Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P13726 (thromboplastin)
 8,888 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The administration of gram-negative bacterial lipopolysaccharide (LPS) to rats results in hepatic parenchymal cell injury within 6 hr. The coagulation system is critical to the pathogenesis, but previously reported results suggested that its critical role is independent of insoluble clot formation and that thrombin may be a key mediator of liver injury. To test the hypothesis that thrombin is involved in LPS-induced liver injury, animals were treated with the selective thrombin inhibitor, hirudin. The hirudin treatment regimen effectively inhibited thrombin, as evidenced by prolonged activated partial thromboplastin time and by maintenance of plasma fibrinogen concentrations in LPS-treated rats. Treatment with hirudin prevented LPS-induced liver injury, assessed by plasma alanine aminotransferase activity and histological evidence of hepatocellular necrosis. Previous studies have shown that LPS exposure results in the accumulation of neutrophils and platelets within the liver and that both of these cell types are critical for the development of LPS-induced liver injury. Hirudin attenuated in part the decrease in blood platelet concentration that accompanied LPS administration, but did not alter hepatic platelet or neutrophil accumulation. These results support the hypothesis that thrombin is required for hepatic injury from LPS exposure, but that it does not act by promoting the accumulation of platelets or neutrophils within the liver.
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PMID:The thrombin inhibitor, hirudin, attenuates lipopolysaccharide-induced liver injury in the rat. 876 73

We compared the antithrombotic effects of the thrombin inhibitor, D-methyl-phenylalanyl-prolyl-arginal (GYKI-14766) with those of heparin in a canine model of arterial and venous rethrombosis. Thrombogenesis was induced by electrolytic injury to the endothelial surface of the carotid artery and jugular vein. Either heparin (300 U/kg, n = 7), GYKI-14766 (0.5 mg/kg/h, n = 7), or saline (n = 10) was administered intravenously (i.v.) immediately after the local administration of anisoylated plasminogen streptokinase activator complex (APSAC 0.1 U/kg). Supplemental doses of heparin (100 U/kg) were administered at 1-h intervals. Infusion of GYKI-14766 was maintained for 5 h throughout the experiment. Ex vivo platelet aggregation in response to ADP or arachidonic acid (AA) was not changed in any of the experimental groups. Both GYKI-14766 and heparin increased the activated partial thromboplastin time (aPTT) over their respective baseline values. Heparin, but not GYKI-14766, increased the bleeding time. After successful thrombolysis, arterial and venous rethrombosis occurred in all saline-treated dogs. GYKI-14766 prevented cyclic flow variations and reocclusion in the artery and the vein (p < 0.01). Heparin had only minimal effects on the artery and no effect on the vein. Arterial thrombus weights were reduced by GYKI-14766 [saline control = 24 +/- 4 mg, GYKI-14766 = 9 +/- 3 mg, (p < 0.05); heparin = 14 +/- 2 mg, p = NS]. The venous thrombus weights were reduced slightly by GYKI-14766 and were unchanged by heparin (saline = 25 +/- 5 mg, GYKI-14766 = 13 +/- 4 mg, heparin = 26 +/- 3 mg). The data suggest that GYKI-14766 is effective in preventing occlusive rethrombosis in both the arterial and venous circulation after thrombolysis without augmenting bleeding time. GYKI-14766 may represent an alternative to heparin as an adjunctive agent during thrombolytic therapy.
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PMID:Antithrombotic effect of GYKI-14766 in a canine model of arterial and venous rethrombosis: a comparison with heparin. 884 72

Thrombin has been implicated as a contributing factor to restenosis after vessel reopening procedures. We compared the ability of the direct thrombin inhibitor recombinant (r-) hirudin to reduce neointimal growth in different animal models of arterial injury. Carotid arteries of rats, rabbits, and hypercholesterolemic minipigs were injured by withdrawal of an inflated balloon catheter. In addition, we used a double-lesion model in rabbits, which involved balloon angioplasty of a preexisting lesion induced by carotid denudation 4 weeks earlier. r-Hirudin was given in all four animal models as a short-term application (bolus of 1 mg/kg i.v. immediately before injury, followed by infusion of 1 mg.kg-1.h-1 for 2 hours, and an injection of 6 mg/kg SC). Additionally, we investigated the effects of prolonged treatment (intravenous infusion for 3 and 14 days) in rats. Inhibition of thrombin was monitored by determination of activated partial thromboplastin time, and histomorphometric analysis of the arteries was performed after 2 (rats) or 4 (rabbits and minipigs) weeks. In rabbits, short-term r-hirudin treatment reduced neointimal area by 59% (single-injury model, P = .05) and 44% (double-injury model, P = .02). In rats and minipigs no inhibition of neointimal growth was observed after short-term r-hirudin application. A 3- or 14-day infusion of r-hirudin in rats, however, resulted in 25% (P = .007) and 27% (P = .003) reductions in neointimal area, respectively. In conclusion, there is considerable interspecies variation in the time frame of susceptibility for reduction of neointimal growth by inhibition of thrombin after arterial injury. These results demonstrate the importance of testing potential antirestenotic treatments in an array of different animal models.
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PMID:Comparison of the effects of the thrombin inhibitor r-hirudin in four animal models of neointima formation after arterial injury. 885 29

The aim of the present work was to study how human umbilical vein smooth muscle cells (HUVSMC) can initiate the coagulation process and to investigate the responses of these cells to thrombin. Exposure of HUVSMC to recalcified human plasma led to a time-dependent production of thrombin, measured both as amidolytic activity and as release of fibrinopeptide A. Thrombin activity was dose-dependently reduced by an anti-human tissue factor antibody (76 +/- 3% at 10 micrograms/ml) and by inhibitors like heparin, rec-hirudin, hirulog 1, Napap and hirunorm, a novel hirudin-like thrombin inhibitor (IC50 = 2 +/- 0.4, 8 +/- 1, 130 +/- 22, 199 +/- 29 and 68 +/- 8 nM, respectively). The release of fibrinopeptide A was similarly prevented (IC50 = 14 +/- 1, 132 +/- 25 and 50 +/- 8 nM for rec-hirudin, Napap and hirunorm, respectively). Exogenously added thrombin increased thymidine incorporation into HUVSMC to 240 +/- 30% of basal (EC50 = 0.49 +/- 0.09 nM) and thrombin inhibitors blocked this effect (IC50 = 10 +/- 3, 37 +/- 17, 343 +/- 165 and 1402 +/- 758 nM for rec-hirudin, hirunorm, Napap and hirulog-1, respectively). Also recalcified human plasma was mitogenic for HUVSMC and its effect was mainly due to endogenously generated thrombin, as shown by the use of thrombin inhibitors. In conclusion, HUVSMC are capable of initiating the extrinsic coagulation cascade, leading to the formation of thrombin which promotes clotting and stimulates DNA synthesis. Thrombin inhibitors prevent both coagulative and cellular effects of thrombin.
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PMID:Human umbilical vein smooth muscle cells as a model to study thrombin generation and function: effect of thrombin inhibitors. 890 3

After a standardized trauma to carotid arteries or femoral veins of hamsters, the antithrombotic effects of two antiplatelet agents (aspirin and the glycoprotein IIb/IIIa antagonist G4120) and two anticoagulants (heparin and the direct thrombin inhibitor r-hirudin) were studied in vivo. The thrombus area volume was assessed by image analysis of the transilluminated experimental vessels. Heparin, r-hirudin, and G-4120 demonstrated a dose-dependent complete inhibition of arterial and venous thrombosis. In contrast, the antithrombotic effect of aspirin was only partial in both vessel types. A significant correlation between activated partial thromboplastin time (aPTT) at the end of the experiments and the antithrombotic effect was observed with the anticoagulant agents. However, only r-hirudin inhibited thrombus formation at a therapeutical prolongation of aPTT, while heparin required supratherapeutical amounts to achieve the same inhibition. The data confirm that the inhibition of aspirin, heparin, r-hirudin, and G-4120 on the formation of platelet-rich thrombi is independent of the blood flow rate.
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PMID:A technique to investigate microvascular mural thrombus formation in arteries and veins: II. Effects of aspirin, heparin, r-hirudin, and G-4120. 901 42

CVS-1123, low-molecular-weight, direct thrombin inhibitor was studied in an anesthetized canine model of arterial and venous thrombosis to determine whether thrombin inhibition could reduce the incidence of occlusive thrombosis in response to vessel-wall injury. The left carotid artery (LCA) and right jugular vein (RJV) were instrumented with a flow probe, intraluminal electrode, and critical stenosis. Either saline (n = 9), or CVS-1123 (n = 12) was administered in a loading dose of 2 mg/kg i.v., followed by an infusion (2.46 mg/kg/h for 180 min). Vessel-wall injury was initiated by applying a 300-microA anodal current to the intimal surface of the LCA and RJV. Platelet aggregation in response to gamma-thrombin remained inhibited by CVS-1123 for 8 h. The activated partial thromboplastin time (aPTT) was increased and remained elevated for the duration of the protocol. The prothrombin time (PT) showed an initial increase and then a rapid decrease after the infusion was discontinued. There was a twofold increase in the bleeding time (BT) at 2 h. The time to occlusion of the LCA was prolonged (380 +/- 22 min in the CVS-1123 group vs. 152 +/- 18 min in the saline group) with seven of 12 patent arteries at 8 h. Similarly, the time to occlusion for RJV was prolonged (415 +/- 16 min in the CVS-1123 group vs. 99 +/- 8 min in the saline group) with eight of 12 veins remaining patent at 8 h. CVS-1123 administration was associated with a decrease in the thrombus weights in both the LCA and RJV as compared with the saline-treated animals. In summary, CVS-1123 modifies the thrombogenic response to deep vessel-wall injury in both the arterial and venous circulations. The results suggest that CVS-1123 is an effective antithrombin and may offer a therapeutic alternative to current antithrombins in the management of arterial and venous thrombosis.
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PMID:CVS-1123, a direct thrombin inhibitor, prevents occlusive arterial and venous thrombosis in a canine model of vascular injury. 905 74

We examined the effect of a specific thrombin inhibitor, Ro 46-6240, alone and combined with an antagonist of the platelet GP IIb/IIIa, Ro44-9883, on the response to tissue-type plasminogen activator in a canine model of thrombolysis. Platelet activity was determined by measuring the excretion of 2,3-dinorthromboxane (TX)B2, an enzymatic metabolite of TXA2. Ro 46-6240 administered before tissue-type plasminogen activator induced a dose-dependent prolongation of the activated partial thromboplastin time and prothrombin time. The time to reperfusion decreased dose-dependently (P < .01) to 10 +/- 6 min vs. 52 +/- 5 min in controls. Ro 46-6240 also prevented reocclusion, which occurred in every case in control experiments. Urinary excretion of 2,3-dinor-TXB2 increased from 3 +/- 1 to 37 +/- 9 ng/mg creatinine in controls after reperfusion. This increase was reduced in a dose-dependent fashion by Ro 46-6240, such that at the highest dose, urinary 2,3-dinor-TXB2 after reperfusion was 5.6 +/- 1 ng/mg creatinine. Similar functional and biochemical effects were seen when a subthreshold dose of Ro 46-6240 was combined with Ro 44-9883. At the dose used, Ro 44-9883 alone abolished platelet aggregation ex vivo but failed to modify the response to tissue-type plasminogen activator or the excretion of 2,3-dinor-TXB2 after reperfusion (51 +/- 6 ng/mg creatinine, n = 3). However, the combination of Ro 44-9883 and Ro 46-6240 reduced the time to reperfusion (40 +/- 8 vs. 68 +/- 15 min; n = 7, P < .05), prevented reocclusion and abolished the rise in urinary 2,3-dinor-TXB2 (5 +/- 1 ng/mg creatinine, n = 4). These findings suggest that thrombin mediates platelet activation during coronary thrombolysis. The increased platelet activity results in platelet aggregation and a subsequent increase in TXA2 formation.
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PMID:Interaction of a thrombin inhibitor and a platelet GP IIb/IIIa antagonist in vivo: evidence that thrombin mediates platelet aggregation and subsequent thromboxane A2 formation during coronary thrombolysis. 919 Aug 51

This study describes the present knowledge regarding the clinical application of argatroban, a direct competitive thrombin inhibitor for heparin-intolerant patients, including those with congenital and acquired antithrombin III deficiencies, those with heparin-induced thrombocytopenia, and those with high levels of polymorphonuclear granulocyte elastase. These patients are often associated with intracircuit clot formation with heparin anticoagulation during extracorporeal circulation. Therefore, argatroban may be chosen as one of the alternate anticoagulants. Because the anticoagulant effect of argatroban is reflected in the prolongation of activated thromboplastin time, monitoring is easy, similar to that for heparin. Because argatroban has a fast acting anticoagulant effect without any cofactors such as antithrombin III, this drug is a favorable anticoagulant for heparin-intolerant patients with antithrombin III deficiencies requiring extracorporeal circulation. In adverse reactions to heparin, heparin acts as an antigen after complexing with platelet factor 4, which leads to life-threatening heparin-induced thrombocytopenia. As argatroban prevents heparin-induced platelet aggregation, it is effective for use as a therapeutic anticoagulant. In other clinical applications, heparin decreases antithrombin activity and causes intracircuit clot formation during extracorporeal circulation when the polymorphonuclear granulocyte elastase level is very high. The antithrombin activity shows less decrease when argatroban is substituted for heparin. These findings indicate that argatroban is a useful alternative anticoagulant in these heparin-intolerant patients.
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PMID:Application of argatroban, direct thrombin inhibitor, in heparin-intolerant patients requiring extracorporeal circulation. 928 75

Argatroban, a direct thrombin inhibitor, is used clinically because of its safe and effective antithrombotic action. This drug of low molecular weight shows reversible inhibition of thrombin irrespective of whether thrombin is fibrin-bound or soluble. Optimal anticoagulant effects can easily be attained by monitoring with the activated partial thromboplastin time or whole-blood activated clotting time when a therapeutic range of argatroban equivalent to that of heparin is used. The antithrombotic action is simply detected with a chromogenic substrate assay. The clinical use of the drug in Japan was approved for the treatment of chronic peripheral arterial obstructive disease and acute ischemic stroke. For coronary artery disease in patients with deficiency of antithrombin activities attributable to either antithrombin III or heparin cofactor II deficiency, argatroban is effective as an anticoagulant. Acute coronary occlusion during and after percutaneous transluminal coronary angioplasty can be treated by argatroban as an alternative to heparin. The presence of platelets activated by a trace amount of thrombin is evidenced by modified methods of platelet aggregometry in acute ischemic stroke. Therefore, argatroban can render the platelets insensitive against the platelet hyperaggregation enhanced by thrombin.
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PMID:Development of argatroban, a direct thrombin inhibitor, and its clinical application. 946 23

Intravenous administration of thrombin inhibitors, such as hirudin, has been shown to decrease the frequency of coronary artery reocclusion after thrombolysis. However, recent findings in large clinical trials in patients with unstable angina and myocardial infarction have failed to demonstrate a sustained antithrombotic effect after cessation of drug treatment. These findings indicate a need for a prolonged antithrombotic regimen, preferably an orally active thrombin inhibitor. To test the hypothesis that a regimen consisting of oral thrombin inhibitor will delay or prevent the formation of occlusive clot, anesthetized dogs were given saline (n = 9) or a single dose of a novel active site low-molecular-weight thrombin inhibitor melagatran by nasogastric tube (1.5 mg/kg, n = 6; 2.5 mg/kg, n = 6), and 15 min later, a potent thrombogenic stimulus in the form of anodal current (100 microA) was applied to the intimal surface of the narrowed left anterior descending coronary artery (LAD). All saline-treated dogs developed stable thrombus, indicated by zero flow at 34 +/- 7 min after initiation of direct current. On the other hand, one of the six dogs given high-dose melagatran did not develop thrombotic occlusion of the LAD during the entire 4 h of observation. Mean time to occlusive thrombus formation in 11 other dogs was prolonged 4-5 times as compared with that in the saline-treated dogs (p < 0.001). Spontaneous thrombolysis was observed in three of 11 dogs after initial clot formation. Overall, the coronary artery was patent for 68% (low dose) and 75% (high dose) of the observation period in melagatran-treated dogs (vs. 14% of observation period in saline-treated dogs). Peak plasma concentration was 0.87 +/- 0.22 microM in dogs given low-dose and 1.38 +/- 0.30 microM in dogs given high-dose melagatran. The activated partial thromboplastin time (aPTT) increased 1.5-fold at peak plasma concentration of melagatran. These observations imply (a) thrombin generation plays a critical role in thrombus formation in narrowed coronary arteries, (b) oral melagatran prevents or delays thrombus formation, whereas the aPTT is only modestly prolonged, and (c) the thrombus formed in the presence of melagatran is prone to spontaneous lysis in this canine model of coronary thrombosis.
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PMID:Melagatran, an oral active-site inhibitor of thrombin, prevents or delays formation of electrically induced occlusive thrombus in the canine coronary artery. 951 77


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