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)

In the current study, we investigated molecular markers of coagulation activity, ie, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin (TAT) complex, soluble fibrin (SF), and D-dimer, and their relation to death, myocardial infarction, and refractory angina during and after anticoagulant treatment in unstable coronary artery disease. Patients with unstable coronary artery disease (N=320) were randomized to a 72-hour infusion with either inogatran, a low-molecular-mass direct thrombin inhibitor, or unfractionated heparin. During the 30-day follow-up, a 40% lower event rate was seen in patients with high compared with low baseline levels of TAT or SF. High baseline levels of coagulation activity were correlated with a larger decrease during treatment. Patients with decreased compared with raised F1+2 or TAT levels after 6 hours of treatment had a 50% lower event rate at 30 days (F1+2, P=0.04; TAT, P=0.02). At the cessation of antithrombin treatment, there was a clustering of cardiac events that tended to be related to a rise in the levels of TAT and the other markers. During long-term follow-up (median, 29 months), there was a relation between higher baseline levels of D-dimer (P=0.003) and increased mortality. High baseline levels of molecular markers of coagulation activity might identify patients with a thrombotic condition (as the major cause of instability) who are good responders to anticoagulant therapy, with a larger decrease in coagulation activity during treatment and a decreased risk of ischemic events. However, this early benefit is lost during long-term follow-up when high baseline levels of coagulation activity are associated with a raised risk of early reactivation and increased mortality.
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PMID:Coagulation activity and clinical outcome in unstable coronary artery disease. 1139 20

Risk stratification of patients with acute coronary syndromes (ACS) is pivotal for correct allocation of health resources and for maximizing the benefit of available treatment modalities. However, clinical and electrocardiographic indicators of high risk lack sufficient sensitivity for the detection of major cardiac events. The complementary information provided by the measurement of different biomarkers is believed to be very useful. Specifically, elevations of cardiac troponin I (cTnI) and T (cTnT) are strongly associated with a high-risk profile both at short- and long-term. This has been definitely demonstrated in many studies as well as in cumulative meta-analysis. The role of different biomarkers, such as those reflecting activation of hemostasis and the presence of inflammation, is however less defined. At the moment, no study has prospectively evaluated these biomarkers in the whole spectrum of unselected patients with ACS. It is also unclear whether these biomarkers add independent prognostic value to the clinical and electrocardiographic indicators of adverse outcome and whether they offer additional information when compared to each other. The Early Prognostic Value of Biochemical Markers of Myocardial Damage, Activation of Hemostatic Mechanism and Inflammation in Acute Ischemic Syndromes (EMAI) study has been prospectively designed to solve these issues. In this study, we have evaluated the prognostic value of cTnI and cTnT, D-dimer, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT) and C-reactive protein (CRP) in patients with ACS at the time of admission. We have enrolled in 31 Italian Coronary Care Units 1971 patients with rest anginal pain within 12 h from admission and electrocardiographic evidence of myocardial ischemia. Of these, 730 patients resulted to have ST-segment elevation myocardial infarction eligible for a reperfusion strategy and 1241, an acute coronary syndrome without persisting ST-segment elevation. Primary outcome measure of the study is the composite of death and non-fatal MI within 30 days from admission, which has occurred in 8.9% of the study population.
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PMID:Cardiac markers and risk stratification: an integrated approach. 1155 47

The treatment of angina is changing, with many new agents being added to those existing agents that have been used for many years. New data regarding the use of glycoprotein IIb/IIIa inhibitors now exist and low molecular weight heparins are used more frequently with greater efficacy than unfractionated heparin. New thrombin inhibitors are also receiving a fresh look. An expert panel has recently published guidelines for the treatment of unstable angina.
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PMID:New approaches to the pharmacological treatment of angina. 1171 89

We measured fibrin monomer (FM), soluble fibrin, as a marker of thrombin activity in plasma samples obtained in parallel with the first two routine samples for cardiac markers in 165 patients with acute chest pain admitted consecutively to our hospital. A reference limit of FM in a healthy population was set at 3.0 mg/l. Elevated plasma FM was observed in 48.8% of patients with acute coronary syndromes, in 42.3% of patients with specific non-coronary disease, in 31.5% of those with stable angina pectoris and in 18.2% of patients with non-specific chest pain. No significant difference was observed between sample 1 and sample 2 in patients not receiving thrombolytic treatment during the sampling period (P = 0.46). In patients with coronary artery disease, FM was significantly related to the level of cardiac troponin T (P = 0.001), but no correlation was observed between the individual plasma FM and cardiac troponin T values. Outcome analysis during the following 30 months after the index event in patients with acute coronary syndromes revealed higher FM levels in those with coronary re-events or death than in patients without new events (P = 0.001). This observation indicates a prognostic potential of FM in risk evaluation of patients with coronary artery disease.
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PMID:Characteristics and prognostic impact of plasma fibrin monomer (soluble fibrin) in patients with coronary artery disease. 1203 95

Membrane-dependent coagulation processes play a key role in acute coronary syndromes (ACS), where the generation of thrombin depends on the complex of activated factors X and V (prothrombinase complex) assembled on activated platelets. The aim of the present study was to evaluate prothrombinase activity in patients with ACS and to examine the effect of treatment with 80 mg/day atorvastatin on prothrombinase activity. Blood samples were obtained at admission from 22 patients with ACS, and then again at 2 weeks and at 16 weeks after double-blind randomization to either placebo or atorvastatin. Prothrombinase activity was evaluated by measuring the generation of thrombin by in vitro reconstructed thrombi, and also by measuring plasma levels of prothrombin fragment F1 + 2. Twenty age-matched subjects with stable angina and 11 without coronary disease were used as controls. At admission, prothrombinase activity and F1 + 2 were significantly higher in ACS patients than in controls. Prothrombinase activity was still high at 2 weeks while it returned to normal levels at 16 weeks. F1 + 2 remained high both at 2 and at 16 weeks. Our data indicate that prothrombinase activity is high in patients with ACS, and that it is not affected by high-dose atorvastatin.
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PMID:High doses of atorvastatin do not affect activity of prothrombinase in patients with acute coronary syndromes. 1203 97

In a large phase III study of patients with unstable angina treated with percutaneous transluminal coronary angioplasty (PTCA), the thrombin-specific anticoagulant bivalirudin produced relative risk reductions of 22% (p = 0.039) for ischemic complications and 62% (p < 0.001) for bleeding complications compared with heparin. Subsequent reports have shown that between-treatment differences favoring fewer complications with bivalirudin also extend to high-risk patients. Early heparinization promotes heparin resistance and decreases activated clotting time achieved during PTCA. These effects are relevant to patients with postinfarction angina, which is associated with a greater likelihood of early vessel closure and procedural failure. In 1006 patients with one or both of these risk factors, bivalirudin significantly reduced combined ischemic and bleeding complications compared with heparin (8.6% vs 18%, p < 0.001). Treatment separations favoring bivalirudin increased with risk, suggesting decreased heparin effectiveness in patients at heightened risk. Findings in three additional risk groups-women, the elderly, and patients not receiving glycoprotein IIb/IIIa inhibitors-also showed fewer complications with bivalirudin therapy. Preliminary data suggest that bivalirudin can be combined safely with glycoprotein IIb/Illa antagonists in percutaneous coronary intervention (PCI), including PTCA. An ongoing trial is aimed at determining the efficacy and safety of heparin with planned glycoprotein IIb/IIIa therapy versus bivalirudin with provisional glycoprotein IIb/IIIa therapy. The use of bivalirudin in patients with heparin-induced thrombocytopenia also is being evaluated after favorable findings in early compassionate-use studies. The fact that between-treatment differences favoring bivalirudin were especially outstanding among the high-risk patients considered in this review reinforces the impression that bivalirudin is a promising and unprecedented alternative to heparin in PCI.
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PMID:Bivalirudin administration during percutaneous coronary intervention: emphasis on high-risk patients. 1206 68

Plasma levels of haemostasis factors (HFs) such as fibrinogen, tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and D-dimer may be markers of arteriosclerosis for the following reasons: There seems to be no difference in levels of HFs between patients with longstanding stable angina and those with an isolated myocardial infarction. HF levels are generally positively associated with subclinical arteriosclerosis as determined by ankle-arm index and carotid ultrasonography in asymptomatic individuals. Levels of most HFs are positively associated with inflammation, which is an essential part of the initiation and progression of the disease. A rough classification is assigned to the associations found in under (2) and (3). Fibrinogen is strongly associated with subclinical arteriosclerosis and with inflammation; Factor VII is not, while an intermediate group is formed by, for instance, von Willebrand Factor (vWF), Factor VIII (F VIII), t-PA, PAI-1, and D-dimer. Also, the associations of HFs with cardiovascular events follow a similar pattern. Fibrinogen is a strong and consistent risk factor in several studies, Factor VII is not, and a similar intermediate group as mentioned under (2) and (3) exists. It suggests that the risk of cardiovascular events in relation to HF levels is explained by their identity as markers of arteriosclerosis. A causal association between HF levels and the disease is not proven. Out of the HF, the markers of coagulation such as thrombin-antithrombin complex and of fibrinolysis such as D-dimer are more likely to act causally. Increased levels indicate that they are markers of arteriosclerosis, but in addition, they may reflect a low-grade, continuous formation and subsequent lysis of fibrin in the disease. As the latter reflects an increased tendency to thrombosis, a causal association of levels of markers of coagulation and fibrinolysis with arteriosclerosis, although not yet proven, seems likely.
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PMID:Levels of haemostatic factors, arteriosclerosis and cardiovascular disease. 1261 75

Direct thrombin inhibitors in cardiovascular patients are discussed. Patients presenting with acute coronary syndromes (ACS) of ST- and non-ST-segment elevation myocardial infarction (STEMI and NSTEMI, respectively) or unstable angina develop mural thrombi within minutes of plaque disruption or erosion. Initial acute therapy includes heparin and aspirin. Up to 60% of patients have coronary revascularization to reduce the high risk of death, new myocardial infarction (MI), or recurrent angina. In addition, heparin may initiate a serious allergic, prothrombotic drug reaction, heparin-induced thrombocytopenia (HIT), in 1-5% of patients. Acute cessation of heparin and initiation of direct thrombin inhibitor (DTI) therapy for suspected HIT are vital and well established. Several clinical trials comparing DTIs with heparin have been done in ACS and percutaneous coronary intervention (PCI), and have shown excellent potency in inhibiting thrombus formation and reducing coronary events. An overview of results from published studies evaluating the use of bivalent and univalent DTIs in the cardiovascular patient is presented. Four DTIs are discussed: two r-hirudins (lepirudin and desirudin), both bivalent with stable chain and renal excretion; bivalirudin, bivalent with rapid-chain metabolism; and argatroban, univalent with hepatic metabolism. The extensive clinical experience with r-hirudin in cardiovascular patients suggests that it is an excellent choice for managing patients with HIT and is easy to use in converting to warfarin, since it does not significantly change the prothrombin time.
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PMID:Direct thrombin inhibitor therapy in the cardiovascular patient. 1459 79

Unstable coronary artery disease is in most cases associated with plaque rupture, activation of the coagulation system and subsequent intracoronary thrombus formation which may cause myocardial cell damage. The aim of the present analysis was to assess the relation between troponin T, markers of coagulation activity, i.e. prothrombin fragment 1+2, thrombin-antithrombin complex, soluble fibrin and D-dimer, and ischemic events, i.e. death, myocardial (re-)infarction or refractory angina. 320 patients with unstable coronary artery disease were randomized to 72 hours infusion with inogatran, a low molecular weight direct thrombin inhibitor, or unfractionated heparin. Patients with elevated troponin levels had higher levels of prothrombin fragment 1+2, soluble fibrin and D-dimer before, during, and at 24 hours after cessation of anticoagulant treatment. These troponin-positive patients tended to have worse short-term clinical outcome, without relation to markers of coagulation activity. Troponin-negative patients with unchanged or early increased thrombin generation during treatment had a cluster of ischemic events within 24 hours after cessation of the study drug. The 30-day ischemic event rate was 19 % in troponin-negative patients with unchanged or early increased prothrombin fragment 1+2, and 5.7 % in patients with decreased prothrombin fragment 1+2, p=0.006, and similarly 15 % in troponin-negative patients with unchanged or early increased thrombin-antithrombin complex and 4.5 % in patients with decreased thrombin-antithrombin complex, p=0.02. In conclusion, in unstable coronary artery disease a troponin elevation indicates higher risk and higher coagulation activity. However, among the troponin negative patients, with a lower risk and lower coagulation activity, a part of the patients seem to be non-responders to treatment with a thrombin inhibitor expressed as unchanged or raised coagulation activity and a raised risk of ischemic events early after cessation of treatment.
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PMID:Myocardial damage, coagulation activity and the response to thrombin inhibition in unstable coronary artery disease. 1496 Nov 68

The conversion from stable to unstable angina and the further progression to myocardial infarction are usually associated with atherosclerotic plaque fissuring or ulceration at sites of coronary artery stenosis and subsequent development of a thrombus. This thrombus formation is initiated by platelet adhesion and aggregation; these, in turn, are promoted by the local release and accumulation of thromboxane A(2) and serotonin. This accumulation and the resulting platelet aggregation at sites of endothelial injury cause dynamic vasoconstriction. With time, the platelet-initiated thrombus expands to include white and red blood cells in a fibrin mesh. Thus, a fully occlusive coronary thrombus may develop and cause the progression from unstable angina to acute myocardial infarction, often Q-wave myocardial infarction. We believe that the connection between unstable angina and acute myocardial infarction is a continuum relative to the processes of coronary artery thrombosis and vasoconstriction. When the period of platelet aggregation or dynamic vasoconstriction at sites of endothelial injury and coronary stenosis lasts only a few minutes and is repetitive, unstable angina or non-Q wave myocardial infarction occurs. However, when complete coronary artery occlusion lasts for longer than 4 hours, a transmural or Q-wave myocardial infarction results. Recently, in experimental animal models with mechanically induced coronary artery stenoses and endothelial injury, we have found that other mediators, including adenosine diphosphate and thrombin, also contribute to coronary artery thrombosis. Moreover, in humans with limiting angina, we have identified spontaneous coronary blood flow variations in a pattern similar to the variations caused by alternating platelet attachment and dislodgement in experimental canine modes. In this review, we add information to our previous observations in order to present the possible mechanisms of conversion from chronic to acute coronary heart disease syndromes.
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PMID:Unstable angina pectoris and the progression to acute myocardial infarction. Role of platelets and platelet-derived mediators. 1522 6


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