Thrombin formation

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. 

Argatroban [74863-84-6] ((2R,4R)-4-methyl-l-[A/ -)(3 methyl l,2,3,4-tetrahydto-8-quiaoIiaesulfonyl)-L-atgiayl]-2-piperidiaecatboxyhc acid monohydrate) is a potent inhibitor of thrombin formation and activity (49). This agent has been studied in vitro and ia a few animal models. Its toxicity and activity ia humans ate unknown. 

While bleeding is the most frequently observed symptom of DIC, thrombotic events cause most of the mortality. Heparin is an effective anticoagulant with the potential to inhibit thrombin formation and function however, its use is limited by the potential for bleeding. Clinical trials of heparin in DIC have not shown a consistent benefit. DIC patients most likely to benefit... 

Protein C and Protein S. PC and PS may inhibit thrombin formation and complex with PAI, thereby promoting fibrinolysis. During sepsis, PC activity is significantly reduced, either by consumption or by TM down-regulation, while increased levels of ClbBP inhibit PS. Infusion of activated PC and PS protected animals from the lethal effect of bacteria. Administration of PC and PS concentrates should be studied carefully in septic patients before their use is recommended (F14). 

Protein C A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and Villa at the rate-limiting steps of thrombin formation. [NIH]... 

The last of the fat-soluble vitamins to be identified was vitamin K, found by Dam to be an anti-hemorrhagic factor for young chicks, distinct from vitamin C. Its structure was determined by Dam in collaboration with Karrer. Interest in the vitamin was intensified when it was discovered (Link, 1941) that dicoumarol, present in spoiled sweet clover, was the agent producing hypothrombinemia (giving prolonged blood-clotting time) in cattle. Since vitamin K is structurally similar to dicoumarol, the vitamin was presumptively implicated in thrombin formation. This has been fully substantiated by recent work on the role of vitamin K in the synthesis of prothrombin in the liver. 

Many studies have shown that ginseng has a protective effect on the development of atherosclerosis that may lead to myocardial infarction and other cardiovascular diseases. The preventive effects on cardiovascular diseases of ginseng include its potential antihypertensive and antiatherosclerotic effects. Ginsenosides are likely to be responsible for some of these effects as they have been shown to have inhibitory effects on platelet aggregation and to suppress thrombin formation as well as an effect on blood vessel contraction. 

Pharmacology The antithrombotic activity is the result of antithrombin III (ATIII)-mediated selective inhibition of Factor Xa. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development. 

R — time corresponding to invisible phases of clotting process, thromboplastin and thrombin formation, cm 2.0 19.0... 

Mann KG, Butenas S, Brummel K. The dynamics of thrombin formation. Arterioscler Thromb Vase Biol. 2003 23 17-25. 

Modesti PA, Colella A, Cedoni I, Costoli A, Biagini D, Migliorini A, Semeri GGN. Increased number of thromboxane Aj-prostaglandin Hj platelet receptors in active unstable angina and causative role of enhanced thrombin formation. Am Heart J 1995 129 873-9... 

The roles of Factors V and VIII in the reaction sequence leading to thrombin formation have slowly become known. Both these proteins are very large in size, serve as cofactors in this cascade reaction sequence, and increase by approximately 100 times their cofactor activity upon exposure to minimal concentrations of thrombin. Likewise, both factors are inactivated by a similar mechanism when attacked by activated protein C (Fll). Tans and coworkers utilized synthetic substrate assays specific for Factor Xa and thrombin to demonstrate that both these factors act predominantly by increasing... 

B4. Bauer, K. A., Teitel, J. M., and Rosenberg, R D., Assays for the quantitation < antitfarombin 111 thrombin-antithrombin complex and prothrombin activation fragments. In Disorders of Thrombin Formation (R W. Colman, ed.), pp. 142-155. Churchill-Ljvingstone, Edinburgh and London, 1983. 

Furthermore, OxPL were shown to modulate the activity of the platelet prothrombinase complex, a major contributor to overall thrombin formation. Platelet-dependent thrombin generation was induced by ethanolamine phospholipids (PE) present in oxidized LDL. It was shown that oxidation products of unsaturated diacyl-PE were mainly responsible for the increased prothrombinase activity and synthetic aldehyde-PE adducts largely reproduced the stimulation of the thrombin generation (Zieseniss et al. 2001). These data suggest that oxidized PE contribute to the prothrombotic phenotype by increasing prothrombinase activity in platelets. 

Fibrinogen is converted to fibrin by the action of thrombin on the a and p chains of fibrinogen. The proteolytic scission events leading up to thrombin formation are complex (Figure 2). Thrombin hydrolyzes each chain at two specific Arg-Gly bonds to release two fibrinopeptides A (from a-chain) and two fibrinopeptides B (from /3-chain). The fibrinopeptides account for ca. 3% of the weight of fibrinogen. This proteolytic step, leading to fibrin formation is critical for clot formation. 

Fondaparinux is a selective inhibitor factor Xa possessing a selective inhibition of antithrombin III (ATIII), which potentiates the innate neutralization of factor Xa by ATIII. Nentralization of factor Xa interrupts the blood coagulation cascade and inhibits thrombin formation and thrombus development. It is indicated for prophylaxis of deep vein thrombosis (DVT) that may lead to pulmonary embolism in patients undergoing hip fracture surgery including extended prophylaxis, hip replacement surgery, or knee replacement surgery. When administered in conjunction with warfarin, fondaparinux is indicated for treatment of acute DVT and acute pulmonary embolism. 

Thrombus (clot) formation is enhanced by thrombin activation, which is mediated by the complex interaction that constitutes the blood coagulation cascade. This cascade (Fig. 45.3) consists primarily of proteins that serve as enzymes or cofactors, which function to accelerate thrombin formation and localize it at the site of injury. These proteins are listed in Table 45.2. All of these proteins are present in the plasma as proproteins (zymogens). These precursor proteins are activated by cleavage of the polypeptide chain at one or more sites. The key to successful and appropriate thrombus formation is the regulation of the proteases that activate these zymogens. 

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