Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the most fascinating findings concerning our knowledge on the physiology of the cardiovascular system, especially the coronary circulation, concerns the modulating capacity of the endothelial cells on the tone of smooth muscle cells. This phenomenon was described for the first time in the aorta of a rabbit in 1980 by Furchgott and Zawadzki using acetylcholine as stimulator. Later, however, it became clear that other substances that are likewise of interest in the context of coronary heart disease, like thrombin, serotonin and histamine, have the same effect on endothelial cells. These effects can also be demonstrated in the human coronary circulation during cardiac catheterization. While normal coronary segments show a vasodilatation (corresponding to the endothelial relaxation in vitro) in arteriosclerotic coronary segments, vasoconstriction is induced by acetylcholine and serotonin. A disturbance of this vasomotor process mediated by endothelial vasomotor processes may be of particular importance in instable angina pectoris and for the development of myocardial infarction.
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PMID:[Clinical significance of endothelial dysfunction: studies of human coronary circulation in vivo]. 824 90

Carvedilol is a cardiovascular drug currently used for the treatment of hypertension. Clinical studies have recently demonstrated efficacy in angina and congestive heart failure. Recently, carvedilol has been shown to attenuate oxygen free radical-initiated lipid peroxidation and to inhibit vascular smooth muscle mitogenesis induced by a wide variety of growth factors. These findings are of interest since smooth muscle proliferation and abnormal lipid metabolism are proposed to play an important role in the pathogenesis of atherosclerotic plaque formation and in development of stenotic lesions following vascular injury by balloon angioplasty and coronary artery bypass grafting. On the basis of these observations, the antiproliferative actions of carvedilol have been explored in detail. In human cultured pulmonary artery vascular smooth muscle cells, carvedilol (0.1-10 microM) produced a concentration-dependent inhibition of the mitogenesis stimulated by platelet-derived growth factor, epidermal growth factor, thrombin, and serum, with IC50 values ranging from 0.3 to 2.0 microM. Carvedilol also produced a concentration-dependent inhibition of vascular smooth muscle cell migration induced by platelet-derived growth factor, with an IC50 value of 3 microM. The extensive neointimal formation that occurs following balloon angioplasty of rat carotid arteries was markedly attenuated by carvedilol (1 mg/kg, i.p.; twice daily starting 3 days before angioplasty and continuing until 14 days after angioplasty). Quantitative image analysis demonstrated that carvedilol reduced the neointimal growth following angioplasty by 84% without altering either medial or adventitial cross-sectional areas. These observations indicate that carvedilol may also be effective in the treatment of pathological disorders principally associated with abnormal vascular smooth muscle growth, such as atherosclerosis and acute vascular wall injury induced by angioplasty or coronary artery bypass grafting.
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PMID:Carvedilol, a cardiovascular drug, prevents vascular smooth muscle cell proliferation, migration, and neointimal formation following vascular injury. 832 99

To evaluate the effects of aspirin on thrombin generation in patients with unstable angina, plasma levels of thrombin-antithrombin III complex (TAT) as a new marker of thrombin generation and of 11-dehydro-thromboxane B2 (11-dehydro-TXB2) as an indicator of platelet activation were measured in 18 patients with unstable angina, including 8 patients with prolonged rest angina (> 15 minutes). Aspirin DL-lysine (900 mg) was administered intravenously to 9 of the 18 patients (aspirin group); the other 9 were not given aspirin during the first 24 hours of hospitalization (non-aspirin group). Clinical characteristics, angiographic features and medications other than aspirin were similar between the 2 groups. Levels of plasma TAT and 11-dehydro-TXB2 were significantly higher (p < 0.05) in patients with prolonged rest angina than in those without the condition (n = 10). In 5 patients with prolonged rest angina who received aspirin, plasma TAT levels (ng/ml) were significantly decreased (4.52 +/- 1.18 at baseline, 2.50 +/- 0.65 at 1 hour and 2.16 +/- 0.42 at 24 hours after aspirin administration, p < 0.01) with a significant decrease in plasma 11-dehydro-TXB2 levels. However, the reduction in TAT after aspirin administration was slight in patients without prolonged rest angina (n = 4). In contrast, levels of plasma TAT and 11-dehydro-TXB2 in the non-aspirin group remained unchanged during the study period. These results suggest that aspirin rapidly reduces thrombin generation through inhibition of platelet activity in patients with unstable angina with prolonged rest angina.
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PMID:Effects of aspirin DL-lysine on thrombin generation in unstable angina pectoris. 848 Jun 41

Heparin cofactor II (HCII) is a serine proteinase inhibitor in human plasma that rapidly inhibits thrombin in the presence of dermatan sulfate or heparin. To understand the molecular mechanism for HCII deficiency in a patient with reduced circulating HCII antigen, we studied a Japanese patient with type I HCII deficiency who suffered from angina pectoris and coronary artery disease. Polymerase chain reaction (PCR)-based sequence analysis showed that the propositus' gene for HCII (HCII Awaji gene) had a thymine insertion after codon (GAT) for Asp88 in exon II, resulting in a frameshift mutation. Consequently, the abnormal HCII Awaji protein was suggested to have an altered amino acid sequence from position 89 and terminate at 107, thus being composed of the NH2-terminal one fifth of normal HCII and dysfunctional for thrombin inhibition. The molecular weight and pI value of HCII Awaji were calculated to be 12,040 and 3.6, respectively, without posttranslational modification. Mutagenic PCR followed by the Tsp509I digestion showed that a half of the PCR products derived from the propositus and his sister was cleaved, suggesting that his sister also has the same mutant allele. Crossed-immunoelectrophoresis and Western blot analyses of plasma and urine from the the propositus and of plasma from his sister did not provide evidence for the existence of the abnormal HCII, suggesting that little truncated HCII was circulating in the patient's blood. However, stable expression assay using human kidney 293 cells transfected with the expression vector containing cDNA encoding wild-type or Awaji-type HCII showed that mutant as well as wild-type HCII was secreted into culture medium normally. These results suggest that the abnormal HCII Awaji protein is secreted normally, but rapidly degraded in the circulating blood.
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PMID:Molecular and cellular basis for type I heparin cofactor II deficiency (heparin cofactor II Awaji). 856 24

The various applications of anticoagulation in cardiology concern primary prevention, treatment of angina and infarction, revascularization either by angioplasty or by bypass grafts, treatment after artificial valve replacement, treatment of atrial fibrillation and, finally, as a precaution in the case of impaired ventricular function. Several methods of anticoagulation can be used in each of these indications: thrombin antagonists, vitamin K antagonists, antiaggregants and thrombolytics, although this last group is not discussed in this article.
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PMID:[Anticoagulation in cardiology]. 878 33

Fibrin generation and lysis were studied in 28 patients with angina pectoris (14 with active disease and 14 with inactive disease) and in 14 normal controls. The fibrinolytic response was evaluated by comparing the ratio between the plasma levels of fibrinopeptide A and fibrin degradation products. Levels of both were higher in patients than in controls (P < 0.001), with higher levels in active than in inactive disease (P < 0.001). The fibrinopeptide A/fibrin degradation products ratio was much higher (P < 0.001) in the active group than in other groups. Thus, in patients with angina pectoris, especially in the active state, the increased thrombin generation is not paralleled by an equivalent increase in fibrinolytic activity.
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PMID:Fibrin generation and digestion in patients with angina pectoris. 878 52

The in vitro effect of acetylsalicylic acid (ASA) on fibrin gel lysis by exogenous t-PA was studied in 13 patients with angina pectoris. Six patients received 75 mg, and seven patients 160 mg of ASA. Plasma clots were formed and lysed in microtiter plate wells and turbidity monitored spectrophotometrically. Mean lysis times in the 75 mg group were 8.7, 11.4 and 11.2 min during ASA treatment, and after 1 and 2 weeks ASA withdrawal respectively. Reduced changes were observed in the 160 mg group. Additionally, a relationship was found between the fibrin fiber mass/length ratio, i.e. fiber thickness in mature clots and lysis times after ASA administration (P = 0.0015). Importantly, fibers are thicker during treatment with ASA. It was subsequently demonstrated that the potential to produce thicker fibers by varying the thrombin concentration has a noticeable effect on turbidimetric profiles in the presence of exogenous t-PA. This effect was similar to the changes observed during and after ASA treatment. Thus, these results suggest that the enhancement of fibrin gel lysis during ASA treatment may be due to alterations in gel structure. In addition, a reduction in the fibrin mass in lower turbidity clots, suggests an added mechanism by which ASA may enhance lysis.
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PMID:The effect of acetylsalicylic acid on fibrin gel lysis by tissue plasminogen activator. 882 21

One of the main areas of interest in interventional cardiology is the understanding, and ultimate prevention of restenosis after an initially successful percutaneous transluminal coronary angioplasty. Restenosis is the recurrence of luminal narrowing following angioplasty, and still frustrates the late results in the treatment of angina pectoris. Experimental, pathological and clinical studies suggest that restenosis may occur via activation of the coagulation cascade, platelet activation and thrombus formation. Thrombin itself is identified as the most potent platelet activator, and has a pivotal role in the coagulation system. Furthermore, thrombin directly mediates smooth muscle cell proliferation by stimulating thrombin receptors at the smooth muscle cell surface. Thrombus indirectly induces excessive intimal smooth muscle cell proliferation by means of released mitogens (growth factors), which may contribute to late restenosis. Therefore direct and irreversible thrombin blockade by hirudin is deemed to be effective in the prevention of restenosis following angioplasty. The HELVETICA trial is a multicentre, randomized, double-blind heparin-controlled study, designed to compare the effects of two dose regimens of recombinant-hirudin (CGP 39,393/TMRevasc) with those of heparin on event-free survival, safety, tolerability and luminal renarrowing using quantitative coronary angiography no later than 26 weeks after the coronary angioplasty procedure.
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PMID:Evaluation of recombinant hirudin (CGP 39,393/TMREVASC) in the prevention of restenosis after percutaneous transluminal coronary angioplasty. Rationale and design of the HELVETICA trial, a multicentre randomized double blind heparin controlled study. 886 20

Myocardial revascularisation is now an integral part of the treatment of unstable angina. Trials comparing the efficacy of coronary surgery and medical therapy date back to the end of the 1970s. They showed a clear benefit of revascularisation on functional status but a less pronounced effect on survival. Thus, at 10 years, half of the patients in the Veterans Administration series initially treated medically, underwent surgery; however the initial therapeutic choice was not a significant prognostic factor except in patients with triple vessel disease and those with left ventricular dysfunction whose survival was better when treated surgically. In the last 10 years, coronary angioplasty has become increasingly important in the treatment of unstable angina. The short-term results are very encouraging although complications are more common during the phase of clinical instability than when symptoms have been managed. The addition of thrombolytics to the conventional heparin and aspirin treatment during angioplasty seems to be potentially harmful rather than beneficial. However, new antithrombotic agents (platelets antiaggregants such as antiglycoprotein IIB-IIIA antibodies or direct inhibitors of thrombin such as hirudin or hirulog) seem to decrease the risks of this procedure. At term, the results obtained after angioplasty for unstable angina are similar to those observed in stable angina: the risk of restenosis seems to be about the same and the prognosis depends mainly on left ventricular function. In practice, the choice of therapeutic strategy in unstable angina remains open: the TIMI IIIB trial reported similar results at 6 months whether patients were treated by immediate coronary angiography or whether a more conservative strategy was adopted; the duration of the initial hospital stay was however shorter and the need for rehospitalisation was less frequent in those undergoing immediate coronary angiography.
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PMID:[Current indications of myocardial revascularization in unstable angina]. 895 17

Patients undergoing angioplasty (PTCA) for unstable angina, postinfarction angina, or complex coronary lesions represent a high risk group for ischemic complications. High dose heparin and aspirin are used routinely to prevent thrombotic complications. However, new approaches designed to avoid platelet aggregation, including development of specific platelet GP IIb/IIIa receptor antagonists and specific thrombin inhibitors, demonstrate a significant reduction of thrombotic events following coronary interventions compared to heparin alone. Bleeding complications are not increased if conjunctive heparin administration is weight-adjusted. Pathophysiology of acute coronary closure, mechanisms of action of the new anti-thrombotic drugs, and current and future clinical applications are discussed.
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PMID:[Current approach in antithrombotic treatment during coronary interventions: specific thrombocyte aggregation inhibitors and direct thrombin antagonists in high-risk patients]. 898 4


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