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)

In 17 unaesthetized dogs several side branches of the left descending coronary artery were ligated. The ST-segment elevation in the epicardial ECG ascended to 22 mV after 5 min and to 19 mV after 20 min. Aortic pressure, left ventricular enddiastolic pressure, heart rate and hemostasiological parameters (thrombin-time, thrombin-coagulase-time, reptilase-time, plasma-fibrinogen, staphylococcal clumping test) did not change significantly. 20 min after the beginning of coronary occlusion, the vessels were reopened. When ST-segment elevation had disappeared, a controlled fibrinolytic therapy (Streptokinase 1.5 Mega I.E. in 30 min, later on 0.75 Mega I.E./h) was induced. When an effective fibrinolysis could be demonstrated by the hemostasiological parameters, the same vessels were occluded again. Now the hemodynamic parameters too did not change significantly, but the ST-segment elevation was significantly diminished for more than 50% compared with simple ligation. A control group, which only got the solvent of the streptokinase, showed the same ST-segment elevation. This effect, induced by streptokinase is ascribed to fibrinogen degradation products and a diminution in the amount of fibrinogen which cause an improvement of microcirculation.
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PMID:[Influence of a streptokinase-induced fibrinolysis on the extent of the acute experimental myocardial infarction (author's transl)]. 116 21

Angiography in patients with unstable angina or myocardial infarction with subtotal coronary occlusion often reveals eccentric stenoses with irregular borders, suggesting ruptured atherosclerotic plaques and thrombosis, as documented by angioscopy and at autopsy. We have simulated and studied these processes in an ex vivo perfusion chamber and in an in vivo swine model. Our results suggest that specific local factors at the time of plaque disruption influence the degree of thrombogenicity, the stability of the growing thrombus, and, therefore, possibly also the various clinical syndromes. These factors can be divided into two groups: local vessel wall-related factors and systemic factors with local action at the area of risk. These factors include the following. 1) Exposed substrate-related effects: Plaque rupture produces a rough surface and stimulates the development of occlusive thrombus in proportion to the degree of damage. 2) Fluid dynamics-related factors: The more severe the stenotic lesion after plaque rupture, the higher the local shear rate, resulting in enhanced platelet deposition and thrombus formation. 3) Vasoconstrictive effects: Vasospasm is an important contributor to the pathogenesis of ischemic heart disease. 4) Systemic factors: There is clinical and experimental evidence to suggest that various systemic factors at the time of plaque rupture may enhance thrombogenicity (i.e., levels of epinephrine, levels of serum cholesterol, impaired fibrinolysis). We have investigated the role of residual thrombus on the process of rethrombosis and found that a residual thrombus is a very thrombogenic surface that may significantly contribute to reocclusion even in heparinized blood. Using recombinant hirudin as a pharmacological tool in our flow studies, we observed that rethrombosis is partially caused by thrombin bound to fibrin in the original thrombus, because the effect is abolished by the specific thrombin inhibitor.
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PMID:Thrombus formation on ruptured atherosclerotic plaques and rethrombosis on evolving thrombi. 142 53

Angiography in patients with unstable angina or myocardial infarction with subtotal coronary occlusion often reveals eccentric stenoses with irregular borders, suggesting ruptured atherosclerotic plaques and thrombosis, as documented by angioscopy and at autopsy. We have studied these processes in an ex vivo perfusion chamber, an in vivo swine model, and in human subjects. Our results, and those of other investigators, suggest that specific local risk factors at the time of plaque disruption influence the degree of thrombogenicity and, therefore, the various clinical syndromes. These risk factors can be divided into 2 groups: local vessel wall-related factors, and local (focal action) systemic factors. These risk factors include the following: 1) Rheological factors. It has been demonstrated that the more severe the stenotic lesion after plaque rupture, the higher the local shear rate with enhanced platelet deposition and thrombus formation; platelet deposition and thrombosis are particularly likely if the rupture includes the apex of the stenotic plaque, because of the high shear rate induced. 2) Degree of plaque damage. Plaque rupture produces a rough surface and stimulates an occlusive thrombus, which is enhanced depending on the degree of damage or amount of collagen type I and macrophage-dependent tissue factor exposed. 3) Residual thrombus. After spontaneous or pharmacological reperfusion, the surface of the residual thrombus is very thrombogenic and may contribute to reocclusion; this is partially due to thrombin bound to fibrin in the original thrombus. 4) Systemic factors. There is clinical and experimental evidence to suggest that 3 systemic factors at the time of plaque rupture may enhance thrombogenicity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vessel wall-related risk factors in acute vascular events. 172 11

Platelet thrombus formation occurs at sites of severe arterial narrowing where shear stress is elevated. Shear stress appears to induce platelet aggregation in vitro by means of initiation of von Willebrand factor binding to platelet glycoprotein Ib. Recent in vitro studies have demonstrated that aurintricarboxylic acid can inhibit shear stress-induced platelet aggregation. This effect is mediated by aurintricarboxylic acid binding to von Willebrand factor; this binding results in inhibition of von Willebrand factor interaction with glycoprotein Ib. In this study, we examined the effect of aurintricarboxylic acid on platelet-dependent cyclic flow reductions (CFRs) in a canine coronary stenosis model. In dose-response experiments, six animals received 4 mg/kg aurintricarboxylic acid by bolus infusion, followed by 1 mg/kg every 10 minutes. Total inhibition of CFRs was observed in all animals after 6.7 mg/kg aurintricarboxylic acid; CFRs could not be reinitiated by the thromboxane A2 analogue U46619. Continuous infusion of epinephrine (0.4 micrograms/kg/min) caused CFRs to return; however, 3.7 mg/kg additional aurintricarboxylic acid again induced total inhibition of CFRs. In addition, five animals received a bolus infusion of 10 mg/kg aurintricarboxylic acid, which caused total inhibition of CFRs. The average area of stenosis in the constricted vessels was 83%, and shear stress at the site of constriction averaged 350 dynes/cm2. Aurintricarboxylic acid did not alter hemodynamics, thrombin time, platelet count, or ADP/epinephrine-induced platelet aggregation. These data indicate that platelet glycoprotein Ib-von Willebrand factor interactions are important during coronary occlusion and that aurintricarboxylic acid can inhibit coronary thrombosis associated with coronary constriction.
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PMID:Aurintricarboxylic acid in a canine model of coronary artery thrombosis. 230 18

Lysis of thrombi by intracoronary application of streptokinase has become a new therapeutic approach in patients with acute myocardial infarction. To simulate the clinical situation of myocardial infarction a new experimental model was developed, which was based on a thrombotic coronary occlusion at the site of a high degree stenosis created by a constrictor. In 20 dogs, two ligations 15 mm apart were prepared at the left anterior descending or circumflex coronary artery. After closure of the distal ligation, 2 IU of thrombin was injected through a catheter directly in front of the proximal ligation. The catheter was withdrawn and the proximal ligation was closed. Occlusion time ranged from 1 to 6 hours. At 1, 2, 4 and 6 hours after occlusion, streptokinase was infused for 1 hour (100,000 IU in 200 ml of saline solution) into the left main coronary artery. Hemodynamic variables and coronary blood flow to the ischemic and normal myocardial areas were recorded continuously. Myocardial perfusion was measured six times with tracer microspheres. Reinstatement of blood flow, as well as normalization of myocardial perfusion in the ischemic area, was achieved by streptokinase at 5 minutes after 1 hour of occlusion, 8 minutes after 2 hours, 15 minutes after 4 hours, and 30 minutes after 6 hours; no hyperemic flow occurred. Postmortem staining of infarct size revealed more than 50% of viable myocardium in the perfusion area of the thrombotic vessel even after 6 hours of occlusion. Hemorrhage occurred only after 6 hours of occlusion and was limited to the central area of necrosis in the subendocardial layer. Serious reperfusion arrhythmias occurred only after 1 and 2 hours of occlusion and seemed to be independent of the mode of reperfusion; however, the total number of episodes of ventricular fibrillation after reperfusion was probably decreased compared with that after sudden and hyperemic reflow.
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PMID:Thrombolysis in acute experimental myocardial infarction. 682 54

The principal new clinical approaches to the treatment of acute coronary thrombosis are reviewed. They include fibrinogen platelet receptor antagonists (anti GP IIb-IIIa) and direct thrombin inhibitors. The anti GP IIb-IIIa have been shown to be effective in unstable angina and in the prevention of acute coronary occlusion after transluminal angioplasty. Thrombin inhibitors, the leader being hirudine, also give promising results. The real clinical benefits of these agents and the risk of haemorrhage that they incur in monotherapy or in association, will only become clear when the results of large scale trials which are under way at present, become available. Other antiplatelet agents (clopidogrel, thromboxane inhibitors) are also discussed.
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PMID:[New therapeutic prospects in acute coronary thrombosis]. 764 55

Over the last few years methods have been developed to assess appearance of thrombin during blood clotting in a clinical setting. This can be achieved either by measurement of the specific thrombin markers or by analysis of the thrombin generation kinetics. Thrombin markers rise following coronary occlusion and, surprisingly, their plasma levels become further increased during and after thrombolytic treatment with streptokinase or tissue-plasminogen activator. In myocardial infarction enhanced thrombin generation extends over the weeks, well beyond the acute phase of the disease. It indicates increased risk to a patient and might call for more anticoagulation or angioplasty. The benefit of aspirin as conjunctive treatment for thrombolysis has been clearly demonstrated. The well-founded concept is that aspirin exerts its anti-thrombotic action through inhibition of platelet cyclooxygenase. Recent evidence indicates that antithrombotic effects of aspirin might be explained, partly at least, by its inhibition of thrombin formation. Indeed, in both healthy subjects and survivors of myocardial infarction, aspirin, either at a single dose of 500 mg or at a dose of 300 mg per day administered over two weeks, effectively inhibits thrombinogenesis. Such response to aspirin is blunted in hypercholesterolemia. Subjects with high serum cholesterol levels might profit less than others from the anti-thrombotic action of aspirin.
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PMID:Thrombin generation in myocardial infarction and hypercholesterolemia: effects of aspirin. 857 30

Acute occlusions after percutaneous transluminal coronary intervention occur in about 5% of cases. The incidence of these serious adverse events may be reduced by the identification of risk factors, appropriate indication for the intervention, and by medical therapy with antiplatelets and antithrombins. The medical management of complications during percutaneous transluminal interventions also may include thrombolytics. Aspirin has been shown to significantly reduce the incidence of procedure-related coronary occlusion and ischaemic events. Available data suggest pre-treatment with 250-500 mg followed by 100-300 mg aspirin after the intervention. Ticlopidine seems to be equally effective; however, because of its side effects it should be used only in cases of a contra-indication to aspirin. The second indispensable therapeutic concept in the prevention of acute thrombotic events during PTCA is thrombin inhibition. The level of anticoagulation achieved by heparin seems to be critically important. Therefore the recommendation for heparin dosing is a bolus of 10,000 U followed by an intravenous infusion over 24 h of either 1000 U.h-1 or an infusion adjusted to keep the aPTT above 3 times control, but lower doses of shorter duration may be equally effective in uncomplicated cases. Prolonged pre-treatment with heparin may be useful if the pre-intervention angiogram is suggestive of intracoronary thrombus. Thrombolysis as an adjunct to PTCA did not reduce the rate of periprocedural coronary occlusions, but pre-treatment with thrombolysis may be useful in patients with recanalization of occluded vein grafts or in patients with large amounts of thrombotic material. In acute coronary occlusion, thrombolysis has rarely been used as a sole rescue therapy and results have not been encouraging, although a thrombotic process often is involved. Thrombolysis as an adjunct to rescue angioplasty showed no better clinical outcome than prolonged balloon inflation or stenting. Because of serious bleeding complications, thrombolysis should only be considered as a treatment option if thrombosis is unequivocally the major cause of the acute occlusion.
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PMID:Prevention and management of thrombotic complications during coronary interventions. Combination therapy with antithrombins, antiplatelets, and/or thrombolytics: risks and benefits. 886 21

The risk of acute coronary occlusion following percutaneous transluminal coronary angioplasty (PTCA) has remained high despite the traditional use of heparin and aspirin. Interest has focused on newer strategies for preventing intracoronary thrombus formation, which is an important mechanism of abrupt vessel closure. Pretreatment with thrombolytic agents has failed vigorous testing in double-blind trials. Retrospective and observational studies have indicated that pretreatment with intravenous heparin is of benefit in patients with unstable symptoms, but prolonged infusion after angioplasty increases bleeding complications without improving outcomes. Subcutaneous heparin may be safer, but has not proved more effective. Oral dipyridamole has shown no advantage over aspirin, although there is evidence to suggest a benefit when given intravenously. Direct thrombin inhibitors (such as hirudin and hirulog) are associated with fewer early complications compared with heparin, but have yielded no apparent long-term benefit. The use of the antiplatelet drug ticlopidine is increasing, although long-term data are lacking. A great deal of recent interest has focused on newer antiplatelet agents, particularly the glycoprotein IIB/IIIa receptor inhibitor c7E3 Fab. In a large-scale trial, c7E3 significantly reduced the 30-day rate of mortality and cardiac events, and these benefits were maintained at 6 mo. This drug, unlike other antiplatelet agents, inhibits the final common pathway of platelet aggregation, which influences not only acute closure but has lasting effects for at least 6 mo. This may reflect a reduction in restenosis, although this remains to be proven. This article gives a brief overview of the pharmacologic agents available for the prophylaxis and treatment of acute ischemic complications of PTCA.
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PMID:Pharmacologic prevention of acute ischemic complications of coronary angioplasty. 936 95

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


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