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:3.4.21.68 (tissue plasminogen activator)
11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent advances in determining anti-thrombogenic functions of vascular endothelial cells are reviewed. The following anticoagulant and fibrinolytic systems of endothelial cells are physiologically important; (1) Endothelial cell-derived metabolites including prostacyclin and nitric oxide (NO) support platelet inactivity. (2) Antithrombin III and tissue factor pathway inhibitor (TFPI) bound to heparin-like proteoglycans on endothelial cell membrane inhibit activated serine protease coagulation factors such as thrombin, factor Xa and factor VIIa-tissue factor complex. (3) Thrombomodulin converts thrombin from procoagulant into anticoagulant. Thrombin associated to thrombomodulin on endothelial cells activates protein C. Activated protein C in concert with protein S bound to endothelial cell membrane inactivates factors Va and VIIIa. (4) A receptor for both tissue plasminogen activator and plasminogen on endothelial cells provides an efficient plasmin generating system. Perturbation of these anti-thrombogenic systems of endothelial cells is caused by endotoxin (LPS), cytokines such as interleukin-1 and tumor necrosis factor (TNF), and risk factors for atherogenesis including lipoprotein(a) and homocysteine may result in arterial or venous thrombosis with subsequent development of atherosclerosis.
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PMID:[Anticoagulant and fibrinolytic systems of the injured vascular endothelial cells]. 817 40

The first generation high-dose ( 80 mcg estrogen) oral contraceptives (OCs) were associated with an increased risk of deep venous thrombosis (DVT). So manufacturers removed the high-dose OCs and first replaced them with OCs with 50 mcg estrogen, resulting in a lower incidence of thromboembolic events (40 vs. 20/100,000 users). When they introduced an even lower dose OC (30 mcg estrogen), the incidence fell further (about 8/100,000 users). Yet, women using the lowest-dose OCs still have DVT more often than do control women. Life-style, age, and smoking may be confounding factors, however. It is not clear whether loss of endogenous ovarian steroid production or the effects of the orally administered contraceptive steroids cause significant changes in hemostatic factors (antithrombin III, protein S, protein C, plasminogen, tissue-type plasminogen activator, plasminogen activator inhibitor 1, histidine-rich glycoprotein, and VII, VIII, X, XII coagulation factors) during OC use. These changes tend to be within normal ranges. There is some doubt that these changes have any clinical significance. In nonsmokers, increased activity of anticoagulant factors and fibrinolytic factors counteract the effects on coagulation factors. Progestin-only OCs appear to affect hemostasis but have not increased the risk of thrombosis. There are considerable differences between people in pharmacokinetics and pharmacodynamics of contraceptive steroids. These differences may account for the increased risk of thromboembolic events in some people. Further research should identify methods of individualizing the dose of contraceptive steroids for a single patient. It should also explore the close interrelationship between hemostasis and lipid metabolism, carbohydrate metabolism, and hypertension in the development of cardiovascular disease in OC users. Providers should discourage women with a past history of DVT from using hormonal contraception.
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PMID:Coagulation and anticoagulation effects of contraceptive steroids. 817 1

Patients with end-stage renal disease (ESRD) are at risk of ischemic cardiovascular complications and vascular thrombosis. These observations prompted the present survey of the blood coagulation, fibrinolytic, and inhibitory proteins in a group of 31 ESRD patients and 32 normal controls. Immunologic and functional assays were used to quantitate plasma antigen concentrations and/or functional activities of factors XII, XI, IX, VIII, VII, X, II, and XIII, von Willebrand factor, fibrinogen, fibronectin, high molecular weight kininogen, D-dimer, antithrombin III, protein C, protein S, plasminogen, tissue-type plasminogen activator, plasminogen activator inhibitor, alpha 2-antiplasmin, alpha 1-antitrypsin, and alpha 2-macroglobulin as well as antiplasmin activity. The coagulant activities of factors XII, IX, X, and II were significantly reduced in ESRD patients despite their normal or increased plasma antigen concentrations. In addition, the ESRD patients showed hyperfibrinogenemia and significant elevations of plasma concentrations of D-dimer, von Willebrand factor, factor VII, and factor XIII antigens. They also exhibited significant reductions of antithrombin III, free protein S, plasminogen, and tissue-type plasminogen activator concentrations. Despite ultrafiltration, plasma factor IX activity and von Willebrand factor and fibrinogen concentrations decreased after hemodialysis with little or slight changes in other measured parameters. The ESRD patients studied here exhibited numerous abnormalities of coagulation, fibrinolytic, and inhibitory proteins at multiple levels. These abnormalities may be involved in the pathogenesis of cardiovascular complications and vascular thrombosis in this population. The precise mechanism(s) and clinical significance of the observed abnormalities are unknown and await further investigation.
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PMID:Blood coagulation, fibrinolytic, and inhibitory proteins in end-stage renal disease: effect of hemodialysis. 820 65

Antithrombin-III (AT) is a key inhibitor of blood coagulation that neutralizes activated serine esterases by forming covalent modified complexes (ATm). A new monoclonal antibody directed against short-lived AT-activated serine protease complexes provides a means of measuring subclinical coagulation activity during cardiopulmonary bypass (CPB). Twelve patients undergoing CPB for coronary artery bypass grafting were studied and AT, ATm, D-dimers (DD), and several other coagulation and fibrinolytic markers were measured during the surgical procedure. There were decreases in AT, factors V, II, X, IX, protein S (total and free), C4b-binding protein, thrombomodulin, and platelets counts, whereas heparin, ACT, thrombospondin, plasminogen activator inhibitor (PAI-1), and tissue plasminogen activator (tPA) increased. ATm and the percentage of ATm available (ATm/AT) showed a peak during CPB. These results demonstrate that during CPB, the use of heparin produces an equilibrium involving increased coagulation activation and consumption in association with increased fibrinolysis. The equilibrated consumption of both coagulation and fibrinolytic factors leads to low levels of all factors after cardiac surgery. The ATm assay allows assessment of the differential effects of CPB and surgical trauma on coagulation activation. It is speculated that ATm levels may be useful in monitoring the consumption of coagulation factors.
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PMID:Assessment of coagulation factor activation during cardiopulmonary bypass with a new monoclonal antibody. 820 8

The plasminogen activator systems in the blood, the coagulation system, and the complement pathways are reviewed. The review describes the role of the vascular intima in activation of coagulation and fibrinolysis and the interrelations between the complement system and haemostatic mechanisms. Physiological activation of fibrinolysis may be triggered by and limited to fibrin because of a special affinity of plasminogen and plasminogen activators. The binding of plasminogen to fibrin is regulated by histidine-rich glycoprotein, and the primary physiological inhibitor of generated plasmin is alpha 2-antiplasmin and especially the plasminogen-binding form of this immediate plasmin inhibitor. Plasminogen activator inhibitors in the blood, that is, notably plasminogen activator inhibitor type 1 (PAI-1), bind circulating tissue-type plasminogen activator (t-PA). However, local fibrinolysis in vivo mediated by t-PA may be independent of complex formation between plasminogen activator inhibitors and t-PA in the fluid phase. Circulating plasminogen activator inhibitors might regulate fibrinolysis by increasing the clearance of t-PA from the blood. The urokinase-type and factor XII-dependent fibrinolytic proactivator system can be activated following t-PA-mediated generation of plasmin, and could thus serve as an amplification system of t-PA-induced fibrinolysis. It is claimed that the as yet uncharacterized proactivator is essential for optimal generation of plasminogen activator activity by the factor XII-dependent fibrinolytic system. The normal antithrombotic condition of the vascular intima probably results from lack of tissue factor activity and the presence of significant antithrombotic components comprising, among others, antithrombin III and the protein C-protein S system. A number of pathophysiologic stimuli, notably mediators of the acute phase response such as the cytokines interleukin-1 and tumour necrosis factor-alpha (cachectin), have the potential to induce the vascular endothelium to express procoagulant activity. Vascular endothelium promoting coagulant activity releases increased amounts of t-PA antigen and PAI-1 antigen into the circulation, and elevated levels in the blood of both may be regarded as a marker of a generalized procoagulant condition involving the vascular endothelium. In a prospective study in patients with unstable angina pectoris, patients in whom disease progresses and acute myocardial infarction develops, have increased amounts of t-PA antigen and PAI-1 antigen in the blood. This suggests that the procoagulant potential and atherosclerotic process of the vascular intima is more pronounced in the risk group.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Fibrinolysis in patients with acute ischaemic heart disease. With particular reference to systemic effects of tissue-type plasminogen activator treatment on fibrinolysis, coagulation and complement pathways. 822 63

The prevalence of abnormalities of fibrinolysis in patients with venous thromboembolism is as yet unknown. Defined abnormalities include congenital dysfunction and deficiency of plasminogen, and probably impaired plasminogen activation secondary to elevated levels of plasminogen activator inhibitor type 1 (PAI-1) or to impaired release of tissue plasminogen activator (tPA). In this preliminary study, we analyzed plasma samples from 21 patients for whom an investigation for possible thrombophilia was requested. Twenty of the patients had venous thromboembolism, and one had arterial thrombosis at an early age. Two patients had deficiency of protein C or protein S, but no other recognized biochemical disturbances related to thrombophilia were identified. Patient samples and plasma from 25 normal controls were assayed for tPA activity, PAI-1 activity, and urokinase (uPA) activity and antigen. tPA activity and antigen were not significantly different in patients than in controls. PAI-1 activity was significantly greater in patients (P < 0.0001). uPA activity was not different in the two groups. However, uPA antigen was significantly reduced in patients compared to controls (P = 0.001). These data suggest that hypofibrinolysis leading to a risk of thrombosis may be caused not only by elevated PAI-1 activity but also by reduced total uPA concentration.
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PMID:Hypofibrinolysis in patients with hypercoagulability: the roles of urokinase and of plasminogen activator inhibitor. 823 97

In 15 patients with systemic sclerosis (SS) and 8 patients suffering from silicosis and/or silica dust exposure-associated scleroderma (SAS), various parameters of endothelial cell and platelet function and of blood coagulation and fibrinolysis were studied. In 9 of the 23 patients the values for the von Willebrand factor antigen were increased, and the same applied to the endothelin levels in 8 of 23 patients. Protein C, protein S, anti-thrombin III and tissue plasminogen activator (before and after 10 min venous occlusion) were normal. The plasminogen activator inhibitor, however, was increased in 5 patients. Increased levels of platelet factor 4 and of beta-thromboglobulin were found in 20 patients, while the ADP- and epinephrine-induced platelet aggregation was reduced in 5 patients. No individual patient was found to have a general disturbance of all parameters. The deviations in the parameters of endothelial cell and platelet function and of blood coagulation and fibrinolysis proved to be rather inconsistent. This suggests different functional stages in dependence on the various influential factors. There was no close correlation either with the severity of Raynaud's phenomenon or with the type of SS. In addition, there were no basic differences between SS and SAS. The disturbances occurred with similar frequency and in similar proportions in both disease groups.
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PMID:[Vascular function parameters in idiopathic and quartz-induced progressive scleroderma]. 827 90

34 healthy women aged 21-30 years were assigned to 12 consecutive menstrual cycles of treatment with monophasic combinations. 15 women with a median age of 24 years received 20 mcg ethinyl estradiol (EE) and 150 mcg desogestrel (DSG) and 19 women with a median age of 23 years were treated with 30 mcg EE and 75 mcg gestodene (GST). Three women from the EE+DSG group and four women from the EE+GST group quit after six months because of personal reasons. Two more women from the EE+GST group quit after six months because of mammary tension and weight gain. Two women in each group smoked between one and ten cigarettes daily, the rest were nonsmokers. The evaluation of the hemostatic system was carried out in the luteal phase before the treatment began and within the last ten days in the third, sixth, and twelfth treatment cycle. In both groups plasma levels of fibrinogen (7.2 mcmol/l pretreatment to 8.7 mcmol/l posttreatment) and factor VIIc (80% pretreatment to 126% posttreatment) increased significantly under treatment, while the capacity of coagulation inhibition was affected after three months by increased protein C concentrations (15% in the EE+DSG group and 14% in the EE+GST group) and significantly decreased levels of protein C's cofactor, protein S levels by 11% and 15%, respectively. Increased fibrinolytic capacity was indicated by elevated activity and reduced antigen levels of tissue plasminogen activator and reduced activity and concentration of tissue plasminogen activator inhibitor. The ratio between thrombin antithrombin-III-complexes (TAT) and fibrin degradation products were unchanged, signifying no effect of hormonal intake on the balance between thrombin formation and fibrinolysis. The dynamic balance between coagulation and fibrinolysis was undisturbed during treatment with both hormonal compounds, and findings do not provide evidence for increased risk of thrombosis in normal women.
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PMID:[Hemostatic balance during treatment with the newest contraceptives]. 829 9

The effect of human activated protein C (APC) on tissue plasminogen activator (tPA)-induced fibrinolysis was studied in cell free plasma and in a system of purified components. Clots were produced by adding plasma or a solution of fibrinogen and plasminogen to the wells of a microtiter plate containing small separated aliquots of Ca2+, thrombin, and tPA, plus and minus APC. Initial clotting and subsequent fibrinolysis were monitored continuously by turbidity. The lysis time of dialyzed normal human plasma (NHP) was longer than that of dialyzed barium citrate-adsorbed plasma (BAP). APC had no effect on the lysis time of BAP but shortened the lysis time of NHP to that of BAP. Two fractions were produced from material eluted from the barium citrate pellet by precipitation of selective components with polyethylene glycol 8000 (PEG). One fraction comprised materials which precipitated at 5% PEG (5% PF) and the other materials which precipitated between 5 and 40% PEG (5-40% PF). Both fractions together, but neither alone, prolonged the lysis time of BAP, an effect which could be reversed by APC. Fractionation of the 5% PF showed that the component with the required activity has properties of the procoagulant surface and can be replaced with vesicles of phosphatidylcholine/phosphatidylserine (PCPS). In addition, the 5-40% PF can be replaced with either the combination of purified coagulation Factors II, IX, and X or Factor II plus the prothrombin activator Factor Xa. When Factor Xa was used as the activator in BAP plus PSPC vesicles, a dose-dependent saturable increase in lysis time was observed with a half-maximal increase occurring at 32 pM Factor Xa. This effect was eliminated by APC. In a system of purified components comprising PCPS vesicles, Factors V and II, protein S, plasminogen and fibrinogen; the prothrombin activators Factor Xa and ecarin both induced a prolongation of the lysis time. APC prevented prolongation by Factor Xa but not by ecarin. The time courses of the generation of thrombin and plasmin during fibrinolysis of clots produced from systems of purified components in the presence and absence of APC, and with Factor Xa as the prothrombin activator, were determined by standardized activity assays using chromogenic substrates. In the absence of APC the lysis time was 145 min, and prothrombin was quantitatively converted to thrombin. In the presence of APC, however, the lysis time was reduced to 100 min with no evidence for the activation of prothrombin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The effect of activated protein C on fibrinolysis in cell-free plasma can be attributed specifically to attenuation of prothrombin activation. 847 6

The natural anticoagulants (antithrombin III, protein C, protein S), plasminogen and tissue plasminogen activator antigen (t-PA ag), were measured in 27 consecutive patients following allogeneic BMT. Thrombosis and veno-occlusive disease were not seen in this study. Changes in the levels of these proteins occurred mainly during acute GVHD. There were 14 patients who had no acute GVHD (group I) and 13 patients who had acute GVHD (group II). No changes in antithrombin III (ATIII), protein C, protein S and t-PA levels were found in group II before the appearance of acute GVHD when compared with group I. However, we noted a significant rise in protein S (p = 0.01), antithrombin III (p = 0.001) and t-PA ag (p = 0.0004) levels during acute GVHD. In contrast, protein C levels decreased early in GVHD (p = 0.005), and then increased progressively over the course of a month post-GVHD. No changes in plasminogen levels were observed. These results might reflect activation of and/or damage to endothelial cells during GVHD.
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PMID:Alterations in natural anticoagulant levels during allogeneic bone marrow transplantation: a prospective study in 27 patients. 848 78


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