Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the anticoagulant activity of two major molecules of soluble thrombomodulin purified from human urine. The apparent molecular weights of these urinary thrombomodulins (UTMs) were 72,000 and 79,000, respectively. Both UTMs showed more potent cofactor activity for protein C activation [specific activity > 5,000 thrombomodulin units (TMU)/mg] than human placental thrombomodulin (2,180 TMU/mg) and rabbit lung thrombomodulin (1,980 TMU/mg). The UTMs prolonged thrombin-induced fibrinogen clotting time (> 1 TMU /ml), APTT (> 5 TMU/ml), TT (> 5 TMU/ml) and PT (> 40 TMU/ ml) in a dose-dependent fashion. These effects appeared in the concentration range of soluble thrombomodulins present in human plasma and urine. In the rat DIC model induced by thromboplastin, administration of UTMs by infusion (300-3,000 TMU/kg) restored the hematological abnormalities derived from DIC in a dose-dependent fashion. These results demonstrate that UTMs exhibit potent anticoagulant and antithrombotic activities, and could play a physiologically important role in microcirculation.
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PMID:Soluble thrombomodulin purified from human urine exhibits a potent anticoagulant effect in vitro and in vivo. 748 7

A normally functioning hemostasis system is closely related to liver function. The liver parenchymal cells produce most of the factors and inhibitors of the clotting and fibrinolytic systems, and the RES of the liver greatly aids in the clearance of activation products. Hemostasis defects thus depend on the extent of liver damage. A wide spectrum of defects is found in patients with liver cirrhosis. Owing to impaired protein synthesis, most factors and inhibitors of the clotting and the fibrinolytic systems are markedly reduced. Additionally, abnormal vitamin K-dependent factor and fibrinogen molecules have been encountered. Most patients have hyperfibrinolysis that could be DIC in nature. Thrombocytopenia and thrombocytopathy are also found. Acute or chronic hepatocellular disease may display decreased vitamin K-dependent factor levels, especially factor VII and protein C, with other factors still being normal. If patients go into hepatic failure, the abnormalities resemble those found in liver cirrhosis. Vitamin K deficiency is associated with the production of poorly functioning vitamin K-dependent factors. All other hemostasis parameters are normal. Disturbances associated with liver surgeries again depend on the underlying liver problem. Peritoneovenous shunts (LeVeen) may lead to DIC; bleeding from partially resected liver surfaces is usually a mechanical problem. Severe bleeding is encountered with orthotopic liver transplantation. It is greatly influenced by the activation of the fibrinolytic system. This occurs during the anhepatic phase and during the reperfusion phase. The hyperfibrinolysis is mediated by an intense release of t-PA. Antifibrinolytic drugs, if used cautiously, have markedly reduced bleeding and thus reduced need for blood and blood product substitution.
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PMID:Coagulation defects in liver disease. 817 Feb 58

The pathophysiology of sepsis and septic shock is extremely complex and ultimately involves every physiological pathway. The initiating event is the entrance of endotoxin or similar substances into the blood which initiates the release of multiple mediators. These are designed to react locally and to protect the organism. Their constant release, however, sets in motion up- and down regulations, ultimately resulting in "metabolic anarchy". Tumor necrosis factor alpha and other cytokines trigger several systems, especially coagulation to yield DIC, and the complement system. Many treatment modalities have been developed, most recently those which substitute inhibitors of various systems. Antithrombin III concentrates and potentially protein C concentrates are designed to arrest DIC. C1-esterase inhibitor concentrates should intercept the activation of the complement system and the contact phase of coagulation and its relationship to kinin generation. Even newer approaches entail antibodies to tumor necrosis factor alpha or endotoxin itself. The complex process of sepsis will undoubtedly require a multifaceted therapeutic approach.
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PMID:Perspectives for the future. 822 36

A 26-year-old pregnant woman was diagnosed as having both lupus anticoagulant (LA) and anticardiolipin antibody (ACA). Her previous pregnancy ended in intrauterine fetal death at 27 weeks' gestation. During the present pregnancy she was treated with aspirin, dipiridamole, predonisolone, and heparin. At 24 weeks, fetal growth became retarded, accompanied by markedly decreased activities of AT-III, protein C, plasminogen and alpha 2-plasmin inhibitor. Supplement of human AT-III led both to prolongation of the gestational period and improvement of fetal growth. The pregnancy ended in cesarean section because of signs of fetal distress at 30 weeks. The infant was a 1025-g male with Apgar scores of 5 and 9 at one and five minutes, respectively, and is healthy. The mother developed DIC after surgery, but recovered after therapy. In this case, TAT, alpha 2PI-plasmin complex, FDP Ddimer, FPB beta 15-42, L-FDP showed little correlation with the clinical course.
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PMID:[Administration of human AT-III in a case of lupus anticoagulant positive pregnancy]. 831 36

Thrombomodulin-protein C system plays a very important role for the blood fluidity converting thrombin from a procoagulant protease to an anticoagulant and degrading activated factors Va and V III a. By their properties, both thrombomodulin and protein C may be expected for therapeutic medicines in DIC and some thromboembolic disorders. We reviewed and evaluated the probability of activated protein C and thrombomodulin for DIC treatment. Both appeared to be a very expectant for DIC medicine based on the preliminary clinical or experimental trials. Activated protein C is now under clinical trial in DIC. Recombinant thrombomodulin is also going to start its clinical trial in very near future.
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PMID:[Therapeutic strategy of newly developing medicines for disseminated intravascular coagulation--activated protein C and thrombomodulin]. 838 87

Reproducible disseminated intravascular coagulation in rabbits was provoked by two intravenous injections 24 hours apart of endotoxin from Salmonella enteritidis. There were mild symptoms of DIC before the second injection which considerably increased thereafter. In detail there was a sharp drop of the platelet count and a considerable diminution of Antithrombin III, of Protein C, Plasminogen and Antiplasmin as well as an appearance of fibrin monomer complexes and an increase of the aPTT. When PEG-hirudin in a single dose of 1 mg/kg BW was given simultaneously with the second injection of endotoxin the following alterations were observed: The drop of the platelet count and of the activities of Antithrombin III, Protein C, Plasminogen and Antiplasmin was significantly less pronounced. The fibrin monomer complexes were lower and the aPTT was less prolonged. The thrombin time, however, as a sign of a direct action of hirudin on thrombin was considerably more prolonged than in the controls. The combined effect of these alterations strongly points in the direction of a favourable influence of PEG-hirudin on the course of DIC. It is of special interest that 6 h after the intravenous injection of PEG-hirudin its full effect on the thrombin time was still detectable. This is apparently due to a longer half-life in circulation of PEG-hirudin than of natural hirudin.
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PMID:The effect of a long-acting recombinant hirudin (PEG-hirudin) on experimental disseminated intravascular coagulation (DIC) in rabbits. 847 80

Coagulation factor V (FV) and factor VIII (FVIII) are usually decreased in septicemic DIC. Low doses of endotoxin administered to healthy volunteers stimulate activation of the fibrinolytic, contact and coagulation systems, but not clinical DIC. Following the administration of endotoxin (4 ng/kg) to normal volunteers (n = 15), we applied new assays for FV antigens using monoclonal antibodies to the activation peptide (C1) and to the light chain of FV. At 5 hours, FV coagulant activity was significantly decreased (64 +/- 9%), as was the FV light chain antigen (74 +/- 6%), without a change in factor V C1 antigen or total protein C. In contrast, FVIII coagulant activity was greater than preinfusion levels at 2-5 hours. The decrease in FV activity may be due to APC cleavage of FV heavy chain, but the loss of light chain antigen suggests that plasmin and/or calpain also contribute. APC may not be the only enzyme responsible for cofactor inactivation. FV is one of the most sensitive markers, even reflecting subclinical activation of coagulation.
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PMID:Cofactors V and VIII after endotoxin administration to human volunteers. 858 99

This review presents the rationale for and main results of coagulation inhibitor substitution during experimental and human sepsis. Activation of the contact system induces activation of the classical complement pathway with generation of anaphylatoxins, of the kinins pathway and of fibrinolysis. Physiologic inhibition depends on the C1-inhibitor (C1-Inh.). Septic patients exhibit a relative deficiency of biologically active C1-Inh. Substitution with concentrations of C1-Inh has been safely performed and preliminary results are consistent with a possible beneficial effect on hypotension and vasopressor requirement in septic shock. The extrinsic pathway is the main initial coagulation process involved in sepsis-induced DIC. Endothelial and monocyte generation of tissue factor (TF) is activated by bacterial products and endotoxin. Activation of TF is counteracted by a specific tissue factor pathway inhibitor (TFPI). The potential for TFPI substitution to inhibit the activation of the coagulation cascade in sepsis requires further study. Thrombin generation is inhibited by antithrombin III (AT III) and the protein C-protein S system. During sepsis, AT III is consumed and degraded by elastase. Animal studies have shown that DIC and death were prevented by high doses of AT III concentrates. Although a significant reduction in the duration of biological symptoms of DIC has been reported in most human studies, the usefulness of AT III substitution in human sepsis is still debated. None of the studies was able to document a statistically significant reduction in mortality. Protein C is activated by thrombomodulin and, with its cofactor protein S, inhibits factors Va and VIIIa. The free level of protein S depends on the level of the C4b binding protein (C4bBP), an acute-phase complement regulatory protein. During sepsis, protein C activity is significantly reduced, either by acute consumption or by thrombomodulin down-regulation, and increased levels of plasma C4bBP inhibit protein S. Infusion of activated protein C and protein S substitution both protect animals from the lethal effects of bacteria. Combining these different coagulation inhibitors should be carefully studied before its use in septic patients is recommended.
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PMID:Coagulation inhibitor substitution during sepsis. 863 34

We examined the incidence of thrombophilia in deep vein thrombosis (DVT). Of 38 cases, we found 4 cases of protein C abnormality, 2 cases each of protein S abnormality and lupus anticoagulant, 1 case of antithrombin III abnormality. The total incidence was 23.7%, whereas only 2 cases (6.2%) of plasminogen abnormality were found among 32 healthy individuals. The incidence of thrombophilia was apparently higher among patients with DVT than that of healthy subjects, although the incidence of Japanese DVT was lower than that of Caucasian DVT, as previously reported. By SSCP analysis in one case of protein C abnormality, we demonstrated an abnormality of exon 9-3. To establish laboratory diagnosis of thrombophilia, it is recommended that (1) severe liver diseases, DIC, and oral anticoagulant be ruled out, (2) abnormality be confirmed by repeated examination, (3) family study determine inheritance mode, if possible. It was strongly suggested that laboratory examination of thrombophilia should be routinely applied to cases of venous thrombosis including DVT, not only for diagnostic interest but also for appropriate treatment of these cases.
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PMID:[Laboratory diagnosis of congenital thrombophilia]. 913 96

The HELLP syndrome (HS) belongs to the list of obstetric complications believed to be associated with coagulation disorders. It was formerly thought that chronic intravascular clotting (DIC) in the placental vessels was the main cause. A hypercoagulable state has been reported in cases of severe HS associated with microvascular abnormalities that may involve cerebral, placental, hepatic and renal vessels. A case of acute pancreatitis and DVT of inferior cava in a pregnant woman, presenting with HS at 29 weeks, who was found to have a R506Q mutation, is reported. Preeclampsia-associated pancreatitis and DVT have rarely been reported. It is hypothesized that APC-R and Factor V Leiden mutation may prove to be new and more important markers capable of predicting a more significant maternal morbidity associated with HS. Thrombosis prophylaxis may be considered during pregnancy in order to reduce hazardous multiorgan failure (MOF) in women who are heterozygous for Factor V Leiden mutation.
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PMID:Acute pancreatitis and deep vein thrombosis associated with HELLP syndrome. 1023 Feb 42


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