thromboplastin and Coronary-Disease

Although, the main physiological role of monocytes is attributed to innate immunity (that is, phagocytosis) and the development of tissue macrophages and dendritic cells, the pathophysiological role of these goes far behind these (simplistic) limits. Indeed, monocytes constitute a major source of blood tissue factor, a key element of the extrinsic coagulation cascade. Monocytes actively bind to platelets, thus forming very prothrombotic monocyte-platelet aggregates. Additionally, these cells link inflammation and the procoagulant state observed in various prothrombotic conditions. However, monocytes are also crucial for successful thrombus recanalisation. In this article, we review the available data on potential mechanisms that link monocytes with thrombosis-related processes.

Topics: Animals; Antiphospholipid Syndrome; Blood Platelets; Cell Adhesion; Cells, Cultured; Coronary Disease; Cytokines; Female; Humans; Inflammation; Male; Mice; Models, Biological; Monocytes; Neovascularization, Physiologic; Platelet Aggregation; Rabbits; Risk Factors; Swine; Thrombophilia; Thromboplastin; Thrombosis

Rupture of an atherosclerotic plaque with subsequent thrombosis and myocardial ischemia is the patho-physiological mechanism in acute coronary syndromes. Tissue factor (TF) as the main initiator of the extrinsic coagulation cascade plays a central role in the pathogenesis of acute coronary syndromes. The extent of the thrombotic process is modulated by local vascular TF of the ruptured plaque as well as by circulating TF. In addition, TF alters signaling pathways and, thereby, contributes to inflammatory reactions and vascular remodeling. This review addresses current concepts of the role of TF in acute coronary syndromes and discusses potential consequences and therapeutic approaches.

Topics: Acute Disease; Arteriosclerosis; Coronary Disease; Humans; Myocardial Ischemia; Syndrome; Thromboplastin

The acute coronary syndromes arise from procoagulant changes in complex plaques, which trigger both platelet activation and coagulation pathways. These 2 pathways intersect at a number of points that form positive-feedback loops to sustain and accelerate thrombus formation. In normal hemostasis and with a healthy endothelium, intravascular thrombosis is prevented, and vascular patency is protected by the fibrinolytic system and a number of antithrombotic factors, such as antithrombin, thrombomodulin, and tissue factor pathway inhibitor. However, atherosclerosis is characterized by a hypercoagulable state, and the fibrinolytic balance is skewed toward occlusive thrombus formation at critical sites on vulnerable plaques. This review focuses on cellular and humoral mechanisms and the antithrombotic strategies that are important during the acute phase of an ischemic coronary syndrome, both in patients managed conservatively and in patients scheduled for an interventional procedure. These strategies include fibrinolytic therapy, antiplatelet therapies (aspirin, clopidogrel, glycoprotein IIb/IIIa receptor inhibitors), and low-molecular-weight heparin.

Topics: Acute Disease; Angiotensin-Converting Enzyme Inhibitors; Blood Coagulation; Coronary Disease; Heparin, Low-Molecular-Weight; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Platelet Activation; Platelet Aggregation Inhibitors; Syndrome; Thrombin; Thromboplastin; Thrombosis

Thrombogenic tissue factor (TF) on cell-derived microparticles is present in the circulating blood of patients with acute coronary syndromes. Recently, we reported that leukocytes transfer TF-positive particles to platelet thrombi, making them capable of triggering and propagating thrombus growth. This observation changes the original dogma that vessel-wall injury and exposure of tissue factor within the vasculature to blood is sufficient for the occurrence of arterial thrombosis. The transfer of TF-positive leukocyte particles is dependent on the interaction of CD15 and TF with platelet thrombi. The inhibition of TF transfer and TF activity suggests a novel therapeutic approach to the prevention of thrombosis that may prove to be effective in disorders associated with increased blood TF.

Topics: Coronary Circulation; Coronary Disease; Coronary Vessels; Humans; Thromboplastin; Thrombosis

Topics: Abciximab; Angioplasty, Balloon, Coronary; Animals; Antibodies, Monoclonal; Anticoagulants; Blood Coagulation; Coronary Disease; Immunoglobulin Fab Fragments; Platelet Aggregation; Recurrence; Thrombin; Thromboplastin

Clinical trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statin therapy have demonstrated that baseline or treated low-density lipoprotein (LDL) cholesterol levels are only weakly associated with net coronary angiographic change or cardiovascular events. The beneficial effects of statins on clinical events may involve nonlipid mechanisms that modify endothelial function, inflammatory responses, plaque stability, and thrombus formation. Experimental animal models suggest that statins may foster stability through a reduction in macrophages and cholesterol ester content and an increase in volume of collagen and smooth muscle cells. The thrombotic sequelae caused by plaque disruption is mitigated by statins through inhibition of platelet aggregation and maintenance of a favorable balance between prothrombotic and fibrinolytic mechanisms. These nonlipid properties of statins may help to explain the early and significant cardiovascular event reduction reported in several clinical trials of statin therapy.

Topics: Animals; Antithrombins; Cardiovascular Diseases; Cholesterol, LDL; Clinical Trials as Topic; Coronary Disease; Endothelium, Vascular; Fibrinogen; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Inflammation; Lovastatin; Muscle, Smooth, Vascular; Platelet Aggregation; Pravastatin; Simvastatin; Thromboplastin; Thrombosis

Observational studies reveal a cardioprotective effect of hormone replacement therapy. The precise mechanisms whereby this treatment influences disease risk are not fully understood. Much attention has been paid to changes in lipid and lipoprotein metabolism, but this explains only part of the protective effect. In this short review, the roles of monocyte and platelet function in atherogenesis and thrombus formation are discussed. It is shown that hormone replacement therapy favourably down-regulates monocyte and platelet reactivity, which may be important in explaining the beneficial effect on the risk of cardiovascular disease.

Topics: Adult; Aged; Blood Platelets; Coronary Artery Disease; Coronary Disease; Coronary Thrombosis; Estrogen Replacement Therapy; Female; Humans; Middle Aged; Monocytes; Thromboplastin; Thromboxanes; Tumor Necrosis Factor-alpha

The role of factor VII in the haemostatic mechanism as well as thrombosis has recently gained new interest. Today's concept that factor VII may be a key regulator in the initiation of blood coagulation is based on studies that provide new evidence for a mandatory activation of factor VII to factor VIIa in blood. Exposure of thromboplastin to the circulation may not trigger activation of blood coagulation before the one chain factor VII is converted to the active two chain form of factor VIIa. A hypothetical model is proposed for the initiation and subsequent activation steps of the blood coagulation process. In this model, it is suggested that circulating activators of factor VII activate inactive complexes of thromboplastin-factor VII. Subsequently, newly generated factor Xa will accelerate this reaction and thereafter be the most potent activator of factor VII. This model would also fit with the clinical observation that moderate factor VII deficiency may be associated with thrombotic episodes discussed in this communication. This article also discusses the role of recombinant factor VIIa in the treatment of factor VIII deficiency patients with acquired factor VIII inhibitors, factor VII and ischemic heart disease and the factor VII-phospholipid complex, and the regulation of the thromboplastin-factor VIIa complex by factor Xa and extrinsic pathway inhibitor (EPI).

Topics: Blood Coagulation; Coronary Disease; Factor VII; Factor VIIa; Hemophilia A; Hemostasis; Humans; Phospholipids; Recombinant Proteins; Thromboplastin

Topics: Administration, Oral; Anticoagulants; Calibration; Clinical Trials as Topic; Coronary Disease; Humans; Prothrombin Time; Quality Control; Thromboplastin

To date, no study has tested the effect of different heparin dosages on the hemostatic changes during off-pump coronary artery bypass graft (OPCABG) surgery, and a wide variety of empirical anticoagulation protocols are being applied. We tested the effect of two different heparin dosages on the activation of the hemostatic system in patients undergoing OPCABG procedures.. Forty-two patients eligible for OPCABG procedures were assigned in a randomized fashion to low-dose heparin (150 IU/kg) or high-dose heparin (300 IU/kg). Prothrombin fragment 1+2, plasmin/alpha(2)-plasmin inhibitor complex, D-dimer, soluble tissue factor, tissue factor pathway inhibitor, total thrombin activatable fibrinolysis inhibitor (TAFI), and activated TAFIa were assayed by specific enzyme-linked immunosorbent assays at six different timepoints, before, during, and after surgery. Platelet function was evaluated by means of an in vitro bleeding time test, platelet function analyzer-100.. The OPCABG surgery was accompanied by significant changes of all plasma biomarkers, indicative of systemic activation of coagulation and fibrinolysis. A significant increase in circulating TAFIa was detected perioperatively and postoperatively, and multiple regression analysis indicated that prothrombin F1+2 but not plasmin/alpha(2)-antiplasmin complex was independently associated with TAFIa level. Platelet function analyzer-100 values did not change significantly after OPCABG. All hemostatic changes were similar in the two heparin groups, even perioperatively, when the difference in anticoagulation was maximal.. Both early and late hemostatic changes, including TAFI activation, are similarly affected in the low-dose and high-dose heparin groups, suggesting that the increase in heparin dosage is not accompanied by a better control of clotting activation during OPCABG surgery.

Topics: Aged; alpha-2-Antiplasmin; Anticoagulants; Bleeding Time; Carboxypeptidase B2; Coronary Artery Bypass, Off-Pump; Coronary Disease; Dose-Response Relationship, Drug; Female; Fibrin Fibrinogen Degradation Products; Fibrinolysin; Fibrinolysis; Hemostasis, Surgical; Heparin; Humans; Lipoproteins; Male; Middle Aged; Peptide Fragments; Postoperative Complications; Prospective Studies; Protein Precursors; Prothrombin; Thromboplastin

Soluble CD40L (sCD40L), a substance that maximally reflects in vivo platelet activation, is increased in patients with hypercholesterolemia. We investigated the relation between sCD40L and platelet CD4OL in hypercholesterolemic patients before and after a short-term treatment with atorvastatin.. Collagen-induced platelet CD40L and plasma levels of sCD40L and prothrombin fragment F1+2, a marker of thrombin generation, were investigated in 30 hypercholesterolemic patients and 20 healthy subjects. Hypercholesterolemic patients were then randomized to either diet (n=15; group A) or atorvastatin 10 mg/d (group B); the aforementioned variables were measured at baseline and after 3 days of treatment. Compared with referents, hypercholesterolemic patients showed higher values of platelet CD40L (P<0.005), sCD40L (P<0.005), and F1+2 (P<0.003). Platelet CD40L was significantly correlated with sCD40L (P<0.001), and the latter was significantly correlated with F1+2 (P<0.001). The intervention trial showed no changes in group A but a significant decrease in platelet CD40L (P<0.01), sCD40L (P<0.002), and F1+2 (P<0.03) in group B. In vitro studies demonstrated that cholesterol enhanced platelet CD40L and CD40L-mediated clotting activation by human monocytes; also, atorvastatin dose-dependently inhibited platelet CD40L expression and clotting activation by CD40L-stimulated monocytes.. This study shows that, in hypercholesterolemia, platelet overexpression of CD40L may account for enhanced plasma levels of sCD40L and F1+2. Atorvastatin exerts a direct antithrombotic effect via inhibition of platelet CD40L and CD40L-mediated thrombin generation, independently of its cholesterol-lowering effect.

Topics: Adenosine Diphosphate; Atorvastatin; Biomarkers; Blood Coagulation; Blood Platelets; CD40 Ligand; Collagen; Coronary Disease; Female; Fibrinolytic Agents; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Monocytes; Multifactorial Inheritance; Peptide Fragments; Prothrombin; Pyrroles; Solubility; Thrombin; Thromboplastin; Treatment Outcome

Statins were previously shown to suppress cellular tissue factor (TF) in vitro. Here, we investigated the effect of atorvastatin on the TF-pathway and thrombin generation after coronary angioplasty and stenting in vivo.. A cohort of 30 patients with coronary artery disease (CAD) was randomised to treatment with either none (n=10), 10 mg (n=10) or 80 mg (n=10) atorvastatin per day for the postinterventional period of 6 months starting the day before percutaneous coronary intervention (PCI). Fasting blood samples were collected on admission and after 6 weeks and 6 months of statin therapy to determine sTF, free tissue factor pathway inhibitor (TFPI) and prothrombin fragment F1.2 by immunoassay.. Soluble TF (sTF) significantly correlated with thrombin generation as measured by prothrombin fragment F1.2 at baseline. This correlation was lost 6 weeks and 6 months after initiation of statin therapy. In vivo, F1.2 was significantly lowered after 6 months of statin therapy by both, low dose (0 vs. 10 mg: 1.3+/-0.3 vs. 0.7+/-0.2 ng/ml; P<0.05) and high dose (0 vs. 80 mg: 1.2+/-0.3 vs. 0.6+/-0.2 ng/ml; P=0.01) atorvastatin compared to control. However, sTF and free TFPI did not change significantly with atorvastatin therapy when compared to baseline or control.. Our results demonstrate reduced in vivo generation of thrombin six months after percutaneous coronary intervention and statin therapy independent of sTF and free TFPI.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Atorvastatin; Cohort Studies; Coronary Disease; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Heptanoic Acids; Humans; Lipids; Lipoproteins; Male; Middle Aged; Prothrombin; Pyrroles; Thrombin; Thromboplastin; Treatment Outcome

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.

Topics: Acute Disease; Aged; Anticholesteremic Agents; Atorvastatin; Coronary Disease; Female; Fibrinogen; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Platelet Aggregation; Pyrroles; Thromboplastin; Thrombosis

The use of magnesium in the treatment of acute myocardial infarction remains controversial despite preliminary experimental evidence that magnesium plays a beneficial role as a regulator of thrombosis. The aim of our study was to determine whether oral magnesium treatment inhibits platelet-dependent thrombosis (PDT) in stable patients with coronary artery disease (CAD). In a randomized prospective, double-blind, cross-over and placebo controlled study, 42 patients with stable CAD (37 men, 5 women, mean age 68 +/- 9 years) on aspirin received either magnesium oxide tablets (800-1,200 mg/day) or placebo for 3 months (Phase 1) followed by a 4-week washout period, and the cross-over treatment for 3 months (Phase 2). PDT, platelet aggregation, platelet P-selectin flow-cytometry, monocyte tissue factor procoagulant activity (TF-PCA) and adhesion molecules density were assessed before and after each phase. PDT was evaluated by an ex-vivo perfusion model using the Badimon chamber. Median PDT was significantly reduced by 35 percent in patients who received magnesium versus placebo (D change from baseline: -24 vs. 26 microm2/mm; p = 0.02, respectively). There was no significant effect of magnesium treatment on platelet aggregation, P-selectin expression, monocyte TF-PCA or adhesion molecules. Oral magnesium treatment inhibits PDT in patients with stable CAD. This effect appears to be independent of platelet aggregation or P-selectin expression, and is evident despite aspirin therapy. These findings suggest a potential mechanism whereby magnesium may beneficially alter outcomes in patients with CAD.

Topics: Administration, Oral; Aged; Aged, 80 and over; Aspirin; Cell Adhesion; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Coronary Disease; Cross-Over Studies; Double-Blind Method; Electrolytes; Female; Fibrinolytic Agents; Flow Cytometry; Humans; Lipids; Magnesium; Magnesium Oxide; Male; Middle Aged; Monocytes; P-Selectin; Placebos; Platelet Aggregation; Prospective Studies; Thromboplastin; Thrombosis

Changes of hemostatic parameters during percutaneous transluminal coronary angioplasty (PTCA) in 75 patients with chronic coronary artery disease were evaluated. Plasma levels of D-dimer, soluble fibrin monomer, plasmin-alpha2 antiplasmin inhibitor complex, and tissue factor (TF) were significantly increased in all patients with chronic coronary artery disease. The activity of antithrombin and protein C and the levels of protein C antigen were significantly decreased 1 hr after PTCA, but they returned to normal range 1 day after PTCA. There was no significant difference in the level of plasma APC-PCI complex before and 1 hr after PTCA. The plasma levels of D-dimer, soluble fibrin monomer, thrombomodulin, TF and PPIC were significantly decreased 1 hr, and the plasma levels of plasmin-alpha2 antiplasmin inhibitor complex 1 day after PTCA. These findings suggest that the decrease of protein C and antithrombin resulted in activation of the coagulation system. One hour after PTCA, the plasma levels of (total-free) TF pathway inhibitor (TFPI) were significantly decreased, but the plasma levels of total and free-TFPI were significantly increased, suggesting that consumption of (total-free) TFPI occurs during PTCA. Overall, these findings suggest that the hypercoagulable state improves during PTCA and that transient decrease of antithrombin, protein C, (total-free) TFPI or plasmin-alpha2 antiplasmin inhibitor complex may cause restenosis of coronary artery.

Topics: alpha-2-Antiplasmin; Angioplasty, Balloon, Coronary; Biomarkers; Blood Coagulation Factors; Chronic Disease; Coronary Disease; Female; Humans; Lipoproteins; Male; Middle Aged; Protein C; Pyrimidine Dimers; Serine Proteinase Inhibitors; Thromboplastin

The application of a centrifugal pump might lead to a reduced release of tissue factor (TF) due to less blood cell damage. This could result in a decrease in activation of the extrinsic pathway of coagulation and embolus formation. In the present study, 60 patients undergoing coronary artery bypass grafting were randomly assigned to a centrifugal or a roller pump. Plasma concentrations of TF, thrombin-antithrombin complex (TAT), and prothrombin fragments F1 + 2 were investigated before, during, and after cardiopulmonary bypass (CPB). Embolus detection was performed at the arterial line of CPB and transcranially by Doppler ultrasound. The centrifugal pump group revealed a lower TF release (area under the curve during CPB) when compared with the roller pump group [5661 (696-10359) vs 12681 (6383-17538) microg x min/l; median (lower - upper quartiles); P = 0.009]. In contrast, TAT and F1 + 2 formation did not differ between the groups, and neither did the total embolus count of both Doppler systems. Embolus counts did not correlate with TAT or F1 + 2 formation. In conclusion, the reduction in TF release by the application of a centrifugal pump seems to have little consequence on total thrombin formation. Since the applied Doppler systems seem to detect mainly microbubbles, conclusions regarding differences between the two pumps in the formation of thrombofibrinous clots cannot be drawn.

Topics: Cardiopulmonary Bypass; Centrifugation; Coronary Artery Bypass; Coronary Disease; Enzyme-Linked Immunosorbent Assay; Female; Heart-Assist Devices; Humans; Intracranial Embolism and Thrombosis; Intraoperative Complications; Male; Middle Aged; Thromboplastin; Treatment Outcome; Ultrasonography, Doppler, Transcranial

Topics: Administration, Oral; Anticoagulants; Calibration; Clinical Trials as Topic; Coronary Disease; Humans; Prothrombin Time; Quality Control; Thromboplastin

Thrombus formation is determined by the balance between pro- thrombotic mediators and anti-thrombotic factors.High-density lipoprotein (HDL) from healthy subjects exerts anti-thrombotic properties. Whether this is also the case for HDL from patients with stable coronary heart disease (CHD) or acute coronary syndrome (ACS) is unknown.In human aortic endothelial cells in culture,HDL (50 µg/ml) from healthy subjects (HS) inhibited thrombin-induced tissue factor (TF) expression and activity, while HDL (50 µg/ml) from CHD and ACS patients did not. Similarly, only healthy HDL increased endothelial tissue factor pathway inhibitor (TFPI) expression and tissue plasminogen activator (tPA) release, while HDL from CHD and ACS patients had no effect. Healthy HDL inhibited thrombin-induced plasminogen activator inhibitor type 1 (PAI-1) expression, while HDL from ACS patients enhanced endothelial PAI-1 expression. Inhibition of nitric oxide (NO) formation with L-NAME (100 µmol/l) abolished the anti-thrombotic effects of healthy HDL on TF, TFPI, and tPA expression. The exogenous nitric oxide donor, DETANO, mimicked the effects of healthy HDL and counterbalanced the loss of anti-thrombotic effects of HDL from CHD and ACS patients in endothelial cells. In line with this observation, healthy HDL, in contrast to HDL from CHD and ACS patients, increased endothelial NO production. In the laser-injured carotid artery of the mouse, thrombus formation was delayed in animals treated with healthy HDL compared with mice treated with vehicle or HDL from patients with CHD or ACS. In conclusion, HDL from CHD and ACS patients loses the ability of healthy HDL to suppress TF and to increase TFPI and t-PA and instead enhances PAI-1 and arterial thrombus formation.

Topics: Acute Coronary Syndrome; Adult; Aged; Animals; Aorta; Blood Coagulation; Carotid Artery Injuries; Cells, Cultured; Coronary Disease; Disease Models, Animal; Endothelial Cells; Humans; Lipoproteins; Lipoproteins, HDL; Mice; Middle Aged; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitroso Compounds; Plasminogen Activator Inhibitor 1; Platelet Aggregation; Thrombin; Thromboplastin; Tissue Plasminogen Activator

There is close relationship between abnormal coagulation system and progression of coronary heart disease (CHD), our purpose is to evaluate the contribution of hematologic factors and some other risk factors to the development of coronary heart disease (CHD) in Chinese population.. 56 patients with CHD at admission and 54 controls were enrolled. Plasma levels of protein C, free protein S, total protein S, thrombomodulin, activated factor VII (FVIIa), factor VII:Ag, P-selectin, tissue-type plasminogen activator, plasminogen activator inhibitor-1 were measured by enzyme linked immunosorbent assay, activity of tissue factor (aTF) by chromogenic activity assay, and activated protein C (APC) ratio, prothrombin time, aPTT, fibrinogen, D-dimmer and thrombin time by full-automated coagulation analyzer.. Compared with controls, plasma level of thrombomodulin, FVIIa, factor VII:Ag and aTF were raised in CHD group (p<0.05, 0.001, 0.05, and 0.05, respectively). The average APC ratio in CHD group was lower than that in controls (p<0.001). The result of binary logistic regression analysis showed that activated factor VII (OR2.680, 95%CI1.539-4.665) and tissue factor activity (OR1.019, 95%CI1.004-1.035) were risk factors and high density lipoprotein (OR0.008, 95%CI0-0.478) and activated protein C ratio (OR0.001, 95%CI0-0.011) were protective factors for CHD.. Low activated protein C ratio, elevated tissue factor activity and increased activated factor VII in plasma may contribute to development of coronary heart disease.

Topics: Asian People; China; Coronary Disease; Enzyme-Linked Immunosorbent Assay; Factor VIIa; Female; Humans; Male; Middle Aged; P-Selectin; Plasminogen Activator Inhibitor 1; Protein C; Protein S; Thrombomodulin; Thromboplastin; Tissue Plasminogen Activator

Increased levels of microparticles exposing tissue factor circulate in the blood of patients with coronary heart disease, possibly disseminating their pro-thrombotic and pro-inflammatory potential. Because diets rich in n-3 (polyunsaturated) fatty acids have been associated with reduced incidence of coronary heart disease-related events, we investigated the in vivo effects of treatments with n-3 fatty acids on levels of circulating microparticles and their tissue factor- dependent procoagulant activity in patients with a previous myocardial infarction.. Forty-six post-myocardial infarction patients were assigned to receive either 5.2 g of n-3 fatty acids daily (n=23) or an olive oil placebo (n = 23) for 12 weeks. Circulating microparticles were isolated from peripheral blood. The number of microparticles, their cellular source and tissue factor antigen were determined by flow cytometry, and their procoagulant potential assayed by a fibrin generation test.. The total number of microparticles, endothelium-derived microparticles and microparticle tissue factor antigen were not significantly different between the two groups. However, the number of platelet-derived microparticles [from a median of 431 (126-1796, range) x 10(6)/L to a median of 226 (87-677, range)] x 10(6)/L and monocyte-derived microparticles [from a median of 388 (9-1681, range) x 10(6)/L to a median of 265 (7-984, range) x 10(6)/L] in plasma were significantly (p < 0.05) decreased by n-3 fatty acids, while they were unchanged in the placebo group. Total microparticle tissue factor-procoagulant activity was also reduced in the n-3 fatty acid group compared to that in the placebo group.. Treatment with n-3 fatty acids after myocardial infarction exerts favorable effects on levels of platelet- and monocyte-derived microparticles, thus possibly explaining some of the anti-inflammatory and anti-thrombotic properties of these natural compounds.

Topics: Aged; Blood Platelets; Coronary Disease; Endothelium, Vascular; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Female; Fibrin; Humans; Male; Middle Aged; Myocardial Infarction; Placebos; Thromboplastin; Thrombosis

To investigate the clinical significance of matrix metalloproteinase-9 (MMP-9) and tissue factor (TF) secreted by cultured monocyte-derived macrophages (HMDM) from patients with coronary heart disease (CHD) in vitro, and to evaluate the intervenient effect of puerarin (Pur) on them.. A total of 40 patients were enrolled, including 12 patients with acute myocardial infarction (AMI), 16 patients with unstable angina pectoris (UAP), 12 patients with stable angina pectoris (SAP). Besides, 8 healthy subjects with normal coronary arteriograph were set as controls. Monocytes acquired from their peripheral blood were incubated for 48 h and induced to differentiate into macrophages by phorbolester 12-myristate 13-acetate (PMA), the contents of MMP-9 and TF in supernatant were assayed, and the relationship of them with patients' age, risk factors of CHD and coronary artery lesion scores were analyzed. HMDMs randomly from selected 12 patients with acute coronary syndrome (ACS) were arranged for observing the intervenient effects of different concentrations of Pur on the levels and activity of MMP-9 and TF.. The levels of MMP-9 and TF in UAP and AMI patients were significantly higher than those in SAP patients and healthy subjects (P < 0.01), but no statistical correlation was found between levels of MMP-9 and TF with different CHD risk factors, as well as patients' age and coronary artery lesion scores. The levels and activity of MMP-9 and TF in the 12 ACS patients were significantly decreased in a dose-dependent manner after Pur intervention when compared with the controt group.. The levels of MMP-9 and TF secreted in vitro by HMDM from CHD patients could be taken as indexes for evaluating patient's condition of ACS. Pur can inhibit the expression and the activity of MMP-9 and TF secreted by HMDM, stabilize the plaque and improve the vulnerability of blood to certain extent.

Topics: Cell Differentiation; Cells, Cultured; Coronary Disease; Female; Humans; Isoflavones; Macrophages; Male; Matrix Metalloproteinase 9; Monocytes; Thromboplastin; Vasodilator Agents

Increased circulating endothelial cells (CECs, reflecting endothelial damage) in acute coronary syndromes (ACS) has been reported. However, the inter-relationships of indices of endothelial damage/injury with development of vascular (dys)function, plasma levels of tissue factor (TF, an index of coagulation) and interleukin-6 (IL-6, a pro-inflammatory cytokine) have not been investigated in ACS. We hypothesized that increased CECs can be related to impaired flow-mediated vasodilatation (FMD, an index of endothelial dysfunction) and elevated plasma von Willebrand factor (vWf, also marking endothelial damage/dysfunction), TF and IL-6 in patients with ACS.. We studied 120 patients with ACS (80 acute myocardial infarction and 40 unstable angina; 86 male, age 65+/-12 years) and 40 matched patients with stable CAD and 40 healthy controls (HC) in a cross-sectional analysis. Plasma vWf, TF and IL-6 levels were measured by ELISA. CECs were quantified using epifluorescence microscope after immunomagnetic separation with CD146. Brachial artery FMD was assessed in a subset of 39 ACS patients.. ACS patients had significantly higher CECs, vWf, TF and IL-6 levels, but lower FMD, when compared to stable CAD and HC (all p<0.001) and all were inter-correlated significantly. In ACS, CECs was strongly correlated with FMD (r=-0.64, p<0.001) and TF (r=0.7, p<0.001). In stable CAD, significant correlations were again found between many indices, but on multivariate analysis, IL-6 and vWf were both independently related to FMD.. Increased CECs in ACS patients are closely associated with endothelial damage/dysfunction (vWf and FMD), coagulation (TF) and inflammation (IL-6). These inter-relationships support the concept of a central role of endothelial damage/injury in the activation of vascular and coagulation abnormalities in ACS.

Topics: Aged; Biomarkers; Blood Flow Velocity; Chest Pain; Coronary Disease; Endothelium, Vascular; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Multivariate Analysis; Thromboplastin; Vasodilation; von Willebrand Factor

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Atorvastatin; Cohort Studies; Coronary Disease; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Lipids; Lipoproteins; Male; Middle Aged; Prothrombin; Pyrroles; Thrombin; Thromboplastin; Treatment Outcome

Histamine plays an important role in vascular disease. Tissue factor (TF) expression is induced in vascular inflammation and acute coronary syndromes.. This study examined the effect of histamine on tumor necrosis factor-alpha- (TNF-alpha-) vs. thrombin-induced endothelial TF expression.. Histamine (10(-8)-10(-5) mol L-1), TNF-alpha (5 ng mL-1), and thrombin (1 U mL-1) induced TF expression in human endothelial cells. Although TF expression by TNF-alpha and thrombin was identical, histamine augmented TNF-alpha-induced expression 7.0-fold, but thrombin-induced expression only 2.6-fold. Similar responses occurred with TF activity. The H1-receptor antagonist mepyramine abrogated these effects. Differential augmentation by histamine was also observed at the mRNA level. Histamine-induced p38 activation preceded a weak second activation to both TNF-alpha and thrombin. Histamine-induced c-Jun NH2-terminal kinase (JNK) activation was followed by a strong second activation to TNF-alpha, and less to thrombin. Selective inhibition of this second JNK activation by SP600125 reduced TF induction to histamine plus TNF-alpha by 67%, but to histamine plus thrombin by only 32%. Histamine augmented TNF-alpha- and thrombin-induced vascular cell adhesion molecule 1 (VCAM-1) expression to a similar extent. Consistent with this observation, VCAM-1 induction to TNF-alpha and thrombin was mediated by p38, but not by JNK.. Histamine differentially augments TNF-alpha- vs. thrombin-induced TF expression and activity, which is mediated by the H1-receptor, occurs at the mRNA level, and is related to differential JNK activation.

Topics: Acute Disease; Anthracenes; Cell Adhesion; Cells, Cultured; Coronary Disease; Endothelial Cells; Enzyme Activation; Gene Expression Regulation; Hemostatics; Histamine; Humans; JNK Mitogen-Activated Protein Kinases; Receptors, Histamine H1; Signal Transduction; Syndrome; Thrombin; Thromboplastin; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Vasculitis

Aims of our study were to evaluate the prevalence of high lipoprotein (a) [Lp(a)] and homocysteine levels - both in the fasting state (FHcy) and post-methionine (PMHcy) - in young coronary artery disease (CAD) patients, and to investigate the role of genetic and environmental factors for hyperhomocysteinaemia.. We studied 140 patients with angiographically documented CAD (24 women

Topics: Adult; Biomarkers; Blood Coagulation; Case-Control Studies; Chelating Agents; Coronary Disease; Fasting; Female; Folic Acid Deficiency; Homocysteine; Humans; Lipoprotein(a); Male; Methionine; Middle Aged; Risk; Statistics, Nonparametric; Thromboplastin; Vitamin B 12 Deficiency

Increased platelet activation is well documented in patients with acute coronary syndromes and can be detected by various methods, including flow cytometry and enzyme-linked immunosorbent assay. However, such techniques require several steps and cannot provide quick results. Platelet activation ultimately results in procoagulant phospholipid exposure and we have previously described a simple activated factor X-activated clotting time (XACT) test that is insensitive to resting platelets but that is significantly shortened by activated platelets, microparticles and procoagulant phospholipids. Our aim was to determine whether the XACT test could be used to distinguish patients with chest pain due to cardiac ischaemia from those having chest pain due to non-cardiac causes. We thus carried out XACT tests on ethylenediamine tetraacetic acid whole blood and plasma samples obtained from 46 patients presenting to the emergency department with chest pain and from 30 controls. Sixteen cases (30%) were subsequently diagnosed as acute coronary syndromes. Blood samples from these patients displayed overall significantly shortened XACT results relative to both healthy controls (P<0.001) and chest pain not due to cardiac ischaemia (P<0.004). This discrimination was much better with whole blood samples than when platelet-poor plasmas were tested (P=0.153), suggesting that free microparticles were not the only factors responsible. Thus, the detection of increased procoagulant phospholipid activity in whole blood by shortened XACT results may be a simple and rapid diagnostic marker of some cardiac ischaemic events.

Topics: Acute Disease; Aged; Angina Pectoris; Blood Coagulation Factors; Blood Coagulation Tests; Chest Pain; Coronary Disease; Factor X; Female; Humans; Male; Middle Aged; Phospholipids; Pilot Projects; Platelet Activation; Predictive Value of Tests; Syndrome; Thromboplastin; Time Factors

Histamine can induce coronary vasospasm, leading to variant angina and acute myocardial infarction. However, the role of histamine in thrombus formation is ill defined. Hence, this study investigates whether histamine induces tissue factor (TF) expression in vascular cells.. Histamine (10(-8) to 10(-5) mol/L) induced TF expression in a concentration-dependent manner in human aortic endothelial and vascular smooth muscle cells, whereas TF pathway inhibitor expression remained unaffected. RT-PCR and Northern blotting revealed that histamine stimulated TF mRNA transcription, peaking at 1 hour. Protein expression increased 18-fold (P<0.02) with a maximum at 5 hours, which was paralleled by a 4-fold augmentation in surface activity (P<0.01). These effects were completely prevented by pretreatment with the H1 receptor antagonists mepyramine (P<0.0001), chlorpheniramine, and diphenhydramine but not the H2 receptor antagonist cimetidine (P=NS). Histamine induced a time-dependent, H1 receptor-mediated activation of p38 MAP kinase (p38), p44/42 MAP kinase (ERK), and c-jun terminal NH2 kinase (JNK). Blocking of p38, ERK, or JNK with SB203580 (P<0.0001), PD98059 (P<0.0001), or SP600125 (P<0.0001), respectively, impaired histamine-induced TF expression in a concentration-dependent manner. In contrast, histamine-stimulated TF expression was increased by phosphatidylinositol 3-kinase inhibition with LY294002 or wortmannin, whereas it was not affected by Rho-kinase inhibition with Y-27632 or hydroxyfasudil.. Histamine induces expression of TF, but not TF pathway inhibitor, in vascular cells via activation of the H1, but not H2, receptor. This effect is mediated by the MAP kinases p38, ERK, and JNK. This observation may open novel perspectives in the treatment of variant angina and acute coronary syndromes.

Topics: Acute Disease; Cells, Cultured; Coronary Disease; Endothelial Cells; Histamine; Histamine H1 Antagonists; Humans; Lipopolysaccharides; Lipoproteins; MAP Kinase Signaling System; Muscle, Smooth, Vascular; Receptors, Histamine H1; rho GTP-Binding Proteins; Thromboplastin; Tumor Necrosis Factor-alpha

Topics: Anticholesteremic Agents; Antineoplastic Agents; Apolipoproteins; Biomarkers; C-Reactive Protein; Coronary Disease; Female; Fibrinogen; Hemostatics; Humans; Hyperlipidemias; Lipoproteins; Male; Matrix Metalloproteinase 9; Middle Aged; Placebo Effect; Protease Inhibitors; Simvastatin; Thromboplastin; Thrombosis; Tissue Inhibitor of Metalloproteinase-1; Tumor Necrosis Factor-alpha

High cholesterol is a well-established risk factor of myocardial infarction (MI). Since monocytes play a pivotal role in the development of atherosclerosis, one might anticipate that their functional properties are very important in relation to MI. In the present study, we have explored how the lipopolysaccharide (LPS)-induced reactivity of monocytes in whole blood in vitro relates to the serum lipid profile of healthy subjects with a history of MI or cancer in their close family. Twenty of the 54 subjects (of the total 266 test subjects) in the MI families had moderately high cholesterol (7.1-10.2 mmol/l), whereas 34 had normal cholesterol. Nineteen of the normocholesterol individuals had hyperactive monocytes (high responders), whereas 15 had monocytes responding normally. Two of the 20 subjects in the high cholesterol group had hyperactive monocytes. LPS-induced tissue factor, tumour necrosis factor-alpha and interleukin-6 were on the average three to four times higher in the normocholesterol group compared with the moderately hypercholesterol group, and hence no positive correlation was found between hyperactive monocytes and cholesterol. The 42 subjects in the families with cancer had normal cholesterol, and two of these subjects had very high LPS-induced tissue factor, tumour necrosis factor-alpha and interleukin-6, whereas eight of the 170 subjects without MI or cancer in their family were high responders. This further substantiates the notion that moderately high cholesterol is not associated with enhanced monocyte activation in whole blood. Hyperactive peripheral blood monocytes are suggested to be associated with a significant risk factor in developing coronary heart disease.

Topics: Adolescent; Adult; Aged; Cholesterol; Coronary Disease; Family Health; Female; Fibrinolysis; Genetic Predisposition to Disease; Humans; Hypercholesterolemia; Infections; Interleukin-6; Lipopolysaccharides; Male; Middle Aged; Monocytes; Myocardial Infarction; Neoplasms; Plasminogen Activator Inhibitor 1; Risk Factors; Thromboplastin; Tissue Plasminogen Activator; Triglycerides; Tumor Necrosis Factor-alpha

On the basis of the role of immuno-mediated inflammation in atherosclerosis we investigated, (1) the prevalence of anti-endothelial cell antibodies (AECA) in ischaemic heart disease (IHD); (2) if beta2-glycoprotein I (beta2-GPI) was the target antigen of AECA; (3) the relationship between AECA, tissue factor (TF) and tissue factor pathway inhibitor (TFPI). In 93 consecutive IHD patients undergoing percutaneous transluminal coronary angioplasty (PTCA) and 105 controls AECA were detected by ELISA on human umbilical vein endothelial cells (HUVEC). AECA positive sera were evaluated for anti-beta2-GPI antibodies by ELISA. TF and TFPI plasma levels were assessed by ELISA. Twelve of 93 (12.9%) IHD patients and only one of 105 controls (0.95%) were AECA positive. The prevalence of AECA was higher in unstable angina (UA) than in effort angina (EA) (P=0.01). Three of 12 AECA positive sera resulted positive for anti-beta2-GPI and showed a marked decrease in EC-binding when tested on HUVEC cultured in serum-free medium. The binding was restored by the addition of beta2-GPI. TF and TFPI levels were similar in AECA positive and AECA negative patients. The rate of angiographically documented clinical recurrences was 66.7% in the AECA positive and 14.8% in the AECA negative group (P=0.0004) with a significant relationship between restenosis and AECA (P<0.0001), unchanged by the inclusion of cardiovascular risk factors in the regression model. Our results suggest a 'role' for AECA in the immune-mediated inflammation in UA beta2-GPI is not the only AECA target antigen. AECA are not responsible for high TF and TFPI levels. The high rate of clinical recurrences after PTCA, confirmed by angiography, in AECA positive patients is in line with such a role and suggests further large-scale 'ad hoc' studies.

Topics: Angioplasty, Balloon, Coronary; Apolipoproteins; Autoantibodies; beta 2-Glycoprotein I; Biomarkers; Coronary Angiography; Coronary Disease; Disease Progression; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Factor Xa Inhibitors; Female; Glycoproteins; Humans; Lipoproteins; Male; Middle Aged; Recurrence; Thromboplastin; Umbilical Veins

The tissue factor and tissue factor pathway inhibitor (TFPI) system has been studied in the acute phase of coronary disease but its prognostic importance has been less well assessed. We evaluated its association with recurrent coronary events during long-term follow-up after a myocardial infarction.. We studied 55 consecutive patients with the following criteria for inclusion: (1) first myocardial infarct; (2) aged < 70 years; (3) non-complicated infarct; (4) low risk effort-test. Blood samples were taken 60-80 days after infarction. Tissue factor, total and free-TFPI were measured. A 4-year follow-up was carried out. Death, unstable angina and new myocardial infarction were considered as poor prognosis.. There were no statistical differences in tissue factor/TFPI levels between patients and controls. Total-TFPI showed statistical correlation with total cholesterol (r = 0.59), triglycerides (r = 0.34), LDL-cholesterol (r = 40) and Lipoprotein(a) (r = 0.48). Patients with high levels of cholesterol, LDL-cholesterol and triglycerides showed elevated levels of total-TFPI with no differences in free-TFPI. During follow-up, 8 patients showed poor prognosis. There were no statistical associations between tissue factor/TFPI levels and prognosis.. After acute myocardial infarction, we did not find any differences in the tissue factor/TFPI system between controls and patients. The tissue factor/TFPI system showed little value as a prognostic factor.

Topics: Aged; Analysis of Variance; Biomarkers; Case-Control Studies; Coronary Disease; Female; Follow-Up Studies; Humans; Lipoproteins; Male; Middle Aged; Myocardial Infarction; Prognosis; Statistics, Nonparametric; Thromboplastin

We investigated changes in blood coagulation in the coronary circulation after percutaneous transluminal coronary angioplasty (PTCA) and its clinical significance. We examined 43 patients with ischemic heart disease who underwent elective PTCA of isolated stenotic lesions in the left coronary artery. Ten patients underwent PTCA alone, 15 received percutaneous transluminal rotational atherectomy (PTRA) and 18 stent implantation. Blood samples were drawn from the coronary sinus before and immediately after PTCA, as well as 4 and 24 h later. Plasma levels of tissue factor (TF), thrombin-antithrombin III complex (TAT) and prothrombin fragment 1+2 (F 1+2) were measured by enzyme-linked immunosorbent assay. Follow-up coronary angiography was performed 6 months after PTCA. Minimal luminal diameter was assessed by quantitative coronary angiography to evaluate late loss index. TF, TAT and F 1+2 levels in the coronary sinus blood showed significant increases 24 h after PTCA. A significant positive correlation was found between changes in TF levels 24 h after PTCA and late loss index 6 months after the procedure. TF levels in the coronary sinus blood were significantly higher in patients with late restenosis than in those without restenosis. These results suggest that TF expression in the coronary circulation after PTCA is a prognostic factor for late restenosis.

Topics: Adult; Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Biomarkers; Blood Coagulation; Coronary Circulation; Coronary Disease; Female; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Prognosis; Recurrence; Thromboplastin

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to reduce cardiac allograft failure and to lower the incidence of transplant coronary artery disease. These effects result from as yet unknown mechanisms not clearly attributable to lipid lowering. We here report that low-dose simvastatin treatment inhibits excessive expression of monocyte tissue factor (TF) and reduces the persistent hypercoagulability state seen in cardiac transplant recipients.. Fifteen consecutive heart transplant recipients receiving standard oral immunosuppression were newly assigned to a 10 mg daily simvastatin therapy. Levels of TF activity in both unstimulated and lipopolysaccharide-stimulated peripheral blood mononuclear cells drawn from transplant recipients before and under simvastatin therapy were evaluated by one-stage clotting assay.. Monocyte TF activity was found to be significantly increased in cardiac transplant recipients when compared with healthy controls. Excessive monocyte procoagulant activity was reduced in cardiac transplant recipients during simvastatin treatment. This effect occurred independently of the reduction of serum low-density lipoprotein cholesterol. As demonstrated by reverse transcriptase-polymerase chain reaction, monocyte TF reduction by simvastatin, observed in 13 of the 15 transplant recipients investigated, could be ascribed to an inhibition of monocyte TF gene transcription. The reduction of monocyte TF activity during treatment with simvastatin paralleled with the normalization of elevated levels of thrombin-antithrombin complex, prothrombin fragment F1+2, and D-dimer, which are markers of thrombin and fibrin formation indicating coagulation activation after cardiac transplantation.. Inhibition of monocyte TF expression and attenuation of the persistent hypercoagulable state observed in cardiac transplant recipients during treatment with simvastatin may represent an important mechanism by which HMG-CoA reductase inhibitors protect against the development of transplant coronary artery disease.

Topics: Adult; Aged; Blood Coagulation Disorders; Coronary Disease; Female; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Middle Aged; Monocytes; RNA, Messenger; Simvastatin; Thromboplastin

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Animals, Genetically Modified; Coronary Disease; Disease Models, Animal; Humans; Hypertension; Mice; Rats; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Thromboplastin; Thrombosis

Tissue factor (TF), a main initiator of clotting, is up-regulated in vasculopathy. We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT(1) receptor blockade inhibits TF expression in a model of ANG II-induced cardiac vasculopathy. Furthermore, we explored the mechanisms by examining transcription factor activation and analyzing the TF promoter. Untreated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) feature hypertension and severe left ventricular hypertrophy with focal areas of necrosis, and die at age 7 weeks. Plasma and cardiac ANG II was three- to fivefold increased compared to Sprague-Dawley rats. Chronic treatment with valsartan normalized blood pressure and coronary resistance completely, and ameliorated cardiac hypertrophy (P < 0.001). Valsartan prevented monocyte/macrophage infiltration, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) activation, and c-fos expression in dTGR hearts. NF-kappaB subunit p65 and TF expression was increased in the endothelium and media of cardiac vessels and markedly reduced by valsartan treatment. To analyze the mechanism of TF transcription, we then transfected human coronary artery smooth muscle cells and Chinese hamster ovary cells overexpressing the AT(1) receptor with plasmids containing the human TF promoter and the luciferase reporter gene. ANG II induced the full-length TF promoter in both transfected cell lines. TF transcription was abolished by AT(1) receptor blockade. Deletion of both AP-1 and NF-kappaB sites reduced ANG II-induced TF gene transcription completely, whereas the deletion of AP-1 sites reduced transcription. Thus, the present study clearly shows an aberrant TF expression in the endothelium and media in rats with ANG II-induced vasculopathy. The beneficial effects of AT(1) receptor blockade in this model are mediated via the inhibition of NF-kappaB and AP-1 activation, thereby preventing TF expression, cardiac vasculopathy, and microinfarctions.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Animals, Genetically Modified; Antihypertensive Agents; Blood Coagulation Factors; Blood Pressure; Cell Line; CHO Cells; Coronary Disease; Coronary Vessels; Cricetinae; Extracellular Matrix Proteins; Heart Ventricles; Humans; Inflammation; Integrin alpha4beta1; Integrins; NF-kappa B; Promoter Regions, Genetic; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Lymphocyte Homing; RNA, Messenger; Tetrazoles; Thromboplastin; Transcription Factor AP-1; Valine; Valsartan; Vascular Resistance

Several studies have shown that thrombosis and inflammation play an important role in the pathogenesis of coronary artery disease (CAD). Tissue factor (TF) is responsible for the thrombogenicity of the atherosclerotic plaque and plays a key in triggering thrombin generation. The aim of this study was to assess the levels of TF and tissue factor pathway inhibitor (TFPI) in patients with angiographically documented CAD and also to evaluate TF induction on monocytes in vitro in the presence of these plasmas from patients with CAD.. Plasma antigen levels of soluble TF and TFPI were measured in 65 CAD patients and 22 healthy controls. Surface TF expression on monocytes from a healthy donor treated with plasma samples was evaluated by flow cytometry with a direct double-color immunofluorescence technique.. Significantly elevated levels of both TF and TFPI were found in CAD patients compared with healthy controls (303.6 +/- 134.1 vs. 187.3 +/- 108.7 pg/ml, p < 0.05; 85.2 +/- 48.6 vs. 65.0 +/- 29.0 ng/ml, p < 0.05). By flow cytometry, monocytes from a healthy donor displayed higher TF antigen expression when incubated in the presence of CAD plasmas than in control plasmas (34.6 +/- 10.7 vs. 23.2 +/- 10.2%, p < 0.05).. The high levels of circulating TF are present in CAD, which were not sufficiently inhibited by the elevated TFPI plasma levels. Although the source of circulating TF is unclear, TF induction of monocytes by plasma from CAD patients may contribute to the hypercoagulable state.

Topics: Adult; Aged; Antigens; Biomarkers; Coronary Disease; Enzyme-Linked Immunosorbent Assay; Factor Xa Inhibitors; Female; Flow Cytometry; Fluorescent Antibody Technique, Direct; Humans; Lipoproteins; Male; Middle Aged; Monocytes; Serine Proteinase Inhibitors; Severity of Illness Index; Thromboplastin

The glycoprotein (GP) IIb/IIIa receptor antagonists used widely in the medical treatment of acute coronary syndromes and during percutaneous coronary interventions, prevent fibrinogen cross-linking and platelet aggregation, critical initiating steps in arterial thrombosis. Their anticoagulant properties, particularly when administered conjunctively with heparin preparations, are less well-characterized. In a series of in vitro studies, increasing concentrations of abciximab, tirofiban, and eptifibatide either alone or in combination with unfractionated heparin (UFH) or fractionated heparin (enoxaparin) were added to washed platelets suspended in Tyrode's buffer. Following platelet activation and prothrombinase assembly, thrombin generation was determined by enzyme-linked immunosorbent assay (ELISA). There was a concentration-dependent reduction in platelet-dependent thrombin generation with each of the GPIIb/IIIa receptor antagonists. The combination of tirofiban and UFH yielded percent, absolute and relative reductions (compared with tirofiban alone) of 48.0%, 16.9%, and 35.2%, respectively. The corresponding values for eptifibatide and abciximab were 38.0%, 13.5%, 35.5%, and 55.1%, 3.8%, 8.4%, respectively. Thrombin generation was decreased by an additional 2 to 3% (absolute reduction) with high concentrations of enoxaparin in combination with either eptifibatide or abciximab. Platelet GPIIb/IIIa receptor antagonists, beyond their ability to prevent fibrinogen-mediated aggregation, inhibit platelet-dependent prothrombinase activity and thrombin generation in a concentration-dependent manner. Heparin facilitates the existing anticoagulant properties, supporting combination therapy in clinical practice. The potential added benefit of fractionated heparin over UFH will require further investigation.

Topics: Abciximab; Acute Disease; Antibodies, Monoclonal; Anticoagulants; Blood Platelets; Coronary Disease; Dose-Response Relationship, Drug; Eptifibatide; Heparin; Humans; Immunoglobulin Fab Fragments; Kinetics; Peptides; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Thrombin; Thromboplastin; Tirofiban; Tyrosine

Cardiac allograft vasculopathy is a major cause of morbidity and mortality of cardiac transplant recipients. The underlying cause of this disease remains unclear. Histological studies have implicated accelerated hemostasis and intravascular fibrin deposition in its pathogenesis. In the present study a defined model of this disease in the rat was used to elucidate the implication of tissue factor in the production of the hypercoagulable state observed in cardiac allograft vessels. Tissue factor protein and mRNA expression were studied in rat heart allografts developing allograft vasculopathy resembling human disease. Immunohistochemistry demonstrated tissue-factor-positive cells present in the allograft coronary intima and adventitia. Significant staining for tissue factor was detected in the endothelium lining coronary lesions in cardiac allografts and in interstitial mononuclear cells, respectively. Both transplant coronary endothelial cells and mononuclear cells contained tissue factor mRNA as indicated by oligo-cell reverse transcription polymerase chain reaction after laser-assisted cell picking. In contrast, tissue factor mRNA and protein were not or negligibly detectable within the coronary intima of nontransplanted control hearts. Thus, the present study clearly demonstrates that aberrant tissue factor expression occurs within the coronary intima after cardiac transplantation. Tissue factor, activating downstream coagulation mechanisms, may account for the intravascular clotting abnormalities observed in cardiac allografts and may represent a key factor in transplant atherogenesis.

Topics: Animals; Coronary Disease; Coronary Vessels; Heart Transplantation; Male; Myocardium; Postoperative Complications; Rats; Rats, Inbred Lew; Reference Values; RNA, Messenger; Thromboplastin; Tunica Intima

To investigate the expression of monocyte tissue factor (MTF) and adhesion molecules in patients with chronic renal failure (CRF) and to look for any correlation with thrombin generation and Lp(a) lipoprotein.. A study of MTF expression and adhesion molecules, prothrombin fragments 1+2 (PTf1+2), an index of thrombin generation, and lipoproteins in patients with CRF and in normal control subjects.. Patients with end stage renal failure have an increased risk of coronary artery disease despite advances in therapy. Stimulated monocytes are potent activators of blood coagulation through the generation of MTF, which was recently implicated in the aetiology of acute coronary ischaemic syndromes.. MTF expression and adhesion molecules were measured in whole blood using immunofluorescence of monocytes labelled with anti-tissue factor antibody and CD11b and c by flow cytometry. PTf1+2 and Lp(a) lipoprotein in plasma were measured by enzyme linked immunosorbent assay (ELISA).. 70 patients with CRF without documented coronary artery disease (30 patients with CRF undialysed, 20 patients undergoing chronic ambulatory peritoneal dialysis (CAPD), and 20 undergoing haemodialysis (HD)), together with 20 normal controls, were studied.. The (mean (SD)) increased MTF of CRF (48.0 (29) v 33.3 (7.2) mesf unit/100 monocytes in controls, p = 0.04) was more pronounced in patients undergoing dialysis (HD 73.1 (32.8) (p < 0.003) and CAPD 62.8 (28.9) mesf unit/100 monocytes, p < 0.04). MTF activity showed a positive correlation with both PTf1+2 and serum creatinine (p < 0.003) but not with Lp(a) lipoprotein. Lp(a) lipoprotein was significantly increased in both dialysis groups compared with controls (p < 0.005) and non-dialysis CRF groups (p < 0.02). Monocyte adhesion molecule (CD11b) was significantly higher in all three CRF groups than in the controls (p = 0.006).. This study has demonstrated a hypercoagulable state in patients with CRF. This was especially pronounced in the dialysis patients. These findings provide a possible explanation for the increased cardiovascular and cerebrovascular morbidity and mortality in these patients.

Topics: Case-Control Studies; Coronary Disease; Flow Cytometry; Humans; Kidney Failure, Chronic; Lipoprotein(a); Macrophage-1 Antigen; Monocytes; Peritoneal Dialysis, Continuous Ambulatory; Prothrombin; Regression Analysis; Renal Dialysis; Statistics, Nonparametric; Thrombin; Thromboplastin

We have reported that the plasma levels of plasma fibrinopeptide A and plasminogen activator inhibitor activity increase in patients with unstable angina and acute myocardial infarction. Tissue factor (TF) is a low-molecular-weight glycoprotein that binds to and acts on essential cofactor VII, and the resulting complex activates factors IX and X, initiating the coagulation cascade. We measured plasma TF antigen levels in 21 patients with unstable angina (on admission and after treatment), 27 patients with stable exertional angina, and 27 control subjects. The 3 groups were matched for age, gender, and other clinical variables. The plasma TF antigen levels were higher in the unstable angina group than in the stable exertional angina and control groups (240 +/- 75 vs 184 +/- 46 and 177 +/- 37 pg/ml, p < 0.01). There were no significant differences in the plasma TF antigen levels between the stable exertional angina and the control groups. Furthermore, the plasma TF antigen levels were reexamined after treatment in the 21 patients with unstable angina. The mean level in these 21 patients decreased after 2 weeks of treatment (from 240 +/- 75 to 206 +/- 57 pg/ml, p < 0.01). This study suggests that the plasma TF antigen levels correlate with disease activity in patients with unstable angina. The increased plasma TF antigen levels in patients with unstable angina may reflect intravascular procoagulant activity.

Topics: Adult; Aged; Angina Pectoris; Angina, Unstable; Case-Control Studies; Coronary Angiography; Coronary Disease; Female; Humans; Male; Middle Aged; Physical Exertion; Severity of Illness Index; Thromboplastin

Balloon coronary angioplasty is a revascularization procedure which increases the luminal diameter at a site of arterial stenosis, leading to mechanical disruption of the atherosclerotic plaque and to stretching of the vascular wall (1). This procedure can be complicated by thrombosis or restenosis, which occur in 5% and 30% of the cases respectively (2). These complications probably result from exposure of blood to components of atherosclerotic plaque, subendothelium and components of vascular wall, leading to activation of coagulation (thrombin generation) and platelets (3,4). Recent data point to simultaneous increase of leukocyte adhesive receptors, indicating an additional process of leukocyte activation, which could play a key role in the vascular healing process after angioplasty (5). These elements could also play a role in the thrombotic and stenotic complications.

Topics: Aged; Angina Pectoris; Angina, Unstable; Angioplasty, Balloon, Coronary; Cells, Cultured; Coronary Disease; Female; Humans; Leukocyte Count; Male; Middle Aged; Monocytes; Peptide Fragments; Protein Precursors; Prothrombin; Thromboplastin; Time Factors

There is a significant direct relationship between steady-state intravenous heparin dose requirements and total body weight. Less is known about whether sex, age, clinical diagnosis, and the thromboplastin used to measure the activated partial thromboplastin time (aPTT) affect heparin dose requirements.. Four cohorts of patients treated with intravenous heparin were gathered from 3 hospitals: 2 cohorts with deep vein thrombosis (DVT) and 2 cohorts with coronary artery disease (CAD). For each clinical diagnosis, half the patients were monitored using one aPTT reagent and the remainder were monitored using a second reagent. Heparin doses and aPTT measurements were recorded, and the dose necessary to achieve an aPTT ratio of 2.0 was calculated using a computer software program.. We analyzed the records of 340 patients: 165 with DVT and 175 with CAD. Using analysis of variance, there was a significant difference in the steady-state heparin requirements among patients with DVT compared with patients with CAD (P < .001). For each clinical diagnosis, the use of a different thromboplastin reagent did not affect heparin dose requirements (P > .42). Linear regression modeling disclosed that the steady-state heparin dose for patients with DVT was a function of weight plus an effect modifier involving weight and age, whereas for patients with CAD there was only a weak relationship with weight.. Steady-state heparin dose requirements were significantly different in patients with DVT compared with patients with CAD, suggesting that different dosing nomograms are needed for each condition. For patients with DVT, the accuracy of the initial heparin dose estimate may be improved by considering the patient's age and weight.

Topics: Aged; Aged, 80 and over; Aging; Anticoagulants; Body Weight; Coronary Disease; Female; Heparin; Humans; Infusions, Intravenous; Linear Models; Male; Middle Aged; Partial Thromboplastin Time; Sex Factors; Thromboplastin; Thrombosis

Topics: Blood Coagulation Factors; Coronary Disease; Fibrinolysis; Fibrinolytic Agents; Humans; Prothrombin; Thromboplastin; Vascular Patency

Tissue factor (TF), a transmembrane surface protein, is known to initiate thrombogenesis through plasmatic and cellular activation processes. Besides complexing with factor VII, eventually leading to fibrin generation via the extrinsic pathway, TF can also activate factor IX, resulting in the intrinsic activation of coagulation. Other functions of TF are currently unknown, although various cells are believed to have TF receptors. Many of the post-surgical and post-interventional thrombotic events are due to the release of TF. Increased levels of TF are associated with several pathologic conditions such as cancer, sepsis and inflammation. Cellular necrosis also results in an increase of TF as the cells in the traumatized area lyse and release endogenous cell surface-bound TF. An ELISA method (American Diagnostica, Greenwich, CT) has been developed to assay TF antigen levels in various biological fluids. This ELISA employs a murine monoclonal antibody raised against native human TF for antigen capture. In this study, cerebrospinal fluid, peritoneal fluid, pleural effusion and urine from patients were assayed for their TF content using this ELISA method. Normal individual serum and plasma were also assayed as controls against which the levels of TF in the patients' body fluids could be compared. The amount of TF antigen in normal human plasma and serum was 165 +/- 139 pg/ml and 165 +/- 110 pg/ml, respectively. Concentrations of TF antigen in other fluids were: cerebrospinal fluid 868 +/- 721 pg/ml, peritoneal fluid 124 +/- 247 pg/ml, pleural effusion 385 +/- 569 pg/ml, synovial fluid 97 +/- 23 pg/ml, seminal plasma 11,485 +/- 875 pg/ml and urine 86 +/- 57 pg/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Sequence; Angioplasty; Ascitic Fluid; Body Fluids; Coronary Angiography; Coronary Disease; Enzyme-Linked Immunosorbent Assay; Humans; Molecular Sequence Data; Pleural Effusion; Semen; Sepsis; Synovial Fluid; Thromboplastin

Plasma from healthy individuals, pregnant women and patients on warfarin were distributed to 3 laboratories supporting major cardiovascular surveys (Northwick Park, Muenster and Houston) for assay of factor VII coagulant activity (VIIc) with their own bio-assays. The mean VIIc in 147 samples agreed to within 1% of standard in Northwick Park and Houston, but was 14% of standard lower in Muenster owing to its more potent standard. In samples with an increased VIIc the Northwick Park assay gave a higher result than the other assays owing to its increased responsiveness to activated factor VII (VIIa). Thus when VIIa concentrations were determined directly with a clotting assay which utilises a soluble recombinant tissue factor, the increase in VIIc with increase in VIIa was considerably greater with the Northwick Park assay than the Muenster assay. This feature of the Northwick Park assay was traced to the virtual absence of protein C in its substrate plasma. Factor Va appears rate-limiting for the coagulant expression of VIIa in test plasma. If the thrombotic response to release of tissue factor is determined by the circulating concentration of VIIa, then the Northwick Park factor VII bio-assay may be preferable to other bio-assays currently employed to estimate risk of acute coronary events.

Topics: Adult; Blood Coagulation Tests; Coronary Disease; Enzyme Activation; Factor VII; Factor VII Deficiency; Female; Humans; Laboratories; Male; Pregnancy; Protein C; Protein S; Reproducibility of Results; Risk Factors; Sensitivity and Specificity; Thromboplastin; Warfarin

Topics: Coronary Disease; Enkephalin, Methionine; Factor VII; Hemostasis; Humans; Protein Precursors; Thromboplastin

This report describes studies on the activation of coagulation factor VII (FVII) and the inhibition of the extrinsic coagulation pathway in acute ischaemic heart disease. FVII and the inhibitor of the tissue thromboplastin-FVII complex, called extrinsic pathway inhibitor (EPI), were determined in plasma from 68 patients and compared to findings in 37 normal individuals. The mean FVII amidolytic activity, the mean FVII clotting activity, as well as the FVII clotting/FVII amidolytic ratio were not significantly different in the patient groups as compared to the controls. The fraction of FVII clotting activity that is sensitive to phospholipase C, 'the FVII-phospholipid complex', was 8% in controls, 19% (P less than 0.05) in patients with acute myocardial infarction, 15% (n.s.) in angina pectoris and 13% (n.s.) in heart failure/arrhythmia patients. The 'FVII-phospholipid complex' was highly significantly correlated to triglycerides in plasma in patients with acute myocardial infarction (r = 0.88, P less than 0.001) and angina pectoris (r = 0.89, P less than 0.001). The mean EPI levels were significantly increased in patients with acute myocardial infarction (132%), angina pectoris (134%), and heart failure (150%) as compared to the control population (110%). The FVII clotting/EPI ratio was significantly decreased both in patients with acute myocardial infarction and heart failure, whereas the FVII amidolytic/EPI ratio was significantly decreased only in the heart failure group. Apparently, in patients with acute ischaemic heart disease, a moderate increase in the procoagulant activity is accompanied by a marked increase in the anticoagulant activity of the extrinsic coagulation pathway, suggesting a balanced activation system.

Topics: Acute Disease; Adult; Aged; Angina Pectoris; Antigens; Coronary Disease; Factor VII; Factor VIIa; Female; Humans; Lipoproteins; Male; Middle Aged; Myocardial Infarction; Phospholipids; Thromboplastin; Triglycerides

The relationship of triglyceride levels to coagulation abnormalities was studied in 43 patients, who were divided into two groups. Group 1 consisted of patients with triglyceride levels less than 200 mg% (range, 75 to 190 mg%), and Group 2 consisted of patients with triglyceride levels greater than 250 mg% (range, 255 to 890 mg%). Analysis of the data revealed that patients with high triglyceride levels also have a high incidence of low antithrombin III activity and increased platelet aggregation. It is likely that hyperlipidemic patients are more prone to thrombosis of diseased coronary arteries or saphenous vein bypass grafts, and should definitely be placed on appropriate anticoagulants.

Topics: Adult; Aged; Anticoagulants; Antithrombin III; Blood Coagulation Disorders; Coronary Disease; Female; Fibrinogen; Humans; Hyperlipidemias; Male; Middle Aged; Platelet Aggregation; Prospective Studies; Thromboplastin; Thrombosis; Triglycerides

Topics: Acute Disease; Adaptation, Physiological; Animals; Blood Coagulation; Blood Coagulation Disorders; Blood Platelets; Cardiovascular Diseases; Chronic Disease; Convalescence; Coronary Disease; Fibrinolysin; Fibrinolysis; Humans; Myocardial Infarction; Rheumatic Diseases; Thrombelastography; Thromboplastin; Time Factors

The amount of antithrombin III in plasma was determined quantitatively in 218 males between 45-60 years of age. The mean antithrombin III value was found to be low in the group with low risk for ischemic heart disease, intermediate in the group with high risk for ischemic heart disease and highest in the group with acute myocardial infarction. Concomitant study of kaolin-activated partial thromboplastin time revealed a sharp decrease in its mean value in the group with acute myocardial infarction. The high correlation between antithrombin III and kaolin-activated partial thromboplastin time for the entire population suggests that the development of ischemic heart disease is a gradual process and that failure of the damping mechanism results as an acute event. These findings may be useful in the determination of the coagulation state of these patients.

Topics: Acute Disease; Antithrombins; Blood Coagulation Tests; Coronary Disease; Humans; Male; Middle Aged; Myocardial Infarction; Thromboplastin

Topics: Animals; Arginine; Benzamides; Cattle; Coronary Disease; Coumarins; Factor VIII; Fibrinogen; Hirudins; Humans; Hydrolysis; Naphthalenes; Protein Binding; Prothrombin; Serum Albumin; Thrombin; Thromboplastin

Topics: Adult; Animals; Arteriosclerosis; Blood Coagulation; Brain Chemistry; Cadaver; Ceramides; Cholesterol; Chromatography, Thin Layer; Coronary Disease; Female; Humans; Male; Marsupialia; Middle Aged; Muscles; Prothrombin Time; Rats; Snakes; Stress, Physiological; Thromboplastin; Venoms

Topics: Blood Coagulation; Blood Coagulation Tests; Clot Retraction; Coronary Disease; Factor VII; Factor VIII; Factor X; Fibrinogen; Fibrinolysis; Humans; Male; Middle Aged; Plasminogen; Prospective Studies; Prothrombin; Prothrombin Time; Sampling Studies; Thromboplastin

Topics: Adult; Aged; Aorta; Arteriosclerosis; Coronary Disease; Fluorescent Antibody Technique; Humans; Lipoproteins; Middle Aged; Thromboplastin

Topics: Anticoagulants; Coronary Disease; Humans; Thromboplastin

Topics: Anticoagulants; Coronary Disease; Humans; Thromboplastin

Topics: Animals; Blood Coagulation; Coronary Disease; Disease Models, Animal; Dogs; Fibrinogen; Fibrinolysis; Heparin; Methods; Prothrombin Time; Thrombelastography; Thromboplastin; Time Factors

Topics: Adult; Aged; Angina Pectoris; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Coronary Disease; Diabetes Complications; Diabetes Mellitus; Female; Fibrinolysis; Humans; Lipids; Male; Middle Aged; Myocardial Infarction; Platelet Adhesiveness; Prothrombin Time; Thromboplastin

Topics: Acute Kidney Injury; Anemia, Hemolytic; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Transfusion; Coronary Disease; Female; Heart Arrest; Hemorrhagic Disorders; Humans; Hyaline Membrane Disease; Infant, Newborn; Ischemia; Kidney Transplantation; Male; Obstetric Labor Complications; Pregnancy; Shock, Septic; Shwartzman Phenomenon; Thrombocytopenia; Thromboembolism; Thromboplastin; Toxemia; Wounds and Injuries

Topics: Adult; Aged; Arteriosclerosis; Blood Coagulation; Blood Platelets; Coronary Disease; Epinephrine; Erythrocytes; Female; Humans; In Vitro Techniques; Male; Middle Aged; Thromboplastin

Topics: Blood Platelets; Coronary Disease; Erythrocytes; Humans; Leukocytes; Mathematics; Probability; Stress, Psychological; Thromboplastin; Time Factors; Vasomotor System

Topics: Adult; Aged; Animals; Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Coronary Disease; Dogs; Female; Heparin; Humans; Male; Middle Aged; Rabbits; Rats; Thrombelastography; Thromboplastin

Topics: Adult; Aged; Arteriosclerosis; Blood Coagulation Disorders; Blood Coagulation Tests; Coronary Disease; Female; Humans; Intracranial Arteriosclerosis; Male; Middle Aged; Thromboplastin; Thrombosis

Topics: Adult; Arteriosclerosis; Blood Coagulation Tests; Cholesterol; Coronary Disease; Female; Fibrinolysin; Heparinoids; Humans; Intracranial Arteriosclerosis; Lipids; Male; Middle Aged; Thromboplastin; Thrombosis

Topics: Adult; Cardiomyopathies; Coronary Disease; Female; Fetomaternal Transfusion; Humans; Myocardium; Pregnancy; Puerperal Disorders; Thromboplastin

Topics: Blood Coagulation Tests; Coronary Disease; Humans; Thromboplastin; Vascular Diseases

Topics: Blood Coagulation Tests; Coronary Disease; Humans; In Vitro Techniques; Thromboplastin

Topics: Adrenal Cortex Hormones; Anticoagulants; Arteriosclerosis; Blood Platelet Disorders; Coronary Disease; Fats; Female; Humans; Intracranial Embolism; Intracranial Embolism and Thrombosis; Neoplasms; Pharmacology; Postoperative Complications; Pregnancy; Pregnancy Complications; Pregnancy Complications, Hematologic; Thrombophilia; Thromboplastin; Thrombosis

Topics: Arteriosclerosis Obliterans; Blood Coagulation; Blood Coagulation Tests; Cerebrovascular Disorders; Coronary Disease; Humans; Myocardial Infarction; Thrombelastography; Thromboplastin

Topics: Adolescent; Blood Coagulation Tests; Blood Platelets; Child; Cholecystitis; Coronary Disease; Duodenal Ulcer; Geriatrics; Glycine max; Hemophilia A; Humans; Lecithins; Myocardial Infarction; Phosphatidylcholines; Polycythemia Vera; Thrombophlebitis; Thromboplastin

Topics: Aorta; Coronary Disease; Fibrinolysis; Humans; Thromboplastin