Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Possible correlation of the effects of pharmacotherapy on the inhibition of the in-vivo generation of thrombin and on the prevention of thrombus extension in patients with deep vein thrombosis (DVT) could help to define patients at higher risk. Patients with symptomatic deep vein thrombosis confirmed by phlebography were randomised to intravenous unfractionated heparin (UFH), or a subcutaneous low-molecular-weight heparin (reviparin) twice daily for one week, or a subcutaneous reviparin once daily for four weeks. The patients were treated with oral anticoagulants for at least 3 months. Main endpoints were regression of thrombus on phlebography on Day 21 and recurrent symptomatic venous thromboembolism up to 3 months. Coagulation parameters, markers of in-vivo thrombin generation, and TFPI-release were determined at randomisation, weeks 1 and 3. Four hundred sixty six responders (reduction of at least 30 per cent in Marder score) and 419 non-responders (Marder score unchanged or changed less than +/-30%) showed no significantly different baseline characteristics. The non-responder group had a higher median Marder score at baseline and after one and three weeks of treatment, and had significantly higher fibrinogen levels, TAT complexes and F1+2 values than responders. There were no significant differences in coagulation parameters between non-responders and patients with asymptomatic + symptomatic VTE with the exception of higher TAT complexes at baseline. Significant differences in Marder score and coagulation parameters at baseline were found between responders and nonresponders. Non-responders have a higher risk tosuffer recurrent VTE and may need intensified treatment.
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PMID:Risk factors and coagulation parameters in relationship to phlebographic response and clinical outcome in the treatment of acute deep vein thrombosis. 1257 6

The last few years have clarified the tight link between inflammation and coagulation. In addition to the identification of new regulatory mechanisms of the coagulation system and of an explosive number of mediators of inflammation, it is now clear that the existence of a positive feed-back between inflammation and coagulation leads to reciprocal activation of both pathways. Plasma levels of acute phase proteins involved in coagulation and fibrinolysis are elevated during inflammation, while natural anticoagulant mechanisms are depressed. Pro-inflammatory cytokines "activate" cell membranes exposed to flowing blood (endothelium, platelets, monocytes, neutrophils) which from physiologically inert or anticoagulant become procoagulant. Increased tissue factor expression results in increased thrombin formation within the microcirculation. Thrombin is central to fibrin deposition but it also plays a key role in cell-mediated mechanisms involving inflammation, cell proliferation and activation of the natural anticoagulant protein C. Depression of natural anticoagulant mechanisms, occurring in severe sepsis, results in uncontrolled thrombin formation, with pro-inflammatory activity prevailing, and the feed-back loop of inflammation and coagulation ultimately leading to multi-organ failure. However, both in the clinical setting and in animal experiments, heparin or direct anticoagulants have shown no effect on survival even if blocking fibrin deposition. Organ failure is only partially due to the thrombotic occlusion of the microcirculation, while other mechanisms of endothelial damage are probably more relevant in the development of ischemia. The endothelium is central to the maintenance of the natural anticoagulant mechanisms (TFPI, antithrombin, protein C). The protein C system, in addition to dumping thrombin formation, specifically modulates inflammation by cell signaling. This system is markedly depressed in severe sepsis. The infusion of activated protein C, or restoring normal levels of protein C within the circulation - depending on the individual bleeding risk are powerful tools to treat the endothelitis responsible for the clinical sequelae of severe sepsis.
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PMID:[Protein C and coagulation in sepsis]. 1518 14

In normal pregnancy, there is a marked increase in the procoagulant activity in maternal blood characterized by elevation of factors VII, X, VIII, fibrinogen and von Willebrand factor, which is maximal around term. This is associated with an increase in prothrombin fragments (PF1+2) and thrombin-antithrombin complexes. There is a decrease in physiological anticoagulants manifested by a significant reduction in protein S activity and by acquired activated protein C (APC) resistance. The overall fibrinolytic activity is impaired during pregnancy, but returns rapidly to normal following delivery. This is largely due to placental derived plasminogen activator inhibitor type 2 (PAI-2), which is present in substantial quantities during pregnancy. D-dimer, a specific marker of fibrinolysis resulting from breakdown of cross-linked fibrin polymer by plasmin, increases as pregnancy progresses. Overall, there is a 4- to 10-fold increased thrombotic risk throughout gestation and the postpartum period. Local haemostasis at the placental throphoblast level is characterized by increased tissue factor (TF) expression and low expression of the inhibitor TFPI. Microparticles derived from maternal endothelial cells and platelets, and from placental throphoblasts may contribute to the procoagulant effect. Local anticoagulant mechanisms on placental throphoblasts are important for counterbalance of the procoagulant milieu. Disruption of anticoagulant mechanisms, for example, autoantibodies, to annexin V may increase pregnancy complications in patients with antiphospholipid antibodies (APLA).
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PMID:Haemostatic changes in pregnancy. 1550 71

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

A mathematical model of intravascular coagulation is presented; it encompasses the biochemistry of the tissue factor pathway, platelet activation and deposition on the subendothelium, and flow- and diffusion-mediated transport of coagulation proteins and platelets. Simulation experiments carried out with the model indicate the predominant role played by the physical processes of platelet deposition and flow-mediated removal of enzymes in inhibiting coagulation in the vicinity of vascular injury. Sufficiently rapid production of factors IXa and Xa by the TF:VIIa complex can overcome this inhibition and lead to formation of significant amounts of the tenase complex on the surface of activated platelets and, as a consequence, to substantial thrombin production. Chemical inhibitors are seen to play almost no (TFPI) or little (AT-III and APC) role in determining whether substantial thrombin production will occur. The role of APC is limited by the necessity for diffusion of thrombin from the site of injury to nearby endothelial cells to form the thrombomodulin-thrombin complex and for diffusion in the reverse direction of the APC made by this complex. TFPI plays an insignificant part in inhibiting the TF:VIIa complex under the conditions studied whether its action involves sequential binding of TFPI to Xa and then TFPI:Xa to TF:VIIa, or direct binding of TFPI to Xa already bound to the TF:VIIa complex.
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PMID:Coagulation under flow: the influence of flow-mediated transport on the initiation and inhibition of coagulation. 1643 11

Developmental haemostasis is a concept, now universally accepted, introduced by Andrew et al. in the late 1980's. However, coagulation analysers and reagents have changed significantly over the past 15 years. Coagulation testing is known to be sensitive to changes in individual reagents and analysers. We hypothesised that the reference ranges developed by Andrew et al. may not be appropriate for use in a modern coagulation laboratory. Our study was designed to determine whether a current day coagulation testing system (STA Compact analyser and Diagnostica Stago reagent system) was sensitive to age-related changes in coagulation assays. This is the first large scale study since Andrew et al. to determine the age associated numerical changes in coagulation proteins. Our results confirm the concepts of developmental haemostasis elucidated by Andrew et al. However, our results clearly demonstrate that the absolute values of reference ranges for coagulation assays in neonates and children vary with analyser and reagent systems. The results confirm the need for coagulation laboratories to develop age-related reference ranges specific to their own testing systems. Without this, accurate diagnosis and management of neonates and children with suspected bleeding or clotting disorders is not possible. Finally we present age related reference ranges for D-dimers, TFPI, and endogenous thrombin potential, previously not described.
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PMID:Developmental haemostasis. Impact for clinical haemostasis laboratories. 1649

Our research aims to provide quantitatively transparent, biologically realistic descriptions of the processes involved in hemostasis which will permit predictions of the behavior of the coagulation system in normal and pathologic states. We use four models of coagulation: (1) numerical approximations of the tissue factor (Tf) pathway of thrombin generation based upon mechanism and dynamics; (2) Tf activation of the "blood coagulation proteome" from isolated cells and proteins; (3) Tf activated contact pathway inhibited whole blood in vitro; and (4) blood shed from standardized microvascular wounds in vivo. The results from these models are integrated in interactive assessments aimed at achieving convergence of biochemical rigor and biological authenticity. Microvascular injury is the most biologically secure but least accessible to mechanistic study. Numerical models while quantitatively transparent are biologically limited. By the integrated analyses of all four models, we establish observations which require inclusion or discovery of new parameters to achieve mechanistically interpretable biological reality. Discoveries made in this fashion have included thrombin's role in the initiation phase, TFPI/ATIII/APC synergy interactions, rfVIIa in fVII deficiency, the roles of fVIII and fIX in the Tf reaction, and the cleavage of fIX by fXa membrane. Ideally, our results will provide descriptions which predict the behavior of the biological blood coagulation system under normal and pathologic conditions.
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PMID:Models of blood coagulation. 1650 Jan 22

For hemophilia patients with inhibitors against FVIII or FIX, the development of recombinant factor VIIa (rFVIIa) raises the possibility of a therapeutic alternative whose availability and convenience of treatment are comparable to those of FVIII or FIX. In support of this new concept for the treatment of bleeding episodes, pharmacological doses of FVIIa have been shown to induce hemostasis. Pharmacological doses of rFVIIa enhance thrombin generation on thrombin-activated platelets, thereby facilitating the formation of strong, well-structured fibrin plugs resistant to premature proteolysis. Modified rFVIIa molecules with a stronger hemostatic potential have been produced. Inhibition of the FVII-TF-dependent pathway (TFPI and rFVIIai) has been tried in attempts to prevent thrombosis, with promising results in animal models so far not confirmed in clinical trials.
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PMID:Tissue factor and factor VIIa as therapeutic targets in disorders of hemostasis. 1784 36

Berberine (BBR) is a novel natural hypolipidemic agent. This study investigates whether BBR, similar to statins, exerts pleiotropic effects on endothelial tissue factor (TF) expression. BBR enhanced tumor necrosis factor-alpha (TNF-alpha) and thrombin induced TF expression in human endothelial cells by 3.5-fold. These effects were paralleled by an enhanced TF surface activity. In contrast, expression of TF pathway inhibitor was impaired. BBR enhanced TNF-alpha induced TF mRNA expression; however, TF promoter activity was inhibited. Activation of ERK and p38 remained unaffected, while c-Jun terminal NH(2) kinase was inhibited. BBR reduced TF mRNA degradation rates, prolonging its half-life from 1.1 to 4.3 h. The HMG-CoA reductase inhibitor simvastatin impaired thrombin induced TF expression, and BBR blunted this inhibition. Simvastatin did not affect TNF-alpha induced TF expression, and BBR enhanced TF under these conditions. Administration of BBR (100 mg/kg/d) increased TF activity and impaired TFPI expression in carotid artery of ApoE(-/-) mice. BBR enhances TF via mRNA stabilization at clinically relevant concentrations. Clinical application of BBR, either as an alternative to or in combination with statins, should be considered with caution.
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PMID:Berberine, a natural lipid-lowering drug, exerts prothrombotic effects on vascular cells. 1901 47


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