Thrombin fibrin clots

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. 

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. 

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... 

Figure 51-5. Formation of a fibrin clot. A Thrombin-induced cleavage of Arg-Gly bonds of the Aaand B(3 chains of fibrinogen to produce fi-brinopeptides (left-hand side) and the a and p chains of fibrin monomer (right-hand side). B Cross-linking of fibrin molecules by activated factor XIII (factor Xllla).

A number of laboratory tests are available to measure the phases of hemostasis described above. The tests include platelet count, bleeding time, activated partial thromboplastin time (aPTT or PTT), prothrombin time (PT), thrombin time (TT), concentration of fibrinogen, fibrin clot stabifity, and measurement of fibrin degradation products. The platelet count quantitates the number of platelets, and the bleeding time is an overall test of platelet function. aPTT is a measure of the intrinsic pathway and PT of the extrinsic pathway. PT is used to measure the effectiveness of oral anticoagulants such as warfarin, and aPTT is used to monitor heparin therapy. The reader is referred to a textbook of hematology for a discussion of these tests. 

The coagulation system that generates thrombin consists of intrinsic and extrinsic pathways. Both pathways are composed of a series of enzymatic reactions eventually producing thrombin, fibrin, and a stable clot. In parallel with the coagulation, the fibrinolytic system is activated locally. Plasminogen is converted to plasmin, which dissolves the fibrin mesh1 2 3 (Fig. 64—1). 

Activated partial thromboplastin time aPTT is performed by adding calcium phospholipids and kaolin to citrated blood and measures the time required for a fibrin clot to form. In this manner, aPTT measures the activity of intrinsic and common pathways. Prolongation of aPTT may be due to a deficiency or inhibitor for factors II, V, VIII, IX, X, XI, and XII. It also may be due to heparin, direct thrombin inhibitors, vitamin K deficiency, liver disease, or lupus anticoagulant. 

Thrombin time is an assessment of the time required for the appearance of the fibrin clot after thrombin is added... 

Von dem Borne P. A. K., Meijers J. C. M., Bouma B. N. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995 86, 3035 -42. 

Hirudin exhibits its anticoagulant effect by tightly binding thrombin, thus inactivating it. In addition to its critical role in the production of a fibrin clot, thrombin displays several other (non-enzymatic) biological activities important in sustaining haemostasis. These include ... 

Blood clotting first received serious scientific attention in the seventeenth century, when Malpighi and BoreUi proposed that a blood clot was formed from the fluid part of the blood. In the eighteenth century, John Hunter established that clots were formed from the coagulable lymph . In 1845, Buchanan showed that a series of enzymes was involved and by 1900 it was accepted that the soluble substance in blood, fibrinogen, was converted into the solid fibrin clot by an enzyme, thrombin. From that time many... 

Mectianism of Action A factorXa inhibitor and pentasaccharide that selectively binds to antithrombin, and increases its affinity for factor Xa, thereby inhibiting factor Xa and stopping the blood coagulation cascade. Therapeutic Effect Indirectly prevents formation of thrombin and subsequently the fibrin clot. 

FIGURE S.4 Relative fibrin-clotting and amidolytic activity of thrombin as a function of the concentration of desalted fermented anchovy sauce (dFAS). Anticoagulation activity was assessed by the increase in the fibrin clotting time (empty circles) and the release of p-nitroaniline (closed circles). Data are presented as the mean SD (n —3). Source Kim et at. (2004). Permission has been obtained for the use of copyrighted material from Elsevier B.V. 

Due to its large molecular size in comparison with direct thrombin inhibitors (DTIs), UFH is unable to penetrate into fibrin clot and to inhibit thrombin trapped in a clot. Hence, its anticoagulant activity is limited only to the inhibition of thrombin in the process of thrombi formation. 

Less than 1% of the applied coagulant activity is recovered in fraction Nos. 1, 2, 3, 4. Fraction 1 however possesses proteolytic activtity which in concentrated solutions would dissolve fibrin clots. The thrombin-like activity is eluted from these columns in significant amounts at a buffer strength of 0.04 M or greater. 

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