thromboplastin and Myocardial-Ischemia

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

Topics: Coronary Thrombosis; Humans; Myocardial Ischemia; Thromboplastin

Postischemic reperfusion may profoundly alter cardiac function. Principal mediators of this phenomenon are oxygen radicals and neutrophils. Upon reflow, oxygen radicals are generated in large amounts, overwhelming cellular defenses and inducing oxidative tissue damage; biochemical markers of oxygen radical formation and attack can be found in postischemic myocardium. Reintroduction of neutrophils in postischemic tissues is accompanied by their activation, with release of lytic enzymes that directly induce tissue damage and proinflammatory mediators that amplify the local inflammatory reaction. Neutrophils may also plug capillaries, mechanically blocking flow. Oxidants can also modulate various events, ultimately leading to tissue injury, such as nitric oxide formation, platelet-activating factor metabolism, tissue factor synthesis, and exposure of adhesion molecules. In the clinical setting, important consequences of postischemic reperfusion are reversible contractile dysfunction ("stunning"), which is mostly caused by oxygen radical attack, and impairment to flow at the microvascular level ("no-reflow") secondary to neutrophil plugging and vasoconstriction.

Topics: Capillaries; Cell Adhesion Molecules; Coronary Circulation; Coronary Vessels; Free Radicals; Heart; Humans; Inflammation Mediators; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardial Stunning; Myocardium; Neutrophil Activation; Neutrophils; Nitric Oxide; Oxidative Stress; Platelet Activating Factor; Reactive Oxygen Species; Thromboplastin

Advances in our knowledge of the biochemistry of coagulation have facilitated the development of sensitive and specific assays that are able to detect the generation of coagulation enzymes in vivo. It has been demonstrated that the factor VII-tissue factor pathway functions under normal conditions to generate factor Xa and convert prothrombin to thrombin. Furthermore, the factor VII-tissue factor pathway is also mainly responsible for the activation of factor IX with minimal contribution from the contact phase. However the relatively high levels of factor IXa generated are unable to convert factor X to factor Xa under basal conditions. Prospective studies are required to determine whether "biochemically" hypercoagulable individuals (i.e., those with elevated levels of free factor VIIa, activation peptides of factor IX, factor X, or prothrombin) are more likely to develop arterial or venous thrombosis.

Topics: Basal Metabolism; Blood Coagulation; Dietary Fats; Factor VIIa; Humans; Myocardial Ischemia; Syndrome; Thromboplastin; Triglycerides

We examined the hypothesis that the +5466A>G variant (rs3917643) of the tissue factor (TF) gene is associated with thrombin formation following simvastatin in patients with ischemic heart disease (IHD).. Prothrombin 1.2 fragments (F1.2) and thrombin-antithrombin complexes (TAT) were assessed in 95 men with stable IHD, aged 54.4+/-6.8 years, in blood collected every 60s from the bleeding-time wounds before and after a 3-month simvastatin administration (40 mg/day). We identified 16 patients with the TF +5466AG genotype and 79 subjects with the +5466AA genotype. Baseline maximum rates of F1.2 and TAT formation and their maximum levels at the site of vascular injury, but not in venous blood, were higher in +5466G allele carriers than in those with +5466AA genotype (P<0.0001). The magnitude of reduction in maximum rates of F1.2 and TAT formation following simvastatin was larger (P<0.001) in +5466G allele carriers than in +5466AA subjects. The degree of decrease in maximum local levels of F1.2 and TAT after simvastatin was similar in both genotype groups. The presence of the +5466G allele was independently associated with the maximum velocity of F1.2 and TAT generation and maximum levels of both markers before and after simvastatin in multiple regression models (P<0.01 for all analyses). Local thrombin generation, in +5466AG and +5466AA subjects, showed no significant correlations with lipid variables.. Thrombin formation following vascular injury and thrombin-lowering effect of statins in patients with IHD are at least in part genetically determined by the TF +5466A>G polymorphism.

Topics: Antithrombin III; Bleeding Time; Fibrinolytic Agents; Gene Frequency; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kinetics; Linear Models; Male; Middle Aged; Myocardial Ischemia; Peptide Fragments; Peptide Hydrolases; Polymorphism, Genetic; Prothrombin; Risk Assessment; Risk Factors; Simvastatin; Thrombin; Thromboplastin; Thrombosis; Treatment Outcome

Interleukin-6 (IL-6) and macrophage colony stimulating factor plasma levels are elevated in acute coronary syndromes. IL-6 has an inherent negative inotropic action and, with tissue factor (TF), mediates the ischemia-reperfusion myocardial injury. We hypothesized that inducible ischemia leads to cytokine production, TF expression, and consequently persistent left ventricular dysfunction after dobutamine stress echocardiography (DSE) in coronary artery disease patients.. DSE was performed in 103 patients with angiographically documented coronary artery disease. Blood samples were obtained at rest, at peak stress, and 30 minutes after cessation of dobutamine infusion for measurement of macrophage colony stimulating factor, IL-6, and TF. New or worsening wall motion abnormalities at peak stress and their duration into recovery were noted. Median IL-6 and TF levels were increased at peak stress and at 30 minutes into recovery compared with rest (2.7 and 2.4 versus 2.1 pg/mL for IL-6, 310 and 385 versus 266 pg/mL for TF [P<0.01] in patients with an ischemic response; n=55). Compared with rest, a greater release of IL-6 at peak stress and recovery was observed in patients with increasing number of ischemic segments at peak DSE (2 versus 3 to 4 versus 5 to 6 versus 7 to 8 segments; P=0.03). The time to recovery of wall motion abnormalities was also associated with IL-6 levels at peak stress and recovery (r=0.51 and r=0.39, P<0.05). Macrophage colony stimulating factor levels remained unchanged throughout DSE.. Reversible ischemia induced during DSE increases IL-6 and TF plasma levels. IL-6 is related to the extent of left ventricular dysfunction at peak stress and to persistent LV dysfunction during recovery.

Topics: Adult; Aged; Biomarkers; Coronary Artery Disease; Echocardiography, Stress; Female; Humans; Interleukin-6; Male; Middle Aged; Myocardial Ischemia; Predictive Value of Tests; Stroke Volume; Thromboplastin; Ventricular Dysfunction, Left

Myocardial ischemic injury after heart transplantation is associated with subsequent development of graft vasculopathy. Both vitronectin receptor (integrin alpha(v)beta3) and tissue factor play key roles in vascular endothelial cell injury. Matrix metalloproteinases (MMPs) are activated in ischemic injury models.. Thirteen patients developed myocardial ischemic injury within 2 weeks of cardiac transplantation (ischemia group). These were compared with 10 transplantation patients who had no evidence of ischemia (control group). Endomyocardial biopsies were evaluated within 2 weeks of transplantation for alpha(v)beta3, tissue factor, and extracellular MMP inducer (EMMPRIN). At 1 year, MMPs were evaluated, and interstitial myocardial fibrosis was quantified. All patients underwent intravascular ultrasound at 1 month and 1 year after transplantation. Compared with control, the ischemia group demonstrated evidence of significant increased expression of alpha(v)beta3 (3.2-fold, P<0.001), tissue factor (2.5-fold, P<0.001), and EMMPRIN (1.9-fold, P=0.01). At 1 year, the ischemia group had a significant increase in myocardial fibrosis (24+/-1.8% versus 14+/-1.1%, P<0.001) and zymographic activity of MMP-2 (1.4-fold, P<0.001), MMP-3 (1.2-fold, P<0.001), and MMP-9 (1.3-fold, P=0.01). Coronary vasculopathy progression was also more advanced in the ischemia group (change in coronary maximal intimal thickness over 1 year 0.54+/-0.1 versus 0.26+/-0.06 mm; P=0.031).. Myocardial ischemic injury after cardiac transplantation is associated with upregulation of alpha(v)beta3, tissue factor, and activation of the MMP induction system, which may contribute to the subsequent development of allograft remodeling and vasculopathy.

Topics: Adult; Disease Progression; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Female; Fibrosis; Heart Transplantation; Humans; Immunoblotting; Immunohistochemistry; Male; Matrix Metalloproteinases; Middle Aged; Models, Cardiovascular; Myocardial Ischemia; Receptors, Vitronectin; Thromboplastin; Ultrasonography; Up-Regulation

Levels of factor VII coagulant activity (FVII:C) and two-chain factor VIIa antigen (FVIIa:Ag) were measured in ten patients before and up to 6 h after receiving a bolus of heparin during percutaneous transluminal coronary angioplasty (PTCA). A significant and sustained post-heparin fall in the level of FVII:C was observed (approximately 30%) without any change in the level of FVIIa:Ag. The level of tissue factor antigen within the circulation remained unchanged. The observed decrease in FVII:C coincided with a significant decrease in triglyceride levels presumably due to lipoprotein and hepatic lipase released by the heparin. These findings appear to demonstrate a lipid (triglyceride) dependence of FVII:C. Thus, heparin may act indirectly as antithrombotic agent by limiting a lipid-dependent activation of the extrinsic pathway of coagulation.

Topics: Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Antigens; Factor VII; Factor VIIa; Female; Heparin; Humans; Immunoassay; Lipolysis; Male; Middle Aged; Myocardial Ischemia; Thromboplastin

Thrombotic risk is increased in eosinophil-mediated disorders, and several hypotheses have been proposed to link eosinophilia and thrombosis. In particular, eosinophils have been described as source of tissue factor (TF), the main initiator of blood coagulation; however, this aspect is still controversial. This study was aimed to evaluate whether TF expression varies in eosinophils isolated from normal subjects and patients with different hypereosinophilic conditions. Eosinophils were immunologically purified from peripheral blood samples of 9 patients with different hypereosinophilic conditions and 9 normal subjects. Western blot analysis and real-time polymerase chain reaction (RT-PCR) were performed to test eosinophil TF expression. For comparison, TF expression was evaluated in monocytes from blood donors and in human endothelial (ECV304) and fibroblast (IMR90) cell lines. Western blot analysis revealed a major band of 47,000 corresponding to native TF in homogenates of purified eosinophils with a higher intensity in the 9 patients than in the 9 controls (p<0.0001). According to RT-PCR cycle threshold (Ct), TF gene expression was higher in eosinophils from patients than in those from controls, median (range) 35.10 (19.45-36.50) vs 37.17 (35.33-37.87) (p = 0.002), and was particularly abundant in one patient with idiopathic hypereosinophilic syndrome and ischemic heart attacks (Ct: 19.45). TF gene expression was moderate in monocytes, Ct: 31.32 (29.82-33.49) and abundant in endothelial cells, Ct: 28.70 (27.79-29.57) and fibroblasts, Ct: 22.77 (19.22-25.05). Our results indicate that human blood eosinophils contain variable amounts of TF. The higher TF expression in patients with hypereosinophilic disorders may contribute to increase the thrombotic risk.

Topics: Adult; Aged; Cell Line; Endothelial Cells; Eosinophils; Female; Fibroblasts; Humans; Hypereosinophilic Syndrome; Male; Middle Aged; Myocardial Ischemia; Thromboplastin; Thrombosis

Topics: Aged; Biomarkers; Electrocardiography; Female; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Percutaneous Coronary Intervention; Postoperative Complications; Prognosis; Thromboplastin; Time Factors

Microthrombosis may be involved in the pathogenesis of cardiac microangiopathy due to diabetes. Recent studies have shown that fibrinogen-like protein 2 (fgl2) plays a pivotal role in microthrombosis in viral hepatitis, acute vascular xenograft rejection and cytokine-induced fetal loss syndrome. The current study was designed to examine the expression of fgl2 in microvascular endothelial cells and investigate the effects of microthrombi due to fgl2 on cardiac function and structure in rats with type 2 diabetes. Following induction of type 2 diabetes, 24 rats were observed dynamically. Fgl2 expression and related cardiac microthrombosis were examined. Local or circulating TNF-α was measured. Coronary flow (CF) per min was calculated as an index of cardiac microcirculation. Cardiac function and morphology were evaluated. It was found that Fgl2 was highly expressed in cardiac microvascular endothelial cells of rats with type 2 diabetes, which was promoted by local or circulating TNF-α. The Fgl2 expression was associated with cardiac hyaline microthrombosis. In parallel with the fgl2 expression, CF per min, cardiac diastolic or systolic function and cardiac morphology were aggravated to some extent. It was concluded that in rats with type 2 diabetes, microthrombosis due to fgl2 contributes to the impairment of cardiac diastolic or systolic function and morphological changes.

Topics: Animals; Coronary Vessels; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endothelial Cells; Fibrinogen; Male; Microvessels; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Thromboplastin; Thrombosis; Tumor Necrosis Factor-alpha

Prompt coronary thrombus resolution, reducing time of ischemia, improves cardiac recovery. The factors triggered by ischemia that contribute to the clinical outcome are not fully known. We hypothesize that unabated inflammation due to cardiac ischemia may be a contributing factor.. As a proof-of-concept, we evaluated the effect of short-term myocardial ischemia on the local and systemic inflammatory response.. Pigs underwent either 90-min mid-left anterior descending (LAD) coronary artery balloon occlusion (infarct size 25% +/- 1% left ventricle; 29% heart function deterioration) or a sham-operation procedure. Peri-infarcted and non-ischemic cardiac tissue was obtained for histopathologic, molecular and immunohistochemical analysis of inflammatory markers [interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), modified C-reactive protein (mCRP), and human alveolar macrophage-56 (HAM-56)]. Blood (femoral vein) was withdrawn prior to myocardial infarction (MI) induction (t = 0) and at 30 and 90 min to evaluate: (i) systemic cytokine levels (IL-6, TNF-alpha, CRP); (ii) proinflammatory gene and protein expression in peripheral blood mononuclear cells (PBMCs) of tissue factor (TF), cyclo-oxygenase-2 (Cox-2), monocyte chemoattractant protein-1 (MCP-1), and CRP; and (iii) platelet activation (assessed by perfusion studies and RhoA activation).. Short-term ischemia triggered cardiac IL-6 and TNF-alpha expression, recruitment of inflammatory cells, and mCRP expression in infiltrated macrophages (P < 0.05 vs. t = 0 and sham). PBMC mRNA and protein expression of MCP-1, Cox-2 and TF was significantly increased by ischemia, whereas no differences were detected in CRP. Ischemia increased cardiac troponin-I, IL-6 and TNF-alpha systemic levels, and was associated with higher platelet deposition and RhoA activation (P < 0.001 vs. t = 0 and sham).. Short-term myocardial ischemia, even without atherosclerosis, induces an inflammatory phenotype by inducing local recruitment of macrophages and systemic activation of mononuclear cells, and renders platelets more susceptible to activation.

Topics: Animals; Biomarkers; C-Reactive Protein; Chemokine CCL2; Cyclooxygenase 2; Cytokines; Immune System; Immunologic Factors; Inflammation; Myocardial Ischemia; Platelet Activation; Swine; Thromboplastin; Up-Regulation

Topics: Angina Pectoris; Biomarkers; Blood Coagulation; Cardiovascular Diseases; Coronary Artery Disease; Humans; Lipoproteins; Myocardial Ischemia; Predictive Value of Tests; Prognosis; Risk Assessment; Severity of Illness Index; Thromboplastin

Inflammation and platelet activation are critical phenomena in the setting of acute coronary syndromes. Platelets may contribute to increase ischemic injury by enhancing the inflammatory response of leukocytes and endothelial myocardial cells. Pharmacological inhibition of platelet activation prevents ischemic complications in patients with coronary diseases. Agents directed against the integrin glycoprotein IIb/IIIa (GP IIb/IIIa) receptor not only inhibit platelet aggregation but also have been demonstrated to limit the inflammatory response in acute coronary syndromes. The question then raised is if the inhibition of platelet activation by other mechanisms than the blockade of GP IIb/IIIa may also exert anti-inflammatory effects. The aim of the present study was to analyze if clopidogrel may exert anti-inflammatory effects during the acute phase of myocardial infarction. A ligature was placed around the left anterior descending coronary artery of New Zealand White rabbits. After 15 min of ischemia, the myocardium was reperfused and the ischemic coronary artery was isolated 24 h after the ischemia. A group of ischemic rabbits was given a single oral dose of clopidogrel (20 mg kg(-1)) just after the arterial occlusion and the animal was recovered. Sham-operated animals served as control. P-selectin expression was significantly increased in infarcted rabbits with respect to control rabbits. Clopidogrel administration reduced P-selectin expression with respect to untreated infarcted rabbits. CD40 ligand and tissue factor expression was increased in the ischemic coronary artery and reduced after clopidogrel administration. Clopidogrel also protected endothelial nitric oxide synthase protein expression in the ischemic coronary artery, a protein that has been found downregulated under inflammatory conditions. In conclusion, inhibition of platelet activation by clopidogrel exerted anti-inflammatory effects on the ischemic coronary artery.

Topics: Animals; Anti-Inflammatory Agents; CD40 Ligand; Clopidogrel; Coronary Vessels; Disease Models, Animal; Male; Myocardial Ischemia; P-Selectin; Platelet Aggregation Inhibitors; Rabbits; Thromboplastin; Ticlopidine

Topics: Biomarkers; Coronary Artery Disease; Echocardiography, Stress; Humans; Interleukin-6; Myocardial Ischemia; Predictive Value of Tests; Thromboplastin

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

In ischemic heart disease (IHD) patients high plasma levels of Tissue Factor (TF), the trigger of coagulation cascade, are present. Homocysteine (Hcy) is a risk factor for coronary artery disease, and several different pathophysiological mechanisms by which Hcy may play a role in thrombus formation have been postulated in "in vitro" studies. We investigated the "in vivo" role of Hcy in affecting plasma levels of TF, its inhibitor Tissue Factor Pathway Inhibitor (TFPI) and hypercoagulability.. We investigated 119 IHD patients who underwent PTCA and compared them with 103 healthy subjects. TF, TFPI, Thrombin-Antithrombin complexes (TAT) and Hcy levels were significantly higher in the patients than in the controls. A positive correlation was found between Hcy and TF (r = 0.54; p < 0.0001), Hcy and TFPI (r = 0.26; p <0.05) as well as Hcy and TAT (r = 0.33; p <0.0001) levels. An inverse correlation existed between folate intake and Hcy levels (r = -0.28; p = 0.001). Hcy levels within the first quartile and in the highest quartile were associated with a lower (p < 0.001) and higher (p <0.0001) rate of clinical recurrences, respectively. Patients with TF values in the first quartile had a lower rate of angiographically documented clinical recurrences as compared to those in the fourth quartile (p <0.01); those in the highest quartile of TF showed a higher rate of recurrences (p = 0.001). Multivariate analysis confirmed these results (first quartile of Hcy: OR 0.02, C1 0.002-0.27; fourth quartile of Hcy: OR 36.5, C1 3.6-365/first quartile of TF: OR 0.006, C1 0.001-0.44; fourth quartile of TF: OR 16.4, C1 3.0 - 90.0), also after adjustment for risk factors and Hcy and TF respectively.. In this study we show that TF, TFPI and TAT levels are correlated with Hcy plasma levels in IHD patients, providing evidence of an "in vivo" pathophysiological mechanism of hyperhomocysteinemia. The observed association between angiographically documented clinical recurrences and TF and Hcy values awaits confirmation in studies designated to evaluate this issue on a larger number of patients.

Topics: Adult; Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Antithrombin III; Coronary Angiography; Female; Homocysteine; Humans; Hyperhomocysteinemia; Lipoproteins; Male; Middle Aged; Myocardial Ischemia; Peptide Hydrolases; Recurrence; Risk Factors; Thrombophilia; Thromboplastin; Vitamins

Functional inhibition of tissue factor (TF) has been shown to improve coronary blood flow after myocardial ischemia/reperfusion (I/R) injury. TF initiates the coagulation protease cascade, resulting in the generation of the serine protease thrombin and fibrin deposition. Thrombin can also contribute to an inflammatory response by activating various cell types, including vascular endothelial cells. We used a rabbit coronary ligation model to investigate the role of TF in acute myocardial I/R injury. At-risk areas of myocardium showed increased TF expression in the sarcolemma of cardiomyocytes, which was associated with a low level of extravascular fibrin deposition. Functional inhibition of TF activity with an anti-rabbit TF monoclonal antibody administered either 15 minutes before or 30 minutes after coronary ligation reduced infarct size by 61% (P = 0.004) and 44% (P = 0.014), respectively. Similarly, we found that inhibition of thrombin with hirudin reduced infarct size by 59% (P = 0.014). In contrast, defibrinogenating the rabbits with ancrod had no effect on infarct size, suggesting that fibrin deposition does not significantly contribute to infarct size. Functional inhibition of thrombin reduced chemokine expression and inhibition of either TF or thrombin reduced leukocyte infiltration. We propose that cardiomyocyte TF initiates extravascular thrombin generation, which enhances inflammation and injury during myocardial I/R.

Topics: Animals; Antibodies, Monoclonal; Antithrombins; Cell Movement; Chemokines; Fibrin; Fibrinogen; Hirudins; Microscopy, Electron; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocarditis; Myocardium; Neutrophils; Rabbits; Thrombin; 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

Tissue factor is a transmembrane protein that activates the extrinsic coagulation pathway by binding factor VII. Endothelial cells, being in contact with circulating blood, do not normally express tissue factor. Here we provide evidence that oxygen free radicals induce tissue factor messenger RNA transcription and expression of tissue factor procoagulant activity in endothelial cells in culture. Isolated, perfused rabbit hearts exposed to exogenous oxygen free radicals also showed a marked increase in tissue factor activity within the coronary circulation. Furthermore, in ex vivo and in vivo hearts subjected to ischemia and reperfusion, a condition associated with a production of oxygen free radicals in large amounts, a marked increase in tissue factor activity occurred. This phenomenon could be abolished by oxygen radical scavengers. This increase in tissue factor activity during postischemic reperfusion was accompanied by a significant decrease in coronary flow, suggesting that increase in tissue factor activity with the consequent activation of the coagulation cascade might impair coronary flow during reperfusion and possibly contribute to the occurrence of reperfusion injury.

Topics: Animals; Blotting, Northern; Cells, Cultured; Coronary Circulation; Cycloheximide; Endothelium, Vascular; Free Radical Scavengers; Free Radicals; Gene Expression; Heart; In Vitro Techniques; Myocardial Ischemia; Myocardial Reperfusion; Oxygen; Rabbits; Regional Blood Flow; RNA, Messenger; Thromboplastin; Xanthine; Xanthine Oxidase; Xanthines

Topics: Adult; Aged; Angina Pectoris; Blood Coagulation; Concanavalin A; Female; Humans; Lymphocyte Activation; Male; Middle Aged; Myocardial Ischemia; Partial Thromboplastin Time; Thromboplastin