Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelium is strategically located at the interface between tissue and blood. It is pivotal for protecting against vascular injury and maintaining blood fluidity. Normal endothelium releases prostacyclin and nitric oxide, potent inhibitors of platelet and monocyte activation and vasodilators. Their syntheses are governed by isoforms of enzymes. Normal endothelial surface expresses ecto-adenosine diphosphatase, which degrades adenosine diphosphate and inhibits platelet aggregation; thrombomodulin, which serves as a binding site for thrombin to activate protein C; and heparin-like molecules, which serve as a cofactor for antithrombin III. Normal endothelium secretes tissue plasminogen activator, which activates the fibrinolysis system. Endothelium produces and secretes von Willebrand factor, which mediates platelet adhesion and shear-stress-induced aggregation. Injury to endothelium is accompanied by loss of protective molecules and expression of adhesive molecules, procoagulant activities, and mitogenic factors, leading to development of thrombosis, smooth muscle cell migration, and proliferation and atherosclerosis.
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PMID:Role of endothelium in thrombosis and hemostasis. 871 85

The direct effects of recombinant human erythropoietin(rHuEPO) on coagulation and fibrinolysis factors were evaluated in a cultured endothelial cell (EC) system. Confluent quiescent ECs were incubated with or without 5.0 U/ml rHuEPO for 1, 6, and 18 hours, and supernatant concentrations of plasminogen activator inhibitor-1 (PAI-1): antigen (Ag), tissue plasminogen activator and thrombomodulin, and supernatant activities of tissue factor pathway inhibitor and von Willebrand factor were measured. The results showed that only PAI-1 levels were increased by the presence of rHuEPO. In order to assess the effect of rHuEPO on PAI-1 production by EC more precisely, confluent ECs were incubated with various doses of rHuEPO (0, 1.0, 2.5, 5.0, 10.0 U/ml) for 1, 6, 12, and 18 hours, and PAI-1:Ag concentrations in the supernatants of media were measured. PAI-1:Ag in the supernatants were increased by the presence of rHuEPO at all incubation times (P < 0.01) and the increase in PAI-1:Ag was dependent on rHuEPO concentration. The increases in PAI-1:Ag by 5.0 U/ml rHuEPO were comparable to those by 0.1 U/ml tumor necrosis factor-alpha, 1.0 microgram/ml lipopolysaccharide, and 0.5 U/ml thrombin. The increase in PAI-1:Ag by rHuEPO was suppressed by pre-incubation with 10 micrograms/ml cycloheximide (P < 0.01) or 0.2 microgram/ml actinomycin D (P < 0.01). These results indicate that rHuEPO directly stimulates PAI-1 production in cultured EC via de novo protein and RNA syntheses.
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PMID:rHuEPO enhances the production of plasminogen activator inhibitor-1 in cultured endothelial cells. 880 78

Coagulation is initiated by the binding of factor VIIa to tissue factor, with resultant limited factor IX and X activation and thrombin production. Owing to the feedback inhibition of the factor VIIa/tissue factor complex by tissue factor pathway inhibitor (TFPI), additional factor X activation and thrombin generation must proceed through a pathway involving factors VIII, IX, and XI. Experiments designed to elucidate the requirement for amplified factor Xa and thrombin generation in normal hemostasis show that the resistance of plasma clots to tissue plasminogen activator (tPA)- and urokinase-induced fibrinolysis is related to the extent of thrombin generation. Inhibition of fibrinolysis is mediated in part by plasma carboxypeptidase-U ([CPU] carboxypeptidase-R, procarboxypeptidase-B, thrombin-activatable fibrinolysis inhibitor), a proenzyme that is proteolytically activated by thrombin in a process enhanced dramatically by the cofactor thrombomodulin. A clot induced in factor IX-deficient plasma with limited amounts of tissue factor in the presence of urokinase (100 U/mL) lyses prematurely, and this defect is corrected by supplementation of the deficient plasma with factor IX (5 micrograms/mL) or thrombomodulin (20 ng/mL). These additions enhance the rate and extent of CPU activation: in the case of factor IX, presumably by permitting amplified generation of factor Xa and thrombin, and in the case of thrombomodulin, presumably by increasing the degree of CPU activation produced by the low levels of thrombin generated in the absence of factor IX. Pretreatment of the factor IX-deficient plasma with specific anti-CPU antibodies prevents the increased resistance to fibrinolysis produced by addition of factor IX and thrombomodulin. Likewise, when coagulation is induced by thrombin (2 U/mL) in the presence of tPA (60 U/mL), clots formed from plasmas deficient in factors VIII, IX, X, or XI lyse prematurely unless the missing factor is replaced or thrombomodulin (20 ng/mL) is added.
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PMID:Coagulation-dependent inhibition of fibrinolysis: role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma. 891 45

Little is known on the haemostatic profiles of human microvascular endothelial cells (MVEC) from different tissues. In addition it is not known whether MVEC from patients display the same haemostatic pattern as MVEC coming from healthy controls. To address these questions MVEC from human lung and brain were isolated and stimulated with tumour necrosis factor alpha (TNF) and E. coli lipopolysaccharide (LPS) for 24 h. The level and the kinetics of procoagulant activity (PCA) and thrombomodulin (TM) expression were found to be different depending on the tissue of origin and on the agonist used. In particular, the inducible PCA was higher in lung than in brain MVEC, an observation that may be related to the frequency of lung involvement in septic shock. Differences were also observed for tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) with MVEC supernatants or cell lysates. These variables were then measured in lung MVEC purified from patients with acute respiratory distress syndrome (ARDS) and compared to controls. Cells from ARDS patients constitutively expressed more PCA and PAI-1 than controls. The fibrinolytic potential, expressed as t-PA/PAI-1 ratio, was lower in ARDS than in lung MVEC. It is concluded that MVEC display different haemostatic features depending on the tissue they come from and that lung MVEC from ARDS patients present a procoagulant profile when compared with those from controls.
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PMID:Haemostatic properties of human pulmonary and cerebral microvascular endothelial cells. 906 14

This study assessed the effects of the angiotensin-converting enzyme (ACE) inhibitor cilazapril on the main haemostatic variables in 22 patients, of either sex, with newly diagnosed uncomplicated essential hypertension. In the patients and in 10 control subjects, plasma levels of thrombomodulin, beta-thromboglobulin, D-dimer, tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) had previously been measured. Only the levels of t-PA and PAI-1 were found to be higher than in controls. All these haemostatic evaluations were carried out after 6 and 12 months of treatment with an ACE inhibitor, cilazapril, 5 mg/day. This treatment significantly lowered the mean arterial pressure in the whole group from 133 to 106 mm Hg (after 6 months) and to 105 mm Hg (after 12 months), p < 0.05. No significant difference in any haemostatic parameters was observed after 6 and 12 months of treatment. The present study confirmed that treatment with cilazapril for 12 months lowers daytime ambulatory mean arterial pressure in patients with essential hypertension, without any significant increase in the tendency of blood to clot.
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PMID:Effects of medium-term antihypertensive therapy on haemostatic parameters in patients with essential hypertension. 909 84

Studies on responses to surgical stress in blood coagulation and fibrinolysis, platelet counts and thromboxane B2 (TXB2) were carried out with 18 esophageal cancer patients who had undergone radical esophagectomy through right thoracotomy and reconstruction with gastric tube. Plasma levels were measured for the following for coagulation assessment: thrombin.antithrombin III complex (TAT), soluble fibrin monomer complex(SFMC), fibrinogen, antithrombin III, protein C and thrombomodulin. Selected fibrinolytic markers are: tissue plasminogen activator.plasminogen activator inhibitor 1 complex (tPA.PAI1C), plasminogen, alpha 2 plasmin inhibitor, plasmin. alpha 2 plasmin inhibitor complex(PIC), FDP and D-dimer. Peripheral venous blood samples were taken from the patients before the operation, immediately after the operation and on each of the first, second, third, seventh and fourteenth day after the operation. It was observed that TAT, SFMC, tPA.PAI-1C and TXB2 were remarkably altered immediately after the operation. This indicates that the major surgical stress significantly activated coagulation, fibrinolysis and platelets. Higher plasma levels of TAT compared to the pre-operation level was recorded for two weeks after the operation. Furthermore, in four cases, SFMC became positive during three to seven days after operation. These facts indicate that the activation of coagulation persisted during the days after operation. PIC began to increase from the 2nd to 3rd days after operation, reaching the maximum on the 7th day. Biphasic changes which peaked twice on the 1st and 7th days after operation were shown in plasma levels of FDP and D-dimer. These results indicate that the activation of fibrinolysis also persisted during the days after operation. The activation of coagulation and fibrinolysis may persist at least for two weeks after major surgical operation. Careful observation for the states of these systems was thought to be needed during the post-operative days, and the molecular markers could be useful to assess subclinical changes of these systems.
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PMID:[Responses to surgical stress in blood coagulation and fibrinolysis, platelet counts and thromboxane B2 after esophageal cancer operation]. 912 Oct 3

Using an in vitro model of clot lysis, the individual response to a pharmacological concentration of recombinant tissue plasminogen activator (rt-PA) and the influence on this response of the physiological variations of blood parameters known to interfere with the fibrinolytic/thrombolytic process were investigated in 103 healthy donors. 125I-fibrin labelled blood clots were submersed in autologous plasma, supplemented with 500 ng/ml of rt-PA or solvent, and the degree of lysis was determined after 3 h of incubation at 37 degrees C. Baseline plasma levels of t-PA, plasminogen activator inhibitor 1 (PAI-1), plasminogen, alpha 2-antiplasmin, fibrinogen, lipoprotein (a), thrombomodulin and von Willebrand factor as well as platelet and leukocyte count and clot retraction were also determined in each donor. rt-PA-induced clot lysis varied over a wide range (28-75%) and was significantly related to endogenous t-PA, PAI-1, plasminogen (p < 0.001) and age (p < 0.01). Multivariate analysis indicated that both PAI-1 antigen and plasminogen independently predicted low response to rt-PA. Surprisingly, however, not only PAI-1 but also plasminogen was negatively correlated with rt-PA-induced clot lysis. The observation that neutralization of PAI-1 by specific antibodies, both in plasma and within the clot, did not potentiate clot lysis indicates that the inhibitor, including the platelet-derived form, is insufficient to attenuate the thrombolytic activity of a pharmacological concentration of rt-PA and that its elevation, similarly to the elevation of plasminogen, is not the cause of clot resistance but rather a coincident finding. It is concluded that the in vitro response of blood clots to rt-PA is poorly influenced by the physiological variations of the examined parameters and that factors other than those evaluated in this study interfere with clot dissolution by rt-PA. In vitro clot lysis test might help to identify patients who may be resistant to thrombolytic therapy.
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PMID:In vitro clot lysis as a potential indicator of thrombus resistance to fibrinolysis--study in healthy subjects and correlation with blood fibrinolytic parameters. 913 50

The precursor of plasma carboxypeptidase B (pCPB) also known as thrombin-activable fibrinolysis inhibitor can be converted by thrombin to an active enzyme capable of eliminating C-terminal Lys- and Arg-residues from proteins. The activation is about 1000-fold more efficient in the presence of thrombomodulin (TM). We investigated the antifibrinolytic potency of maximally activated pCPB in plasma and explored the antifibrinolytic mechanism of pCPB. During clotting of plasma in the presence of 3.3 NIH units/ml thrombin and 1 microg/ml soluble TM, more than 80% pro-pCPB was converted into the active form causing an increase of plasma carboxypeptidase activity from 100 units/liter (constitutive activity ascribed to plasma carboxypeptidase N) to 430 units/liter as measured with furoylacroleyl-alanyl-arginine substrate. Under these conditions, lysis of a plasma clot induced by a range of tissue-type plasminogen activator (t-PA) concentrations (0.2-2 microg/ml) was retarded more than 4-fold. A considerable retardation of fibrinolysis was observed upon addition of as little as 12 ng/ml soluble TM, a concentration comparable with physiological concentrations of soluble TM in human plasma. The presence of Ca2+ appeared to be a critical requirement for effective activation of pro-pCPB by thrombin-TM in plasma. Plasminogen-binding sites (C-terminal lysines) on the surface of a plasmin-treated fibrin clot were eliminated within 1-3 min by plasma with maximally activated pCPB, as studied in a recently described model involving fluorescence microscopy. Confocal fluorescence microscopy showed that in the absence of TM plasminogen strongly accumulated on fibrin fibers during t-PA-induced lysis of a plasma clot. In the presence of TM (and a concomitant pro-pCPB activation), lysis was slow and was not accompanied by accumulation of plasminogen on the fibers. In conclusion, generation of active pCPB during clotting of plasma in the presence of Ca2+ and TM leads to a retardation of plasma clot lysis in a wide range of t-PA concentrations, from low to therapeutic, and to a fast elimination of plasminogen-binding sites on partially degraded fibrin. This is a likely mechanism for the antifibrinolytic effect of active pCPB.
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PMID:On the mechanism of the antifibrinolytic activity of plasma carboxypeptidase B. 916 90

To investigate abnormalities in the hemostatic and fibrinolytic system in CAPD patients, parameters of coagulation, anticoagulation, fibrinolysis, and platelet function were measured in 21 CAPD patients and 20 healthy controls. The CAPD patients had significantly higher levels of factor (F) IX, FVII, FX, antithrombin III, thrombin/antithrombin III complex, protein C, protein S, thrombomodulin, fibrinogen, fibrinopeptide A, plasminogen, FXIII, alpha2-plasmin inhibitor, alpha2-plasmin inhibitor/plasmin complex, D-dimer, fibrinopeptide B beta 15-42, and beta-thromboglobin than the healthy controls. The CAPD patients also showed a shorter prothrombin time. However, tissue plasminogen activator, plasminogen activator inhibitor-1 and platelet factor-4 did not show any significant differences from the levels in healthy controls. There was a significant positive correlation between many of the blood parameters and serum lipids. These results demonstrate that hypercoagulability and secondary hyperfibrinolysis occur in CAPD patients, and suggest that these changes may be related to abnormalities in lipid metabolism.
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PMID:Hypercoagulability and secondary hyperfibrinolysis may be related to abnormal lipid metabolism in patients treated with continuous ambulatory peritoneal dialysis. 917 1

Few studies of activated protein C resistance (APCR) and thromboembolism in childhood have been published. In the majority of childhood thromboses reported, the factor V Leiden mutation was associated with venous thromboses; however, one case report and three studies described arterial thromboembolism in infants and children due to the common mutation in the factor V gene. In one neonate purpura fulminans occurred, and heparin-induced thrombocytopenia type II was additionally documented. Two case reports and seven of nine studies reported associated clinical conditions together with inherited coagulation disorders. In three studies homozygous patients were mentioned. There are few studies describing the interaction between APCR and coagulation or the fibrinolytic system in symptomatic and nonsymptomatic infants. Compared with healthy brothers or sisters and a healthy age-matched control group, thrombin generation, D-dimer, PAI-1 activity, and t-PA antigen were found clearly elevated in children with APCR. In addition, infants and children with the Arg506-to-Gln mutation in the factor V gene showed significantly increased thrombomodulin concentrations along with normal protein C activities compared with relatives and healthy controls. No difference was recorded in these studies between heterozygous infants and children without vascular occlusion and patients who previously had suffered from thromboembolism. Until long-term data are available for the treatment of patients with APCR, such children should be treated in the same way as patients with deficiencies of protein C, protein S, or antithrombin.
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PMID:APC resistance in childhood thromboembolism: diagnosis and clinical aspects. 925 6


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