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)

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

Plaque rupture of the thinned, weak fibrous cap infiltrated by macrophages and overlying a pool of lipid in the arterial wall initiates the acute thrombotic event of unstable angina. Thrombosis may be advanced within minutes. Most lesions that precede plaque rupture are minor (less than 50% stenosis); thus, thrombus greatly contributes to sudden flow limitation and onset of symptoms. If thrombosis can be totally blocked (not possible with current antithrombotic agents), clinical events should be preventable, and endogenous thrombolysis may be possible within days. Local and systemic factors contribute to arterial thrombosis. With type III injury (fissure into plaque or media) platelet-rich thrombus anchors in the fissure, tracks along the site of deep injury, extends into the lumen, and requires the highest blood level of specific thrombin inhibition (a molar concentration that inhibits the total concentration of prothrombin in circulating blood). Thus, the thrombin content requiring inhibition in type III injury is highest. Local factors for thrombosis associated with type III injury include the rheology of blood flow (increased shear rate forces platelets to the periphery) and substrates in the arterial wall. Plaque substrates include the more thrombogenic collagens (types I and III and diabetic or glycosylated collagen), tissue thromboplastin, lipid gruel, thrombin bound to arterial wall matrix, and decreased prostacyclin. There is a direct relation between platelet deposition (thrombus) and local vasoconstriction, which may perpetuate each other. Thrombus as a substrate is more thrombogenic than type III arterial injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pathogenesis of thrombosis in unstable angina. 189 63

Fibrinogen may play an active role in the development and progression of atherosclerotic plaques. We assessed the association between fibrinogen levels and atherosclerotic plaques over three different arterial sites in an asymptomatic never-treated male population with increased cardiovascular risk. We included 652 men aged 40 to 60 years old with at least one of the following cardiovascular risk factors: cholesterol > 6.2 mmol/L and/or systolic blood pressure > or = 160 mm Hg and/or diastolic blood pressure > or = 95 mm Hg, and/or because they smoked. Carotid and femoral arteries and the abdominal aorta were assessed by using ultrasonographic methods for the presence of plaque, and subjects were categorized according to the presence (or absence) and extent (one versus two or three sites) of plaque. Plasma fibrinogen was measured according to the thrombin-time method of Clauss. While the presence of atherosclerosis was significantly related to age, current smoking, systolic pressure, LDL cholesterol, and fibrinogen levels, the extent of atherosclerosis was related to age and triglyceride and fibrinogen levels. Multiple regression analysis indicated independent associations between fibrinogen and the presence and extent of atherosclerosis. Plaque prevalence was significantly more pronounced with increasing tertile of fibrinogen levels. The odds ratio of the upper to lower fibrinogen tertiles for the presence of plaque was 1.6 (95% confidence interval, 1.4 to 1.8) and 1.4 (95% confidence interval, 1.2 to 1.7) for its extent. Adjustment for other risk factors slightly reduced the association between fibrinogen and atherosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fibrinogen and silent atherosclerosis in subjects with cardiovascular risk factors. 767 Sep 37

Acute coronary syndromes are responsible for more than half a million hospital admissions each year in the United States alone. Plaque rupture is the precipitating pathophysiologic event. The degree of narrowing of plaques that rupture is not necessarily severe, in the range of 30% to 70% diameter stenosis. Plaques containing large lipid pools with only thin fibrous caps are most at risk. The site of rupture is most often at the shoulder of the plaque, where stress is highest. Clusters of macrophages are often seen at these points. Most plaque ruptures heal without causing symptoms, perhaps leaving a narrowing somewhat more severe than before. Plaque ruptures that expose larger areas of thrombogenic intramural debris to flowing blood in areas of high turbulence are most likely to provoke more extensive thrombosis. Risk factors, particularly smoking and hypercholesterolemia, cause increased thrombin deposition at the site of deep arterial injury. Thrombin deposition causes local coronary vasoconstriction that may contribute to the development of ischemia. Whether plaque rupture with thrombosis causes infarction, unstable angina, or no symptoms at all depends on the site of the lesion, its severity, and whether the jeopardized myocardium is served by collaterals. Aspirin, heparin, and, potentially, the newer agents provide benefit in each of the acute coronary syndromes.
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PMID:Pathophysiology and initial management of the acute coronary syndromes. 887 45

The dynamics of coronary thrombosis and reocclusion may seem straightforward, but in actuality they are complex and incompletely understood. The pathobiology of coronary thrombosis begins with the development of the atherosclerotic plaque. The initial step in the process, endothelial cell dysfunction, alters vascular thromboresistance. Plaque erosion or overt disruption is followed by platelet adherence, aggregation, and thrombin generation that stimulates the conversion of soluble fibrinogen to fibrin. Thrombolytic therapy, although able to dissolve a high proportion of occlusive thrombi, creates a procoagulant environment by generating plasmin which, in turn, activates platelets and generates thrombin, increasing the likelihood of vessel reocclusion. Thrombin is therefore considered an important target for research, and several thrombin inhibitors have been developed. Antiplatelet agents such as aspirin are currently employed to prevent reocclusion following thrombolytic therapy; however, several new and more potent platelet antagonists are being investigated with considerable enthusiasm.
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PMID:Dynamics of coronary thrombolysis and reocclusion. 942 55

Plaque rupture, platelet aggregation and thrombosis have central roles in the pathogenesis of acute coronary syndromes. Despite several trials showing the benefit of aspirin and heparin in patients presenting with unstable angina and acute myocardial infarction, these patients are still at risk. This has prompted the development and evaluation of several new therapeutic agents including low molecular weight heparin, new antiplatelet drugs (e.g. ticlopidine and clopidogrel), direct thrombin inhibitors, and intravenous and oral glycoprotein IIb/IIIa antagonists. The IIb/IIIa receptor is the final common pathway involved in platelet aggregation. Thus, whatever the stimulus for platelet activation, subsequent aggregation is mediated by the IIb/IIIa receptor binding fibrinogen. A variety of antibody, peptide and non-peptide compounds that block the IIb/IIIa receptor have been developed, and several studies have investigated the role of these agents in patients with acute coronary syndromes both within and outside the setting of percutaneous intervention. This article summarises the studies to date using IIb/IIIa antagonists, and discusses their role in patients with non-ST segment elevation acute coronary syndromes.
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PMID:Glycoprotein IIb/IIIa antagonists: do they have a role in the management of unstable angina? 1069 57

Overexpression and exposition of tissue factor (TF) in atherosclerotic plaques and/or arterial thrombi are critical events in atherothrombosis. TF, the receptor for factor VII (FVII) and activated factor VII (FVIIa), is the principal initiator of blood coagulation and induces thrombin generation leading to fibrin formation and platelet activation. TF also plays a major role in cell migration and angiogenesis. TF activity is downregulated by Tissue Factor Pathway Inhibitor (TFPI), a Kunitz-type inhibitor, which forms a neutralizing complex with TF, FVIIa and activated factor X. In physiological conditions, TF is absent from vascular cells which come into contact with flowing blood and is present as an inactive pool in fibroblasts and smooth muscle cells (SMC). In contrast, TF is widely expressed in atherosclerotic plaques and is found in macrophages, SMCs, and foam-cells and also in extracellular matrix and acellular lipid-rich core. TF expression is up-regulated by inflammatory cytokines and oxidized lipids. Plaque thrombogenicity is directly correlated to their TF content. After fibrous cap disruption, TF is exposed on plaque surface and triggers thrombus formation leading to arterial lumen occlusion and/or downstream embolization. In coronary and carotid plaques, TF content was found to be higher in plaques from symptomatic than asymptomatic patients. Soluble forms of TF and microparticles of monocyte and platelet origin, and bearing TF, constitute "blood-born TF". The contribution of this TF pool to arterial thrombosis is still under discussion. TF pathway is a target for new therapeutic agents that can decrease TF activity, such as active site-inactivated factor VIIa, recombinant TFPI and antibodies against TF or peptides interfering with TF-FVIIa complex activity.
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PMID:Relevance of tissue factor in cardiovascular disease. 1600 22

Plaque disruption and subsequent thrombus formation play a critical role in the clinical manifestations of atherothrombosis. Vulnerable lesions are characterized by the existence of core rich in lipid, macrophages and tissue factor (TF). Plaque disruption facilitates the interaction between flowing blood with the inner components (TF) of disrupted atherosclerotic lesions triggering the coagulation cascade. TF, thrombin, platelets, fibrin and inflammatory cells are involved in this process of acute thrombus formation. This pathologic process is significantly accelerated by several "cardiovascular risk factors" such as diabetes, smoking, dyslipemia, etc. We will review on the role of TF, plaque cell apoptosis and blood thrombogenicity acting as a thread of inflammatory and prothrombotic mediators. We will also review the role of activated platelets as source for pro-inflammatory cytokines and enunciation of thrombotic process. Overall, we will try to emphasize the most recent understanding of the concepts involved in the interaction between inflammation and coagulation within the setting of atherothrombotic disease.
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PMID:Links between inflammation and thrombogenicity in atherosclerosis. 1691 70

The formation of an intravascular thrombus underlies the clinical symptoms associated with acute coronary syndromes (ACS). Plaque rupture signals the recruitment and activation of platelets, initiation of the coagulation cascade, and generation of thrombin, resulting in the formation of a platelet-rich thrombus. Use of antithrombotic therapy, including antiplatelet and anticoagulant agents, is a crucial element in reducing the overall morbidity and mortality in patients with ACS. Current antiplatelet and anticoagulant therapies act on distinct sites in platelet activation pathways and the coagulation cascade, but because these agents target pathways necessary for protective hemostasis, their use increases the risk for bleeding complications. Previously, bleeding was considered an unavoidable side effect of ACS management with few clinical implications; however, bleeding has since been shown to be an independent predictor of short- and long-term mortality in patients with ACS. Therefore, the prevention of bleeding has become equally as important as the prevention of further ischemic events. Strategies to limit bleeding include bleeding risk stratification, appropriate dosing of antithrombotic drugs, use of the lowest dose of aspirin with proven efficacy, avoidance of combinations of antithrombotic agents unless for a proven indication, use of drugs proven to reduce the risk of bleeding, and choice of radial access over femoral access in case of invasive strategy. In this context, several novel therapeutic approaches are currently under clinical evaluation, including new antiplatelet agents, such as protease-activated receptor 1 antagonists, and new anticoagulants, such as direct-acting antagonists of factor Xa and factor IIa (thrombin). This review discusses antiplatelet and anticoagulant treatment strategies for the management of ACS, with a particular focus on their associated bleeding risks.
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PMID:Current antithrombotic agents for acute coronary syndromes: focus on bleeding risk. 2210 Jan 80


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