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:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical and experimental data have recently accumulated for antithrombotic action of angiotensin-converting enzyme inhibitors (ACE-1s). We have shown previously that captopril (which contains a thiol group in the moiety) exerts more pronounced antithrombotic activity than does an equipotent dose of enalapril (the drug devoid of the thiol group). To clarify the relative importance of the presence of the thiol group in the molecule versus angiotensin-converting enzyme (ACE) inhibitory properties in the antithrombotic action of captopril, rats were treated with captopril (5 mg/kg twice daily; CAP), epicaptopril (stereoisomer of captopril devoid of ACE-inhibitory properties; 5 mg/kg twice daily; EPI), N-acetylcysteine (3.75 mg/kg twice daily; ACC), enalapril (3 mg/kg once daily; ENA), or distilled water (VEH) for 10 days, per os. After ligation of the vena cava, the incidence of the venous thrombosis and/or the thrombus weight decreased significantly in all but the ENA-treated groups when compared with control rats. The effect of CAP, EPI, and ACC was accompanied by a marked reduction of euglobulin clot lysis time and, with the exception of ACC, by an increase in prothrombin time in the blood collected from the site of the thrombus formation. Antithrombotic activity of EPI was completely abolished by nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) or indomethacin, with the parallel reversal of fibrinolytic and coagulation parameters toward normal. Activated partial thromboplastin time, mean blood pressure, and bleeding time were not altered by either of the administered drugs. Thus, we demonstrated that thiol compounds exert antithrombotic activity by increasing fibrinolysis and/or suppression of the extrinsic pathway of the coagulation cascade in a nitric oxide/prostacyclin-dependent manner.
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PMID:Thiol repletion prevents venous thrombosis in rats by nitric oxide/prostacyclin-dependent mechanism: relation to the antithrombotic action of captopril. 1102 53

In acute myocardial infarction (AMI), monocyte procoagulant activity is increased and may contribute to the risk for recurrence and other thrombotic events. This study sought to investigate the role tissue factor (TF) and tissue factor pathway inhibitor-1 (TFPI-1) in the regulation of monocyte procoagulant activity in AMI. Serial venous blood samples were obtained from 40 patients with AMI undergoing revascularization by stent placement. Twenty patients with elective stenting for stable angina served as control subjects. TF proteolytic activity was measured with spectrozyme factor Xa (FXa), TF and TFPI-1 surface expression on monocytes by flow cytometry, RNA expression in whole blood by reverse transcription-polymerase chain reaction, and concentrations of plasma prothrombin fragments F(1 + 2) by immunoassay. Forty-eight hours after AMI, an increase was found in TF RNA, followed by an increase in TF surface expression by 24% +/- 4% and in plasma concentration of F(1 + 2) by 103% +/- 17% (P <.05). These changes could not be attributed to the intervention because they did not occur in the control group. TFPI-1 RNA and binding to the monocyte surface remained unchanged. FXa generation by monocytes of patients with AMI increased 53.6% +/- 9% in the presence of polyclonal antibodies to TFPI-1, indicating that cell-associated TFPI-1 inhibits monocyte TF activity. The increased monocyte procoagulant activity in AMI was caused by an up-regulation of TF that was partially inhibited by surface-bound TFPI-1. Anticoagulant therapy by direct inhibition of TF activity may, thus, be particularly effective in AMI. (Blood. 2001;97:3721-3726)
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PMID:Regulation of monocyte procoagulant activity in acute myocardial infarction: role of tissue factor and tissue factor pathway inhibitor-1. 1138 8

Excessive production of nitric oxide (NO) by the inducible form of NO synthase (iNOS) plays a key role in the development of endotoxin shock. Tumor necrosis factor-alpha (TNF-alpha) induces iNOS, thereby contributing to the development of shock. We recently reported that recombinant tissue factor pathway inhibitor (r-TFPI), an important inhibitor of the extrinsic pathway of the coagulation system, inhibits TNF-alpha production by monocytes. In this study, we investigated whether r-TFPI could ameliorate hypotension by inhibiting excessive production of NO in rats given lipopolysaccharide (LPS). Pretreatment of animals with r-TFPI prevented LPS-induced hypotension. Recombinant TFPI significantly inhibited the increases in both the plasma levels of NO2-/NO3- and lung iNOS activity 3 h after LPS administration. Expression of iNOS mRNA in the lung was also inhibited by intravenous administration of r-TFPI. However, neither DX-9065a, a selective inhibitor of factor Xa, nor an inactive derivative of factor VIIa (DEGR-F.Vlla) that selectively inhibits factor VIIa activity, had any effect on LPS-induced hypotension despite their potent anticoagulant effects. Moreover, neither the plasma levels of NO2-/NO3- nor lung iNOS activity were affected by administration of DX-9065a and DEGR-F.VIIa. These results suggested that r-TFPI ameliorates LPS-induced hypotension by reducing excessive production of NO in rats given LPS and this effect was not attributable to its anticoagulant effects, but to the inhibition of TNF-alpha production.
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PMID:Recombinant tissue factor pathway inhibitor prevents lipopolysaccharide-induced systemic hypotension in rats by inhibiting excessive production of nitric oxide. 1177 29

Activation of the extrinsic pathway of blood coagulation plays the key role in the process of blood coagulation. The hemostasis is influenced by the activity of procoagulant factors and its inhibitors. In this work we summarize existing data on tissue factor pathway inhibitors: TFPI and TFPI-2. Despite structural similarity between them, they exhibit many differences in synthesis, distribution and mechanism of action. TFPI inhibits the activity of factor Xa and the complex of tissue factor and factor VIIa (TF/VIIa). Conversely, TFPI-2 does not inhibits factor Xa, but it is a strong inhibitor of factor XIa, plasma kallikrein, plasmin and trypsin.
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PMID:[Tissue factor pathway inhibitors]. 1236 12

Disseminated intravascular coagulation (DIC) is a systemic thrombohemorrhagic disorder seen in association with many clinical situations, e.g. sepsis, malignancy, obstetrical complications and intravascular hemolysis. In our model, disseminated intravascular coagulation was induced in rabbits by two consecutive intravenous bolus injections of endotoxin from Escherichia coli, 80 and 40 microg/kg. The control group was treated with 0.9% saline. The activity of thioglycosides was compared to unfractionated heparin (UFH) and efegatran with and without administration of endotoxin. Drugs were administered in the following doses: heparin 50 and 100 IU/kg/h i.v. infusion; efegatran 0.25 and 0.5 mg/kg/h i.v. infusion; GYKI 39521 (RGH-1875) as well as GYKI 39541 (RGH-1962) 12.5 and 25 mg/kg per os. Thioglycosides did not modify coagulation parameters in this model [prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT)] as compared with endotoxin/vehicle group. The changes in TFPI level after administration of thioglycosides and heparin were similar in the mentioned model to those without endotoxin. Endotoxin-induced changes of leukocyte count were not affected by GYKI 39521 and GYKI 39541 treatment in our model. Diminution of fibrinogen level and platelet count was prevented by GYKI 39521 and GYKI 39541. Fibrin degradation products and fibrinolysis were significantly decreased by GYKI 39521 and GYKI 39541. The thioglycosides may have a lower risk of bleeding in the treatment of disseminated intravascular coagulation than heparin.
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PMID:Effect of some new thioglycosides on endotoxin-induced disseminated intravascular coagulation in rabbits. 1256 24

As apoptosis of neo-intimal SMCs is a feature of advanced atherosclerotic plaques, the procoagulant properties of SMCs of synthetic phenotype undergoing apoptosis were investigated. SMCs isolated from rat aorta obtained 10 days after balloon injury, previously found to up-regulate Tissue Factor (TF) and Tissue Factor Inhibitor (TFPI) and to release large amounts of TFPI (Ghrib et al. Thromb Haemost 2002;87:1043-50), were sensitive to the apoptosis induced by Fas-ligand. During this process, surface TF activity rose by a factor 10 over 6 hours, in parallel with a proportional increase in prothrombinase, while TF protein expressed at the membrane significantly decreased. The microparticles (MPs) produced during SMC death bore intact and functional TF, but the release of TFPI did not change, so that the balance shifted to a procoagulant state during apoptosis. Shed MPs enhanced thrombus formation in flowing whole blood over collagen coated-glass slides. Apoptotic SMCs in atherosclerotic plaques represent a reservoir of highly thrombogenic material, released into the blood stream in case of spontaneous or mechanical plaque disruption.
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PMID:Shedding of active tissue factor by aortic smooth muscle cells (SMCs) undergoing apoptosis. 1295 21

The cellular initiation of coagulation by the tissue factor (TF)-activated factor VII complex is transiently inhibited by endogenous tissue factor pathway inhibitor-1 (TFPI-1), whereas exogenously added TFPI-1 is targeted to a degradation pathway. This study investigates the relevance of glycosyl phosphatidylinositol (GPI) anchoring for the anticoagulant properties of TFPI-1. Experiments were performed with the human cell line ECV304 using liposomal gene transfer. For GPI anchoring of TFPI-1 we used a fusion protein of TFPI-1 and the GPI attachment sequence of decay-accelerating factor (GPI-TFPI-1), and compared it with wild-type TFPI-1. We measured TF and TFPI-1 surface expression by flow cytometry and TF proteolytic activity by a chromogenic assay for activated factor X generation. After transfection of GPI-TFPI-1, surface expression of TFPI-1 increased to 134 +/- 9% of mock transfected cells (mean +/- SEM, P = 0.004), and transfection with wild-type TFPI-1 did not significantly alter TFPI-1 surface expression. After transfection with GPI-TFPI-1, TF activity was reduced by 18 +/- 9% compared with mock transfections (P = 0.003), whereas after transfection with TFPI-1 wild type no significant inhibition was observed. This effect was not due to altered TF expression. GPI anchoring is an essential prerequisite for surface expression of TFPI-1 and inhibition of TF activity. Gene transfer of GPI-anchored TFPI, therefore, may be an efficient tool to inhibit local TF-induced coagulation.
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PMID:Overexpression of glycosyl phosphatidylinositol-anchored tissue factor pathway inhibitor-1 inhibits tissue factor activity. 1296 Jun 6

Ixolaris is a two-Kunitz TFPI (tissue factor pathway inhibitor) from the tick salivary gland. In contrast with human TFPI, Ixolaris binds tightly to the zymogen FX (Factor X) and to dansyl-Glu-Gly-Arg-chloromethyl ketone-treated FXa (DEGR-FXa; active-site-blocked FXa), indicating that exosites are involved in the FX(a)-Ixolaris interaction. Here we provide evidence that Ixolaris binds specifically to the FXa HBE (heparin-binding exosite), since (i) it markedly decreases the inhibition of FXa by the antithrombin-heparin but not the antithrombin-pentasaccharide complex, (ii) it impairs FXa binding to Sepharose-immobilized heparin, and (iii) it allosterically modulates the catalytic activity of FXa for small chromogenic substrates (S-2765). By using a series of recombinant FXa mutants in which the HBE is mutated, we have identified the importance of amino acids involved in the enzyme-inhibitor interaction as being in the following order: Arg-93>>Arg-165> or =Lys-169>Lys-236>Lys-96>Arg-240>Arg-125. Ixolaris at appropriate concentrations also inhibits thrombin formation in vitro by the assembled prothrombinase complex, a process that is critically dependent on the FXa HBE. Ixolaris is the first inhibitor characterized to date that binds specifically to the FXa HBE.
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PMID:Ixolaris: a factor Xa heparin-binding exosite inhibitor. 1561 17

Current antithrombotic agents include anticoagulants (unfractionated and low-molecular-weight heparin, and antivitamin K) and platelet aggregation inhibitors (aspirin, ticlopidine, clopidogrel). Two areas are under particular investigation: specific inhibition, direct or indirect, of factor Xa and factor IIa. Pentasaccharide, an indirect anti-Xa, has proved effective in curing deep-vein thrombosis and more effective than enoxaparin for prophylactic treatment after orthopedic surgery. Administered in a single subcutaneous injection daily, it has no risk of thrombocytopenia; laboratory surveillance is based on anti-Xa activity. Hirudin and melagatran act by direct thrombin inhibition. Unlike hirudin (which requires monitoring of active coagulation time or ecarin clotting time), melagatran requires no laboratory monitoring. It is not associated with an increased risk of hemorrhage. But there is no true antidote at this time. If its efficacy is confirmed, ximelagatran, the orally active prodrug of melagatran, may facilitate the long-term treatment now reserved for antivitamin K. Three antagonists of the tissue factor-factor VIIa complex are also under development: rNAPc2 (Recombinant Nematode Anticoagulant Protein C2), ASIS (Active Site Inhibitor Factor Seven) and recombinant TFPI (Tissue Factor Pathway Inhibitor). Antiplatelet drugs are the reference antithrombotic agents for the prevention and treatment of arterial thrombosis. Aspirin remains in first place (75 to 300 mg/d) but the modest superiority of the thienopyridines (clopidogrel and ticlopidine) is established. Hemogram monitoring is no longer necessary for clopidogrel. Use of aspirin + a thienopyridine after placement of a coronary stent has been validated. Laboratory monitoring of antiplatelet treatments has not been codified.
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PMID:[The new antithrombotic agents]. 1626 95

Chronic hypertriglyceridemia is thought to be atherogenic and is associated with an elevated thrombotic potential, both of which may be improved with aerobic exercise training. Eight subjects were tested for aerobic capacity, body composition, and postprandial lipemia (PPL), followed by 6 mo of exercise training and final testing. Blood samples were obtained for measurement of free fatty acid (FFA), triglycerides (TG), insulin (Ins), and glucose (Glu). Hemostatic variables including factor VII activity (FVIIa), tissue factor pathway inhibitor-factor Xa complex (TFPI/Xa), and plasminogen activator inhibitor-1 (PAI-1) antigen/activity as well as leukocyte tumor necrosis factor-alpha (TNF-alpha) gene expression were determined among four subjects. We found that the exercise training was of sufficient intensity to increase aerobic capacity (P < 0.0001) and improve body composition (P = 0.04). There were no differences between tests among PPL responses of FFA, TG, Ins, or Glu; however, the mean TG response and fat oxidation rate improved. PAI-1 antigen/activity, FVIIa, TFPI/Xa, and TNF-alpha gene expression were all improved after exercise training after adjusting for confounders. We conclude that aerobic exercise training reduces the potential for coagulation, improves fibrinolytic potential, and reduces leukocyte TNF-alpha gene expression after the ingestion of a high-fat meal.
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PMID:Hemostatic response to postprandial lipemia before and after exercise training. 1649 41


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