyme, factor XIII present in... 

Heparin inhibits the formation of fibrin clots, inhibits the conversion of fibrinogen to fibrin, and inactivates several of the factors necessary for the clotting of blood. Heparin cannot be taken orally because it is inactivated by gastric acid in the stomach therefore, it must be given by injection. Heparin has no effect on clots that have already formed and aids only in preventing the formation of new blood clots (thrombi). The LMWHs act to inhibit clotting reactions by binding to antithrombin HI, which inhibits the synthesis of factor Xa and the formation of thrombin. 

Ginseng Rg2 has shown inhibitory effects on platelet aggregation similar to aspirin, and R0 reportedly inhibits the conversion of fibrinogen to fibrin [27]. The amount of ginseng administered may also influence the effect(s) produced. In rats and mice, small doses of ginseng extract result in increased spontaneous motor activity, whereas larger doses produce an inhibitory effect on the central nervous system [28]. 

Activated factor X, along with Ca++ ion, factor V, and PF3 (collectively referred to as the prothrombin activator), catalyzes the conversion of prothrombin into thrombin. Thrombin then catalyzes the conversion of fibrinogen into fibrin, an insoluble, thread-like polymer. The fibrin threads form a meshwork that traps blood cells, platelets, and plasma to form the blood clot. The clotting cascade may be elicited by means of two mechanisms (see Figure 16.1) ... 

Induction of the blood coagulation cascade. This culminates in the conversion of a soluble serum protein, fibrinogen, into insoluble fibrin. Fibrin monomers then aggregate at the site of... 

I Fibrinogen Both Forms structural basis of clot after its conversion to fibrin... 

Both intrinsic and extrinsic pathways generate activated factor X. This protease, in turn, catalyses the proteolytic conversion of prothrombin (factor II) into thrombin (Ha). Thrombin, in turn, catalyses the proteolytic conversion of fibrinogen (I) into fibrin (la). Individual fibrin molecules aggregate to form a soft clot. Factor XHIa catalyses the formation of covalent crosslinks between individual fibrin molecules, forming a hard clot (Figures 12.3 and 12.4). 

The Fibrinogen-Fibrin Conversion Harold A. Scheraga and Michael Laskowski, Jr. 

Structural Aspects of the Fibrinogen to Fibrin Conversion R. F. Doolittle... 

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. 

Figure 9.7. Diagrammatic representation of the fibrinogen molecule and its conversion to the soft clot of fibrin. Reproduced (in modified form) by permission from Textbook of Biochemistry with Clinical Correlations (3rd Ed.) Devlin (1992). This material is used by permission of John Wiley Sons, Inc.

Aminocaproic acid and tranexamic acid inhibit fibrinolysis by inhibiting plasminogen binding to fibrin or fibrinogen and the conversion of plasminogen to plasmin. 

Physiologically, the maintenance of blood circulating freely in the vascular system reflects a meticulous balance between coagulation and fibrinolysis. After microvascular injury subendothelial structures are exposed to which platelets adhere. This is followed by their aggregation and activation of the coagulation cascade with the ultimate conversion of fibrinogen to fibrin. 

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