Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The explosive nature of the coagulation cascade led many scientists to investigate how it is regulated. Proteinase inhibitors such as antithrombin III inhibit active proteases of the coagulation cascade. Cofactors such as factor Va and factor VIIIa are proteolytically inactivated by activated protein C. Protein C is activated by the thrombin-thrombomodulin complex on the endothelial cell surface. Thus, the independent actions of the proteinase inhibitor system and the thrombomodulin-protein C system complement each other to maintain regulation of blood coagulation. The thrombin binding site of thrombomodulin was identified to be the fifth and sixth repeats of the epidermal growth factor-like domain. The same binding template contains sufficient information to block the functions of thrombin as a procoagulant. However, additional repeats are required for the activation of protein C. Thrombomodulin is the first example which illustrates that the epidermal growth factor-like domain functions as a binding template for thrombin and as a switch to turn off the procoagulant activity of thrombin as well as to trigger the protein C anticoagulant pathway. Epidermal growth factor-like structures are found in many of the coagulation factors. Complex formation is a repeated theme not only in the blood coagulation cascade but also in the thrombomodulin-protein C anticoagulant pathway.
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PMID:The role of complex formation and epidermal growth factor-like domains in the regulation of blood coagulation by the thrombomodulin-protein C system. 256 Aug 86

Combined deficiency of factor V and factor VIII, a rare bleeding disorder, was found in a 43 year-old male. He had often presented manifestations of easy bruising since childhood, but none of his family had shown evidence of a bleeding tendency. We examined him and his family as far as we could and his abnormality of blood coagulation was apparent, but the members of his family were normal. The prothrombin time and activated partial thromboplastin time of this patient were prolonged, but his thrombin time was normal. Factor V and factor VIII coagulant activity were low, but von Willebrand factor antigen and activity (ristocetin cofactor activity) levels were normal. Protein C and Protein C inhibitor antigen and activity levels were also found to be normal. Following 1-deamino-8-D-arginine vasopressin (DDAVP) injection, he had immediate increases in factor VIII coagulant activity, but both von Willebrand factor antigen, activity levels and factor V coagulant activity remained low. Moreover, there was no rapid decline in factor VIII complex activity. These findings suggest that the endogenous factor VIII in this patient is metabolized normally and that at least the deficiency of factor VIII does not result from accelerated degradation in plasma.
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PMID:[DDAVP administration in a case of congenital combined factor V and factor VIII deficiency]. 260 19

The antithrombotic action of thrombomodulin was studied in mice. Rat and mouse thrombomodulin were isolated from lung acetone powders, and anti-rat thrombomodulin antibodies were prepared in rabbits. The antibodies neutralized both mouse (Kd approximately 150 nM) and rat thrombomodulin (Kd approximately 50 nM). A role for thrombomodulin in vivo was shown in mice injected intravenously (IV) with thrombin. All mice injected with 15 U thrombin (bolus) died of thromboembolism (mean survival 55 minutes), whereas those injected with a lower dosage survived. Prior injection with anti-rat thrombomodulin (1.8 mg IgG/mouse) potentiated the lethal effects of subsequent thrombin, whereas injection of thrombomodulin (isolated from mouse lung) prior to thrombin prolonged survival in a thrombomodulin concentration-dependent manner. The protective effect of thrombomodulin persisted for 30 minutes but after one hour thrombin injection was as toxic as in control animals. The half life (t1/2) for plasma clearance of 125I-mouse lung thrombomodulin was nine minutes. The major site of clearance was the liver, although thrombomodulin accumulated in several organs ten minutes after injection. The mechanism by which antithrombomodulin antibodies potentiated the lethal effects of thrombin was studied by measuring the protein C activating cofactor activity on vena cava removed from animals injected with antibodies. Protein C activation was inhibited by antibodies, suggesting a role for activated protein C in prevention of lethal thromboembolism. We found no effect of antibodies on the clearance of thrombin from mouse plasma, suggesting that blockade of endothelial endocytosis of thrombin does not play a significant role in the effects of antibodies. These results indicate that thrombomodulin participates in the defense against thrombosis in vivo.
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PMID:A role for thrombomodulin in the pathogenesis of thrombin-induced thromboembolism in mice. 283 Sep 28

Control of the coagulation pathway requires mechanisms that limit and localize the clotting process. The vascular endothelium has been shown to play an active role in preventing blood clot formation in vivo. The endothelial cell surface contains a thrombin-binding protein, thrombomodulin, which, when complexed with thrombin, activates vitamin K-dependent protein C, an endogenous anticoagulant. Protein C and its cofactor, protein S, inhibit the clotting process by inactivating factors Va and VIIIa and, additionally, enhance the lysis of fibrin. It has been demonstrated by the detection of heterozygous and homozygous protein C-deficient patients with severe thrombotic complications that protein C is a major regulatory protein of hemostasis and thrombosis. This endogenous anticoagulant pathway is providing a better understanding of both congenital and acquired thrombotic disorders.
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PMID:The role of protein C in congenital and acquired thrombotic disorders. 284 84

We found functionally active thrombomodulin in human platelets (60 +/- 18 molecules per platelet). Protein C appeared not to be activated by thrombin with gel-filtered platelets. However, the activation of protein C by thrombin was accelerated by thrombin-stimulated and washed platelets. This cofactor activity of the platelets was neutralized by the anti-lung thrombomodulin-F(ab')2. From the Triton X-extract of platelets, thrombomodulin was partially purified by diisopropylphosphoryl-thrombin-agarose affinity chromatography. The Mr of the predominant platelet thrombomodulin was 78,000 before and 109,000 after reduction on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, values identical to those of placental thrombomodulin. The specific activity of the cofactor activity, apparent Kd (0.4 nM) for thrombin and Km (0.67 microM) for protein C of platelet thrombomodulin were also identical to those of placenta thrombomodulin. Thrombomodulin may play a role in activation of protein C on the surface of platelets.
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PMID:Functionally active thrombomodulin is present in human platelets. 285 10

Inopportune coagulation of blood in vessels is prevented by defense mechanisms, in which plasma inhibitors play an important role. The inhibitors are glycoproteins and belong to two different groups, according to their mechanism of action. The first group consists of the inhibitors of serine proteases, which form inactive complexes with various coagulation enzymes; it includes antithrombin III, heparin cofactor II, alpha 2-macroglobulin, alpha 1-antitrypsin and C1S-inhibitor. The second group includes protein C and its cofactor, protein S. Protein C, activated by thrombin complexed with a protein cofactor present on the endothelial cell surface (thrombomodulin), is responsible for the proteolytic degradation of two coagulation cofactors (Va and VIII: Ca). The clinical importance of both antithrombin III, protein C and protein S is attested by the strong association between recurrent venous thromboembolic manifestations and inherited deficiencies of one or the other of these proteins.
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PMID:[General mechanisms of coagulation and their physiological inhibition. II. The regulation of coagulation by physiological inhibitors]. 286 16

Protein C has been purified from the plasma of a patient with thrombotic diathesis. Both before and after isolation, the protein showed reduced capacity to hydrolyze synthetic substrates and to anticoagulate plasma. Proteolysis with the soluble thrombin-thrombomodulin complex proceeded normally and to completion as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. Approximately one-third of the protein is functional, indicating a heterozygous defect. Indirect studies suggest that the abnormal component can bind to protein S and phospholipids. Both forms of activated protein C can also incorporate radiolabeled diisopropylfluorophosphate.
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PMID:Isolation of an abnormal protein C molecule from the plasma of a patient with thrombotic diathesis. 296 7

Protein C activation by thrombin is significantly accelerated by the endothelial cell cofactor, thrombomodulin. In this study, we have developed a radioimmunoassay for thrombomodulin and have measured the cofactor content in several human tissues. The assay method detects as little as 2 ng of thrombomodulin. The highest thrombomodulin content was found in lung and placenta, but the antigen was also detected in spleen, pancreas, liver, kidney, skin, heart, and aorta. Unexpectedly, thrombomodulin was absent from brain. Extracts from cerebral cortex, cerebellum, centrum semiovale, midbrain, basal ganglia, pons, and medulla were devoid of thrombomodulin. In contrast, thrombomodulin antigen is present in extracerebral intracranial vessels, including basilar and internal carotid arteries and choroid plexus, as well as in endothelium of the pia-arachnoid.
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PMID:Thrombomodulin, an endothelial anticoagulant protein, is absent from the human brain. 300 24

A simplified assay for protein C activity in plasma is described which uses the ability of rabbit lung thrombomodulin to inhibit the procoagulant activity of thrombin while stimulating protein C activation. Barium eluates of plasma are activated for one hour at 37 degrees C by a mixture of human thrombin and rabbit lung thrombomodulin at concentrations which neutralize each other's effect on the kaolin-cephalin activated partial thromboplastin time (PTT). Protein C anticoagulant activity in the activated eluates is then measured directly in the PTT. The method is independent of protein S levels in the test samples, and is suitable for warfarinized and heparinized plasma. Protein C levels obtained with this method correlate closely with functional levels of vitamin K-dependent procoagulants as measured by the prothrombin and proconvertin time (P&P) in normal subjects and in patients receiving warfarin, indicating specificity for gamma-carboxylated protein C. The method has the potential to detect molecular variants defective in any of the interactions required for generation of anticoagulant activity in vivo.
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PMID:A simplified PTT-based protein C activity assay using the thrombin-thrombomodulin complex. 301 Apr 89

We investigated the effect of protein C on the endocytosis of thrombin-thrombomodulin complexes. We previously showed that exposure of umbilical vein endothelial cells to thrombin stimulated the internalization and degradation of thrombin. A similar internalization was stimulated by a monoclonal antithrombomodulin antibody. We have repeated these studies in the presence of protein C and found that endocytosis of 125I-thrombin-thrombomodulin complexes, but not 125I-antithrombomodulin-thrombomodulin complexes, is inhibited. Activated protein C did not inhibit endocytosis of thrombin-thrombomodulin complexes. Protein C inhibited both internalization and degradation of 125I-thrombin and diisopropylphosphoryl (DIP) 125I-thrombin in human lung cancer cells (A549). These effects were observed at protein C concentrations found in human plasma. Protein S had no effect on the inhibition of endocytosis of thrombin-thrombomodulin complexes by protein C. We propose that protein C may regulate the rate of endocytosis of thrombin-thrombomodulin complexes in vivo and thereby control the capacity for endothelium to activate protein C.
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PMID:Protein C inhibits endocytosis of thrombin-thrombomodulin complexes in A549 lung cancer cells and human umbilical vein endothelial cells. 303 8


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