thromboplastin and Angina--Unstable

Tissue factor (TF) is a transmembrane glycoprotein, currently considered as being the major regulator of the coagulation cascade and the initiator of thrombogenesis in vivo. When TF comes in contact with blood, it forms a high-affinity complex with factors VII/VIIa, activating factors IX and X and thus leading to the formation of an insoluble fibrin clot. The regulation of TF-VIIa activity plays a key role in blood-vessel wall interactions. Selective patterns of cellular expression of TF are observed in tissues. TF is constitutively localized only on the surface of cells anatomically separated from the blood, where it plays an essential role in hemostasis by limiting hemorrhage after vessel wall injury. A number of pathophysiologic stimuli are capable of inducing TF transcription and activity in endothelial cells and monocytes. An aberrant TF expression in contact with blood is implicated in thrombotic complications of atherosclerosis, including acute myocardial infarction. Recent findings have demonstrated cell-derived microparticles containing TF in the circulating blood of patients with acute coronary syndromes, capable of triggering and propagating thrombus growth. This observation suggests a new view of thrombosis that does not necessarily require the exposure of vessel wall-derived TF at the site of vascular injury to initiate and propagate thrombosis.

Topics: Angina, Unstable; Animals; Arteriosclerosis; Blood Coagulation; Cardiovascular Diseases; Disease Models, Animal; Factor IX; Factor VII; Factor VIIa; Factor X; Fibrinolytic Agents; Helminth Proteins; Hemostasis; Humans; Myocardial Infarction; Syndrome; Thromboplastin; Thrombosis

Thrombosis at the site of atherosclerotic plaque disruption is the principal cause of acute coronary syndromes. The severity of the clinical consequences is determined by the extent and the progression of the thrombus that are caused by local and systemic factors. In atherosclerotic lesions mediators induce tissue factor (TF) in macrophages, smooth muscle cells, and endothelial cells. Procoagulant microparticles in the lipid core further enhance the thrombogenicity of the plaque. In addition, in acute coronary syndromes circulating monocytes and microparticles express TF and, thereby, contribute to systemic procoagulant activity. As a regulatory mechanism surface-bound, endogenous tissue factor pathway inhibitor-1 (TFPI) inhibits TF activity by translocation of the quaternary complex TF-FVIIa-FXa-TFPI into glycosphingolipid-rich microdomains more efficiently than exogenously added TFPI. This inhibition occurs not only in endothelial cells but also on circulating monocytes and presumably microparticles. Because therapeutic thrombolysis in acute myocardial infarction degrades TFPI, a prothrombotic state due to unopposed TF activity may occur. Several studies have demonstrated a contribution of local and bloodborne TF to thrombus formation; a direct relationship with the clinical outcome, however, awaits further studies. This article discusses the current understanding of the role of TF and its regulation by TFPI in acute coronary syndromes.

Topics: Angina, Unstable; Antithrombin III; Coronary Artery Disease; Coronary Thrombosis; Humans; Lipoproteins; Myocardial Infarction; Thromboplastin

Thrombus formation on a disrupted atherosclerotic plaque is a threatening event that leads to vessel occlusion and acute ischemia. In this current perspective, we present evidence for apoptosis as a major determinant of the thrombogenicity of the plaque lipid core and a potential contributor to plaque erosion and associated thrombosis. Moreover, apoptosis may directly affect blood thrombogenicity through the release of apoptotic cells and microparticles into the bloodstream.

Topics: Angina, Unstable; Animals; Apoptosis; Arteriosclerosis; Blood Coagulation; Embolism; Humans; Inflammation; Myocardial Infarction; Phosphatidylserines; Stroke; Thromboplastin; Thrombosis

The acute coronary syndromes, that include unstable angina, acute myocardial infarction, and many cases of sudden cardiac death, exact a considerable price on society in terms of mortality, morbidity, and health care costs. The coronary atherosclerotic lesion is often an indolent and progressive entity that can destabilize causing an acute syndrome with or without warning. The majority of acute coronary syndromes result from events such as rupture or disruption of the atherosclerotic plaque with intracoronary thrombosis and ischemia of the distal myocardium as a result. Advances in our understanding of the process underlying the acute coronary syndromes has allowed for the identification of targets and rational therapeutic strategies for the prevention and treatment of these syndromes. Many of these therapeutic strategies involve the reversal of prethrombotic forces that often coexist with coronary atherosclerosis. Even with recent advances in our approach to atherosclerosis, intracoronary thrombosis, and the resulting acute coronary syndromes, an unacceptably high event rate persists after these syndromes. Further advances in the prevention and treatment of coronary atherosclerosis and its thrombotic complications depends on a more thorough understanding of the biology of the atherosclerotic plaque and the factors which influence its stability.

Topics: Angina, Unstable; Blood Coagulation; Coronary Vessels; Disease Progression; Humans; Life Style; Myocardial Infarction; Rupture, Spontaneous; Syndrome; Thrombolytic Therapy; Thromboplastin; Treatment Outcome

The disruption of an atherosclerotic plaque in a coronary artery, appears to be fundamental for the development of arterial thrombosis and resultant ischaemia. Platelets play a central role in the pathogenesis of unstable angina; they can aggregate and cause mechanical obstruction if large enough. In addition, they can lead to fibrin deposition and extension of the thrombus. The fundamental goal in the treatment of unstable angina is to control the acute disease process that leads to vascular occlusion. In addition to the currently available pharmacological agents used to treat unstable angina, newer agents such as the direct thrombin inhibitors and the glycoprotein IIb/IIIa receptor antagonists may be more effective in achieving 'passivation'. This article summarizes the role of the vessel wall and its interaction with platelets in arterial thrombosis. The different pharmacological approaches used in achieving passivation of platelets in unstable angina are described.

Topics: Acute Disease; Angina, Unstable; Angioplasty, Balloon, Coronary; Animals; Anticoagulants; Antithrombins; Blood Platelets; Coronary Artery Disease; Coronary Thrombosis; Drug Delivery Systems; Drug Therapy, Combination; Endothelium, Vascular; Humans; Infusions, Intra-Arterial; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Rabbits; Thromboplastin

We sought to quantify the impact of adding an intravenous loading dose to a subcutaneous regimen of enoxaparin in patients with an acute coronary syndrome (ACS).. It is unclear whether an intravenous (i.v.) loading dose of enoxaparin should be added to a subcutaneous (s.c.) regimen in patients with ACS.. Patients admitted with ACS were randomized to i.v.+s.c.(n = 14) or s.c. alone (n = 11) enoxaparin treatment. Coagulation markers were measured at nine time points during the first 24 h of treatment.. The i.v.+s.c. therapy immediately resulted in therapeutic anti-Xa levels, which remained significantly higher for 6 h compared with s.c. alone, without reaching excessively high levels. A rapid decrease of plasma prothrombin fragments 1+2 (F(1+2)) levels was observed as soon as 5 min after the i.v. injection (33% lower; p = 0.007), and these levels remained lower up to 2 h after the start of treatment compared with SQ alone. The ex vivo thrombin generation time was maximally prolonged at 5 min post-injection in the i.v.+s.c. group and remained significantly prolonged up to 6 h post-injection compared with s.c. alone. The tissue factor pathway inhibitor plasma activity was immediately increased by 194% with i.v.+s.c., whereas the maximum increase with s.c. alone was 47% at 3 h.. Therapeutic plasma levels of enoxaparin are achieved significantly earlier by an i.v.+s.c. regimen compared with s.c. alone, without leading to unacceptably high levels. As the risk of thrombotic complications is greatest early after admission, the observed differences in antithrombotic effects may translate into a clinical benefit. However, this remains to be established.

Topics: Aged; Angina, Unstable; Anticoagulants; Blood Coagulation; Enoxaparin; Factor Xa; Female; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Myocardial Infarction; Prothrombin; Thromboplastin; Treatment Outcome

A different rate and timing of subacute stent thrombosis after percutaneous coronary intervention was reported with various peri-interventional antithrombotic regimens. Next to platelet activation, coagulation triggered by tissue factor (TF) may play a key role in this process. Thirty-one consecutive patients with stable and unstable angina undergoing coronary stenting were randomly assigned to adjunct oral anticoagulation/anti-platelet therapy (coumadin, dipyridamole, aspirin and heparin; n = 16) or adjunct anti-platelet therapy with thienopyridin (ticlopidine, aspirin and heparin; n = 15). Antigen levels of plasma TF, total tissue factor pathway inhibitor (TFPI) and TFPI/ activated factor X (TFPI/FXa) complex were determined before and for up to 6 days after intervention by immunoassay. At baseline, significantly higher levels of plasma TF and TFPI/FXa were found in patients with unstable angina [TF, 161 pg/ml (126-191 pg/ml); TFPI/FXa, 7.8 ng/ml (6.1-9.6 ng/ml)] compared with stable angina [TF, 62 pg/ml (46-82 pg/ml), P < 0.0001; TFPI/FXa, 4.5 ng/ml (3-7.6 ng/ml), P= 0.003]. One hour after intervention, an increase of plasma TF and TFPI/FXa was seen in both treatment groups. In unstable angina patients, plasma levels of TF, TFPI and TFPI/FXa were more efficiently reduced by adjunct ticlopidine therapy compared with adjunct coumadin/dipyridamole. These data suggest reduced release of circulating TF by combined anti-platelet therapy with ticlopidine and aspirin after coronary artery stenting, which may-contribute to the lower incidence of subacute stent thrombosis previously observed.

Topics: Adult; Angina Pectoris; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Aspirin; Coronary Angiography; Coronary Stenosis; Dipyridamole; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Factor Xa; Female; Follow-Up Studies; Hemorrhage; Heparin; Humans; Lipoproteins; Male; Middle Aged; Statistics as Topic; Stents; Thromboplastin; Thrombosis; Ticlopidine; Time Factors; Warfarin

Patients with unstable angina have an increased activation of the coagulation system. Aspirin and ticlopidine given in combination may potentiate each other by the combination of different action mechanisms and may reduce the risk of coronary occlusion and clinical instability. Plasma tissue factor (TF) levels collected into the stenotic coronary artery may be an index of TF expression within the vasculature. In 160 patients undergoing angioplasty for a 81+/-5% coronary lesion, we measured TF in blood samples collected from a vein and from the coronary ostium. Immediately after and 10 minutes after the dilation procedures the samples were withdrawn also beyond the lesion. Heparin 150 U/kg was given as an anticoagulant. All patients were pretreated with 250 mg/day of aspirin. One hundred twenty patients were randomly assigned to receive 24, 48, or 72 hours of ticlopidine treatment (250 mg/twice daily). TF levels did not increase during angioplasty but there was a significantly higher TF expression in unstable than in stable patients, irrespective of the invasiveness of debulking procedures. When ticlopidine was given for 72 hours, TF levels were similar to normal laboratory values both in stable and unstable patients. This combined antiplatelet pretreatment may be of benefit in unstable angina patients, with a favorable cost/benefit ratio.

Topics: Angina Pectoris; Angina, Unstable; Angioplasty, Balloon, Coronary; Antithrombin III; Aspirin; Atherectomy, Coronary; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Peptide Hydrolases; Platelet Aggregation Inhibitors; Premedication; Stents; Thromboplastin; Ticlopidine; Time Factors

The activation of a hemostatic system plays a critical role in the incidence of acute coronary events. Hemostatic proteins may be regulated by microRNAs (miRNAs). Microparticles (MPs) are the major carrier of circulating miRNAs. The aim of this study was to determine the potential role of miRNAs in regulating gene expression involved in the hemostatic system in patients with unstable angina (UA). MiRNA expression profiles in the plasma from patients with UA (UA group, n=9) compared with individuals with clinical suspicion of coronary artery disease (CAD) but negative angiography (control group, n=9) showed that among 36 differentially expressed miRNAs, miR-19b was the most obvious one. Using real-time PCR, 5 selected miRNA levels in plasma (UA group, n=20; control group, n=30) and plasma MPs (UA group n=6; control group n=6) were proved to be consistent with the miRNA array. Flow cytometry analysis indicated that the amounts of plasma endothelial microparticles (EMPs) were increased in UA patients (UA group, n=4) compared to controls (control group, n=4). In cultured endothelial cells (ECs), TNF-α increased miR-19b release and expression. Tissue factor (TF) was predicted to be the target of miR-19b by bioinformatics analysis. Luciferase reporter assays demonstrated that miR-19b binds to TF mRNA. Overexpression of miR-19b inhibited TF expression and procoagulant activity. This study indicates that in UA patients, the increase of miR-19b wrapped in EMPs due to endothelial dysfunction may partially contribute to the circulating miR-19b elevation and miR-19b may play an anti-thrombotic role by inhibiting the expression of TF in ECs.

Topics: Angina, Unstable; Antithrombins; Base Sequence; Blood Coagulation; Case-Control Studies; Cell-Derived Microparticles; Cohort Studies; Endothelial Cells; Female; Gene Expression Profiling; Humans; Male; MicroRNAs; Middle Aged; Molecular Sequence Data; Reproducibility of Results; Thromboplastin; Tumor Necrosis Factor-alpha

Heat shock proteins (HSPs) are among the most highly conserved and immunogenic proteins shared by microbial agents and mammals. Human (h) HSP60 is upregulated under stress conditions and serves as a target for cross-reactive cytotoxic HSP-serum-antibodies. The present study evaluates the expressions of hHSP60 and its homologue chlamydial (c) HSP60 in advanced human coronary lesions and correlates intimal tissue-bound HSP expressions with circulating HSP-antibodies. Coronary atherectomy specimens retrieved from 100 primary target lesions of patients with unstable angina (UA; n = 40) or stable angina (SA; n = 60) were assessed immunohistochemically for the presence of hHSP60 and cHSP60. In a subgroup (n = 40), blood samples were tested for anti-Chl. pn.-IgG/IgA-titers and anti-HSP65-antibody titers. Coronary plaques revealed immunoreactive hHSP60 in 55% and cHSP60 in 45% of the lesions. Expression of both HSP homologues was significantly (each p < 0.001) higher in UA lesions compared with SA lesions (7.4 vs. 1.2% and 6.0 vs. 1.1%). HSP homologues showed positive correlations both in UA- and SA-lesions (r = 0.41, 0.33; p < 0.05). cHSP60 showed no association with anti-Chl. pn.-IgG/IgA-titers, whereas expressions of both homologues correlated positive with anti-HSP65-Ab titers (r = 0.42, p < 0.05; r = 0.50, p < 0.01). Intimal amounts of HSP60 homologues were associated with increased expressions of C-reactive protein, Toll-like receptor-4 and tissue factor. Human and chlamydial HSP60 colocalize within coronary atheroma, most prevalent in lesions associated with UA. Our data demonstrate a significant correlation between the intimal expressions of HSP60 homologues and serum HSP65 antibodies, thereby suggesting that humoral immune reactions may play an important role in coronary atherosclerosis and plaque instability.

Topics: Aged; Angina, Unstable; Antibodies; C-Reactive Protein; Chaperonin 60; Coronary Artery Disease; Female; Heat-Shock Proteins; Humans; Immunohistochemistry; Male; Middle Aged; Thromboplastin; Toll-Like Receptor 4

Tissue factor (TF), the major procoagulant in vivo, is usually absent from blood cells. However, since both monocyte TF (MoTF) expression and platelet activation are present in acute coronary syndrome we hypothesized that MoTF expression may in part depend on monocyte platelet aggregate (MPA) formation in coronary artery disease (CAD). Patients with unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI, n = 20) had significantly higher levels of MoTF (17.4 ± 3.1MFI) and MPAs (CD42b:273 ± 183MFI; CD62P:256.3 ± 48.5MFI) than patients with stable angina (SA, n = 40; MoTF:13.2 ± 2.2MFI, p = 0.001; CD42b:160 ± 113MFI, p = 0.025; CD62P:118.7 ± 24.5MFI, p = 0.018) as measured by whole blood flow cytometry on CD14+-cells. TF-activity of isolated mononuclear cells (MNC) was elevated in UA/NSTEMI (75 ± 27 pg/mL) in comparison to SA (47 ± 17 pg/mL, p = 0.001) as determined by chromogenic assay, and TF mRNA expression in isolated MNC was more frequent in UA/NSTEMI than in SA (50% vs. 18.2%; p = 0.017). MoTF expression significantly correlated with the constitutive platelet marker CD42b (r = 0.69, p < 0.001) and the platelet activation marker CD62P (r = 0.47, p = 0.001) on CD14+-cells suggesting its association with MPAs in UA/NSTEMI. In addition, MoTF expression correlated with MoTF activity of isolated MNC (r = 0.41, p = 0.01) and plasma levels of the F1.2 prothrombin fragment (r = 0.35, p = 0.02). In conclusion, MoTF and MPAs are elevated in UA/NSTEMI compared with SA. MoTF expression correlates with platelet mass and activity attached to monocytes.

Topics: Adult; Aged; Aged, 80 and over; Angina, Stable; Angina, Unstable; Blood Platelets; Cell Communication; Female; Humans; Male; Middle Aged; Monocytes; Myocardial Infarction; RNA, Messenger; Thromboplastin

Tissue factor (TF) is a low-molecular-weight glycoprotein responsible for the initiation of the coagulation cascade. The relation between oxidized low-density lipoprotein (Ox-LDL), that has been shown to be involved in atherogenesis, and TF has not been evaluated before in circulating plasma. The aim of this study was to determine plasma levels of TF and Ox-LDL in acute coronary syndrome (ACS) and stable coronary artery disease (SCAD).. The study group consisted of 41 patients with ACS and 26 patients with SCAD. Among the ACS patients, 12 were diagnosed with unstable angina pectoris (UAP) and 29 were diagnosed with acute myocardial infarction (AMI). The control group consisted of 30 healthy volunteers. TF and Ox-LDL levels were evaluated by ELISA kits.. Ox-LDL levels were significantly higher in UAP and AMI patients compared with the control (p < 0.001) and SCAD (p < 0.01 and p < 0.001, respectively) groups. TF levels were significantly higher in the UAP, AMI and SCAD groups compared with the control group (p < 0.001, p < 0.001 and p < 0.01, respectively). In the AMI group a significant increase was observed in TF levels when compared with the SCAD group (p < 0.01). Plasma Ox-LDL levels were significantly and positively correlated with TF levels in the UAP and AMI groups (p < 0.05, r = 702, and p < 0.0001, r = 0.679, respectively).. The potential link between Ox-LDL and TF in circulating blood in ACS may strengthen the evidence supporting a relationship between oxidant stress, lipids and thrombosis and consequently may contribute to understanding the mechanism through which Ox-LDL and TF may mediate the pathogenesis of CAD.

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Angina, Unstable; Blood Coagulation; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lipoproteins, LDL; Male; Middle Aged; Myocardial Infarction; Oxidative Stress; Thromboplastin

Risk stratification at presentation with acute coronary syndromes (ACS) on the basis of the TIMI risk score for unstable angina and non-ST-elevation myocardial infarction (UAP/NSTEMI) identifies patients at high risk of recurrent cardiac events and those who benefit from more aggressive treatment strategy. We hypothesised the following: (a) that a high TIMI risk score brings a greater degree of acute changes in endothelial damage/dysfunction (circulating endothelial cells [CECs], von Willebrand factor [vWf]), inflammation (interleukin-6, IL-6) and blood thrombogenicity (plasma tissue factor, TF); and (b) that these indices are higher in those with high TIMI risk score who experienced recurrent cardiac event at day 14 and day 30. TIMI risk scores were determined at admission and 48 hours later in 88 ACS patients (60 male, age 67+/-12 yrs) with UAP or NSTEMI. CECs, IL-6 and TF levels were measured at both time points and the acute change (delta) calculated. Patients were split into high (score > or =4) or low (<4) TIMI score groups. The composite end point of death, myocardial infarction, and refractory angina requiring revascularisation following 14 and 30 days' follow-up was ascertained. Fifty-eight patients with high TIMI risk score (mean 4.7) had significantly higher baseline and 48 h CEC, vWf, IL-6,TF and deltaTF levels, compared to low TIMI risk score (mean 2.4) patients (all p<0.05). Multivariate Cox regression analysis adjusted for clinical variables and TIMI risk score expressed as either continuous or categorical variable identified baseline CECs and deltavWf levels (both p< or =0.01) as independent predictors of subsequent cardiac events at both 14 days and 30 days. TIMI risk score for UA/NSTEMI identifies those patients with more profound vascular insult, inflammation and thrombogenicity that, in the 'high risk' patient group, predicts short-term outcomes, although vascular damage was the more sensitive predictor. These indices may further refine global risk stratification for short-term adverse cardiac events in these patients.

Topics: Acute Disease; Aged; Aged, 80 and over; Angina, Unstable; Biomarkers; Endothelium, Vascular; Female; Follow-Up Studies; Humans; Interleukin-6; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Risk Factors; Thromboplastin; Thrombosis; von Willebrand Factor

The tissue factor plays a crucial role in initiating blood coagulation after plaque rupture in patients with acute coronary syndrome. It is abundant in atherosclerotic plaques. Moreover, P-selectin, some cytokines, endotoxin and immune complexes can stimulate monocytes and induce the tissue factor expression on their surface. The aim of the study was to compare plasma levels of the tissue factor, tissue factor pathway inhibitor, P-selectin, E-selectin and ICAM-1 in patients with acute myocardial infarction, unstable angina pectoris, stable coronary artery disease and normal control subjects. In addition, plasma levels of the tissue factor, tissue factor pathway inhibitor, P-selectin, E-selectin and ICAM-1 were measured in the blood withdrawn from the coronary sinus in a subgroup of patients with unstable angina pectoris and stable coronary artery disease in which the difference between concentrations in the coronary sinus and systemic blood was calculated. A significant increase in tissue factor pathway inhibitor plasma levels was detected in patients with acute myocardial infarction (373.3+/-135.1 ng/ml, p<0.01) and unstable angina pectoris (119.6+/-86.9 ng/ml, p<0.05) in contrast to the patients with stable coronary artery disease (46.3+/-37.5 ng/ml) and normal subjects (45.1+/-14.3 ng/ml). The plasma levels of tissue factor pathway inhibitor were significantly increased both in the coronary sinus and systemic blood in the patients with unstable angina pectoris. There was only a non-significant trend to higher plasma levels of the tissue factor in patients with acute myocardial infarction and unstable angina pectoris as compared to the patients with stable coronary artery disease and normal subjects, the values being 129.1+/-30.2 pg/ml, 130.5+/-57.8 pg/ml, 120.2+/-45.1 pg/ml and 124.9+/-31.8 pg/ml, respectively. Plasma levels of soluble P-selectin was only slightly, but non-significantly higher in patients with unstable angina pectoris and stable coronary artery disease (184.2+/-85.4 ng/ml and 201.6+/-67.9 ng/ml, respectively) than in patients with the acute myocardial infarction (157.4+/-88.4 ng/ml) or normal subjects (151.4+/-47.1 ng/ml). The difference in plasma levels of soluble ICAM-1 between the blood withdrawn from the coronary sinus and systemic circulation correlated significantly with the corresponding difference in plasma levels of soluble P-selectin and E-selectin. In conclusion, the tissue factor and the tissue factor pathway inhibitor play

Topics: Adult; Aged; Angina, Unstable; Cell Adhesion Molecules; Coronary Artery Disease; E-Selectin; Female; Humans; Intercellular Adhesion Molecule-1; Linear Models; Lipoproteins; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; P-Selectin; Thromboplastin

The pathogenesis of atherosclerosis and acute coronary syndromes involves inflammation and immunological mechanisms. We hypothesized that patients with unstable angina may have an imbalance between inflammatory and anti-inflammatory cytokines.. Plasma levels of tumour necrosis factor (TNF)alpha and interleukin (IL)-10 were analyzed in 44 patients with stable angina, 29 patients with unstable angina and 20 controls. mRNA levels of these cytokines were analyzed in peripheral blood mononuclear cells (PBMC). We also studied the in vitro effects of IL-10 in PBMC from unstable angina patients.. Our main findings were: (1) the angina patients and particularly those with unstable disease had significantly raised TNFalpha in comparison with the controls, both at the protein and mRNA level; (2) in contrast, the levels of IL-10 were not different in the angina patients in comparison with the healthy controls, resulting in a markedly enhanced TNFalpha:IL-10 ratio, particularly in the unstable angina patients; (3) while exogenously added IL-10 markedly inhibited the release of TNFalpha, IL-8 and tissue factor as well as impairing the gelatinolytic activity and mRNA production of matrix metalloproteinase-9, it enhanced the tissue inhibitor of this metalloproteinase (i.e. TIMP-1) in PBMC from the unstable angina patients.. Patients with unstable angina appear to have an imbalance between TNFalpha and IL-10, possibly favouring inflammatory net effects. IL-10 may have beneficial effects on mechanisms that are important in plaque rupture and thrombus formation.

Topics: Adult; Aged; Angina Pectoris; Angina, Unstable; Case-Control Studies; Cells, Cultured; Female; Humans; Interleukin-10; Interleukin-8; Leukocytes, Mononuclear; Male; Matrix Metalloproteinase 9; Middle Aged; RNA, Messenger; Stimulation, Chemical; Thromboplastin; Tissue Inhibitor of Metalloproteinase-1; Tumor Necrosis Factor-alpha

High tissue factor (TF), tissue factor pathway inhibitor (TFPI) levels and a hypercoagulability state have been documented in unstable angina patients. We evaluated whether short-term enoxaparin administration (100 IU/kg b.i.d. for 3 d) reduces the high TF levels and the hypercoagulability state, and whether it influences the fibrinolytic system in 20 unstable angina patients. On d 3, we observed a significant reduction in TF levels both 1 h and 4 h after the morning injection (-25.6% and -21.7%; P < 0.001 respectively) in comparison with the base-line levels. Both 1 and 4 h after the morning injection on the d 3, TFPI levels significantly (P < 0.001) increased (+96.4%, +96.9% respectively) with respect to the base-line values. After enoxaparin administration, at all observation times, thrombin-antithrombin complexes and prothrombin fragment F1 + 2 levels were significantly (P < 0.001) lower with respect to base-line levels. We observed a slight but significant increase in tissue plasminogen activator antigen levels in preinjection samples, as well as 1 h and 4 h after enoxaparin administration, in comparison with the base-line values. This study provides evidence that low-molecular-weight heparin (LMWH) administration, in addition to a reduction of hypercoagulability and a mild fibrinolytic activation, is associated with decreased TF levels, so indicating a novel mechanism of interference of LMWH with the haemostatic system.

Topics: Adult; Aged; Angina, Unstable; Anticoagulants; Antithrombin III; Drug Administration Schedule; Enoxaparin; Female; Fibrinolytic Agents; Humans; Lipoproteins; Male; Middle Aged; Peptide Fragments; Peptide Hydrolases; Protein Precursors; Prothrombin; Thromboplastin; Tissue Plasminogen Activator

Chemokines play a pathogenic role in atherogenesis and plaque destabilization by activating and directing leukocytes into the atherosclerotic plaque. However, stromal cell-derived factor (SDF)-1 was recently found to have antiinflammatory effects, and we hypothesized that this chemokine could play a beneficial role in coronary artery disease.. Plasma levels of SDF-1alpha were significantly decreased in patients with stable (n=30) and unstable angina (n=30) compared with healthy control subjects (n=20), particularly in those with unstable disease. By flow cytometry and RNase protection assay, we found decreased surface expression but increased gene expression of the SDF-1alpha receptor CXCR-4 in peripheral blood mononuclear cells (PBMC) from patients with stable angina and patients with unstable angina. In vitro, SDF-1alpha (500 ng/mL) reduced both unstimulated and endotoxin/mitogen-stimulated mRNA and protein levels of monocyte chemoattractant protein-1, interleukin-8, matrix metalloproteinase-9, and tissue factor while increasing tissue inhibitor of metalloproteinases-1 in PBMC from patients with unstable angina. The SDF-1alpha-mediated suppression of monocyte chemoattractant protein-1 and interleukin-8 appears to involve cAMP/protein kinase A type I-dependent pathways. Finally, although SDF-1alpha suppressed the spontaneous release of these inflammatory mediators in unstable angina, enhancing effects were seen in unstimulated PBMC from healthy control subjects, possibly reflecting that PBMC in unstable angina are preactivated in vivo.. In contrast to several other chemokines, our findings suggest that SDF-1alpha, at least in high concentrations, may mediate antiinflammatory and matrix-stabilizing effects in unstable angina. These effects may promote plaque stabilization, and therapeutic intervention that enhances SDF-1alpha activity could potentially be beneficial in acute coronary syndromes.

Topics: Angina, Unstable; Anti-Inflammatory Agents; Cells, Cultured; Chemokine CCL2; Chemokine CXCL12; Chemokines, CXC; Cyclic AMP-Dependent Protein Kinases; Cytokines; Dose-Response Relationship, Drug; Extracellular Matrix; Female; Humans; Interleukin-8; Leukocytes, Mononuclear; Male; Matrix Metalloproteinase 9; Middle Aged; Receptors, CXCR4; RNA, Messenger; Thromboplastin; Tissue Inhibitor of Metalloproteinase-1

Platelet activation is known to participate to the pathogenesis of acute coronary syndromes. Aminophospholipid exposure and microparticles shedding are hallmarks of full platelet activation and may account for the dissemination of prothrombotic seats. Using flow cytometry analysis of annexin V binding to externalized aminophospholipids, we followed platelet procoagulant activity (PPA) and platelet microparticles (PMP) shedding in venous and coronary whole blood samples from 30 patients with unstable angina before and after percutaneous coronary angioplasty (PTCA) and stent implantation. Baseline values of PPA and PMP were significantly more elevated in patients than in control subjects (p < 0.005). PMP percentage was significantly higher in coronary than in venous blood, and in coronary blood of patients with proximal instead of mid/distal lesions of coronary arteries. No enhancement of platelet reactivity to TRAP and collagen was induced by procedure. Whereas activated GpIIb-IIIa and P-selectin expression decreased 24 h and 48 h after procedure, PPA and PMP remained as elevated as before. Thus, flow cytometry is a reliable method for detection of fully activated platelets in whole blood samples. Annexin V binding analysis demonstrates the persistance of in vivo platelet activation, despite the use of antiaggregating agents.

Topics: Aged; Angina, Unstable; Angioplasty, Balloon, Coronary; Annexin A5; Biomarkers; Collagen; Combined Modality Therapy; Comorbidity; Coronary Angiography; Coronary Stenosis; Coronary Vessels; Diabetes Mellitus; Female; Flow Cytometry; Humans; Hypercholesterolemia; Male; Middle Aged; Obesity; P-Selectin; Platelet Activation; Platelet Count; Platelet Glycoprotein GPIIb-IIIa Complex; Proteins; Receptors, Thrombin; Risk Factors; Stents; Thromboplastin; Veins

The available evidence suggests strongly that intravascular thrombosis is mediated predominantly by tissue-factor and its activation of factor X, which in the presence of factor Va, calcium, and phospholipid (prothrombinase complex) effectively converts prothrombin to thrombin. In vitro experiments have shown that low molecular weight heparins (LMWHs) have greater anti-Xa activity than unfractionated heparin; however, it remains unclear as to whether their antithrombotic effects in vivo are determined by a similar mechanism. We determined the ability of plasma obtained from patients with either unstable angina or non-ST segment elevation myocardial infarction (MI) receiving the LMWH enoxaparin (anti Xa:IIa ratio 3:1) to inhibit tissue factor-mediated thrombin generation and to inactivate platelet prothrombinase.. Platelet rich plasma was prepared by suspending washed donor platelets in the plasma of 7 patients participating in the TIMI 11A study. Samples were obtained before, 1 hour after a 30-mg IV bolus of enoxaparin and 6 hours after the third subcutaneous injection (1. 0-1.25 mg/kg given subcutaneously every 12 hrs). Tissue factor (0.1 ng/ml) and 10 mM CaCl(2) were added to initiate extrinsic coagulation. At timed intervals prothrombin activation fragment 1.2 (F1.2) levels (thrombin generation) were measured using an ELISA technique. Inactivation of reformed platelet prothrombinase by samples obtained at the same time points was also determined.. Patient plasma obtained 1 hr after treatment initiation and 6 hours after the third subcutaneous injection inhibited tissue factor mediated prothrombinase assembly by 31% and 11%, respectively and platelet prothrombinase activity by 27% and 22%, respectively.. We conclude that enoxaparin in plasma concentrations achieved routinely in clinical practice is able to: (1) inhibit tissue factor mediated extrinsic coagulation by preventing platelet surface prothrombinase assembly, and (2) inactivate platelet prothrombinase activity and resulting thrombin generation. These observations suggest that a LMWH's anti-Xa activity (and anti-Xa:IIa profile) is important in determining its overall antithrombotic potential. Clinical trials comparing agents with differing anti-Xa:IIa properties will be required, however, to provide proof of concept.

Topics: Angina, Unstable; Blood Platelets; Enoxaparin; Factor Xa; Heparin, Low-Molecular-Weight; Humans; Myocardial Infarction; Thromboplastin; Time Factors

High circulating levels of the procoagulant molecule tissue factor (TF) are associated with thrombosis in a variety of diseases including unstable angina, cancer, and sepsis. Currently, there are no clinical assays to measure the level of TF activity in whole blood. We present an assay called Tissue Factor Clotting Time ("TiFaCT") that detects fibrin formation in human blood. The mean baseline clotting time in a healthy population was 472 +/- 94 s (mean +/- SD, n = 150). Bacterial lipopolysaccharide (LPS or endotoxin) shortened the clotting time in a time-dependent manner. Inhibitory anti-TF antibodies prolonged the clotting time of LPS-stimulated blood, indicating that the shortened clotting time was due to induction of TF expression. Patients with unstable angina had shortened mean baseline clotting time (284 +/- 86, n = 13) compared with healthy volunteers (474 +/- 98, n = 30), suggesting that these patients had elevated levels of circulating TF. The TiFaCT assay should prove clinically useful in quantifying the levels of circulating TF in patients at risk of thrombosis.

Topics: Adult; Aged; Angina, Unstable; Animals; Antibodies; Blood Chemical Analysis; Endotoxemia; Evaluation Studies as Topic; Female; Humans; In Vitro Techniques; Lipopolysaccharides; Male; Middle Aged; NF-kappa B; Partial Thromboplastin Time; Prothrombin Time; Rabbits; Recombinant Proteins; Reference Values; Risk Factors; Thromboplastin; Thrombosis

Elevated plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) and large amounts of monocyte procoagulant activity (PCA) have been documented in unstable angina (UA) patients. In in vitro experiments heparin is able to blunt monocyte TF production by inhibiting TF and cytokine gene expression by stimulated cells and after in vivo administration it reduces adverse ischemic outcomes in UA patients. TF and TFPI plasma levels and monocyte PCA have been investigated in 28 refractory UA patients before and during anticoagulant subcutaneous heparin administration (thrice daily weight- and PTT-adjusted for 3 days) followed by 5000 IU X 3 for 5 days. After 2-day treatment, immediately prior to the heparin injection, TF and TFPI plasma levels [(median and range): 239 pg/ml, 130-385 pg/ ml and 120 ng/ml, 80-287 ng/ml] were lower in comparison to baseline samples (254.5 pg/ml, 134.6-380 pg/ml and 135.5 ng/ml, 74-306 ng/ml). Four h after the heparin injection TF furtherly decreased (176.5 pg/ml, 87.5-321 pg/ml; -32.5%. p<0.001) and TFPI increased (240.5 ng/ml, 140-450 ng/ml; +67%, p<0.0001). After 7-day treatment, before the injection of heparin, TF and TFPI plasma levels (200 pg/ml, 128-325 pg/ml and 115 ng/ml, 70-252 ng/ml) significantly decreased (p<0.05) in comparison to the pre-treatment values. On the morning of the 8th day, 4 h after the injection of heparin TF plasma levels and monocytes PCA significantly decreased (156.5 pg/ml, 74-259 pg/ml and from 180 U/105 monocytes, 109-582 U/10(5) monocytes to 86.1 U/10(5) monocytes, 28-320 U/10(5) monocytes; - 38% and -55% respectively) and TFPI increased (235.6 ng/ml, 152-423 ng/ ml; +70%, p<0.001). In conclusion, heparin treatment is associated with a decrease of high TF plasma levels and monocyte procoagulant activity in UA patients. These actions of heparin may play a role in determining the antithrombotic and antiinflammatory properties of this drug.

Topics: Adult; Aged; Angina, Unstable; Anticoagulants; Blood Coagulation Factors; Female; Hemostatics; Heparin; Humans; Leukocytes, Mononuclear; Lipoproteins; Male; Middle Aged; Monocytes; Oxidation-Reduction; Thromboplastin; Time Factors

This study was designed to evaluate the plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with unstable angina and investigate whether there is a relationship between these levels and unfavorable outcome.. The plasma TF and free TFPI antigen levels were determined in plasma samples taken from 51 patients with unstable angina, 56 with stable exertional angina, and 55 with chest pain syndrome. The plasma TF and free TFPI antigen levels were higher in the unstable angina group than in the stable exertional angina and chest pain syndrome group. There was a good correlation between TF and TFPI. We established borderline as maximum level in the patients with chest pain syndrome. Seven patients (of the 22 in the high TF group) required revascularization to control their unstable angina during in-hospital stay. On the other hand, only 1 of the 29 patients in the low TF group required myocardial revascularization. Four patients of the 14 patients in the high free TFPI group required myocardial revascularization during in-hospital stay, and 4 of the 37 patients in the low free TFPI group required myocardial revascularization. We compared the TF and free TFPI levels between the cardiac event (+) group and cardiac event (-) group. TF levels were significantly higher in the cardiac event (+) group than in the cardiac event (-) group.. We have demonstrated that not only the plasma TF levels but also the plasma-free TFPI levels are elevated in patients with unstable angina. Patients with unstable angina and heightened TF and free TFPI are at increased risk for unfavorable outcomes. The heightened TF level was a more important predictor in patients with unstable angina.

Topics: Adult; Aged; Aged, 80 and over; Angina, Unstable; Female; Follow-Up Studies; Humans; Lipoproteins; Male; Middle Aged; Peptide Fragments; Prognosis; Prothrombin; 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

Several studies have shown that thrombosis and inflammation play an important role in the pathogenesis of Ischaemic Heart Disease (IHD). In particular, Tissue Factor (TF) is responsible for the thrombogenicity of the atherosclerotic plaque and plays a key role in triggering thrombin generation. The aim of this study was to evaluate the TF/Tissue Factor Pathway Inhibitor (TFPI) system in patients with IHD. We have studied 55 patients with IHD and not on heparin [18 with unstable angina (UA), 24 with effort angina (EA) and 13 with previous myocardial infarction (MI)] and 48 sex- and age-matched healthy volunteers, by measuring plasma levels of TF, TFPI, Prothrombin Fragment 1-2 (F1+2), and Thrombin Antithrombin Complexes (TAT). TF plasma levels in IHD patients (median 215.4 pg/ml; range 72.6 to 834.3 pg/ml) were significantly (p<0.001) higher than those found in control subjects (median 142.5 pg/ml; range 28.0-255.3 pg/ml). Similarly, TFPI plasma levels in IHD patients were significantly higher (median 129.0 ng/ml; range 30.3-316.8 ng/ml; p<0.001) than those found in control subjects (median 60.4 ng/ml; range 20.8-151.3 ng/ml). UA patients showed higher amounts of TF and TFPI plasma levels (TF median 255.6 pg/ml; range 148.8-834.3 pg/ml; TFPI median 137.7 ng/ml; range 38.3-316.8 ng/ml) than patients with EA (TF median 182.0 pg/ml; range 72.6-380.0 pg/ml; TFPI median 115.2 ng/ml; range 47.0-196.8 ng/ml) and MI (TF median 213.9 pg/ml; range 125.0 to 341.9 pg/ml; TFPI median 130.5 ng/ml; range 94.0-207.8 ng/ml). Similar levels of TF and TFPI were found in patients with mono- or bivasal coronary lesions. A positive correlation was observed between TF and TFPI plasma levels (r = 0.57, p<0.001). Excess thrombin formation in patients with IHD was documented by TAT (median 5.2 microg/l; range 1.7-21.0 microg/l) and F1+2 levels (median 1.4 nmol/l; range 0.6 to 6.2 nmol/l) both significantly higher (p<0.001) than those found in control subjects (TAT median 2.3 microg/l; range 1.4-4.2 microg/l; F1+2 median 0.7 nmol/l; range 0.3-1.3 nmol/l). As in other conditions associated with cell-mediated clotting activation (cancer and DIC), also in IHD high levels of circulating TF are present. Endothelial cells and monocytes are the possible common source of TF and TFPI. The blood clotting activation observed in these patients may be related to elevated TF circulating levels not sufficiently inhibited by the elevated TFPI plasma levels present.

Topics: Adult; Angina, Unstable; Blood Coagulation; Female; Humans; Lipoproteins; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Thrombin; Thromboplastin

The levels of circulating monocyte chemoattractant protein-1 (MCP-1) and tissue factor (TF) were examined on admission in 46 consecutive patients with acute coronary syndromes (ACS) and 30 patients with stable exertional angina (SEA). The plasma levels of both MCP-1 and TF were higher in the ACS patients than in the SEA patients (MCP-1: p<0.001; TF: p<0.001). Only the circulating TF level related to the number of diseased vessels. A positive correlation between plasma MCP-1 and TF levels was found (r=0.476, p<0.001). These results suggest that circulating MCP-1 plays an important role in the pathogenesis and/or development of ACS.

Topics: Acute Disease; Aged; Angina Pectoris; Angina, Unstable; Chemokine CCL2; Female; Humans; Inflammation; Male; Middle Aged; Monocytes; Myocardial Infarction; Thromboplastin

Coronary atherosclerotic-plaque thrombosis is a key event in the pathogenesis of unstable angina and myocardial infarction. Although plaque rupture or fissuring frequently occurs in atherosclerosis, only a small proportion of ruptured plaques develop thromboses.. Tissue-factor antigen and activity were measured in atherectomy samples from 50 consecutive patients with coronary artery disease (stable angina n = 19, unstable angina n = 24, and myocardial infarction n = 7).. Median tissue-factor antigen and activity concentrations were significantly higher in plaques from patients with unstable angina and myocardial infarction than in those from patients with stable angina (antigen: 66.1 pg/mg [interquartile range 43.8-82.5] vs 32.4 pg/mg [9.8-43.4], p = 0.0001; activity: 0.22 mU/mg [0.17-0.41] vs 0.13 mU/mg [0.05-0.16], p = 0.0004).. Tissue-factor, an initiator of the coagulation cascade, may account for the different thrombotic responses to the rupture of human coronary atherosclerotic plaques.

Topics: Angina Pectoris; Angina, Unstable; Antigens; Coronary Artery Disease; Humans; Myocardial Infarction; Thromboplastin

Topics: Angina, Unstable; Blood Coagulation; Cardiac Surgical Procedures; Flow Cytometry; Humans; Monocytes; Thrombin; Thromboplastin

Tissue factor (TF) is a low molecular weight glycoprotein that initiates the clotting cascade and is considered to be a major regulator of coagulation, hemostasis, and thrombosis.. We examined plasma TF levels in 31 consecutive patients with acute myocardial infarction (AMI) (within 6 hours after the onset of symptoms), 27 patients with stable exertional angina, and 27 control subjects. Ten patients with AMI had a history of unstable angina before infarction, and 21 had a sudden onset of infarction. The plasma TF level was higher in the AMI group than in the stable exertional angina and control groups (240 +/- 112 vs 184 +/- 46 pg/ml [p < 0.05] vs 177 +/- 37 pg/ml, p < 0.01, respectively). TF levels were decreased in the chronic phase (2 weeks after admission) compared with the acute phase of infarction (from 240 +/- 112 pg/ml to 222 +/- 97 pg/ml, p < 0.05). In addition, plasma TF levels were higher in patients with AMI with prodromal unstable angina than in patients with a sudden onset of infarction (300 +/- 169 pg/ml vs 212 +/- 57 pg/ml, p < 0.05). TF levels were similar in the acute and chronic phases in the patients with AMI with prodromal unstable angina (300 +/- 169 pg/ml vs 290 +/- 136 pg/ml, p = not significant) but were decreased in the chronic phase in the patients with AMI with sudden onset (from 212 +/- 57 pg/ml to 190 +/- 49 pg/ml, p < 0.05).. Increased plasma TF levels in patients with AMI may reflect enhanced intravascular procoagulant activity. The higher TF levels in patients with AMI with prodramol unstable angina may be associated with repeated episodes of myocardial ischemia and reperfusion.

Topics: Aged; Angina Pectoris; Angina, Unstable; Female; Humans; Male; Middle Aged; Myocardial Infarction; Reference Values; Thromboplastin

Tissue factor is a membrane-bound glycoprotein that functions in the extrinsic pathway of blood coagulation by acting as a cofactor for factor VII, and the resulting complex leads to thrombin production in vivo. The purpose of the present study is to determine whether macrophages express tissue factor in human coronary atherosclerotic plaques. We examined directional coronary atherectomy specimens from 24 patients with unstable angina and 23 with stable exertional angina. In these specimens, macrophages were detected in 22 (92%) of 24 patients with unstable angina versus 12 (52%) of 23 with stable exertional angina (P = .003). The percentage of macrophage infiltration area was significantly larger in patients with unstable angina than in those with stable exertional angina (17 +/- 3% versus 6 +/- 2%, P = .008). The immunohistochemical double staining revealed the expression of tissue factor on macrophages in 18 (75%) of 24 patients with unstable angina versus 3 (13%) of 23 with stable exertional angina (P < .0001). Thrombus was identified in 20 (83%) of 24 patients with unstable angina versus 12 (52%) of 23 with stable exertional angina (P = .02). Fibrin deposition was mainly observed around macrophages expressing tissue factor in the patients with unstable angina. We have shown that tissue factor expression on macrophages was more frequent in coronary atherosclerotic plaques in patients with unstable angina. Tissue factor expressed on macrophages may play an important role in the thrombogenicity in coronary atherosclerotic plaques of these patients.

Topics: Aged; Aged, 80 and over; Angina, Unstable; Coronary Vessels; Female; Humans; Immunohistochemistry; Macrophages; Male; Middle Aged; 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

Macrophage expression of tissue factor may be responsible for coronary thrombogenicity in patients with plaque rupture. In patients without plaque rupture, smooth muscle cells may be the thrombogenic substrate. This study was designed to identify the cellular correlations of tissue factor in patients with unstable angina.. Tissue from 50 coronary specimens (1560 pieces) from patients with unstable angina and 15 specimens from patients with stable angina were analyzed. Total and segmental areas (in square millimeters) were identified with trichrome staining. Macrophages, smooth muscle cells, and tissue factor were identified by immunostaining. Tissue factor content was larger in unstable angina (42 +/- 3%) than in stable angina (18 +/- 4%) (P = .0001). Macrophage content was also larger in unstable angina (16 +/- 2%) than in stable angina (5 +/- 2%) (P = .002). The percentage of tissue factor located in cellular areas was larger in coronary samples from patients with unstable angina (67 +/- 8%) than in samples from patients with stable angina (40 +/- 5%) (P = .00007). Multiple linear stepwise regression analysis showed that coronary tissue factor content correlated significantly (r = .83, P < .0001) with macrophage and smooth muscle cell areas only in tissue from patients with unstable angina, with a strong relationship between tissue factor content and macrophages in the atheromatous gruel (r = .98, P < .0001).. Tissue factor content is increased in unstable angina and correlates with areas of macrophages and smooth muscle cells, suggesting a cell-mediated thrombogenicity in patients with acute coronary syndromes.

Topics: Adult; Aged; Angina Pectoris; Angina, Unstable; Atherectomy, Coronary; Coronary Artery Disease; Coronary Vessels; Female; Humans; Immunohistochemistry; Lipids; Macrophages; Male; Middle Aged; Muscle, Smooth, Vascular; Regression Analysis; Thromboplastin

Tissue factor (TF) is a cell membrane-associated protein that catalyzes the rate-limiting step of the extrinsic coagulation pathway, which is the major source of thrombin production in vivo. To explore the potential role that TF may play in ischemic coronary syndromes, directional coronary atherectomy specimens were tested for the presence of TF protein using immunohistochemical techniques.. Frozen sections from atherectomy specimens in 61 patients were examined for TF expression using an IgG murine monoclonal antibody against human TF. Patients were classified according to their admission diagnosis as having either an unstable or a stable coronary syndrome. An unstable coronary syndrome was defined as either angina pectoris occurring at rest or post-myocardial infarction (< 1 week) angina. Stable coronary syndromes included patients with stable, progressive, and new-onset (< 6 weeks) angina without rest pain. TF was detected in 15 (43%) of 35 patients with unstable coronary syndromes versus only 3 (12%) of 26 patients with stable coronary syndromes (odds ratio, 5.7; 95% confidence interval, 1.3 to 24.3; P = .018). Within the subgroup of patients with unstable coronary syndromes, TF was detected in 14 (60%) of 25 patients with de novo lesions versus only 1 (10%) of 10 patients with a restenosis lesion (P < .02). An additional 8 patients with stable coronary syndromes due to a restenosis lesion were also negative for TF. Therefore, the overall incidence of TF expression was only 6% (1 of 18) in restenosis lesions compared with 33% (14 of 43) in de novo lesions (P < .03).. This study provides the first description of TF protein expression in human coronary artery lesions in vivo. Tissue factor was readily detected in de novo lesions in patients with unstable coronary syndromes, suggesting a role for TF in the pathogenesis of this disease process. Conversely, TF was rarely detected in patients with restenosis lesions even if the resulting clinical presentation was an unstable coronary syndrome. These results may have implications for the management of patients with unstable angina from de novo lesions and patients with ischemic symptoms from a restenosis lesion.

Topics: Angina Pectoris; Angina, Unstable; Atherectomy, Coronary; Female; Humans; Male; Middle Aged; Thromboplastin

Platelet activation plays a pivotal role in the pathogenesis of acute coronary disease. Monocytes are involved in the progression of atherosclerosis and are potent activators of blood coagulation through their ability to synthesize tissue factor (TF). The aim of this study was to compare markers of monocyte and coagulation activation in the systemic blood of patients with unstable angina, acute myocardial infarction, or stable angina.. We studied 26 patients with unstable angina (10 +/- 5 hours after the onset of the last episode of pain), 18 patients with acute myocardial infarction (5 +/- 4 hours after the onset of pain), and 34 patients with stable angina. We measured levels of TF expression in peripheral blood mononuclear cells (isolated by gradient centrifugation and incubated for 16 hours, with or without endotoxin stimulation), levels of plasma prothrombin fragment 1 + 2 (F1 + 2), and levels of fibrinogen in peripheral blood. In patients with unstable angina, both stimulated and unstimulated cells exhibited higher levels of TF expression than in patients with stable angina (P = .0001). In patients with acute myocardial infarction, monocyte TF activity did not differ from that in patients with stable angina. Mean levels of F1 + 2 and of fibrinogen did not differ significantly between groups. Only in the unstable angina group, a modest correlation was found between fibrinogen (r = .72, P = .005) and F1 + 2 levels (r = .54, P = .001) levels and the degree of monocyte TF expression. In patients with unstable angina, monocyte TF expression (both stimulated and unstimulated, assessed by biological activity and by antigen techniques) and fibrinogen levels were correlated with the time elapsed from the beginning of the most recent episode of pain (.61 < r < .72, .02 < P < .0001). By contrast, there was no correlation between these variables and the time from onset of pain in patients with acute myocardial infarction.. A time-dependent activation of systemic monocytes and a time-dependent increase in fibrinogen levels occurs in unstable angina but not in myocardial infarction. These findings provide further evidence that a specific inflammatory process occurs in unstable angina. Further studies are required to determine whether monocyte activation is a cause or a consequence of plaque instability in patients with unstable angina and to clarify the interrelations between platelet and monocyte activation in these circumstances.

Topics: Adult; Aged; Aged, 80 and over; Angina Pectoris; Angina, Unstable; Blood Coagulation; Female; Fibrinogen; Humans; Male; Middle Aged; Monocytes; Myocardial Infarction; Peptide Fragments; Prospective Studies; Prothrombin; Thromboplastin; Time Factors