Thrombomodulin

Protein G. This vitamin K-dependent glycoproteia serine protease zymogen is produced ia the Hver. It is an anticoagulant with species specificity (19—21). Proteia C is activated to Proteia by thrombomodulin, a proteia that resides on the surface of endothefial cells, plus thrombin ia the presence of calcium. In its active form, Proteia selectively iaactivates, by proteolytic degradation. Factors V, Va, VIII, and Villa. In this reaction the efficiency of Proteia is enhanced by complex formation with free Proteia S. la additioa, Proteia activates tissue plasminogen activator, which... 

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. 

Protein C Activated to protein Ca by thrombin bound to thrombomodulin then degrades factors Villa and Va. 

There are various inhibitors within the coagulation system that counterregulate activation of the coagulation cascade. Among them, antithrombin III (AT-III) and protein C (PC) are the most important (SI). AT-III binds in the presence of heparin the activated factors F-IXa, F-Xa, and F-IIa (thrombin). PC is activated by a complex formed between thrombin and thrombomodulin, a surface protein of endothelial cells. Once activated, PC in the presence of protein S (PS) specifically degrades activated factors F-Va and F-VIIIa. PC decreases in the course of sepsis in relation to the severity of the condition (L15). Experimental studies have... 

The antithrombotic factors produced by endothelial cells are thrombomodulin (TM) and protein S (PS), components of the vitamin K-dependent protein C (PC) anticoagulant pathway, inhibiting F-Va-F-Villa (E15) tissue plasminogen activator (tPA), responsible for fibrinolysis (N2, LI8) and the lipoprotein-associated coagulation inhibitor (LACI), which inhibits F-VIIa-TF complex and F-Xa (B51). 

Thrombomodulin. In patients with SIRS and DIC due to sepsis the serum soluble TM level was higher than in nonseptic and non-DIC patients (A9, B32, G3, II, K7). In experimental ARDS in rats induced by LPS, administration of soluble recombinant TM inhibited the occurrence of intravascular coagulation and prevented the increase in pulmonary vascular permeability (Ul). 

A9. Asakura, H., Jokaji, H., Saito, M Uotani, C., Kumabashiri, I., Morishita, E., Yamazaki, M and Matsuda, T., Plasma levels of soluble thrombomodulin increase in cases of disseminated intravascular coagulation with organ failure. Am. J. Hematol. 38,281-287 (1991). 

D30. Drake, T. A., Cheng, J., Chang, A. C., and Taylor, F. B., Expression of tissue factor, thrombomodulin, and E-selectin in baboons with lethal Escherichia coli sepsis. Am. J. Pathol. 142, 1458-1470(1993). 

G3. Gando, S., Kameue, T., Nanzaki, S and Nakanishi, Y., Cytokines, soluble thrombomodulin and disseminated intravascular coagulation in patients with systemic inflammatory response syndrome. Thomb. Res. 80,519-526 (1995). 

Iba, T., Yagi, Y Kidokoro, A., Fukunaga, M., and Fukunaga, T Increased plasma levels of soluble thrombomodulin in patients with sepsis and organ failure. Surg. Today 25,585 -590 (1995). 

Ishii, H. Uchiyama, H., and Kazama, M., Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells. Thromb. Haemost. 65,618-623 (1991). 

Tl. Takakuwa, T., Endo, S Nakae, H., Suzuki, T Inada, K., Yoshida, M Ogawa, M., and Uchi-da, K Relationships between plasma levels of type-II phospholipase A2, PAF-acetylhydrolase, leukotriene B4, complements, endothelin-1, and thrombomodulin in patients with sepsis. Res. Commun. Chem. Pathol. Pharmacol. 84,271-281 (1994). 

U1. Uchiba, M., Okajima, K Murakami, K., Nawa, K., Okabe, H and Takatsuki, K., Recombinant human soluble thrombomodulin reduces endotoxin-induced pulmonary vascular injury via protein C activation in rats. Thromb. Haemost. 74, 1265-1270 (1995). 

A type I transmembrane protein called endothelial cell protein C receptor (EPCR), which is expressed at high levels exclusively on a subset of endothelial cells, has also been identified. EPCR has a role in the protein C pathway (30). EPCR binds to both protein C and activated protein C (APC) with equal affinity. Activation of protein C presumably requires interaction of the protein C-EPCR complex with the thrombin-thrombomodulin complex. APC that is formed as a result of this interaction is reversibly bound to EPCR until it dissociates to react subsequently with protein S. The APC-protein S complex inactivates activated factor V (Va). 

Although the fibrinolytic pathway is activated when thrombin binds to thrombomodulin, the thrombin-thrombomodulin complex, in addition to activating protein C (APC), activates a fibrinolysis inhibitor called the thrombin-activatable fibrinolysis inhibitor (TAFIa). Thus plasmin generation and, in turn, fibrinolysis are... 

Release of markers bound to the endothelial cell such as thrombomodulin is indicative of vascular damage. Increased levels of soluble thrombomodulin in plasma are diagnostic (93). Other endothelium-derived markers such as 6-keto-prostaglandin F a, which is a metabolite of prostacyclin, are useful in the assessment of endothelial function, with lower levels indicative of inability to synthesize this marker due to defective or damaged endothelium through plaque formation (93). 

Nesheim M., Wang W., Bofta M., et al. Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis. Thromb Haemost 1997 78,386-91. 

Thrombomodulin is a protein on the endothelium that (1) binds with thrombin, reducing its availability for the clotting process and (2) activates protein C, which acts as an anticoagulant by inactivating factors V and VIII. 

Ogata, M., Marumoto, Y., Oh-I, K., Shimizu, S., and Katoh, S., Continuous Culture of CHO-K1 Cells Producing Thrombomodulin and Estimation of Culture Conditions, J. Ferm. Bioeng., 77.46 (1994)... 

Chen H, Teramura Y, Iwata H (2011) Co-immobilization of urokinase and thrombomodulin on islet surfaces by poly(ethylene glycol)-conjugated phospholipid. J Control Release 150 229-234... 

Some active materials are carriers for drugs (drug delivery systems), some have immobilized peptides to enable cell adhesion or migration, some are degradable by hydrolysis or by specific enzyme action. Some contain bioactive agents (e.g., heparin, thrombomodulin) to prevent coagulation or platelet activation while others incorporate bioactive groups to enhance osteo-conduction. Many include polyethylene oxide to retard protein adsorption and this is perhaps the closest we have come to a kind of inertness. 

Thrombolytic agents, 5 172t, 175-179 Thrombomodulin, 4 84, 88 Thrombosis, 4 83, 84 risk factors for, 4 90t Thromboxane, 4 103-104 Thromboxane A2, 4 85 Throttling devices, in refrigeration systems, 21 538... 

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]... 

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