Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fish oils rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been demonstrated to alter coagulation and fibrinolysis variables. This study compared the effects of a traditional cholesterol-lowering diet and a similar diet, which had 50% of the linoleic acid (LA) replaced with the 18 carbon n-3 fatty acid, alpha-linolenic acid (ALA), on selected hemostatic variables. After a 2-week run-in diet with 39.5% total energy (en) from fat, 29 healthy male subjects consumed a 31.5% en fat diet with approximately 7% en from polyunsaturated fat and an ALA:LA ratio of either 1:1.2 (ALA-rich, n=15) or 1:21 (LA-rich, n=14) for 6 weeks. Blood was collected at the beginning, middle and end of test diets for analysis of Factor VIIc and VIIIc, fibrinogen, von Willebrand factor, activated protein C resistance (APC resistance), tissue plasminogen activator and plasminogen activator inhibitor type-1 activities and/or protein concentrations and platelet fatty acids. The ALA-rich diet tripled the percentage of platelet EPA, (P < 0.0005) but had little effect on coagulation and fibrinolysis. The APC ratio demonstrated increased anticoagulant activity on the ALA-rich diet (P < 0.001) only. Studies in patients with vascular pathologies are indicated to corroborate the current findings. Greater ratios of ALA:LA, achievable only with greater amounts of polyunsaturated fat, may be necessary to produce the effects demonstrated after feeding fish oils.
Atherosclerosis 1999 Jan
PMID:Comparison of the effects of two low fat diets with different alpha-linolenic:linoleic acid ratios on coagulation and fibrinolysis. 992 May 17

BACKGROUND: Thrombophilia may be associated with premature atherosclerosis, an increased susceptibility to primary arterial thrombosis and an increased failure rate for peripheral vascular or endovascular interventions. The aim of this study was to determine the prevalence of thrombophilia in patients with intermittent claudication (IC). METHODS: This was a prospective study of 116 consecutive new patients (70 men; median age 65 (range 43-84) years) referred to this regional vascular surgery unit with IC. Patients on warfarin, or who had previously undergone lower limb reconstruction and/or angioplasty, were excluded. RESULTS: Thrombophilia was demonstrated in 24 patients (21 per cent). The commonest abnormality (15 patients, 13 per cent) was a raised level of anticardiolipin antibody (ACLA) (11 immunoglobulin (Ig) M, four IgG). Other abnormalities comprised: lupus anticoagulant (one), protein C deficiency (two), protein S deficiency (two), activated protein C resistance (one) and factor V Leiden heterozygosity (three). All abnormalities were confirmed on repeat testing. No patient had a history of venous thrombosis. There was no statistically significant relationship between ACLA status and age, sex, ankle : brachial pressure index, previous myocardial infarction or stroke, previous carotid endarterectomy or coronary artery surgery, serum cholesterol, current use of antiplatelet agents or current smoking status. CONCLUSION: Almost one-quarter of new patients referred to this regional vascular unit with IC have thrombophilia; over half of those affected have a raised ACLA level compatible with the antiphospholipid syndrome. At present, the clinical significance and management implications of these abnormalities remain unknown.
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PMID:Vascular surgical society of great britain and ireland: prevalence and significance of thrombophilia in patients with intermittent claudication 1036 36

To examine the effects of atherosclerosis on the protein C anticoagulant pathway in vivo, we measured anticoagulant responses to intravenous administration of human alpha-thrombin or activated protein C (APC) in cynomolgus monkeys. Two groups of monkeys were fed either a control diet (n=18) or an atherogenic diet (n=12) that produces both hypercholesterolemia and moderate hyperhomocyst(e)inemia. A third group (n=8) was fed an atherogenic diet for 15 months, and then fed the atherogenic diet supplemented with B vitamins for 6 months to correct the hyperhomocyst(e)inemia. The plasma homocyst(e)ine level was higher in monkeys fed the atherogenic diet (9.6+/-1.0 micromol/L) than in monkeys fed the control diet (3.7+/-0.2 micromol/L) or the atherogenic diet with B vitamins (3.6+/-0.2 micromol/L) (P<0.001). Infusion of thrombin produced a much greater prolongation of the activated partial thromboplastin time in monkeys fed the control diet (52+/-10 seconds) than in monkeys fed the atherogenic diet either with (24+/-4 seconds) or without (27+/-5 seconds) supplemental B vitamins (P<0.02). Thrombin-dependent generation of circulating APC was higher in control (294+/-17 U/mL) than in atherosclerotic (240+/-14 U/mL) monkeys (P<0.05), although levels of fibrinogen, plasminogen, D-dimer, and thrombin-antithrombin complexes were similar in each group. Injection of human APC produced a similar prolongation of the activated partial thromboplastin time in control (31+/-3 seconds) and atherosclerotic (29+/-2 seconds) monkeys. These findings provide evidence for impaired anticoagulation, due partly to decreased formation of APC, in atherosclerosis. The blunted anticoagulant response to thrombin in hypercholesterolemic monkeys was not corrected by supplementation with B vitamins.
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PMID:Impaired anticoagulant response to infusion of thrombin in atherosclerotic monkeys associated with acquired defects in the protein C system. 1039 93

Vascular brain diseases are ranked the third as the cause of morbidity and mortality, in spite of the progress in diagnostic, therapeutic and preventive procedures. In the majority of cases of vascular brain diseases, it is ischemic brain disease, which is the final and the most severe stage of cerebral arteries atherosclerosis. Etiopathogenesis of atherosclerosis is not closer defined yet, but oxidative hypothesis is distinguished among the numerous theories. Within this theory, main place is attached to oxidative modification of LDL and Lp(a), together with numerous physiopathologic facts with the central role of reactive oxidative matters, where endothelial dysfunction is the main disorder responsible for the onset of numerous impairments, such as changes in coagulation-anticoagulation system. Considering these facts, it was established the hypothesis that in patients with IBD existed changes in hemostatic system, which were in positive correlation with the degree of cerebral atherosclerosis. The study comprised 36 patients with acute IBD and 28 patients with atherosclerotic encephalopathy. Control group was comprised of 30 patients with non-vascular diseases of similar characteristics. We investigated the correlation of the changes in hemostatic system (platelet aggregation, anti-thrombin III, D-dimer, protein C, factor VII, factor VIII, PAI-1) compared to the degree of cerebral atherosclerosis (ultrasonographically) and compared to the observed groups of patients. On the basis of all, the results of this study revealed significant increase of procoagulant factors concentration in patients with IBD, and similar changes were observed in patients with atherosclerotic encephalopathy, but less pronounced. All these changes in the total sample of patients, and particularly in patients with the pronounced cerebral atherosclerosis, are of primary and chronic character.
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PMID:The influence of the degree of cerebral atherosclerosis on the changes in hemostatic system in patients with ischemic brain disease and atherosclerotic encephalopathy. 1064 49

Lipoprotein and hemostatic profiles including coagulation inhibitors were determined in 136 patients with acute ischemic stroke. Based on clinical examination, cerebral computed tomography, Doppler ultrasonography of precerebral arteries and transthoracic echocardiography, the strokes were classified as cardioembolic (n = 38), non-cardioembolic (n = 92), and mixed cardioembolic/hypertensive (n = 6). Patients with cardioembolic stroke were older than patients with non-cardioembolic stroke. Lipoprotein(a) was higher in the cardioembolic than in the non-cardioembolic group. Lipoprotein(a) was not significantly correlated to the other lipid levels and may represent an independent lipid risk factor. The non-cardioembolic group had higher levels of total cholesterol, triglycerides, total cholesterol/high-density lipoprotein cholesterol ratio, low-density lipoprotein cholesterol, apolipoprotein A1, and apolipoprotein B. The cardioembolic group had higher concentrations of fibrinogen and D-dimer, and lower levels of antithrombin, protein C, protein S and heparin cofactor 2 than the non-cardioembolic group. The differences in the hemostatic profile are consistent with thrombosis due to activated coagulation being more involved in the pathogenesis of cardioembolic than of non-cardioembolic stroke. Lipoprotein(a) seems to be more associated with coagulation markers of thrombosis than with atherosclerosis, whereas the other lipids mainly seem to be risk factors for atherosclerosis.
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PMID:Lipoprotein(a), other lipoproteins and hemostatic profiles in patients with ischemic stroke: the relation to cardiogenic embolism. 1068 49

The vascular endothelium influences not only the three classically interacting components of hemostasis: the vessel, the blood platelets and the clotting and fibrinolytic systems of plasma, but also the natural sequelae: inflammation and tissue repair. Two principal modes of endothelial behaviour may be differentiated, best defined as an anti- and a prothrombotic state. Under physiological conditions endothelium mediates vascular dilatation (formation of NO, PGI2, adenosine, hyperpolarizing factor), prevents platelet adhesion and activation (production of adenosine, NO and PGI2, removal of ADP), blocks thrombin formation (tissue factor pathway inhibitor, activation of protein C via thrombomodulin, activation of antithrombin III) and mitigates fibrin deposition (t- and scuplasminogen activator production). Adhesion and transmigration of inflammatory leukocytes are attenuated, e.g. by NO and IL-10, and oxygen radicals are efficiently scavenged (urate, NO, glutathione, SOD). When the endothelium is physically disrupted or functionally perturbed by postischemic reperfusion, acute and chronic inflammation, atherosclerosis, diabetes and chronic arterial hypertension, then completely opposing actions pertain. This prothrombotic, proinflammatory state is characterised by vaso-constriction, platelet and leukocyte activation and adhesion (externalization, expression and upregulation of von Willebrand factor, platelet activating factor, P-selectin, ICAM-1, IL-8, MCP-1, TNF alpha, etc.), promotion of thrombin formation, coagulation and fibrin deposition at the vascular wall (expression of tissue factor, PAI-1, phosphatidyl serine, etc.) and, in platelet-leukocyte coaggregates, additional inflammatory interactions via attachment of platelet CD40-ligand to endothelial, monocyte and B-cell CD40. Since thrombin formation and inflammatory stimulation set the stage for later tissue repair, complete abolition of such endothelial responses cannot be the goal of clinical interventions aimed at limiting procoagulatory, prothrombotic actions of a dysfunctional vascular endothelium.
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PMID:Endothelial function and hemostasis. 1079 71

The influence of thyroid failure on haemostasis is controversial, both hypocoagulable and hypercoagulable states have been reported. Since both subclinical and overt hypothyroidism have been associated with atherosclerosis, a hypercoagulable state in addition might represent a risk factor for thromboembolic disease. We investigated various haemostatic variables in 42 women with subclinical hypothyroidism and compared them to 66 euthyroid controls. Prothrombin time, activated partial thromboplastin time, fibrinogen, factor VII activity (FVII:C), factor VII antigen (FVII:Ag), factor VIII activity, von Willebrand factor (vWF), antithrombin III, heparin cofactor II, protein C, protein S, plasminogen, antiplasmin, plasminogen activator inhibitor and tissue plasminogen activator, as well as common lipid variables, were measured. Factor VII:C (P < 0.02) and the ratio FVII:C/FVII:Ag (P < 0.01) were significantly increased in subclinical hypothyroid patients compared to the control group. Both parameters remained higher in hypothyroid patients after exclusion of 18 women on oestrogen replacement therapy. No differences were found between the groups with respect to vWF or the other haemostatic and lipid variables tested. Patients with subclinical hypothyroidism had significantly higher levels of FVII:C. The greater increase in FVII:C compared to that of FVII:Ag, as shown by the increase in their ratio, might reflect the presence of activated FVIIa. This might mean a hypercoagulable state, which could contribute to the increased prevalence of coronary heart disease reported in such patients. A hypercoagulable state might be another argument in favour of thyroxine replacement treatment in subclinical hypothyroidism, especially in patients with additional risk factors for vascular disease.
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PMID:Haemostatic profile in hypothyroidism as potential risk factor for vascular or thrombotic disease. 1116 51

We describe a woman with an unusual case of thromboembolism of the mesenteric artery in whom multiple thrombi were subsequently found in the aorta and right heart chambers on transesophageal echocardiography. Further evaluation revealed a deficiency of protein C and S plasma proteins, inhibitors of the clotting system. The patient was treated successfully with systemic anticoagulation. Aortic thrombus is common in the setting of underlying atherosclerosis. However, the association of aortic thrombus with a deficiency of protein C and S is rare. To our knowledge, this is the first reported case of mural thrombus of the thoracic aorta associated with combined protein C and S deficiency. Our report underscores the important role of transesophageal echocardiography in the evaluation of patients with arterial thromboembolism.
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PMID:Multiple aortic thrombi associated with protein C and S deficiency. 1149 32

Thrombomodulin is an important endothelial anticoagulant protein that decreases thrombin activity and activates protein C. Our recent study has shown that the G-33A promoter mutation of thrombomodulin gene is associated with coronary artery disease. This study was conducted to determine whether the G-33A mutation in the promoter region of thrombomodulin gene is a genetic risk factor for ischemic stroke or carotid atherosclerosis. The functional significance of this mutation was also evaluated. We recruited 333 patients (mean age 64 years, 59% male) with ischemic stroke and 257 age- and sex-matched controls. In all study participants, carotid atherosclerosis was assessed by Duplex scanning, and thrombomodulin G-33A promoter mutation was detected by single-strand conformation polymorphism. Luciferase reporter gene assay was used to assess the influence of this mutation on thrombomodulin promoter activity. There was no significant difference in the thrombomodulin G-33A mutation frequency (GA+AA genotypes) between the stroke and the control groups (18.3 vs. 24. 1%, P=0.105). The G-33A mutation frequency was also similar between the study participants with and without carotid atherosclerosis (22.2 vs. 19.8%, P=0.550). When only younger subjects (age </=60 years) were included in the analysis, however, we found the mutation occurred more frequently in participants with carotid atherosclerosis (33.3 vs. 17.3%, odds ratio [OR]=2.38, 95% confidence interval [CI]=1.16-4.90, P=0.027). Multiple logistic regression analyses showed that only diabetes mellitus (OR=3.11, 95% CI=1.33-7.30, P=0.009) and G-33A mutation (OR=2.46, 95% CI=1.14-5.29, P=0.021) were associated independently with carotid atherosclerosis in younger subjects. As assessed by luciferase reporter gene assays, the contructs bearing the G-33A mutation showed a significant decrease (36+/-12%) in transcriptional activity in comparison with the wild type constructs. Our findings suggest that G-33A mutation reduces the thrombomodulin promoter activity and is associated with carotid atherosclerosis in younger subjects.
Atherosclerosis 2001 Feb 15
PMID:Functional mutation in the promoter region of thrombomodulin gene in relation to carotid atherosclerosis. 1220 14

The activation of the matrix metalloproteinase progelatinase A (MMP-2) has been of keen interest because an increase in MMP-2 activity has been implicated in disease states such as cancer and atherosclerosis. Activation of MMP-2 occurs on the surface of specific cell types in two steps. In the first step, primary cleavage of MMP-2 by a membrane-type matrix metalloproteinase generates an intermediate. A secondary cleavage and activation of the intermediate is thought to occur autocatalytically. Previous studies have shown that thrombin can also activate progelatinase A in the presence of endothelial cells. We show that this cell-dependent mechanism of MMP-2 activation also occurs with THP-1 cells and involves binding of thrombin to thrombomodulin present on the cell surface and generation of the anti-coagulant protein, activated protein C. We demonstrate that activated protein C is directly responsible for activation and cleavage of the gelatinase A intermediate. This work contributes new mechanistic insights into the activation of MMP-2 and provides a novel link between matrix metalloproteinase activation and anti-coagulation.
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PMID:Thrombin-thrombomodulin activation of protein C facilitates the activation of progelatinase A. 1129 49


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