Thrombin mechanism

Cell—Cell Interactions. Older generations of leukocyte filters depended partly on the formation of platelet—leukocyte—thrombin formations. It is not clear whether this mechanism plays a role in third-generation filters. 

Dismption of the endothehal surface of blood vessels expose coUagen fibers and connective tissue. These provide surfaces that promote platelet adherence, platelet release reaction, and subsequent platelet aggregation. Substances Hberated from the platelets stimulate further platelet aggregation, eg, adenosine diphosphate maintain vasoconstriction, eg, serotonin and participate in blood coagulation, eg, platelet Factors III and IV. In addition, the release reaction modifies platelet membranes in a manner that renders phosphoHpid available for coagulation. The thrombin [9002-04-4] elaborated by the coagulation mechanism is a potent agent in the induction of the platelet release reaction. 

Components/ mechanism of action Human plasma, fibrinogen and thrombin, virally inactivated, hemostat, sealant. Autologous fibrinogen -t-platelet-rich plasma, hemostatic gel. Bovine collagen, bovine thrombin, plus autologous human plasma, hemostatic agent. Bovine collagen and bovine thrombin. Expands 20% which aids in hemostatic effect. 

The release of arachidonate and the synthesis or interconversion of eicosanoids can be initiated by a variety of stimuli, including histamine, hormones such as epinephrine and bradykinin, proteases such as thrombin, and even serum albumin. An important mechanism of arachidonate release and eicosanoid syn-... 

The protein-C pathway is one of the most important anticoagulant mechanisms. It is activated by thrombin. Thrombin binds to a cofactor in the membrane of endothelial cells, thrombomodulin (TM). TM bound thrombin no longer activates clotting factors or platelets but becomes an effective protein C (PC) activator. Activated PC (APC) forms a complex with Protein S, which inactivates FVIIIa and FVa. Hereby generation of Flla by the prothrombinase complex is inhibited (Fig. 9). Thus, the PC-pathway controls thrombin generation in a negative feedback manner. 

The release of NO from the endothelium is induced by various chemical substances, including acetylcholine polypeptides such as substance P, bradykinin, and arginine vasopressin histamine ATP/ADP a2-adrenoceptor agonists thrombin and Ca2+ iono-phores. NO formed in response to mechanical stimuli like shear stress or transmural pressure plays an important role in maintaining basal blood flow. Endothelial NO causes vasodilatation, decreased... 

The mechanisms involved in platelet activation are discussed in Chapter 51 (see Figure 51-8). The process involves interaction of the stimulus (eg, thrombin) with a receptor, activation of G proteins, stimulation of phospholipase C, and hberation from phosphatidylinositol... 

Mor, A. Maillard, J. Favreau, C. Reboud-Ravaux, M. Reaction of thrombin and proteinases of the fibrinolytic system with a mechanism-based inhibitor, 3,4-dihydro-3-benzyl-6-chloromethyl-coumarin. Biochim. Biophys. Acta 1990, 1038, 158-163. 

Frederick, R. Robert, S. Charlier, C. de Ruyck, J. Wouters, J. Masereel, B. Pochet, L. Mechanism-based thrombin inhibitors design, synthesis, and molecular docking of a new selective 2-OXO-2/7- l-benzopyxan derivative. J. Med. Chem. 2007, 50, 3645-3650. 

Wakselman, M. Mazaleyrat, J.-P. Lin, R. C. Xie, J. Vigier, B. Vilain, A. C. Fesquet, S. Boggetto, N. Reboud-Ravaux, M. Design, synthesis and study of a selective cyclopeptidic mechanism-based inhibitor of human thrombin. In Peptides Chemistry, Structure... 

FIGURE 7-7. Mechanism of action of direct thrombin inhibitors. 

The concept that different structural domains on the heparin chains are principally involved for optimal activity in the foregoing interactions could not be perceived in early work on structure-activity correlations, because the activity of heparin has been most frequently evaluated only with whole-blood-clotting tests (such as the U.S.P. assay). Development of assays for specific clotting-factors (especially Factor Xa and thrombin) has permitted a better insight into the mechanism of action of heparin at different levels of the coagulation cascade. 

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) ... 

Kamm, W., Hauptmann, J., Behrens, I., Sturzebecher, J., Dullweber, F., Gohlke, H., Stubbs, M., Klebe, G., Kissel, T., Transport of peptido-mimetic thrombin inhibitors with a 3-amidino-phenylalanine structure permeability and efflux mechanism in monolayers of a human intestinal cell line (Caco-2), Pharm. Res. 2001, 18, 1110-1118. 

Sjosteom, M., Lindfors, L., Ungell, A. L., Inhibition of binding of an enzymatically stable thrombin inhibitor to lumenal proteases as an additional mechanism of intestinal absorption enhancement, Pharm. Res. 1999, 26, 74-79. 

Walker, C. and Royston, D. 2002. Thrombin generation and its inhibition a review of the scientific basis and mechanism of action of anticoagulant therapies. British Journal of anaesthesia 88(6), 848-863. 

Fas ligand and interleukin-ip), the neurotransmitter glutamate and thrombin. Like tumor necrosis factor (TNF) receptors, Fas is coupled to downstream death effector proteins that ultimately induce caspase activation (Ch. 22). Fas and TNF receptors recruit proteins called FADD and TRADD respectively FADD and TRADD then activate caspase-8, which, in turn, activates caspase-3 (Fig. 35-4). Calcium ion influx mediates neuronal apoptosis induced by glutamate receptor activation calcium induces mitochondrial membrane permeability transition pore opening, release of cytochrome c and caspase activation. Interestingly, in the absence of neurotrophic factors some neurotrophic factor receptors can activate apoptotic cascades, the low-affinity NGF receptor being one example of such a death receptor mechanism [23],... 

Coughlin, S. R. (1994) Molecular mechanisms of thrombin signaling. Semin. Hematol. 31, 270-277. 

Sugano et al. studied the membrane permeation of 51 benzamidine-based thrombin inhibitors in a rat everted sac permeability model [197]. They reported significant membrane permeabilities in this in vitro model, which they attributed to passive paracellular transport, a different absorption mechanism to transcellular permeability. 

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