thromboplastin and Heart-Diseases

Atherothrombosis, defined as atherosclerotic lesion disruption with superimposed thrombus formation, is the major cause of acute coronary syndromes and cardiovascular deaths. It is the leading cause of morbidity and mortality in the industrialized world. Plaque composition, rather than luminal stenosis, is recognized as the major determinant of this disease. Since tissue factor is found within atheroma and also in the bloodstream of atherosclerotic patients, it likely plays a key role in determining both plaque and blood thrombogenicity. Ongoing clinical and preclinical studies are evaluating the therapeutic possibilities of specific inhibition of the tissue factor pathway. Here, we will review the role of tissue factor in atherothrombosis.

Topics: Arteriosclerosis; Heart Diseases; Humans; Thromboplastin; Thrombosis

Cardiovascular damage induced by pulmonary exposure to environmental chemicals can result from direct action or, secondarily from pulmonary injury. We have developed a rat model of pulmonary exposure to zinc to demonstrate cardiac, coagulative, and fibrinolytic alterations. Male Wistar Kyoto rats were instilled intratracheally with saline or zinc sulfate, 131 microg/kg (2 micromol/kg); the alterations were determined at 1, 4, 24, and 48 h postexposure. High-dose zinc enabled us to show changes in circulating levels of zinc above normal and induce significant pulmonary inflammation/injury such that cardiac impairments were likely. At 1-24 h postexposure, plasma levels of zinc increased to nearly 20% above the base line. Significant pulmonary inflammation and injury were determined by analysis of bronchoalveolar lavage fluid and histopathology in zinc-exposed rats at all time points. Starting at 4 h postexposure, pulmonary damage was accompanied by persistently increased gene expressions of tissue factor (TF) and plasminogen activator-inhibitor-1 (PAI-1), but not thrombomodulin (TM). Cardiac tissues demonstrated similar temporal increases in expressions of TF, PAI-1, and TM mRNA following pulmonary instillation of zinc. In contrast to extensive pulmonary edema and inflammation, only mild, and focal acute, myocardial lesions developed in a few zinc-exposed rats; no histological evidence showed increased deposition of fibrin or disappearance of troponin. At 24 and 48 h postexposure to zinc, increases occurred in levels of systemic fibrinogen and the activated partial thromboplastin time. These data suggest that cardiovascular blood coagulation impairments are likely following pulmonary zinc exposure and associated pulmonary injury and inflammation.

Topics: Air Pollutants; Animals; Blood Coagulation; Bronchoalveolar Lavage Fluid; Gene Expression Regulation; Heart; Heart Diseases; Intubation, Intratracheal; Lung; Lung Diseases; Male; Myocardium; Plasminogen Activator Inhibitor 1; Rats; Rats, Inbred WKY; RNA, Messenger; Thrombomodulin; Thromboplastin; Zinc

Cocaine consumption can lead to myocardial infarction. Tissue factor (TF) has been implicated in acute coronary syndromes, and the balance of TF and tissue factor pathway inhibitor (TFPI) determines initiation of thrombus formation. This study was designed to investigate the effect of cocaine on endothelial TF and TFPI expression. Cocaine (10(-8)-10(-5) mol/l) increased thrombin-induced TF expression by 24% at 10(-7) mol/l (P < 0.001) without affecting basal TF expression. In contrast, cocaine reduced endothelial TFPI expression by 47% at 10(-7) mol/l (P < 0.01). Moreover, thrombin impaired endothelial TFPI expression, and cocaine (10(-8) mol/l) further reduced TFPI expression by 33% as compared to thrombin (P < 0.02). These effects occur at cocaine concentrations usually present in plasma of consumers. Given the importance of TF in the pathogenesis of acute coronary syndromes, TF induction in conjunction with TFPI suppression may be relevant for the increased frequency of myocardial infarction observed in cocaine consumers.

Topics: Acute Disease; Aorta; Atherosclerosis; Cells, Cultured; Cocaine; Endothelial Cells; Endothelium, Vascular; Gene Expression Regulation; Heart Diseases; Humans; Lipoproteins; Myocardial Infarction; Thrombin; Thromboplastin; Vasoconstrictor Agents

In endothelial cells (EC), celecoxib inhibits expression of tissue factor (TF), a key protein for initiation and propagation of thrombus formation. The current study was designed to examine the effect of celecoxib on TF expression and activity in VSMC. In contrast to EC, celecoxib increased TNF-alpha-induced TF expression and surface activity in VSMC by 33% and 20%, respectively, as compared to TNF-alpha alone, while rofecoxib or NS-398 had no effect. Celecoxib increased p38 MAP kinase (p38), p44/42 MAP kinase (ERK), and p70S6 kinase (p70S6K) phosphorylation while leaving JNK activation unaffected. Simultaneous inhibition of p38 and ERK reduced TNF-alpha-induced TF expression by 59%, while inhibition of JNK with SP600125 did not affect TF expression. Thus, in contrast to endothelial cells, celecoxib does not inhibit TF expression in VSMC, but instead enhances it. As neither rofecoxib nor NS-398 affected TF expression, this effect does not seem to be related to COX-2 inhibition but rather appears to be mediated by an increase in p38, ERK, and p70S6K activation. The observation that the inhibiting effect of celecoxib on endothelial TF expression does not extend to VSMC may have important implications for patients with cardiovascular disease.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Atherosclerosis; Celecoxib; Cell Line; Endothelium, Vascular; Gene Expression Regulation; Heart Diseases; Humans; Lactones; Muscle, Smooth, Vascular; Pyrazoles; Sulfonamides; Sulfones; Thromboplastin; Thrombosis; Transcription, Genetic; Tumor Necrosis Factor-alpha

Moderate consumption of red wine has been epidemiologically associated with a reduction in cardiovascular disease, but its mechanism of action is not fully understood. The objective was to study whether the protective effects of a daily intake of red wine (Tempranillo, 12.8% alcohol vol/vol) could be related to inhibition of thrombosis in an experimental model of diet-induced hyperlipemia.. For 100 days, animals were fed a western-type proatherogenic diet containing 2% cholesterol and 20% saturated fat. Three doses of red wine were studied (20, 30, and 40 g wine-ethanol/d) and compared with placebo-control animals not taking any wine. Thrombosis under flow conditions was evaluated by radioisotopic quantification of deposited platelets on damaged arteries. Changes in RhoA translocation in platelets and monocyte tissue factor expression were also analyzed. Mural platelet deposition was significantly reduced in animals ingesting red wine with their food. Expression of RhoA in the platelet cytoplasm (inactive form) was increased in wine-fed animals. Tissue factor mRNA expression in lipopolysaccharide-stimulated monocytes was reduced in wine-fed animals. Total cholesterol levels were not significantly different among groups.. Moderate red wine intake significantly reduces platelet deposition triggered by damaged vessel wall, partially explained by inhibition of RhoA translocation to the platelet membrane. Hence, a daily moderate intake of wine seems to inhibit different pathways that converge in a reduced thrombotic risk on vessel wall injury.

Topics: Animals; Blood Platelets; Cholesterol; Diet, Atherogenic; Dose-Response Relationship, Drug; Drug Administration Schedule; Heart Diseases; Lipoproteins, LDL; Male; Monocytes; Platelet Aggregation; Protein Transport; rhoA GTP-Binding Protein; RNA, Messenger; Sus scrofa; Thromboplastin; Thrombosis; Wine

We studied the relationships between albuminuria, tissue factor-induced coagulation, and endothelial cell dysfunction in 67 patients with non-insulin-dependent diabetes mellitus (NIDDM) who were divided into three groups on the basis of their urinary albumin excretion rate (AER). To assess the early phase of tissue factor-induced coagulation, activated factor VII (FVIIa) levels in plasma were measured by a direct fluorogenic assay. As markers of endothelial cell dysfunction, levels of von Willebrand factor (vWF), tissue-type plasminogen activator-plasminogen activator inhibitor-1 (TPA-PAI-1) complex, PAI-1, and tissue factor pathway inhibitor (TFPI) were measured. FVIIa levels were increased in normoalbuminuric NIDDM patients (AER < 15 micrograms/min) when compared with normal control subjects. This FVIIa increase was accompanied by an increase in thrombin-antithrombin III complex (TAT) levels, indicating increased activation of coagulation even in normoalbuminuric patients. In NIDDM patients with microalbuminuria (AER = 15-200 micrograms/min), the FVIIa level, the FVIIa-FVII antigen (Ag) ratio (an indicator of activation of FVII zymogen to FVIIa), and the TAT level were further increased. This group also had higher levels of endothelial cell-derived factors (vWF, TPA-PAI-1 complex, and PAI-1) than the control group. The levels of endothelial cell-derived factors (including TFPI) were highest in the NIDDM patients with overt albuminuria (AER > 200 micrograms/min). In all 67 diabetic patients, AER showed a strong positive correlation with FVIIa (r = .574, P < .0001) and a weakly but still significant correlation with FVIIa-FVII:Ag (r = .365, P = .01), vWF (r = .315, P < .01), and TAT (r = .323, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Coagulation; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Electrocardiography; Endothelium, Vascular; Enzyme Activation; Factor VII; Female; Heart Diseases; Humans; Male; Middle Aged; Proteinuria; Thromboplastin; von Willebrand Factor

Topics: Adult; Aerosols; Alanine Transaminase; Alkaline Phosphatase; Blood Proteins; Chemical and Drug Induced Liver Injury; Creatine Kinase; Female; Heart Diseases; Humans; Isoenzymes; L-Lactate Dehydrogenase; Male; Metaproterenol; Middle Aged; Phenols; Thromboplastin