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:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The management of unstable angina/non ST elevation myocardial infarction (UA/NSTEMI) has evolved substantially in recent years. Multiple new antithrombotic options are available; in addition, the use of interventional strategies in patients with UA/NSTEMI has become the dominant strategy, particularly in tertiary centers. On the one hand, we are doing more percutaneous interventions more rapidly in ACS patients. On the other hand, we have an ever-expanding therapeutic armamentarium to apply in these complex clinical circumstances. Much of the controversy surrounding modern-day management is not so much about the specific the choice of agent or strategy, but rather how to use these agents most effectively in a clinical environment where patients may come forward to the catheterization laboratory, sometimes rapidly, and may require percutaneous or surgical revascularization. All available antithrombotic agents act on one (or more) of the four steps of coagulation: platelet activation, platelet aggregation, thrombin generation, and thrombin activity. The antiplatelet agents, aspirin, thieno-pyridines, and glycoprotein (GP) IIb/IIIa antagonists, target the early steps of platelet activation and aggregation. The antithrombin agents, unfractionated heparin, low molecular weight (LMW) heparin, Xa inhibitors, and direct thrombin antagonists, act specifically to target thrombin generation, thrombin activity, or both. We will review the major recent trials that comprise the current state of knowledge regarding these new antithrombotic agents in ACS, and discuss some of the near-future additions to our armamentarium, including prasugrel, Cangrelor, and AZD6140. The most recent ACC/AHA and ESC unstable angina guidelines have emphasized that multiple options are available, and no one agent can be recommended over the others in all cases. There is NOT one perfect antithrombotic regimen for all patients. Antithrombotic therapy needs to be individualized, and that so-called ''standard'' therapy may need to be supplemented (or even replaced) in specific circumstances. Ultimately, determining optimal therapy means understanding the physiology, understanding the therapeutic options - not just how they work, but how they may work together, and being able to interpret a never-ending supply of new clinical trial data that have to be applied in the ''real world''.
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PMID:Antithrombotic therapy and the transition to the catheterization laboratory in UA/NSTEMI. 1791 62

Thromboelastography (TEG) assesses the global pattern of blood coagulation in the whole blood. Present day management of haemophilia is based on replacement therapy with lost factor by parenteral administration of factor concentrates. It is very well known that interaction of cellular components in the blood also affect the thrombin generation which in turn might produce varied TEG patterns that might reflect the clinical severity in haemophilia patients. We evaluated 66 severe haemophilia A and B patients (as assessed by one-stage assay) by TEG and correlated the varied TEG patterns with the clinical severity in the patients. Four distinct TEG patterns were observed; Group A consisted of eight patients with hypercoagulable patterns while group B consisted of two patients showing hyperfibrinolytic patterns. Group C comprised of 17 patients whose TEG tracings did not show the initiation of clot formation at all while group D comprising of 39 patients showed varied clot initiation times ranging from almost normal pattern to a highly prolonged split times. Groups A and D patients were relatively milder clinically while groups B and C were clinically severe as assessed by the number of bleeding episodes, the frequency of transfusion and joint deformity. Subsequently we also evaluated the in vitro efficacy of the antifibrinolytic drug, EACA in normalizing the TEG patterns in 12 patients (group C) who did not show the initiation of clot formation in the TEG tracings to see the contribution of fibrinolysis in producing such patterns. The use of EACA in vitro in this group improved the TEG profile of these patients. In conclusion, the classification of severe haemophilia patients based on TEG patterns correlated well with the clinical severity and the ex vivo use of antifibrinolytics like EACA are effective in improving the TEG profile of all patients who had an abnormal TEG pattern without any clot initiation.
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PMID:Correlation of thromboelastographic patterns with clinical presentation and rationale for use of antifibrinolytics in severe haemophilia patients. 1797 50

Management of venous thromboembolism disease could be improved by new drugs with lower risk of bleeding and without the need of regular monitoring of anticoagulant effect. In this way, idraparinux, anti-Xa inhibitor, has been compared to conventional therapy (coumarins) for the treatment of deep vein thrombosis and pulmonary embolism. Is it worth to treat patients more than six months? This has been evaluated in an interesting study. Prophylaxis after hip replacement surgery is indicated to reduce the risk of venous thromboembolism, new drugs are under investigation. Dabigatran etexilate, a direct thrombin inhibitor, has been shown as effective as enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery. In 2007, new european guidelines for non-STsegment elevation acute coronary syndromes have been published. Two new antithrombotic drugs, bivalirudin and fondaparinux, are now part of the different possible choices according to specific considerations. New factor Xa and factor IIa inhibitors are under investigation and are compared to heparin in PCI for NSTE-ACS. Fondaparinux and more recently otamixaban have given interesting results. These new recommendations have not yet taken into account new data published in 2007. What will be the positioning of prasugrel, a new thienopyridine, after the results of theTRITON trial? In patients with SCA treated by PCI, prasugrel reduced the ischemic events, while increasing major bleedings. In 2007, numerous publications and meta-analyses on drug-eluting stents (DES) have been published and tempered the fear about a possible increase in mortality with the use of DES.
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PMID:[What's new on antithrombotics?]. 1895 Jul 43

A series of logic gates, "AND", "OR", and "XOR", are designed using a DNA scaffold that includes four "footholds" on which the logic operations are activated. Two of the footholds represent input-recognition strands, and these are blocked by complementary nucleic acids, whereas the other two footholds are blocked by nucleic acids that include the horseradish peroxidase (HRP)-mimicking DNAzyme sequence. The logic gates are activated by either nucleic acid inputs that hybridize to the respective "footholds", or by low-molecular-weight inputs (adenosine monophosphate or cocaine) that yield the respective aptamer-substrate complexes. This results in the respective translocation of the blocking nucleic acids to the footholds carrying the HRP-mimicking DNAzyme sequence, and the concomitant release of the respective DNAzyme. The released product-strands then self-assemble into the hemin/G-quadruplex-HRP-mimicking DNAzyme that biocatalyzes the formation of a colored product and provides an output signal for the different logic gates. The principle of the logic operation is, then, implemented as a possible paradigm for future nanomedicine. The nucleic acid inputs that bind to the blocked footholds result in the translocation of the blocking nucleic acids to the respective footholds carrying the antithrombin aptamer. The released aptamer inhibits, then, the hydrolytic activity of thrombin. The system demonstrates the regulation of a biocatalytic reaction by a translator system activated on a DNA scaffold.
ACS Nano 2009 Jul 28
PMID:Logic gates and antisense DNA devices operating on a translator nucleic Acid scaffold. 1950 21

Owing to its beneficial pharmacological profile, the low-molecular-weight heparin (LMWH) enoxaparin is increasingly being taken as an alternative to UFH in the treatment of ACS with an early invasive strategy and in elective percutaneous coronary interventions (PCI). Insufficient anticoagulation increases the risk of catheter thrombus formation during PCI. The aim of the present study was to test in vitro the hypotheses that (i) inhibiting thrombin or thrombin generation by administering LMWH is a critical intervention in preventing catheter thrombus formation and (ii) other LMWH such as certoparin or dalteparin are as effective as enoxaparin. Blood pre-treated with the anticoagulants of interest was continuously circulated through a guiding catheter by using a roller pump for a maximum experimental period of 60 min or until the catheter became occluded. Overall thrombus weight, anti-Xa activity and electron microscopic features such as deposits of platelets, erythrocytes and fibrin on the catheter surface were quantified as endpoints. All LMWH tested significantly reduced catheter thrombus generation comparable to UFH treatment whereas there was no difference between the specific LMWH with respect to catheter thrombus formation or deposition of platelets, erythrocytes and fibrin. Thrombus generation was found to negatively correlate with anti-Xa activity. The additional use of eptifibatide did not affect thrombus formation. These data suggest that modulating plasmatic coagulation by employing LMWH is critical for preventing catheter thrombus formation and at the same time offer a potential for administering LMWH other than enoxaparin, such as certoparin or dalteparin, in the setting of PCI.
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PMID:Efficacy of enoxaparin, certoparin and dalteparin in preventing cardiac catheter thrombosis: an in vitro approach. 1951 16

Morbidity and mortality in patients with atherothrombotic disease remain high despite the use of antiplatelet therapy with aspirin and an ADP receptor antagonist. Selective inhibition of the principal protease-activated receptor (PAR)-1 for thrombin, the most potent agonist for platelet activation, represents a promising novel strategy to reduce thrombosis and ischaemic events. SCH 530348, a potent thrombin receptor antagonist (TRA) selective for PAR-1, has been evaluated in preclinical studies, demonstrating complete and sustained inhibition of thrombin/TRAP-induced platelet aggregation without a concomitant increase in the risk of bleeding. Phase 2 studies in patients undergoing non-urgent or urgent PCI showed that treatment with SCH 530348 in addition to the standard of care (aspirin plus an ADP receptor antagonist) is not associated with an increased risk of TIMI bleeding and is well tolerated, with a rate of adverse events comparable to standard therapy alone. These studies also demonstrated that the use of SCH 530348 in combination with aspirin and an ADP receptor antagonist may reduce the incidence of major adverse cardiac events, specifically periprocedural myocardial infarction, vs aspirin plus an ADP receptor antagonist alone. On the basis of these encouraging results, 2 ongoing large phase 3 randomized trials are evaluating the efficacy and safety of SCH 530348 in combination with the standard-of-care therapy in approximately 35,000 patients with NSTE ACS or established atherosclerosis.
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PMID:Improving antiplatelet therapy for atherothrombotic disease: preclinical results with SCH 530348, the first oral thrombin receptor antagonist selective for PAR-1. 1988 73

Eight short peptides containing L-lysine and epsilon-aminocaproic acid were obtained and their effect on the amidolytic activities of plasmin, thrombin and trypsin was examined. Tripeptide amide Boc-EACA-L-Lys-EACA-NH2 was the most effective and specific plasmin inhibitor.
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PMID:Short peptides containing L-lysine and epsilon-aminocaproic acid as potential plasmin inhibitors. 2009 24

The biocompatibility of iron-polysaccharide complexes has been well-documented. Herein, a stable thrombo-resistant coating was fabricated by consecutive adsorption of Fe (III) and polysaccharides including heparin (Hep) and dextran sulfate (DS) onto various surface by layer-by-layer self-assembly technique via both electrostatic interaction and chemical complexation process. The absorbance at 350 nm increased linearly with the number of Fe3+/Hep multilayer, indicating the formation of multilayer structure and the uniform coating. Compared with (Fe3+/Hep)10, the (Fe3+/DS/Fe3+/Hep)5 coating was more hydrophilic and stable due to the incorporation of DS. The activated partial thromboplastin time (APTT) and platelet adhesion assays showed that both (Fe3+/Hep)10 and (Fe3+/DS/Fe3+/Hep)5 coated surfaces were anticoagulant. The complexing with ferric ions did not compromise the catalytic capacity of heparin to promote antithrombin(III)-mediated thrombin inactivation. Chromogenic assays for heparin activity proved definitively that the inhibition of locally produced thrombin was contributed to the thromboresistance of the surface-bound heparin. The surface with Hep or DS as the outmost layer showed stronger anticoagulant activity than Fe3+, indicating that the outermost layer of the coating played a key role in anticoagulant activity. The utilization of dextran sulfate/heparin surfaces was more advantageous than merely the heparin surface for improving blood-contacting medical devices for long-term usage.
ACS Appl Mater Interfaces 2009 Jan
PMID:Novel thrombo-resistant coating based on iron-polysaccharide complex multilayers. 2035 62

Composite materials made up from a pyridinium polymer matrix and silver bromide nanoparticles embedded therein feature excellent antimicrobial properties. Most probably, the antimicrobial activity is related to the membrane-disrupting effect of both the polymer matrix and Ag(+) ions; both may work synergistically. One of the most important applications of antimicrobial materials would be their use as surface coatings for percutaneous (skin-penetrating) catheters, such as central venous catheters (CVCs). These are commonly used in critical care, and serious complications due to bacterial infection occur frequently. This study aimed at examining the possible effects of a highly antimicrobial pyridinium polymer/AgBr composite on the blood coagulation system, i.e., (i) on the coagulation cascade, leading to the formation of thrombin and a fibrin cross-linked network, and (ii) on blood platelets. Evidently, pyridinium/AgBr composites could not qualify as coatings for CVCs if they trigger blood coagulation. Using a highly antimicrobial composite of poly(4-vinylpyridine)-co-poly(4-vinyl-N-hexylpyridinium bromide) (NPVP) and AgBr nanoparticles as a thin adherent surface coating on Tygon elastomer tubes, it was found that contacting blood platelets rapidly acquire a highly activated state, after which they become substantially disrupted. This implies that NPVP/AgBr is by no means blood-compatible. This disqualifies the material for use as a CVC coating. This information, combined with earlier findings on the hemolytic effects (i.e., disruption of contacting red blood cells) of similar materials, implies that this class of antimicrobial materials affects not only bacteria but also mammalian cells. This would render them more useful outside the biomedical field.
ACS Appl Mater Interfaces 2009 Sep
PMID:Disruption and activation of blood platelets in contact with an antimicrobial composite coating consisting of a pyridinium polymer and AgBr nanoparticles. 2035 31

Noble metals are interesting biomaterials for a number of reasons, e.g., their chemical inertness and relative mechanical softness, silver's long known antimicrobial properties, and the low allergenic response shown by gold. Although important for the final outcome of biomaterials, little is reported about early events between pure noble metals and blood. In this article, we used whole blood in the "slide chamber model" to study the activation of the immune complement activation, generation of thrombin/antithrombin (TAT) complexes, and platelet depletion from blood upon contact with silver (Ag), palladium (Pd), gold (Au), titanium (Ti), and Bactiguard, a commercial nanostructured biomaterial coating comprised of Ag, Pd, and Au. The results show the highest TAT generation and platelet depletion on Ti and Au and lower on Pd, Ag, and the Bactiguard coating. The immune complement factor 3 fragment (C3a) was generated by the surfaces in the following order: Ag > Au > Pd > Bactiguard > Ti. Quartz crystal microbalance adsorption studies with human fibrinogen displayed the highest deposition to Ag and the lowest onto the Bactiguard coating. The adsorbed amounts of fibrinogen did not correlate with thrombogenicity in terms of TAT formation and platelet surface accumulation in blood. The combined results suggest, hence, that noble metal chemistry has a different impact on the protein adsorption properties and general blood compatibility. The low thrombogenic response by the Bactiguard coating cannot be explained by any of the single noble metal properties but is likely a successful combination of the nanostructure, nanogalvanic effects, or combinatory chemical and physical materials properties.
ACS Appl Mater Interfaces 2009 May
PMID:Blood interactions with noble metals: coagulation and immune complement activation. 2035 91


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