thromboplastin and Myocardial-Infarction

An enhanced risk of cardiovascular mortality has been observed after pneumonia. Epidemiological studies have shown that respiratory tract infections are associated with an increased risk of thrombotic-related vascular disease such as myocardial infarction, ischemic stroke and venous thrombosis. Myocardial infarction and stroke have been detected essentially in the early phase of the disease (i.e. within 48 h from hospital admission), with an incidence ranging from as low as 1% to as high as 11%. Age, previous cardiovascular events and high pneumonia severity index were independent predictors of myocardial infarction; clinical predictors of stroke were not identified. Deep venous thrombosis and pulmonary embolism may also occur after pneumonia but incidence and clinical predictors must be defined. The biological plausibility of such an association may be deduced by experimental and clinical studies, showing that lung infection is complicated by platelet aggregation and clotting system activation, as documented by up-regulation of tissue factor and down-regulation of activated protein C. The effect of antithrombotic drugs has been examined in experimental and clinical studies but results are still inconclusive.

Topics: Age Factors; Anticoagulants; Blood Coagulation; Clinical Trials as Topic; Fibrinolytic Agents; Humans; Myocardial Infarction; Patient Admission; Platelet Aggregation; Pneumonia; Protein C; Research Design; Stroke; Thromboplastin; Thrombosis; Treatment Outcome; Vascular Diseases

Tissue factor is the primary initiator of coagulation cascade and plays an essential role in haemostasis and thrombosis. In addition, tissue factor and coagulation proteases contribute to many cellular responses via activation of protease activated receptors. The heart is an organ with high levels of constitutive tissue factor expression. This review focuses on the role of tissue factor, coagulation proteases and protease activated receptors in heart haemostasis and the pathological heart remodelling associated with myocardial infarction, viral myocarditis and hypertension.

Topics: Animals; Blood Coagulation Factors; Fibrosis; Heart Valve Diseases; Hemostasis; Humans; Hypertension; Hypertension, Pulmonary; Hypertrophy; Models, Cardiovascular; Myocardial Infarction; Myocarditis; Myocytes, Cardiac; Receptors, Proteinase-Activated; Renin-Angiotensin System; Thromboplastin; Ventricular Remodeling

Inflammation and oxidative stress play key roles in atherosclerotic plaque instability, and plaque rupture/erosion and subsequent thrombus formation constitute the principal mechanisms of total vessel occlusion and acute ST-elevation myocardial infarction (STEMI). Plaque disruption triggers the formation of initial platelet aggregates that grow in association with an increase in fibrin formation, leading to persistent coronary flow obstruction and blood coagulation. The fibrin network may trap large numbers of erythrocytes and inflammatory cells to form an erythrocyte-rich thrombus. In fact, previous clinical studies have shown that not only platelet-rich white thrombi, but also erythrocyte-rich red thrombi can be visualized using angioscopy in patients with acute coronary syndrome. Recently, the development of thrombus aspiration and distal protection devices has significantly improved the clinical outcomes of percutaneous intervention in STEMI patients and has enabled the evaluation of antemortem coronary artery thrombi. This is important because previous autopsy studies were unable to differentiate coronary thrombi responsible for myocardial ischemia from postmortem clots. Using frozen samples of aspirated thrombi and specific monoclonal antibodies, we investigated the cellular components of thrombi (platelets, erythrocytes, fibrin and inflammatory cells, such as myeloperoxidase-positive cells) and pathologically evaluated the relationships between erythrocyte-rich thrombi and inflammation, oxidative stress and clinical outcomes in STEMI patients. Therefore, this review article focuses on the efficacy of thrombus aspiration therapy and the components of aspirated intracoronary thrombi in STEMI patients and presents the results of recent studies regarding the relationship between the composition of aspirated intracoronary thrombi and clinical outcomes.

Topics: Cell-Derived Microparticles; Coronary Thrombosis; Erythrocytes; Humans; Inflammation; Myocardial Infarction; Oxidative Stress; Plaque, Atherosclerotic; Suction; Thrombectomy; Thromboplastin

Protease-activated receptors (PARs) are widely expressed within the heart. They are activated by a myriad of proteases, including coagulation proteases. In vitro studies showed that activation of PAR-1 and PAR-2 on cardiomyocytes induced hypertrophy. In addition, PAR-1 stimulation on cardiac fibroblasts induced proliferation. Genetic and pharmacologic approaches have been used to investigate the role of the different PARs in cardiac ischemia/reperfusion (I/R) injury. In mice and rats, PAR-1 is reported to play a role in inflammation, infarct size, and remodeling after cardiac I/R injury. However, there are notable differences between the effect of a deficiency in PAR-1 and inhibition of PAR-1. For instance, inhibition of PAR-1 reduced infarct size whereas there was no effect of a deficiency of PAR-1. These differences maybe due to off-target effects of the inhibitor or PAR-4 compensation of PAR-1 deficiency. Similarly, a deficiency of PAR-2 was associated with reduced cardiac inflammation and improved heart function after I/R injury, whereas pharmacologic activation of PAR-2 was found to be protective due to increased vasodilatation. These differences maybe due to different signaling responses induced by an endogenous protease versus an exogenous agonist peptide. Surprisingly, PAR-4 deficiency resulted in increased cardiac injury and increased mortality after I/R injury. In contrast, a pharmacological study indicated that inhibition of PAR-4 was cardioprotective. It is possible that the major cellular target of the PAR-4 inhibitor is platelets, which have been shown to contribute to inflammation in the injured heart, whereas PAR-4 signaling in cardiomyocytes may be protective. These discrepant results between genetic and pharmacological approaches indicate that further studies are needed to determine the role of different PARs in the injured heart.

Topics: Animals; Humans; Myocardial Infarction; Myocardium; Protein Isoforms; Receptors, Proteinase-Activated; Thromboplastin

The exposure of tissue factor (TF) to blood flow is the initial step in the coagulation process and plays an important role in thrombogenesis. We investigated the role of genetic polymorphisms and haplotypes of the TF gene in the risk of ischemic vascular disease.. Four hundred and twenty-two Italian patients with juvenile myocardial infarction (MI) and 434 controls, 808 US cases with MI and 1005 controls, 267 Italian cases with juvenile ischemic stroke and 209 controls and 148 German cases with juvenile ischemic stroke and 191 controls were studied. rs1361600, rs3917629 (rs3354 in the US population), rs1324214 and rs3917639 Tag single nucleotide polymorphisms were genotyped. Additionally, a meta-analysis of all previous studies on TF loci and the risk of ischemic coronary disease (ICD) was performed.. After multivariable analysis none of the SNPs, major SNP haplotypes or haplotype-pairs showed any consistent association with MI. Pooled meta-analysis of six studies also suggested that TF polymorphisms are not associated with CHD. A significant, independent association between SNP rs1324214 (C/T) and juvenile stroke was found in Italian and German populations (OR for TT homozygotes = 0.47, 95% CI 0.24-0.92, in combined analysis). Pooled analysis also showed a significant association for haplotype H3 (OR = 0.76, 95% CI 0.57-1.00) and haplotype-pair H3-H3 (OR = 0.43, 95% CI 0.20-0.92).. TF genetic variations were associated with the risk of ischemic stroke at young age, but did not affect ischemic coronary disease.

Topics: Adult; Case-Control Studies; Female; Genetic Variation; Haplotypes; Homozygote; Humans; Interleukin-1beta; Ischemia; Italy; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Risk; Stroke; Thromboplastin

Topics: Angina Pectoris; Coronary Thrombosis; Humans; Myocardial Infarction; Syndrome; Thromboplastin

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

Tissue factor is a key enzyme in coagulation process. It is primary known as a cofactor for factor VIIa-mediated triggering of blood coagulation, which proceeds in a cascade of extracellular reactions. Tissue factor forms a catalytic complex with VIIa and intitiates coagulation by activating factor IX and X, ultimately resulting in thrombin formation. Being a transmembranic glycoprotein it takes a signalling information to another cell activity after endothelium or other tissue damage. Tissue factor plays a pivotal role in blood clotting physiology and pathology especialy in atherothrombosis. Thrombogenic tissue factor on cell-derived microparticles is present in the circulating blood of patients with acute coronary syndromes. Tissue factor is found in adventitia of blood vessels and the lipid core of atherosclerotic plaques (but not in vascular cells contacting directly with blood). Although the molecular mechanisms responsible for these phenomena remain unclear, it is thought that they are brought about by the action of intracellular signaling, resulting in gene transcription and subsequent protein synthesis. By expressing on monocyte or macrofage cell membrane surface it is involved in proinflammatory action and plaque destabilisation. This shifted the emphasis to investigations of what happened on the cell surface, and later to the cell biology of tissue factor and its inducibility in monocytes/macrophages and endothelial cells. Recent studies have suggested that tissue factor also plays non-hemostatic roles in blood vessel development, tumor angiogenesis and metastasis, inflamation. Tissue factor upregulates a number of genes involved in regulation of growth, transcription, and cellular motility, as well as cytokines, makes it possible to suggest a link between the formation of the tissue factor / VIIa complex and the cellular processes. Regulation of tissue factor activity by natural tissue factor pathway inhibitor (synthesized by vascular endothelial cells) or by special drugs is a new insight in thrombosis and vessel reocclusion preventive therapy. Tissue factor concentration in circulating blood has a higher informativity comparing to troponine and CRB values.

Topics: Age Factors; Aged; Arteriosclerosis; Blood Coagulation; C-Reactive Protein; Diabetes Complications; Female; Humans; Hypercholesterolemia; Hypertension; Male; Myocardial Infarction; Risk Factors; Sex Factors; Syndrome; Thromboplastin; Thrombosis; Troponin T

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

Topics: Adult; Aged; Animals; Cardiovascular Diseases; Cerebrovascular Disorders; Cohort Studies; Cross-Sectional Studies; Epidemiologic Methods; Europe; Factor VII; Female; Fibrinogen; Hemostasis; Humans; Hyperlipidemias; Lipoproteins; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Risk Factors; Thromboplastin; Triglycerides; United States

Topics: Animals; Anticoagulants; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Myocardial Infarction; Prothrombin Time; Rabbits; Thrombophlebitis; Thromboplastin

Topics: Anticoagulants; Blood Coagulation Tests; Cerebral Hemorrhage; Cerebrovascular Disorders; Coumarins; Heparin; Humans; Middle Aged; Myocardial Infarction; Phenindione; Postoperative Care; Prothrombin Time; Rheumatic Heart Disease; Thromboembolism; Thrombophlebitis; Thromboplastin

To investigate the influence of Anxin granules combined with tirofiban on acute myocardial infarction (AMI) Patients after elective percutaneous coronary intervention (PCI). One hundred and twenty AMI patients were randomly divided into treatment group and control group. The patients in the two groups were all given Tirofiban 30mins before PCI . The treatment group was added Anxin granules 30 mins before and after PCI. Tissue factor (TF) and von willebrand factor (vWF) were tested at 6 hours after operation. Syndromatology alteration of traditional Chinese medicine (TCM) and bleeding complications were observed at 4 weeks after operation. Both TF and vWF at 6 hours after operation of the treatment group was lower than the control group significantly (P < 0.01), while the condition of myocardial ischemia at 90 mins after operation of the treatment group was better than control group with significance. The syndromatology alteration of TCM especially spontaneous perspiration and hypodynamia of the treatment group were improved significantly compared to control group 4 weeks after operation. All patients in both groups had no bleeding complications and thrombopenia. The study suggests that Anxin granules combined with tirofiba can improve the clinical efficacy and the endothelial function of AMI patients after PCI with no increase in bleeding events.

Topics: Aged; Angioplasty, Balloon, Coronary; Drugs, Chinese Herbal; Female; Humans; Middle Aged; Myocardial Infarction; Postoperative Hemorrhage; Thromboplastin; von Willebrand Factor

The effects of intracoronary injection of mononuclear bone marrow cells (mBMC) on haemostasis are not clarified. The aim of the present substudy of the autologous stem cell transplantation in acute myocardial infarction (ASTAMI) trial was to investigate the influence of intracoronary injection of mBMC on selected circulating prothrombotic markers.. One hundred patients with ST-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI) on the left descending coronary artery were randomized to receive mBMC (Tx) (median 6 days after the STEMI) or to a control group. Fasting blood samples were drawn the day before Tx (day-1, 4-5 days after the STEMI), and 1 day, 3 days, 2-3 weeks and 3 months after Tx.. No significant differences in changes between the groups were observed from day-1 to any later time points in the levels of TF (tissue factor), F1+2 (prothrombin fragment 1+2), D-dimer, ETP (endogenous thrombin potential), PAI-1 (plasminogen activator inhibitor 1) or tissue plasminogen activator. However, TF and F1+2 decreased from day-1 to the subsequent time points in both groups, except from a small increase of TF at 3 months in the control group. In both groups, D-dimer and ETP decreased from day-1 to 2-3 weeks and 3 months, whereas PAI-1 increased to 2-3 weeks and 3 months.. Intracoronary injection of mBMC did not influence on prothrombotic markers in patients with STEMI. Reduction in several prothrombotic markers from day-1 to 2-3 weeks and 3 months could be demonstrated in both groups indicating decreased hypercoagulability. This is a substudy of the ASTAMI trial which is registered at www.clinicaltrials.gov, NCT 00199823.

Topics: Biomarkers; Bone Marrow Transplantation; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Plasminogen Activator Inhibitor 1; Protein Precursors; Prothrombin; Thrombin; Thromboplastin; Tissue Plasminogen Activator; Transplantation, Autologous; Treatment Outcome

Thrombin has a role not only in the coagulation process but also in inflammatory responses. Oral direct thrombin inhibitors (DTIs) are currently being evaluated in patients with thromboembolic diseases.. To investigate whether an oral DTI affects markers for platelet and inflammatory activity after myocardial infarction (MI).. A total of 518 patients with MI were randomly assigned to ximelagatran treatment (four different dose groups) in combination with aspirin, or aspirin alone for 6 months. The levels of soluble (s) P-selectin, soluble tissue factor, C-reactive protein (CRP), interleukin (IL)-10 and IL-18 were analysed in serial blood samples.. sP-selectin concentration increased after 1 week and persisted at an elevated level for 6 months in all study groups (P < 0.001). In the two highest ximelagatran dose groups, there was a reduced increase in sP-selectin compared to treatment with lower doses of ximelagatran and aspirin alone (P = 0.01 and P = 0.002, respectively). IL-18 levels did not change in the aspirin alone treatment group. By contrast, there was an elevation in IL-18 level in the lower and higher ximelagatran dose groups after 6 months (P = 0.006 and P < 0.001, respectively). Ximelagatran increased IL-10 levels (P = 0.002) and reduced the decrease in CRP levels after 6 months compared to treatment with aspirin alone (P = 0.002).. A persistent elevation of platelet activity is found in patients with a recent MI after the cessation of acute antithrombotic treatment, and the addition of an oral DTI at higher doses decreases the activity. By contrast, long-term treatment with a DTI increases the levels of several markers of inflammation. Further studies with prolonged exposure of oral DTIs are needed for evaluation of the effect on inflammatory processes and to determine whether these agents influence clinical outcomes.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antithrombins; Aspirin; Azetidines; Benzylamines; Biomarkers; Blood Platelets; C-Reactive Protein; Comorbidity; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Inflammation; Interleukin-10; Interleukin-18; Male; Middle Aged; Myocardial Infarction; P-Selectin; Platelet Activation; Risk Factors; Thromboplastin; Time Factors; Treatment Outcome

In acute myocardial infarction (AMI), increased Tissue Factor (TF) expression on circulating monocytes and microparticles (MP) may contribute to thrombotic events. Because surfacebound Tissue Factor Pathway Inhibitor-1 (TFPI) inhibits TF activity on monocytes and endothelial cells decreased TFPI expression may reinforce the procoagulant activity of circulating MP. Aim of the study was to analyze TFPI expression and TF activity after stenting and thrombolysis inAMI. Thirty-nine patients of a randomized study comparing intravenous thrombolysis (n=19) and stenting (n=20) were included. Before and after therapy blood samples for analysis of MPs, TF antigen and activity, prothrombin fragment F1+2 and D-dimer were obtained. TFPI expression on TF positive MPs was decreased after thrombolysis but not after stenting. In contrast, TF plasma levels and TF positive MP remained unchanged in both treatment groups. After thrombolysis increased D-dimer and F1+2 plasma concentrations indicated activation of fibrinolysis and coagulation. Significance of MPTFPI for inhibition of TF activity was measured using inhibitory TFPI antibodies. Membrane-associated TFPI inhibited TF activity on circulating MPs. After thrombolysis inhibition of TF activity by TFPI was decreased as compared to stenting. Correlation of circulating TF with F1+2 only after thrombolysis, suggests a role for TF-induced activation of coagulation after thrombolysis. Enhanced TF activity on circulating MPs in AMI is inhibited by endogenous surface-boundTFPI. After thrombolysis but not after stenting MPTFPI is degraded and may induce thrombin generation due to unopposed tissue factor activity. Anti-TF therapies during thrombolysis may reduce thrombin generation in AMI.

Topics: Aged; Blood Coagulation; Female; Fibrin Fibrinogen Degradation Products; Humans; Lipoproteins; Male; Middle Aged; Myocardial Infarction; Particle Size; Peptide Fragments; Prothrombin; Stents; Thrombolytic Therapy; Thrombophilia; Thromboplastin; Thrombosis; Treatment Failure

Increased numbers of CD146-defined circulating endothelial cells (CECs), as are present in the peripheral blood of patients suffering acute coronary syndromes, imply injury to the endothelium. Endothelial damage can also be assessed by the measurement of plasma levels of von Willebrand factor (vWf). Increased levels of procoagulant plasma tissue factor (TF), arising from monocytes/macrophages and endothelial cells, is present in atherosclerosis. We hypothesised increased CECs in patients with ischaemic rest pain (IRP) of the lower limb due to peripheral atherosclerosis and comparable to that seen in patients with acute myocardial infarction (AMI), when compared to patients with intermittent claudication (IC) or healthy controls that would correlate with vWf and TF.. We recruited 20 patients in each of four groups: (i) IRP of the lower limb; (ii) AMI; (iii) 'stable' IC; and (iv) healthy controls. CD146-expressing CECs were measured by immumomagnetic separation and counting under a fluorescence microscope; plasma vWf and TF by ELISA.. In IRP, median (IQR) CEC levels were 3.5 (2.0-5.8) cells/ml, in IC were 1.1 (0.6-2.9) cells/ml, and in healthy controls were 1.0 (0.5-1.7) cells/ml (p<0.001). The levels of vWf (p=0.034) and TF (p=0.007) were also significantly different between the groups, with the highest levels in patients with IRP. Levels of CECs correlated with vWf (rs=0.4, p=0.002) and TF ( rs=0.296, p=0.021 ). In AMI, CEC levels were higher than those in IRP at 4.9 (3.6-8.4) cells/ml (p=0.0385).. This study demonstrates evidence of direct endothelial cell injury (i.e. raised CECs) in patients with IRP that correlated with vWf and TF, but that this is less severe than in AMI.

Topics: Aged; Analysis of Variance; Antigens, CD; Arteriosclerosis; CD146 Antigen; Endothelial Cells; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Intermittent Claudication; Ischemia; Leg; Male; Membrane Glycoproteins; Middle Aged; Myocardial Infarction; Neural Cell Adhesion Molecules; Pain; Thromboplastin; von Willebrand Factor

Antithrombotic treatment with warfarin and/or aspirin is widely used in preventing recurrence of thrombotic events after an acute myocardial infarction (AMI). The objective of this study was to evaluate the long-term influence of warfarin at different INR levels and/or aspirin on some hemostatic variables in patients after an AMI. A subpopulation of the WARIS-II trial in which patients after an acute MI were randomly assigned to treatment with aspirin 160 mg d(-1), aspirin 75 mg d(-1) and warfarin (target INR 2.0-2.5) or warfarin (target INR 2.8-4.2) was studied. Fasting blood samples were collected before randomization 5-7 days after the AMI, after 6 weeks and 4 years for determinations of prothrombin fragment 1 + 2 (F1 + 2), soluble tissue factor (sTF), D-dimer and fibrinogen. In the warfarin-alone group as compared with the aspirin-alone group significantly lower levels of F1 + 2 and D-dimer (P < 0.001 for both), but significantly higher levels of sTF (P = 0.007) were found after 6 weeks. The same pattern was found after 4 years. When comparing the combined group with the aspirin alone group, similar profiles were seen. The levels of F1 + 2 in the combined group were, however, significantly higher than in the warfarin alone group after 6 weeks and 4 years (both P < 0.01). During long-term treatment with warfarin in patients after an AMI increased levels of sTF were found. However, significantly reduced levels of the coagulation products were obtained, indicating reduced thrombin generation. The increased levels of sTF during warfarin therapy are suggested to appear on the basis of reduced consumption.

Topics: Adult; Aged; Aspirin; Biomarkers; Blood Coagulation Factors; Drug Therapy, Combination; Female; Hemostasis; Humans; International Normalized Ratio; Longitudinal Studies; Male; Middle Aged; Myocardial Infarction; Solubility; Thromboplastin; Time Factors; Warfarin

Few data exist on the effects of n-3 polyunsaturated fatty acids (PUFAs) on the initiators and endstage products of coagulation following an acute myocardial infarction (MI). We assessed the long-term effects of n-3 PUFAs on postinfarct variations of tissue factor (TF), activated factor XII (FXIIa) and fibrin monomer (FM), and expected additional statin treatment to modify thrombogenicity. Acute MI patients (n = 300) were randomly allocated to a high dose of n-3 PUFAs or corn oil for at least one year. Plasma concentrations of TF, FXIIa and FM were unaffected by n-3 PUFAs as compared to corn oil, and were uninfluenced by additional statin treatment in subgroup analyses. TF decreased (p = 0.0001), while FXIIa increased during the first 6 weeks (p = 0.001). FM remained essentially unchanged during the entire observation period. In conclusion, TF, FXIIa and FM were unaffected by long-term treatment with high- dosed n-3 PUFAs and by additional statin treatment.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Blood Coagulation; Cholesterol; Corn Oil; Double-Blind Method; Factor XIIa; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Female; Fibrin; Humans; Lipid Metabolism; Male; Middle Aged; Models, Statistical; Myocardial Infarction; Prospective Studies; Random Allocation; Thromboplastin; Triglycerides

During myocardial infarction (MI), high levels of circulating procoagulant microparticles (MP) shed from endothelial cells and platelets diffuse prothrombotic and proinflammatory potentials crucial for the coronary prognosis. In addition to conventional treatments, we evaluated whether vitamin C treatment could modify circulating levels of procoagulant MP. Upon admission, 61 patients with MI were prospectively randomized for immediate additional vitamin C treatment. Circulating MP were quantified by functional prothrombinase assay before and after 5 days of vitamin C administration (1 g day-1). The cellular origin of MP was also assessed. In vitamin C-treated patients, the reduction in platelet-derived MP was 10% higher (P = 0.01). In patients with diabetes mellitus, dyslipidemia or more than two cardiovascular risk factors, vitamin C decreased endothelial and platelet-derived MP levels by approximately 70% and 13%, respectively. This early effect on circulating platelet and endothelial-derived MP, testifies to the importance of oxidative stress during MI. Vitamin C could prove beneficial for the outcome of patients at higher thrombotic risk.

Topics: Acute Disease; Aged; Ascorbic Acid; Blood Platelets; Cardiotonic Agents; Coronary Angiography; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Activation; Prospective Studies; Risk Factors; 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

Topics: Adult; Aged; Aspirin; Biomarkers; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Predictive Value of Tests; Regression Analysis; Thromboplastin; Warfarin

In acute myocardial infarction (AMI), surface-bound tissue factor pathway inhibitor-1 (TFPI-1) inhibits an increased monocyte procoagulant activity. In addition, TFPI-1 is released from microvascular endothelial cells after treatment with heparin and thereby contributes to its antithrombotic properties.. We examined 19 patients in a randomized study comparing intravenous fibrinolysis with alteplase (n=9) and revascularization by stent placement with additional abciximab treatment (n=10). We obtained blood samples for analysis of monocytic TFPI-1 surface expression by flow cytometry and plasma TFPI-1 concentrations by immunoassay before and after therapy. We found a significant decrease in surface TFPI-1 on circulating monocytes 24 hours after thrombolysis (P=0.006) that was not observed after stenting. Systemic plasma TFPI-1 concentrations increased immediately after stenting by 71+/-14% (P=0.008), whereas after thrombolysis, a decrease in TFPI-1 plasma concentrations of 21+/-11% was observed (P=0.075). In vitro experiments confirmed that plasmin decreased TFPI-1 surface expression dose-dependently.. Activation of the fibrinolytic system by alteplase in AMI decreases surface-associated TFPI-1 on circulating monocytes and plasma TFPI-1. Reduced TFPI-1 may contribute to thrombotic complications after fibrinolysis in AMI.

Topics: Abciximab; Adult; Aged; Antibodies, Monoclonal; Cell Line; Cells, Cultured; Coronary Angiography; Electrocardiography; Female; Fibrinolysin; Fibrinolytic Agents; Humans; Immunoglobulin Fab Fragments; Kinetics; Lipoproteins; Male; Middle Aged; Monocytes; Myocardial Infarction; Stents; Thrombolytic Therapy; Thromboplastin; Tissue Plasminogen Activator

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Blood Coagulation Factors; Double-Blind Method; Enalapril; Female; Fibrinolysis; Humans; Losartan; Male; Middle Aged; Myocardial Infarction; Plasminogen Inactivators; Thrombolytic Therapy; Thromboplastin; Tissue Plasminogen Activator

We investigated the effects of enalapril therapy on plasma tissue factor (TF), tissue factor pathway inhibitor (TFPI) and monocyte chemoattractant protein-1 (MCP-1) levels in patients with acute myocardial infarction.. Macrophages express TF in human coronary atherosclerotic plaques. Both TF and TFPI are major regulators of coagulation and thrombosis. Monocyte chemoattractant protein-1 is a monocyte and macrophage chemotactic and activating factor.. In a randomized, double-blind, placebo-controlled study beginning about two weeks after myocardial infarction, 16 patients received four weeks of placebo (placebo group) and another 16 patients received four weeks of enalapril 5 mg daily therapy (enalapril group). We performed blood sampling after administration of the doses.. There were no significant differences in the serum angiotensin-converting enzyme (ACE) activity, plasma TF, free TFPI or MCP-1 levels before administration between the enalapril and placebo groups. In the enalapril group, ACE activity (IU/liter) (14.0 before, 5.2 on day 3, 5.8 on day 7, 6.3 on day 28), TF levels (pg/ml) (223, 203, 182, 178) and MCP-1 levels (pg/ml) (919, 789, 790, 803) significantly decreased by day 28. However, the free TFPI levels (ng/ml) (28.2, 26.5, 26.8, 28.4) did not change. These four variables were unchanged during the study period in the placebo group.. This study demonstrated that administration of enalapril reduces the increased procoagulant activity in patients with myocardial infarction associated with inhibition of the activation and accumulation of macrophages and monocytes.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Chemokine CCL2; Double-Blind Method; Enalapril; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lipoproteins; Macrophages; Male; Middle Aged; Monocytes; Myocardial Infarction; Thromboplastin

In a randomized, double-blind, placebo-controlled study beginning 4 weeks after uncomplicated acute myocardial infarction, it was established that the baseline plasma tissue factor antigen level was significantly higher in patients with myocardial infarction than in control subjects, and enalapril therapy significantly reduced the elevated plasma tissue factor antigen level. This may be associated with the reduction in the risk of coronary thrombosis seen with the use of angiotensin-converting enzyme inhibitors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Double-Blind Method; Drug Therapy, Combination; Enalapril; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Myocardial Infarction; Peptidyl-Dipeptidase A; Thromboplastin; Time Factors

Various methods have been described to evaluate efficacy of anticoagulant therapy using the international normalized ratio (INR). We compared the following approaches: (1) total INR's or the most recent measurement; (2) percent time within therapeutic range, with INR changing directly or halfway between visits; and (3) total observation time assuming INR changing linearly. The study population comprised 1700 post myocardial infarction patients. Treatment comprised 3725 patient-years. There were 61,471 INR assessments with target therapeutic level of 2.8-4.8. Acenocoumarol as well as phenprocoumon were employed. Therapeutic achievement in the first months of treatment was low: less than 60% of INR's were in range. Treatment stabilized after 6 months. Patients on acenocoumarol were within range 70% of the time compared to 80% for phenprocoumon. Method 3 is preferred because it incorporates time and is capable of calculating incidence rates at different INR levels. Our findings call for an urgent improvement of standard of anticoagulant control in the first months following commencement of treatment.

Topics: Acenocoumarol; Aged; Anticoagulants; Cardiovascular Diseases; Convalescence; Double-Blind Method; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Phenprocoumon; Prothrombin Time; Quality Control; Reference Standards; Thromboplastin; Treatment Outcome

Among 100 consecutive patients receiving heparin in therapeutic dosage, major bleeding occurred in 21, and minor bleeding in 16. Two patients died from bleeding, and two had recurrent pulmonary embolism. Major bleeding occurred in 21% when therapy was regulated with whole-blood clotting time and in 20% when heparin was given without clotting tests. In a subsequent prospective trial patients received heparin by intermittent intravenous injection with or without laboratory control according to the partial thromboplastin time or continuously by intravenous infusion. Recurrent thromboembolism occurred once in each group. Major bleeding was seven times more frequent with intermittent injection than with continuous infusion. Control with the partial thromboplastin time did not prevent major bleeding in patients receiving intermittent injections. With continuous infusion, one-fourth less heparin was required than with intermittent injections. Administration of heparin by continuous infusion appears safer than intermittent injection with or without laboratory control and is no less effective for prevention of thromboembolism.

Topics: Administration, Oral; Adolescent; Adult; Aged; Arterial Occlusive Diseases; Blood Coagulation Tests; Cerebrovascular Disorders; Clinical Trials as Topic; Hemorrhage; Heparin; Humans; Infusions, Parenteral; Injections, Intravenous; Middle Aged; Myocardial Infarction; Prospective Studies; Prothrombin Time; Pulmonary Embolism; Recurrence; Thromboembolism; Thromboplastin; Thrombosis; Time Factors

Topics: Adult; Aged; Blood Coagulation Tests; Blood Transfusion; Clinical Trials as Topic; Female; Femoral Fractures; Femoral Vein; Fibrinogen; Hematocrit; Heparin; Hip; Humans; Injections, Subcutaneous; Iodine Isotopes; Male; Middle Aged; Myocardial Infarction; Phlebography; Popliteal Vein; Postoperative Complications; Prospective Studies; Radionuclide Imaging; Thrombophlebitis; Thromboplastin; Thrombosis

Tissue factor (TF) and activated factor XI (FXIa) have been associated with acute coronary syndrome, ischemic stroke and venous thromboembolism. Their predictive value in stable coronary artery disease (CAD) is unclear. We investigated whether active TF and FXIa were associated with clinical outcomes in CAD patients in long-term observation.. In 124 stable patients with multivessel CAD, we assessed the presence of circulating, active TF and FXIa by measuring a response of thrombin generation to respective inhibitory antibodies. We recorded the composite endpoint of myocardial infarction (MI), stroke, systemic thromboembolism and cardiovascular death during follow-up (median 106 months, interquartile range 95-119).. Circulating FXIa and active TF were detected in 40% and 20.8% of the 120 patients (aged 65.0 [57.0-70.3] years, men, 78.3%), who completed follow-up. The composite endpoint occurred more frequently in patients with detectable active TF and FXIa present at baseline (hazard ratio [HR] 4.02, 95% confidence interval [CI] 2.26-7.17, p < 0.001 and HR 6.21, 95% CI 3.40-11.40, p < 0.001, respectively). On multivariate analysis FXIa, but not active TF, was an independent predictor of the composite endpoint, as well as MI, stroke/systemic thromboembolism, and cardiovascular death, when analyzed separately.. To our knowledge, this study is the first to show that circulating FXIa predicts arterial thromboembolic events in advanced CAD, supporting a growing interest in FXIa inhibitors as novel antithrombotic agents.

Topics: Aged; Blood Coagulation Tests; Coronary Artery Disease; Factor IX; Factor XIa; Female; Humans; Male; Middle Aged; Myocardial Infarction; Risk Factors; Stroke; Thromboembolism; Thromboplastin

Coronary artery disease (CAD) is associated with a prothrombotic tendency including increased factor (F) VIIa-antithrombin (FVIIa-AT) complexes, a measure of tissue factor (TF) exposure, and activated FXI (FXIa). We investigated whether increased FVIIa-AT complexes are associated with FXIa and active TF and if major adverse clinical outcomes are predicted by the complexes in CAD.. In 120 CAD patients, we assessed FVIIa-AT complex concentrations and the presence of circulating FXIa and active TF. Levels of 8-iso-prostaglandin F2α (8-iso-PGF2α), interleukin-6, high-sensitivity C reactive protein, prothrombin fragment 1 + 2, and free Tissue Factor Pathway Inhibitor were determined. Myocardial infarction (MI), ischemic stroke, systemic thromboembolism (SE), and cardiovascular (CV) death were recorded separately and as a composite endpoint, during follow-up.. FVIIa-AT complexes were positively associated with current smoking and multivessel CAD. Elevated FVIIa-AT complexes characterized patients with circulating FXIa and/or active TF in association with increased plasma isoprostanes but not with thrombin generation or inflammatory markers. During a median follow-up of 106 months (interquartile range 95-119), high baseline levels of FVIIa-AT complexes predicted ischemic stroke/SE (HR 4.61 [95% CI 1.48-18.42]) and a composite endpoint of MI, stroke/SE, and CV death (HR 7.47 [95% CI 2.81-19.87]).. This study is the first to show that high FVIIa-AT complexes characterize advanced CAD patients with detectable FXIa and active TF, which is, in part, driven by oxidative stress. High FVIIa-AT complexes were associated with the risk of ischemic stroke/SE during long-term follow-up, highlighting the need for effective antithrombotic agents in CAD.

Topics: Anticoagulants; Antithrombin III; Antithrombins; Coronary Artery Disease; Factor VIIa; Factor XIa; Humans; Ischemic Stroke; Myocardial Infarction; Thromboplastin

Coagulation is involved in fibroproliferative responses following acute myocardial infarction (AMI). Left ventricular (LV) remodeling following AMI is closely associated with progression to heart failure. This study aims to assess the association between plasma tissue factor activity and LV remodeling in post-AMI patients.. We studied 228 patients with AMI and 57 healthy subjects. Patients with AMI were categorized into two age- and sex-matched groups: patients with adverse LV remodeling or reverse LV remodeling, defined by an increase or decrease, respectively, in LV end systolic volume by ≥15% over 6 months. TF activity was measured in plasma collected at baseline (within 72 hours of revascularization), 1 month and 6 months post-AMI. Multiple level longitudinal data analysis with structural equation (ML-SEM) model was used to assess the impact of various clinical variables on TF activity in post-AMI.. Plasma TF activity in post-AMI patients at baseline (29.05 ± 10.75 pM) was similar to that in healthy subjects but fell at 1 month (21.78 ± 8.23, p<0.001) with partial recovery by 6 months (25.84 ± 8.80, p<0.001) after AMI. Plasma TF activity at 6 month post-AMI was better restored in patients with reverse LV remodeling than those with adverse LV remodeling (27.35 ± 7.14 vs 24.34 ± 9.99; p=0.009) independent of gender, age and relevant cardiovascular risk factors.. Plasma TF activity decreased after AMI but was better restored at 6 months in patients with reverse LV remodeling. The clinical significance of changes in post-AMI plasma TF activity needs further investigation.

Topics: Heart Failure; Humans; Myocardial Infarction; Thromboplastin; Ventricular Function, Left; Ventricular Remodeling

The aim of the study was to evaluate diurnal changes of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) concentrations in relation to on-treatment platelet reactivity. The study group included 51 patients with acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention and dual antiplatelet therapy. TF and TFPI concentrations were assessed using enzyme-linked immunosorbent assay kits. We found a significant increase of TF concentration in clopidogrel-resistant, but not clopidogrel-sensitive, patients at 10.00 a.m. (410.66 pg/mL) in comparison with 6.00 a.m. (250.99 pg/mL), 14.00 p.m. (255.12 pg/mL) and 19.00 p.m. (267.58 pg/mL). Moreover, TF concentration at 10.00 a.m. was 30% higher in clopidogrel-resistant than clopidogrel-sensitive patients (

Topics: Blood Platelets; Circadian Rhythm; Cohort Studies; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Prospective Studies; Thromboplastin

Smoking increases the risk of atherothrombotic events. Tissue factor (TF) mainly expressed on monocytes plays an important role in thrombosis and atherosclerosis. Metabolic syndrome (MetS) is being increasingly recognized as a major atherothrombotic risk factor, but the effects of smoking on monocyte TF activity (MTFA), carotid atherosclerosis estimated on carotid intima-media thickness (CIMT), and long-term prognosis in MetS remain unclear.Methods and Results:A total of 301 MetS patients lacking any known cardiovascular disease were prospectively investigated and classified into 4 groups according to smoking status at entry and at 12 months as follows: never smokers, past smokers, quitters, and persistent smokers. Peripheral blood mononuclear cells (PBMC) were isolated, and MTFA was measured using a coagulation assay. Linear trends for higher baseline MTFA and CIMT were observed among persistent smokers, quitters, and past smokers compared with never smokers. At 12 months, MTFA and CIMT decreased in never and past smokers and quitters but increased in persistent smokers. Six acute myocardial infarctions and 8 strokes occurred during a median follow-up of 66.0 months. Persistent smoking was associated with an increased risk of events (P<0.001).. Smoking is associated with upregulated MTFA and progression of CIMT, which may be related to the risk of atherothrombotic events in MetS patients.

Topics: Aged; Carotid Artery Diseases; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Monocytes; Myocardial Infarction; Prognosis; Smoking; Stroke; Thromboplastin

Microparticles (MPs) are formed from platelets (PMPs), endothelial cells (EMPs) and monocytes (MMPs), and in acute myocardial infarction (MI), there is an increase of MPs in the culprit artery. In this study MPs were evaluated in whole blood in 105 patients with MI at five time-points during a two-year follow-up (FU). Patients with non-ST-elevated MI had higher concentrations of CD41+MPs compared to ST-elevated MI patients (p=0.024). The concentrations of PMPs in whole blood increased during the time period (p<0.001), but no significant change over time was found for EMPs and MMPs. CD62P+MP counts were higher in MI patients with diabetes (p=0.020), and patients with hypertension had increased levels of CD14+MPs (p=0.004). The amount of CD62P+TF+MPs increased significantly during FU (p<0.001). Patients with atherosclerosis in three arterial beds, i. e. coronary, carotid and peripheral arteries, had lower concentrations of CD62P+TF+MPs (p=0.035) and CD144+TF+MPs (p=0.004) compared to patients with atherosclerosis in one or two arterial beds. Higher concentrations of CD62P+MPs early after MI were associated with an increased risk of cardiovascular events during FU, hazard ratio 3.32 (95 %CI1.20-9.31). Only small variations in PMP, EMP and MMP concentrations were found during long-term FU after MI and their levels seem to reflect the underlying cardiovascular disease rather than the acute MI. PMPs expressing P-selectin might be a promising biomarker for predicting future cardiovascular events, but further studies are needed to confirm these results.

Topics: Aged; Annexin A5; Antigens, CD; Biomarkers; Blood Platelets; Cadherins; Carotid Artery Diseases; Cell-Derived Microparticles; Comorbidity; Coronary Artery Disease; Endothelial Cells; Female; Follow-Up Studies; Humans; Lipopolysaccharide Receptors; Male; Middle Aged; Monocytes; Myocardial Infarction; P-Selectin; Peripheral Arterial Disease; Prognosis; Risk Assessment; Risk Factors; Sweden; Thromboplastin; Time Factors

As US healthcare expenditures continue to rise, there is significant pressure to reduce the cost of inpatient medical services. Studies have estimated that over 70% of routine labs may not yield clinical benefits while adding over $300 in costs per day for every inpatient. Although orthopaedic trauma patients tend to have longer inpatient stays and hip fractures have been associated with significant morbidity, there is a dearth of data examining pre-operative labs in predicting post-operative adverse events in these populations. The purpose of this study was to assess whether pre-operative labs significantly predict post-operative cardiac and septic complications in orthopaedic trauma and hip fracture patients.. Between 2006 and 2013, 56,336 (15.6%) orthopaedic trauma patients were identified and 27,441 patients (7.6%) were diagnosed with hip fractures. Pre-operative labs included sodium, BUN, creatinine, albumin, bilirubin, SGOT, alkaline phosphatase, white count, hematocrit, platelet count, prothrombin time, INR, and partial thromboplastin time. For each of these labs, patients were deemed to have normal or abnormal values. Patients were noted to have developed cardiac or septic complications if they sustained (1) myocardial infarction (MI), (2) cardiac arrest, or (3) septic shock within 30 days after surgery. Separate regressions incorporating over 40 patient characteristics including age, gender, pre-operative comorbidities, and labs were performed for orthopaedic trauma patients in order to determine whether pre-operative labs predicted adverse cardiac or septic outcomes.. 749 (1.3%) orthopaedic trauma patients developed cardiac complications and 311 (0.6%) developed septic shock. Multivariate regression demonstrated that abnormal pre-operative platelet values were significantly predictive of post-operative cardiac arrest (OR: 11.107, p=0.036), and abnormal bilirubin levels were predictive (OR: 8.487, p=0.008) of the development of septic shock in trauma patients. In the hip fracture cohort, abnormal partial thromboplastin time was significantly associated with post-operative myocardial infarction (OR: 15.083, p=0.046), and abnormal bilirubin (OR: 58.674, p=0.002) significantly predicted the onset of septic shock.. This is the first study to demonstrate the utility of pre-operative labs in predicting perioperative cardiac and septic adverse events in orthopaedic trauma and hip fracture patients. Particular attention should be paid to haematologic/coagulation labs (platelets, PTT) and bilirubin values.. Prognostic Level II.

Topics: Aged; Bilirubin; Cost-Benefit Analysis; Diagnostic Tests, Routine; Female; Fractures, Bone; Humans; Male; Multiple Trauma; Myocardial Infarction; Orthopedic Procedures; Orthopedics; Platelet Count; Postoperative Complications; Predictive Value of Tests; Preoperative Period; Prognosis; Shock, Septic; Surgical Wound Infection; Thromboplastin; United States; Unnecessary Procedures

Neutrophil extracellular traps (NETs) are chromatin filaments released by activated polymorphonuclear neutrophils (PMNs) and decorated with granule proteins with various properties. Several lines of evidence implicate NETs in thrombosis. The functional significance and the in vivo relevance of NETs during atherothrombosis in humans have not been addressed until now.. Selective sampling of thrombotic material and surrounding blood from the infarct-related coronary artery (IRA) and the non-IRA was performed during primary percutaneous revascularization in 18 patients with ST-segment elevation acute myocardial infarction (STEMI). Thrombi isolated from IRA contained PMNs and NETs decorated with tissue factor (TF). Although TF was expressed intracellularly in circulating PMNs of STEMI patients, active TF was specifically exposed by NETs obtained from the site of plaque rupture. Treatment of NET structures with DNase I abolished TF functionality measurement. In vitro treatment of control PMNs with plasma obtained from IRA and non-IRA was further shown to induce intracellular up-regulation of TF but not NET formation. A second step consisting of the interaction between PMNs and thrombin-activated platelets was required for NET generation and subsequent TF exposure.. The interaction of thrombin-activated platelets with PMNs at the site of plaque rupture during acute STEMI results in local NET formation and delivery of active TF. The notion that NETs represent a mechanism by which PMNs release thrombogenic signals during atherothrombosis may offer novel therapeutic targets.

Topics: Analysis of Variance; Case-Control Studies; Coronary Thrombosis; Coronary Vessels; Extracellular Traps; Female; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Neutrophils; Percutaneous Coronary Intervention; Plaque, Atherosclerotic; Platelet Activation; Rupture, Spontaneous; Thrombin; Thromboplastin

Topics: Coronary Vessels; Extracellular Traps; Female; Humans; Male; Myocardial Infarction; Neutrophils; Thromboplastin

Mesenchymal stem cells (MSCs) are currently under investigation as tools to preserve cardiac structure and function following acute myocardial infarction (AMI). However, concerns have emerged regarding safety of acute intracoronary (IC) MSC delivery. This study aimed to characterize innate prothrombotic activity of MSC and identify means of its mitigation toward safe and efficacious therapeutic IC MSC delivery post-AMI. Expression of the initiator of the coagulation cascade tissue factor (TF) on MSC was detected and quantified by immunofluorescence, FACS, and immunoblotting. MSC-derived TF antigen was catalytically active and capable of supporting thrombin generation in vitro. Addition of MSCs to whole citrated blood enhanced platelet thrombus deposition on collagen at arterial shear, an effect abolished by heparin coadministration. In a porcine AMI model, IC infusion of 25 × 10(6) MSC during reperfusion was associated with a decrease in coronary flow reserve but not when coadministered with an antithrombin agent (heparin). Heparin reduced MSC-associated thrombosis incorporating platelets and VWF within the microvasculature. Heparin-assisted therapeutic MSC delivery also reduced apoptosis in the infarct border zone at 24 hours, significantly improved infarct size, left ventricular (LV) ejection fraction, LV volumes, wall motion, and attenuated histologic evidence of scar formation at 6 weeks post-AMI. Heparin alone or heparin-assisted fibroblast control cell delivery had no such effect. Procoagulant TF activity of therapeutic MSCs is associated with reductions in myocardial perfusion when delivered IC may be successfully managed by heparin coadministration. This study highlights an important mechanistic insight into safety concerns associated with therapeutic IC MSC delivery for AMI.

Topics: Animals; Blood Coagulation; Bone Marrow; Cells, Cultured; Coronary Vessels; Female; Fibrinolytic Agents; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Microvessels; Myocardial Infarction; Swine; Thromboplastin

This study aimed to simultaneously observe the expression of mononuclear cells (Mo) and plasma tissue factor (TF) in patients with ischemic cardiocerebrovascular diseases during the stage of acute onset and after the following three weeks and three months for exploration of the clinical implications concerned.. MoTF mRNA and plasma TF antigen (TFAg) from 76 patients with acute myocardial infarction (AMI) together with 46 patients with acute ischemic stroke (AIS) and 61 healthy controls were quantitated respectively through RT-PCR and ELISA.. Compared with the results in the control group, the level of MoTFmRNA and plasma TF in the other groups increased simultaneously and dramatically in the acute stage, which showed a good correlation among the groups (P<0.01), especially in AIS group. The quantitative data showed that both MoTF mRNA and plasma TF remained higher than that of the control group (P<0.01 and P<0.05) after three weeks from the acute onset. It was after three months that the content of MoTF mRNA, in spite of its relatively high level (P<0.05), began to decline in AMI and AIS groups. In this stage the level of MoTFmRNA in AIS group was lower than that in the acute onset stage (P<0.05), while the reduction of plasma TF in AMI and AIS groups was not significantly different from that of the control group (P>0.05). However, the reduced level of plasma TF was still different from that in the acute onset stage (P<0.05).. The simultaneous increase of the level of peripheral MoTF mRNA and plasma TF in the acute onset stage of ischemic cardiocerebrovascular diseases shows a good correlation and suggests the up-regulation of MoTF mRNA's expression participates in the maintenance and expansion of thrombotic formation. Dynamic monitoring of MoTF mRNA and plasma TF at different time points after acute onset has important clinical implications for prevention and treatment of arterial thrombotic diseases.

Topics: Adult; Aged; Aged, 80 and over; Cerebrovascular Disorders; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Myocardial Infarction; Reverse Transcriptase Polymerase Chain Reaction; Stroke; Thromboplastin

Atherosclerotic plaque thrombogenicity is a critical factor that affects thrombus formation and the onset of acute myocardial infarction (AMI). The aim of this study was to identify the vascular factors involved in thrombus formation and AMI onset.. Culprit lesions in 40 coronary arteries with thrombi at autopsy after lethal AMI and non-cardiac death (asymptomatic plaque disruption) were analyzed on histology. Thrombus size, ratio of thrombus to lumen area, length of plaque disruption, and immunopositive areas for tissue factor (TF) and hexokinase (HK)-II were significantly larger in coronary arteries with AMI than with asymptomatic plaque disruption. The size of coronary thrombus positively correlated with the length of plaque disruption (r=0.80) and with immunopositive areas for TF (r=0.38) and HK-II (r=0.40). Because both M1 and M2 macrophages express TF and HK-II in symptomatic plaques, we assessed TF and HK-II expression in M1- and M2-polarized macrophages. The expression of TF was increased and that of HK-II was decreased in M2-, compared with M1-polarized THP-1 macrophages. Inhibiting glycolysis enhanced TF expression in the macrophages partly via hypoxia inducible factor-1α.. The degree of plaque disruption and expression of TF and HK-II appear to be important vascular factors for AMI onset, and polarized macrophages make a distinct contribution to thrombogenicity and glucose metabolism.

Topics: Autopsy; Case-Control Studies; Cause of Death; Cell Line; Coronary Artery Disease; Coronary Thrombosis; Coronary Vessels; Gene Expression Regulation; Glycolysis; Hexokinase; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Macrophages; Myocardial Infarction; Phenotype; Plaque, Atherosclerotic; Thromboplastin

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

Thrombin is a key protease in coagulation also implicated in complex pathology including atherosclerosis. To address the role of thrombin in relation to myocardial infarction (MI) we explored thrombin generation analysis in plasma from patients and controls that had participated in the Glasgow MI Study (GLAMIS).. Thrombin generation at 1 and 2 pM TF and with and without thrombomodulin (TM) was performed on plasmas from 356 subjects (171 cases, 185 age and sex matched controls) from GLAMIS collected between 3 and 9 months after the MI event.. Although thrombin generation was slightly delayed in cases (lag time increased from 3.3 to 3.6 min) at the highest trigger, the overall potential to generate thrombin was increased by 7% for the ETP and by 15% for the peak height (both at the 1 pM TF trigger) in cases. Addition of TM did not reveal differences. Furthermore, an increased thrombin generation was associated with MI [normalized ETP: adjusted OR for the highest percentile = 2.4 (95% CI 1.3-4.5) and normalized peak height: adjusted OR = 2.6 (1.3-5.0)] at the lowest trigger; normalized ETP and peak height being 2.1 (1.1-3.8) and 2.0 (1.0-4.1) at the higher 2 pM trigger.. In GLAMIS, patients with a previous MI had an increased thrombin generation compared to controls. The absence of a clear difference in TM reduction suggests an unaltered anticoagulant activity in these patients. Further research is needed in order to unravel the underlying mechanisms of enhanced thrombin generation after MI.

Topics: Female; Humans; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Risk Factors; Scotland; Thrombin; Thromboplastin

Although ruptured atherosclerotic plaques have been extensively analyzed, the composition of thrombi causing arterial occlusion in patients with ST-segment elevation acute myocardial infarction has been less thoroughly investigated. We sought to investigate whether coagulant active tissue factor can be retrieved in thrombi of patients with STEMI undergoing primary percutaneous coronary intervention.. Nineteen patients with ST-segment elevation acute myocardial infarction referred for primary percutaneous coronary intervention were enrolled in this study. Coronary thrombi aspirated from coronary arteries were routinely processed for paraffin embedding and histological evaluation (4 patients) or immediately snap frozen for evaluation of tissue factor activity using a modified aPTT test (15 patients). Immunoprecipitation followed by immunoblotting was also performed in 12 patients.. Thrombi aspirated from coronary arteries showed large and irregular areas of tissue factor staining within platelet aggregates, and in close contact with inflammatory cells. Some platelet aggregates stained positive for tissue factor, whereas others did not. Monocytes consistently stained strongly for tissue factor, neutrophils had a more variable and irregular tissue factor staining, and red blood cells did not demonstrate staining for tissue factor. Median clotting time of plasma samples containing homogenized thrombi incubated with a monoclonal antibody that specifically inhibits tissue factor-mediated coagulation activity (mAb 5G9) were significantly longer than their respective controls (88.9 seconds versus 76.5 seconds, respectively; p<0.001). Tissue factor was also identified by immunoprecipitation in 10 patients, with significant variability among band intensities.. Active tissue factor is present in coronary artery thrombi of patients with ST-segment elevation acute myocardial infarction, suggesting that it contributes to activate the coagulation cascade ensuing in coronary thrombosis.

Topics: Aged; Coronary Thrombosis; Coronary Vessels; Female; Humans; In Vitro Techniques; Male; Middle Aged; Myocardial Infarction; Thromboplastin

Pro-coagulant and pro-inflammatory intramyocardial (micro)vasculature plays an important role in acute myocardial infarction (AMI). Currently, inhibition of serine protease dipeptidyl peptidase 4 (DPP4) receives a lot of interest as an anti-hyperglycemic therapy in type 2 diabetes patients. However, DPP4 also possesses anti-thrombotic properties and may behave as an immobilized anti-coagulant on endothelial cells. Here, we studied the expression and activity of endothelial DPP4 in human myocardial infarction in relation to a prothrombogenic endothelial phenotype. Using (immuno)histochemistry, DPP4 expression and activity were found on the endothelium of intramyocardial blood vessels in autopsied control hearts (n = 9). Within the infarction area of AMI patients (n = 73), this DPP4 expression and activity were significantly decreased, coinciding with an increase in Tissue Factor expression. In primary human umbilical vein endothelial cells (HUVECs), Western blot analysis and digital imaging fluorescence microscopy revealed that DPP4 expression was strongly decreased after metabolic inhibition, also coinciding with Tissue Factor upregulation. Interestingly, inhibition of DPP4 activity with diprotin A also enhanced the amount of Tissue Factor encountered and induced the adherence of platelets under flow conditions. Ischemia induces loss of coronary microvascular endothelial DPP4 expression and increased Tissue Factor expression in AMI as well as in vitro in HUVECs. Our data suggest that the loss of DPP4 activity affects the anti-thrombogenic nature of the endothelium.

Topics: Adult; Aged; Aged, 80 and over; Coronary Thrombosis; Coronary Vessels; Dipeptidyl Peptidase 4; Female; Human Umbilical Vein Endothelial Cells; Humans; Male; Microvessels; Middle Aged; Myocardial Infarction; Myocardium; Platelet Adhesiveness; Thromboplastin

Despite improvements in treatment, myocardial infarction (MI) remains an important cause of morbidity and mortality. Inflammation arising from ischaemic and reperfusion injury is a key mechanism which underpins myocardial damage and impairment of cardiac function. Early growth response-1 (Egr-1) is an early immediate gene and a master regulator that has been implicated in the pathogenesis of ischaemia-reperfusion (IR) injury. This study sought to examine the effect of selective inhibition of Egr-1 using catalytic deoxyribonucleic acid molecules (DNAzymes, DZs) delivered via the clinically relevant coronary route in a large animal model of myocardial IR. It was hypothesized that Egr-1 inhibition with intracoronary DZ would reduce infarction size by modulating its downstream effector molecules. Egr-1 DZs inhibited the adherence of THP-1 monocytes to IL-1β-activated endothelial cells in vitro and retained its catalytic activity up to 225 min after in vivo administration. In a porcine model of myocardial IR (45 min ischaemia/3 h reperfusion), DZ was taken up in the cytoplasm and nuclei of cardiomyocytes and endothelial cells in the myocardium after intracoronary delivery. Egr-1 DZs reduced infarct size and improved cardiac functional recovery following intracoronary delivery at the initiation of IR in this large animal model of MI. This was associated with inhibition of pro-inflammatory Egr-1 and ICAM-1 expression, and the reduced expression of TNF-α, PAI-1, TF, and myocardial MPO activity in tissue derived from the border zone of the infarct. Taken together, these data suggest that strategies targeting Egr-1 via the intracoronary route after IR injury in pigs have potential therapeutic implications in human MI.

Topics: Animals; Cell Adhesion; Cells, Cultured; Disease Models, Animal; DNA, Single-Stranded; Early Growth Response Protein 1; Endothelial Cells; Female; Genetic Therapy; Humans; Injections; Intercellular Adhesion Molecule-1; Interleukin-1beta; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Monocytes; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Peroxidase; Plasminogen Activator Inhibitor 1; Recovery of Function; Swine; Thromboplastin; Time Factors; Transfection; Tumor Necrosis Factor-alpha

Intracoronary administration of glycosaminoglycan analogs, including the complement inhibitor dextran sulfate, attenuates myocardial ischemia/reperfusion injury (I/R injury). However, dextran sulfate has a distinct anticoagulatory effect, possibly limiting its use in specific situations in vivo. We therefore developed multimeric tyrosine sulfate (sTyr-PAA), a novel, minimally anticoagulatory, fully synthetic non-carbohydrate-containing polyacrylamide conjugate, for in vivo testing in an acute closed-chest porcine model of acute myocardial infarction.. Following balloon occlusion of the left anterior descending artery just after the first diagonal branch (60-minute ischemia), sTyr-PAA (approx. 10 mg/kg bodyweight, fraction with strongest complement-inhibitory and minimal anticoagulatory properties, n = 11) or phosphate-buffered saline (controls, n = 9) was administered intracoronarily into ischemic myocardium prior to 120 min of reperfusion.. sTyr-PAA significantly reduced infarct size (from 61.0 ± 12.0% of the ischemic area at risk to 39.4 ± 17.0%), plasma creatine kinase, local complement deposition and tissue factor upregulation, without affecting systemic coagulation. Protection was associated with significantly reduced myocardial neutrophil extravasation and translated into a significant improvement of ejection fraction and left ventricular enddiastolic pressure.. sTyr-PAA protected significantly against myocardial I/R injury without substantially affecting systemic coagulation. Local intravascular sTyr-PAA administration may prove advantageous in situations where bleeding complications are likely or are to be avoided at all costs.

Topics: Animals; Anticoagulants; Complement Inactivating Agents; Complement Pathway, Classical; Cytoprotection; Dose-Response Relationship, Drug; Granulocytes; Hemodynamics; Myocardial Infarction; Myocardial Reperfusion; Myocardial Reperfusion Injury; Neutrophils; Sus scrofa; Thromboplastin; Tyrosine; Ventricular Fibrillation

Mechanisms to explain the different course of coronary thrombosis between ST elevation myocardial infarction (STEMI) and non-STEMI patients remain poorly defined. We hypothesize, however, that STEMI patients may present lower tissue factor plasma inhibition to partly account for their more persistent coronary thrombotic occlusion.. Total (t-TFPI ) and free tissue factor plasma inhibitor (f-TFPI), thrombin-antithrombin complex (TAT), plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor (vWF), and fibrinogen were measured on admission and at 3 and 6 months in patients with a first STEMI (n:69) or non-STEMI (n:60). C reactive protein (CRP) was also measured on admission and at 3 months.. STEMI patients showed lower admission levels of t-TFPI (p=0.001), f-TFPI (p=0.030) and fibrinogen (p=0.022), and higher vWF levels (p=0.005) than non-STEMI whereas TAT, PAI and CRP levels were comparable. At 3 and 6 months VWF, t-TFPI, f-TFPI, and TAT levels declined significantly in the 2 groups (p=0.002) reaching similar values. CRP levels also declined at 3 months (p=0.002). Moreover, the rate of cardiac mortality, non fatal MI or stroke during a 6 year follow-up were unrelated to admission coagulation parameters.. The lower inhibition of tissue factor and greater endothelial dysfunction in STEMI than in non-STEMI patients may enhance thrombosis at the culprit lesion and adjacent coronary plaques, and hence, account at least in part for their different pathophysiology. This condition, however, is limited to the acute phase.

Topics: Biomarkers; Blood Coagulation Factors; Comorbidity; Coronary Thrombosis; Female; Fibrinogen; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Plasminogen Activator Inhibitor 1; Reproducibility of Results; Sensitivity and Specificity; Spain; Thromboplastin

The objective of this study was to investigate the effects of irbesartan, carvedilol, and irbesartan plus carvedilol on the expression of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) mRNA and protein in rat myocardium after myocardial infarction (MI). MI was induced in male Wistar rats by ligation of the anterior descending branch of the left coronary artery. Irbesartan at 50 mg/kg/day, carvedilol at 1 mg/kg/day, irbesartan plus carvedilol, or placebo was administered intragastrically; expression of TF and TFPI mRNA and protein was determined by RT-PCR and Western blot analysis. The relative left ventricle weights were lower in all three treatment groups than in the placebo group, with the lowest relative weight in the irbesartan plus carvedilol group (P < 0.001). The size of the infarcted area was lower in the carvedilol and the combined groups than in the placebo group (P < 0.001). The levels of expression of TF and TFPI mRNA and protein were lower in the combined group than in the placebo group or the carvedilol group (P < 0.001). Treatment with irbesartan plus carvedilol reduced the expression of TF and TFPI mRNA and protein after MI in rats, and combined treatment with both agents had greater effects than the single agents alone. These findings suggest that the beneficial effects of these drugs may include anticoagulation and that combined therapy with both agents is an option that should be evaluated further.

Topics: Adrenergic Antagonists; Angiotensin II Type 1 Receptor Blockers; Animals; Biphenyl Compounds; Blood Coagulation; Blotting, Western; Carbazoles; Carvedilol; Disease Models, Animal; Down-Regulation; Drug Therapy, Combination; Irbesartan; Lipoproteins; Male; Myocardial Infarction; Myocardium; Propanolamines; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrazoles; Thromboplastin

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

Topics: Adult; Aged; Case-Control Studies; Convalescence; Female; Humans; Male; Middle Aged; Monocytes; Myocardial Infarction; Thromboplastin

Tissue factor (TF)-induced thrombin generation (TG) ex vivo has been suggested to be an important method to assess thrombotic risk. No studies have investigated the impact of postprandial lipemia on TF-induced TG. Since myocardial infarction (MI) is associated with elevated postprandial levels of triglycerides, we hypothesized a differential impact of postprandial lipemia on coagulation activation in MI-patients and healthy controls.. Elderly survivors of acute MI (n=44) and healthy age-and sex matched controls (n=43) underwent a fat tolerance test (1 gram per kg body weight) to assess coagulation activation during postprandial lipemia.. The incremental area under the curve (AUCi) for serum triglycerides was higher in MI-patients than in healthy age-and sex matched controls (5.64±0.52 mmol/L*h and 3.94±0.39 mmol/L*h, p=0.012) during the postprandial phase. Subsequent endogenous activation of coagulation, assessed by FVIIa and thrombin generation (F1+2), was similar among groups and not related to levels of triglycerides during the postprandial phase. Healthy individuals had a gradual decline in TF-induced thrombin generation ex vivo, assessed by endogenous thrombin potential (ETP) (AUCi=-542.4±71.4 nM*min*h, p<0.001), whereas MI-patients retained their ETP (AUCi=127.4±89.0 nM*min*h, p=0.47) in plasma during the postprandial phase (p for group difference=0.005).. MI-patients had elevated postprandial lipemia and retained their ability for TF-induced TG in plasma ex vivo in the postprandial phase, whereas the capacity gradually decreased in healthy individuals. Further studies are warranted to reveal underlying mechanism(s) and clinical implications.

Topics: Aged; Aged, 80 and over; Blood Coagulation; Fasting; Female; Humans; Hyperlipidemias; Male; Myocardial Infarction; Postprandial Period; Thrombin; Thromboplastin

High concentrations of platelet-monocyte aggregates (PMAs) have been found in patients with myocardial infarction (MI). Oral direct thrombin inhibitors (DTIs) are under evaluation as long-term antithrombotic treatment. The aim was to evaluate whether DTIs affect the formation of platelet-leukocyte aggregates, TF expression and procoagulant microparticles (MPs).. DTIs were added to an experimental whole blood model before platelet activation with thrombin or ADP. The concentrations of PMAs, platelet-granulocyte aggregates (PGAs), the amount of platelets bound per leukocyte and MPs were investigated by flow cytometry. TF mRNA and activity were recorded in all settings. TF activity was evaluated in a MI population treated with or without an oral DTI.. In vitro, thrombin and ADP increased the formation of PMAs and PGAs as well as TF mRNA expression. DTIs reduced the amount platelets bound to monocytes (p=0.02) and to granulocytes (p=0.001) upon thrombin stimulation together with a reduction of TF mRNA. In contrast, the ADP-induced formation of PMAs, PGAs and TF mRNA was not affected by the DTIs. Both thrombin and ADP stimulation increased the amount of TF-expressing MPs, which was effectively inhibited by the DTIs (p=0.02-0.002). In the MI population, the DTI reduced the TF activity (p<0.001).. DTIs modulate the formation of PMAs, PGAs and the TF production therein. Together with a reduction of procoagulant MPs, these results may contribute to the clinical benefit found of oral DTIs. Targeting different mechanisms in platelet and coagulation activation may be of importance due to the lack of effect of DTIs on ADP-induced platelet-leukocyte aggregates and TF production.

Topics: Antithrombins; Azetidines; Benzimidazoles; Benzylamines; beta-Alanine; Blood Platelets; Cell-Derived Microparticles; Dabigatran; Gene Expression; Humans; Leukocytes; Myocardial Infarction; Platelet Activation; Platelet Aggregation; RNA, Messenger; Thromboplastin

During myocardial infarction, platelet activation and endothelial apoptosis are responsible for the release of procoagulant membrane-derived microparticles (MPs) in the bloodstream. Few data are available on the potential role played by MPs in coronary atherothrombosis. In the present study, we investigated the levels and cellular origins of MPs within the occluded coronary artery of patients with ST-segment elevation myocardial infarction (STEMI) treated by primary angioplasty (PCI).. A total of 12 patients with STEMI treated by primary PCI within 24h of symptom onset were included in this study. MPs procoagulant activity and cellular origin were characterized within the occluded coronary artery before PCI (C(0)), after restoration of the epicardial blood flow (C(1)), and in blood collected from the femoral artery (F).. Levels of leukocyte-derived CD11a(+) MPs, endothelial-derived CD105(+) MPs, and tissue factor (TF)-bearing MPs were significantly higher within the occluded coronary artery than in peripheral blood samples. Restoration of the epicardial blood flow led to a significant reduction of procoagulant CD11a(+) and CD105(+) MPs by 30% and 42%, respectively (p<0.05).. Elevation of procoagulant MPs within the occluded coronary artery of patients with STEMI suggests their pathophysiological role in coronary atherothrombosis.

Topics: Adult; Angioplasty, Balloon, Coronary; Antigens, CD; Apoptosis; CD11a Antigen; Cell-Derived Microparticles; Coronary Circulation; Coronary Occlusion; Coronary Thrombosis; Endoglin; Endothelium, Vascular; Female; Humans; Leukocytes; Male; Middle Aged; Myocardial Infarction; Receptors, Cell Surface; Thromboplastin; Treatment Outcome; Up-Regulation

This study was aimed to investigate the change of tissue factor pathway (TFP) ratio during the attack of acute myocardial infarction (AMI) and its clinical significance. Plasma recalcification time was assayed by manual operation. Plasma tissue factor (TF), TF pathway inhibitor (TFPI) antigen, FVII:Ag, activated FVII (FVIIa) and D-Dimer were measured by enzyme linked immunoabsorbent assay (ELISA). TF activity was determined by chromogenic assay, plasma FVII coagulation activity (FVII:C) was detected by one-stage system. Blood samples were taken from 59 patients with AMI and 84 healthy volunteers. The results indicated that (1) plasma recalcification time was significantly shorter in the AMI group than that in the control; (2) compared with the control, TF activity in AMI patients showed no significant change (p > 0.05); the antigen levels of TF and TFPI in patients with AMI were remarkably increased (p < 0.05), and the increment degree of TF was remarkably higher than that of TFPI, therefore the TF/TFPI ratio was enlarged; total TFPI (t-TFPI) and full-length TFPI (fl-TFPI) were significantly higher (p < 0.01), truncated TFPI (tr-TFPI) was significantly lower (p < 0.01); the TF/t-TFPI ratio was higher than that in normal group, the TF/t-TFPI ratio was lower than that in normal group (p < 0.01), but the TF/tr-TFPI and fl-TFPI/t-TFPI ratios in AMI group were more remarkably higher than that in control group (p < 0.01), the tr-TFPI/t-TFPI and tr-TFPI/fl-TFPI ratios were significantly lower (p < 0.01). (3) compared with the control, the levels of plasma FVIIa and FVII:C in AMI group were higher (p < 0.05), FVII:Ag did not significatly change; FVIIa/FVII: Ag ratio was more remarkably higher (p < 0.01), but the elevation of FVIIa/FVII:C and FVII:C/FVII:Ag ratios showed no significant change (p > 0.05); (4) plasma D-dimer was significantly higher, compared with the normal control (p < 0.01). It is concluded that TFP is initiated during the attack of AMI, suggesting the circulating blood in AMI patients is in hypercoagulable status, therefore the simultaneous detection of multiple coagulation factors is necessary for evaluating risk factors in AMI patients, and the use of ratio for reflecting hypercoagulable status and risk factors is more reliable to detect each of them separately.

Topics: Aged; Blood Coagulation; Case-Control Studies; Factor VII; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Myocardial Infarction; Thromboplastin

Fibrinolysis for acute ST-segment elevation MI achieves early recanalisation of the infarct artery in approximately 60% of cases. The aim of the study was to determine whether failure to achieve recanalisation was associated with differences in haemostasis biomarkers compared to patients with successful fibrinolysis. Fourty-three patients were prospectively enrolled in a case-control study. All patients had received tenecteplase (TNK-tPA) together with aspirin (500 mg) and heparin (5,000 IU). Emergency angiography within 90 minutes of bolus TNK-tPA identified 13 TIMI 0-2 patients (cases) and 30 TIMI 3 patients (controls). Blood samples were collected before angiography to determine tissue factor activity associated with microparticles (TF-MP); soluble platelet glycoprotein V (sGPV) and thrombin-antithrombin complexes (TAT) as markers of thrombin generation; tissue plasminogen activator (endogenous tPA+ TNK-tPA), plasminogen activator inhibitor (PAI-1) and plasmin-antiplasmin complexes (PAP) as markers of plasmin generation. The baseline characteristics of the two patients' groups were similar with respect to sex, age, and risks factors. Cases differed from controls by higher TF-MP levels (1.9 [1-13] vs. 1 [0.6-1.3] pM), sGPV (67 [51-126] vs. (48 [39-72] ng/ml), p = 0.039 and TAT (10 [4-37.5] vs. 4 [2.9-7.2] ng/ml), p = 0.035. TAT correlated with TF-MP (r = 0.51, p = 0.0064) and sGPV (r = 0.51, p = 0.0018). No significant difference was observed in tPA or PAI-1 levels. PAP were lower in cases (18.83 [14.83-40.43] mug/ml) than in controls (35.83 [27.9-43.94] mug/ml), p = 0.045. In conclusion, fibrinolysis failure in AMI is characterised by a higher procoagulant state associated with TF-MP and a lower plasmin generation.

Topics: Adult; Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Anticoagulants; Aspirin; Biomarkers; Case-Control Studies; Cell-Derived Microparticles; Coronary Angiography; Coronary Circulation; Drug Administration Schedule; Drug Therapy, Combination; Emergency Treatment; Female; Fibrinolysin; Fibrinolytic Agents; Hemostasis; Heparin; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Prospective Studies; Thrombin; Thrombolytic Therapy; Thromboplastin; Time Factors; Tissue Plasminogen Activator; Treatment Failure

Topics: Aged; Anticoagulants; Dose-Response Relationship, Drug; Drug Administration Routes; Electrocardiography; Enoxaparin; Heparin, Low-Molecular-Weight; Humans; Myocardial Infarction; Secondary Prevention; Thrombolytic Therapy; Thromboplastin; Treatment Outcome

Topics: Case-Control Studies; Cell-Derived Microparticles; Coronary Thrombosis; Humans; Monocytes; Myocardial Infarction; Thromboplastin; Up-Regulation

Several studies have indicated an association between haemostatic markers and acute myocardial infarction, but few or no studies refer to their activity. We studied plasma levels of 10 coagulation factors (fibrinogen, protein C, protein S, von Willebrand factor, D-dimers, factor VIIa, free tissue factor pathway inhibitor, tissue-type plasminogen activator, plasminogen activator inhibitor-1, thrombomodulin) and using new specific assays analysed the activity of plasma tissue factor (TFa), thrombomodulin (TMa), and procoagulant phospholipid in 46 consecutive patients with acute myocardial infarction at the time of hospital admission, and compared them with 34 healthy normal volunteers. Plasma levels of TFa, TMa, and procoagulant phospholipid were significantly higher in cases than in control patients (P < 0.001). In addition the ratio of TFa/free tissue factor pathway inhibitor was higher in patients than in controls, whereas the tissue-type plasminogen activator (t-PA)/plasminogen activator inhibitor-1 ratio was lower in patients. Interestingly, patients with an unfavourable outcome during a 2-month follow-up had higher levels of TFa, TMa, procoagulant phospholipid, a higher ratio of TFa/free tissue factor pathway inhibitor and a lower ratio of t-PA/plasminogen activator inhibitor-1 than patients who recovered. The combination of these different parameters reveals an increase in procoagulant activity as well as impaired fibrinolytic activity during the acute phase of an acute myocardial infarction. The association of the level of the activity of these three factors may provide a new tool to assess the prognosis of acute myocardial infarction. Further studies are needed to support our findings and to elucidate the clinical interest of measuring these factors.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Coagulation Factors; Case-Control Studies; Female; Hemostasis; Hospitals; Humans; Male; Middle Aged; Myocardial Infarction; Phospholipids; Prognosis; Thrombomodulin; Thromboplastin

To compare plasma tissue factor (TF) and tissue factor pathway inhibitor (TFPI) levels before, immediately and 24 hours after percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) patients with or without no-reflow.. Plasma TF and TFPI in AMI patients underwent PCI were measured by enzyme linked immunoadsorbent (ELISA) before, immediately and 24 hours after PCI.. The levels of TF and TFPI of no-reflow patients (n = 17) were significantly higher than those of reflow patients (n = 36) at baseline, immediately and 24 hours after PCI [TF: (275.3 +/- 46.2) ng/L vs. (236.8 +/- 44.3) ng/L, (332.7 +/- 41.3) ng/L vs. (282.3 +/- 38.7) ng/L, (315.5 +/- 47.8) ng/L vs. (248.1 +/- 46.9) ng/L; TFPI: (165.2 +/- 38.4) microg/L vs. (128.5 +/- 18.7) microg/L, (176.3 +/- 36.8) microg/L vs. (135.6 +/- 20.3) microg/L, (149.8 +/- 31.7) microg/L vs. (118.7 +/- 19.2) microg/L; all P < 0.01]. Plasma TF was significantly increased in both groups (all P < 0.01) immediately post PCI and the TF was still higher than that before PCI in no-reflow patients (P < 0.05) and returned to baseline level in reflow patients at 24 hours after PCI (P > 0.05), TFPI levels were similar before and after PCI in both groups (all P > 0.05).. Plasma tissue factor and tissue factor pathway inhibitor might play important roles in the development of no-reflow during PCI in AMI patients.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Female; Humans; Lipoproteins; Male; Middle Aged; Myocardial Infarction; No-Reflow Phenomenon; Prognosis; Thromboplastin

It has been established that inflammation and enhanced pro-coagulant activity are associated with the pathogenesis of atherosclerotic vascular disease. We evaluated and compared the contributions of the factor (F)XIa and tissue factor (TF) activity in plasma of patients with coronary artery disease (CAD). Citrate plasma was obtained prior to therapy from 53 patients with stable angina (29 with a history of previous myocardial infarction; CAD-MI) and 30 with acute coronary syndrome (ACS) within 12 hours from pain onset. Four ACS patients treated with heparin were excluded. FXIa and TF activity were determined in clotting assays based upon the prolongation of clotting time by inhibitory monoclonal antibodies. Twenty-five of 26ACS patients (96%) and 22 of 29 CAD-MI patients (76%) had quantifiable FXIa (50 +/- 33 and 42 +/- 45pM, respectively). Ten of 26 (38%) ACS patients and only three of 53 (6%) stable CAD patients showed TF activity (<0.4pM). No FXIa or TF activity was observed in age-matched healthy controls (n = 12). For both CAD-MI and ACS patients, there were correlations (p < 0.05) between FXIa and interleukin-6 (R(2) = 0.59 and 0.39, respectively) and between FXIa and TAT (R(2) = 0.64 and 0.63, respectively). In conclusion, the majority of ACS and CAD-MI patients have circulating FXIa that correlates with markers of coagulation and inflammation.

Topics: Acute Coronary Syndrome; Aged; Angina Pectoris; Antithrombin III; Biomarkers; Blood Coagulation; Blood Coagulation Tests; Case-Control Studies; Coronary Artery Disease; Factor Xa; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Myocardial Infarction; Peptide Hydrolases; Thromboplastin

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

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

Tissue factor (TF) and its specific inhibitor, tissue factor pathway inhibitor (TFPI), are important contributors to the initiation of the coagulation process.. To compare plasma levels of soluble TF (sTF) and free-TFPI (f-TFPI) between patients with stable angina pectoris (SAP) and acute coronary syndrome (ACS) and to assess the impact of the two variables on long-term prognosis.. Patients with SAPs (n = 1146) and acute coronary syndrome (n = 523) from the AtheroGene study were included and followed for 2.3 years. Because of the strong impact of unfractionated heparin (UFH) on f-TFPI levels, but not on sTF levels, patients having received UFH before blood drawing were excluded from the analyses on f-TFPI (n = 226).. On admission, no significant differences in sTF levels were observed between SAP and ACS patients. By comparison to patients with stable angina, f-TFPI levels significantly increased in patients with acute unstable angina and further increased in patients presenting with non-ST-elevation myocardial infarction and ST-elevation myocardial infarction (P < 10(-4)). Among the 1669 individuals with a coronary artery disease, 56 died from a cardiovascular cause. In prospective analyses, high sTF levels were independently associated with an increased risk of cardiovascular death in individuals with ACS (fully adjusted hazard ratio associated with one quartile increase = 2.06; 95% confidence interval 1.24-3.45; P = 0.006) but not in those with SAP (hazard ratio = 1.07; 95% confidence interval 0.78-1.46; P = 0.67). In SAP and ACS patients, high f-TFPI levels were not independently associated with an increased risk of cardiovascular death.. Plasma sTF levels were predictive of cardiovascular mortality in individuals with ACS, whereas f-TFPI levels were associated with the severity of myocardial damage on admission but were not independently related to outcome.

Topics: Aged; Angina Pectoris; Biomarkers; Cardiovascular Diseases; Cohort Studies; Coronary Stenosis; Female; Follow-Up Studies; Germany; Humans; Lipoproteins; Male; Middle Aged; Myocardial Infarction; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prospective Studies; Risk Assessment; Severity of Illness Index; Syndrome; Thromboplastin; Time Factors

Tissue factor (TF), the initiator of coagulation, circulates in blood and contributes to thrombosis in patients with coronary artery disease (CAD). TF is present in the alpha-granules of platelets. Therapy with clopidogrel results in inhibition of platelet degranulation. Whether clopidogrel affects circulating TF is unknown. This study examined the effect of clopidogrel on TF level in the blood of patients with stable CAD and ST-elevation myocardial infarction (STEMI) as well as healthy controls.. Thirty-three patients with CAD and twenty with STEMI were studied pre and post clopidogrel therapy (loading dose 300 mg, then 75 mg daily). All were treated with aspirin 100 mg/d. The control groups consisted of thirty healthy male volunteers also treated with clopidogrel and ten patients with CAD treated with aspirin only. TF concentration in blood drawn pre and 96 h post clopidogrel administration was measured by enzyme-linked immunosorbent assay.. Patients with CAD and STEMI had significantly more TF in blood than healthy controls. Clopidogrel reduced TF in stable CAD patients to levels seen in healthy controls. No alterations in TF were found in controls and patients with STEMI post clopidogrel therapy. Clopidogrel reduced sCD40L level in stable CAD patients, but not in STEMI patients. A correlation between TF and sCD40L was found for the combined CAD and control, but not STEMI group.. Clopidogrel leads to a reduction of not only sCD40L but also TF in stable CAD. The reduction of TF may lead to a reduced thrombogenicity, contributing to the benefits of clopidogrel therapy.

Topics: Adult; CD40 Ligand; Clopidogrel; Coronary Artery Disease; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Solubility; Thromboplastin; Ticlopidine; Treatment Outcome

Topics: Angioplasty, Balloon, Coronary; Biopsy; Blood Cell Count; Bone Marrow; Coronary Occlusion; Coronary Thrombosis; Humans; Incidental Findings; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Myocardial Infarction; Pancytopenia; Radiography; Thromboplastin

Recent findings indicate that atherosclerosis, a chronic inflammatory process, might start during childhood. Nevertheless, the expression of inflammation-related molecules of endothelial cell isolated from healthy neonates with a strong family history of myocardial infarction (SFHMI) has been rarely analyzed.. Human umbilical vein endothelial cells (HUVECs) from children with SFHMI were assessed for the expression of CD40 and CD40L, in the presence of TNF-alpha and oxLDL. The intracellular content of CD80, CXCL8 and tissue factor by HUVECs stimulated with a CD40 agonist monoclonal antibody as well as monocytes/lymphocyte adhesion to TNF-alpha-stimulated HUVECs was also evaluated.. The basal expression of CD40 and CD40L was higher in SFHMI-positive HUVECs in comparison to controls. TNF-alpha and oxLDL upregulated the expression of CD40 and CD40L in SFHMI versus control HUVECs (p<0.001). The intracellular expression of CXCL8, tissue factor and CD80 was also higher than in controls, and the adhesion of lymphocyte- and monocyte-like cells augmented upon TNF-alpha stimulation.. It is possible that the modifications observed in the SFHMI-positive HUVECs, all of them relevant to the atherosclerosis process, may lead to early inflammatory reactions, thus contributing to the premature initiation of atherosclerotic lesions in these children.

Topics: CD40 Antigens; CD40 Ligand; Cell Adhesion; Endothelial Cells; Humans; Infant, Newborn; Inflammation; Interleukin-8; Lipoproteins, LDL; Lymphocytes; Monocytes; Myocardial Infarction; Thromboplastin; Tumor Necrosis Factor-alpha; Umbilical Veins

Protease-activated receptor-1 (PAR-1) is the high-affinity receptor for the coagulation protease thrombin. It is expressed by a variety of cell types in the heart, including cardiomyocytes and cardiac fibroblasts. We have shown that tissue factor (TF) and thrombin contribute to infarct size after cardiac ischemia-reperfusion (I/R) injury. Moreover, in vitro studies have shown that PAR-1 signaling induces hypertrophy of cardiomyocytes and proliferation of cardiac fibroblasts. The purpose of the present study was to investigate the role of PAR-1 in infarction, cardiac remodeling, and hypertrophy after I/R injury. In addition, we analyzed the effect of overexpression of PAR-1 on cardiomyocytes.. We found that PAR-1 deficiency reduced dilation of the left ventricle and reduced impairment of left ventricular function 2 weeks after I/R injury. Activation of ERK1/2 was increased in injured PAR-1(-/-) mice compared with wild-type mice; however, PAR-1 deficiency did not affect infarct size. Cardiomyocyte-specific overexpression of PAR-1 in mice induced eccentric hypertrophy (increased left ventricular dimension and normal left ventricular wall thickness) and dilated cardiomyopathy. Deletion of the TF gene in cardiomyocytes reduced the eccentric hypertrophy in mice overexpressing PAR-1.. Our results demonstrate that PAR-1 contributes to cardiac remodeling and hypertrophy. Moreover, overexpression of PAR-1 on cardiomyocytes induced eccentric hypertrophy. Inhibition of PAR-1 after myocardial infarction may represent a novel therapy to reduce hypertrophy and heart failure in humans.

Topics: Animals; Cardiomegaly; Cardiomyopathy, Dilated; Echocardiography; Gene Expression; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Myocardial Infarction; Myocytes, Cardiac; Phenotype; Receptor, PAR-1; Reperfusion Injury; Thromboplastin; Ventricular Myosins; Ventricular Remodeling

To study the clinical implications of changes in plasma tissue factor (TF), tissue factor pathway inhibitor (TFPI) and factor VII (FVII) after the onset of acute myocardial infarction (AMI) and acute cerebral infarction (ACI).. Sixty-nine patients with AMI, 71 with ACI and 50 age-matched healthy volunteers were enrolled in this study. Blood samples were obtained from the healthy subjects and from the patients at the early stage of AMI and ACI onset for examination of plasma TF and TFPI activity using chromogenic assay, and the plasma TF and TFPI antigens were measured by enzyme-linked immunosorbent assay (ELISA). The plasma FVII coagulation activity (FVII:C) was also measured, and the plasma FVIIa determined using soluble TF assay.. Compared with the healthy control group, AMI patients had significantly enhanced plasma TF and TFPI activities and elevated TF and TFPI antigen levels (P<0.05), with also markedly increased FVIIa (P<0.05) but comparable FVII:C (P>0.05). In ACI patients, the plasma TF activity and antigen were obviously increased in comparison with the control group (P<0.05), but plasma TFPI activity and antigen were lowered (P<0.05), and both the FVII:C and FVIIa were markedly higher (P<0.05). Significant differences were noted in plasma TF and TFPI activities and their antigen levels as well as in FVII:C, but not in FVIIa between AMI and ACI patients.. V Following the onset of AMI and ACI, TF pathway is initiated and the risk of thrombogenesis increases, and the assessment of TF pathway is therefore of value for understanding the development of the condition.

Topics: Aged; Aged, 80 and over; Case-Control Studies; Cerebral Infarction; Factor VII; Female; Humans; Lipoproteins; Male; Middle Aged; Myocardial Infarction; Thromboplastin

Besides distal embolization of thrombus and plaque debris, locally increased inflammatory markers at the site of ruptured plaque in acute myocardial infarction (AMI) are thought to have an adverse impact on myocardial reperfusion during primary percutaneous coronary intervention (PCI). However, there is lack of data on such factors. Therefore, we investigated the presence of locally increased inflammatory and vasoactive factors in culprit coronary artery.. We performed primary PCI with PercuSurge GuideWire system in 18 AMI patients. We collected blood samples from the femoral artery before PCI and from culprit coronary artery after first predilation while inflating the distal protection balloon and after completing PCI. We determined concentrations of C-reactive protein, soluble CD40 ligand, Interleukin (IL-6), serotonin, tissue factor, and factor VIIa.. While the concentrations of soluble CD40 ligand (2.84+/-3.74 vs 0.98+/-0.63 ng/mL, p=0.004), IL-6 (33.67+/-32.63 vs 17.08+/-21.41 pg/mL, p<0.001), serotonin (2.05+/-0.76 vs 0.92+/-0.60 ng/mL, p<0.001), tissue factor (257.17+/-84.34 vs 154.60+/-87.99 pg/mL, p<0.001) and factor VIIa (34.30+/-27.30 vs 24.19+/-28.00 ng/mL, p=0.016) were significantly higher in the culprit coronary artery than in the femoral artery, CRP levels did not differ. The locally elevated concentrations of various factors were successfully reduced after multiple aspirations of blood using the PercuSurge GuideWire system.. We found increased levels of soluble CD40 ligand, IL-6, serotonin, tissue factor and factor VII in the culprit coronary artery compared to those in peripheral blood. The clinical impact of such locally increased soluble factors in the culprit coronary artery needs to be investigated in further studies.

Topics: Aged; Angioplasty, Balloon, Coronary; Biomarkers; C-Reactive Protein; CD40 Ligand; Coronary Circulation; Coronary Vessels; Factor VIIa; Female; Femoral Artery; Humans; Inflammation Mediators; Interleukin-6; Male; Middle Aged; Myocardial Infarction; Serotonin; Thromboplastin

The rapid closure of coronary arteries due to occlusive thrombi is the major cause of acute myocardial infarction. However, the mechanisms of coronary thrombus formation have not been elucidated. We immunohistochemically assessed the localizations and their changes over time of glycoprotein IIb/IIIa, fibrin, von Willebrand factor (vWF), and tissue factor (TF), after the onset of chest pain (<4, 4 to 6, or 6 to 12 hours), in fresh coronary thrombi causing acute myocardial infarction. The occlusive thrombi were consistently composed of platelets, fibrin, vWF, and TF from the early phase of onset, and glycoprotein IIb/IIIa and fibrin were closely associated with vWF and TF, respectively. vWF and/or TF may contribute to occlusive thrombus formation and be novel therapeutic candidates for treating patients with coronary thrombosis.

Topics: Aged; Blood Platelets; Coronary Thrombosis; Female; Fibrin; Humans; Immunohistochemistry; Male; Middle Aged; Myocardial Infarction; Platelet Glycoprotein GPIIb-IIIa Complex; Thromboplastin; von Willebrand Factor

Detailed histochemical analysis of coronary thrombi obtained freshly from acute phase of myocardial infarction patients may provide information necessary to understand the mechanism of coronary occlusive thrombus formation.. Coronary thrombi causing myocardial infarction were obtained from 10 consecutive patients of myocardial infarction in the acute phase, using a newly developed aspiration catheter. All the fixed specimens of coronary thrombi, by hematoxylin and eosin staining, were found to contain three major constituents, namely, platelets, densely packed fibrin and inflammatory cells, including polymorphonuclear and mononuclear cells, although their distribution in each specimen is totally heterogeneous. Immunohistochemical staining revealed the prominent presence of von Willebrand factor (VWF) at the sites of platelet accumulation, presence of tissue factor and platelets at the sites of deposition of fibrin fibrils. It also revealed the presence of CD16-, CD45- and CD34-positive cells, yet the functional roles of these cells have still to be elucidated. There are weak positive correlation between the number of inflammatory cells involved in the unit area of coronary thrombi specimen and the time of collection of the specimens after the onset of chest pain.. In spite of various limitations, our results contain information suggesting the possible role of VWF in platelet-thrombus formation, possible important role played by tissue factor and activated platelets in the formation of fibrin fibrils, and the positive relationship between inflammatory cells migration and the formation of occlusive thrombi in human coronary arteries.

Topics: Adult; Aged; Aged, 80 and over; Biopsy, Needle; Blood Platelets; Coronary Thrombosis; Female; Fibrin; Humans; Immunohistochemistry; Inflammation; Male; Middle Aged; Myocardial Infarction; Thromboplastin; von Willebrand Factor

Cigarette smoking is associated with an increased risk to develop myocardial infarction and ischemic stroke. However, the mechanisms responsible for these effects are still poorly understood.. To investigate whether nicotine, the major component of cigarette smoking, and its main metabolite, cotinine, might induce a pro-thrombotic state via stimulation of tissue factor (TF) expression in two cell population widely represented in the arterial wall such as endothelial cells (ECs), and smooth muscle cells (SMCs).. Incubation of ECs and SMCs with nicotine and cotinine induced TF expression in both cell types in a dose-dependent fashion, exerting its effect at the transcriptional level, as demonstrated by semiquantitative and by real-time PCR. Nicotine- and cotinine-induced TF expression was mediated by the activation of the transcription factor, nuclear factor-kappa B (NF-kappaB), as demonstrated by electrophoretic mobility shift assay and by the suppression of TF expression by the NF-kappaB inhibitor, pyrrolidine dithio carbamate ammonium.. These data indicate that nicotine and cotinine exert direct effects on ECs and SMCs, shifting them toward a pro-thrombotic state via induction of TF expression. These effects on cells of the vessel wall might explain, at least in part, the deleterious cardiovascular consequences of cigarette smoking.

Topics: Animals; Base Sequence; Cells, Cultured; Cotinine; DNA, Complementary; Endothelium, Vascular; Gene Expression; Humans; Muscle, Smooth, Vascular; Myocardial Infarction; NF-kappa B; Nicotine; Rabbits; Risk Factors; RNA, Messenger; Smoking; Stroke; Thromboplastin; Thrombosis; Transcription, Genetic

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

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

We investigated in patients with ongoing myocardial infarction (MI) whether coagulation factor VII (FVII) and tissue factor (TF) levels are affected at admission by genetic components and whether they may predict subsequent cardiovascular events.. 256 patients admitted for MI were evaluated for FVII and TF antigen levels before any treatment at entry, and were genotyped for FVII and TF polymorphisms. FVII gene insertions at -323, 11293 and the -402G/A change predicted FVII levels and explained 14% of variance. The -603 TF gene polymorphism failed to affect significantly TF levels (P=0.07). These variables were correlated with the incidence of death (36 patients) and reinfarction (9 patients) after a median follow-up of 397 days. Events were independently predicted by FVII (HR 2.1, 95% CI 1.2 to 5.7) and TF (HR 4.1, 95% CI 2 to 11) levels. Composite end point was significantly worse when both parameters were above the receiver-operating characteristics (ROC) values (HR 8.3, 95% CI 5 to 18, compared with FVII and TF below), and above the ROC value of TF (>630 pg/mL) it differed among FVII genotype groups.. Admission FVII and TF antigen levels, partially predicted by polymorphisms, are independent predictors of mortality and reinfarction in patients with acute MI.

Topics: Aged; Disease Progression; Factor VII; Female; Genotype; Humans; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Predictive Value of Tests; Recurrence; Risk Factors; Thromboplastin

To investigate the role of interleukin-1beta (IL-1beta) gene polymorphisms as a link between inflammation, coagulation, and risk of ischemic vascular disease at young age.. A total of 406 patients with myocardial infarction (MI) at young age, frequency-matched for age, sex, and recruitment center, with 419 healthy population-based controls and 134 patients with ischemic stroke at young age, matched by age and sex, with 134 healthy population-based controls, were studied. Subjects carrying the TT genotype of the -511C/T IL-1beta polymorphism showed a decreased risk of MI (odds ratio [OR], 0.36; 95% CI, 0.20 to 0.64) and stroke (OR, 0.32; 95% CI, 0.13 to 0.81) after adjustment for conventional risk factors. In both studies, the T allele showed a codominant effect (P=0.0020 in MI; P=0.021 in stroke). Mononuclear cells from volunteers carrying the T allele showed a decreased release of IL-1beta and a decreased expression of tissue factor after stimulation with lipopolysaccharide compared with CC homozygotes. The presence of a monoclonal antibody against IL-1beta during cell stimulation resulted in a marked reduction of tissue factor activity expression.. -511C/T IL-1beta gene polymorphism affects the risk of MI and ischemic stroke at young age and the response of mononuclear cells to inflammatory stimulation.

Topics: Adolescent; Adult; Child; Child, Preschool; Cytosine; Female; Genetic Predisposition to Disease; Humans; Infant; Interleukin-1; Leukocytes, Mononuclear; Linkage Disequilibrium; Lipopolysaccharides; Male; Myocardial Infarction; Polymorphism, Genetic; Promoter Regions, Genetic; Risk Factors; Stroke; Thromboplastin; Thymine

To study the state and diagnostic value of plasma tissue factor (TF) in patients with acute coronary syndromes (ACS), we quantitatively compared plasma TF antigen and TF activity in 90 early-hospitalised patients with chest pain. Using high-affinity antibodies, a sensitive assay for TF antigen was developed with a detection limit of 40 fmol/l. One of the antibodies was used to capture TF from plasma and, after elution and dialysis-free reconstitution in phospholipid-glucoside micelles, absolute amounts of TF activity could be measured with a detection limit of 80 fmol/l. All TF in plasma was found to be exposed, and a value of 2.5(1.1-14.8) pmol/l (median with range) was found for TF antigen. Most of this TF antigen (70-80%) circulated in a (potentially) functional state. Left in its in vivo state, however, TF captured from plasma was totally inactive, probably because of the lack of a procoagulant matrix. Compared with controls with non-cardiac chest pain, TF activity was unchanged and TF antigen about 25% elevated in ACS patients. Combined with the markers prothrombin fragment F1+2 and fatty acid-binding protein, TF did not improve the early diagnosis of ACS.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Antigens; Biomarkers; Case-Control Studies; Chest Pain; Electrocardiography; Enzyme-Linked Immunosorbent Assay; Female; Hospitalization; Humans; Male; Middle Aged; Myocardial Infarction; Predictive Value of Tests; ROC Curve; Thromboplastin; Troponin T

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

Formation of an occlusive thrombus by exposure of tissue factor (TF) to circulating blood and subsequent triggering of coagulation by TF-FVIIa complexes on ruptured atherosclerotic plaques is thought to be a key event in acute MI. Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of TF-induced coagulation by neutralizing FXa and inhibiting the TF-FVIIa complex. A case control study was conducted to investigate the role of coagulation activation in MI. Sixty-two patients with verified MI, 40-60 yrs of age, were recruited into the study and examined 1-4 years after the acute coronary event. Thrombin-antithrombin complex (TAT) was significantly increased in MI patients (8.2 +/- 12.9 microg/l vs. 3.9 +/- 2.6 microg/l, p=0.01). In contrast, FVIIa was lower in MI patients (41 +/- 13 mU/ml vs. 48 +/- 15 mU/ml, p=0.003) accompanied by an increase in plasma free TFPI antigen (20.9 +/- 5.0 ng/ml vs. 19.2 +/- 4.9 ng/ml, p=0.03). Significant trends for increase in triglycerides and total cholesterol across quartiles of free TFPI Ag were found in both groups, whereas HDL cholesterol decreased across quartiles of TFPI among control subjects. The compensatory increase in plasma free TFPI with established lipid and haemostatic risk factors were abrogated in the MI patients. An apparent increase in the basal activation of the coagulation system was observed in young patients with MI. Enhanced coagulation activation was accompanied by a decrease in FVIIa and increase in free TFPI Ag, probably reflecting a modest triggering of TF-induced coagulation in these patients.

Topics: Adult; Antithrombin III; Blood Coagulation; Case-Control Studies; Cholesterol; Cholesterol, HDL; Factor VIIa; Female; Humans; Lipoproteins; Male; Middle Aged; Myocardial Infarction; Peptide Hydrolases; Thromboplastin; Triglycerides

Tissue factor (TF), the main initiator of the extrinsic coagulation cascade is expressed in atherosclerotic lesions and contributes to coronary thrombus formation in myocardial infarction (MI). Circulating TF reflects intravascular TF activation but also adds to prothrombotic activation. Because the G allele of the TF promotor polymorphism -603 A/G is associated with monocytic mRNA expression we evaluated its association with myocardial infarction, based on a recessive deleterious effect assumption. Patients with MI (MI; n=793) and age and sex matched control subjects without coronary artery disease (C; n=340) undergoing coronary angiography were included. In patients with MI, the -603 G (MI: 76%, C: 70%) allele was prevalent compared to the control group (P=-0.04). Multivariate analysis revealed an odds ratio of 1.44 (confidence interval 1.07-1.93). Carriage of the -603 G allele is associated with an increased risk for myocardial infarction. Because higher plasma TF concentrations are found in -603 G carriers enhanced TF expression may be the mechanism underlying this association.

Topics: Adenine; Alleles; Female; Guanine; Humans; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Promoter Regions, Genetic; 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

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

Data about the effects of smoking on thrombo-hemostatic factors (tissue factor [TF] and tissue factor pathway inhibitor [TFPI-1]) are limited and on fibrinolytic factors (tissue plasminogen activator [t-PA] and plasminogen activator inhibitor-1 [PAI-1]) are debatable. The present study investigated the smoking-related, endothelial cell (EC)-specific responses for these factors and their relation to nitric oxide (NO) production in vitro.. Serum from 8 nonsmokers and 15 smokers were incubated with confluent (approximately 85%) human umbilical vein endothelial cells (HUVECs) in 24-well tissue-culture plates for 12 hours. After the incubation, basal NO, t-PA, PAI-1, TF, TFPI-1 production, and substance P (SP)-stimulated NO, t-PA, and PAI-1 production were determined. HUVECs treated with smokers' serum showed lower basal (P<0.02) and SP-stimulated (P=0.059) t-PA production but similar basal and stimulated PAI-1 production (P=0.9 and P=0.6) compared with nonsmokers. Basal t-PA/PAI-1 molar ratio was significantly reduced in smokers (P<0.005). TFPI-1 level in the cell culture supernatant was also significantly lower in smokers compared with the nonsmoker group (P<0.05) with no difference in TF level between both groups (P=0.5). As previously reported, both basal (P<0.001) and SP-stimulated (P<0.05) NO production were significantly reduced in smokers. Basal TFPI-1 in culture correlated positively with basal NO production (r=0.42, P=0.04) and negatively with serum cotinine level (r=-0.6, P=0.01).. These results indicate that cigarette smoking is associated with alterations in EC-derived fibrinolytic (t-PA) and antithrombotic (TFPI-1) factors. To our knowledge, this is the first demonstration that EC-derived TFPI is affected by smoking and endogenous NO or that the degree of smoke exposure may influence TFPI levels in an EC milieu.

Topics: Adult; Cells, Cultured; Cotinine; Death, Sudden, Cardiac; Endothelium, Vascular; Fibrinolytic Agents; Humans; Lipoproteins; Male; Myocardial Infarction; Nitric Oxide; Plasminogen Activator Inhibitor 1; Smoking; Thromboplastin; Tissue Plasminogen Activator

It is widely recognized that thrombosis is the major event in the evolution of acute myocardial infarction (AMI) and acute ischemic stroke (AIS). But the contribution of coagulation factors to the development of ischemic arterial diseases is still not clearly established. The goal of this study was to establish the possible relationship between coagulation factors as well as anticoagulant and the onset of AMI and AIS. The study population consisted of 69 patients with AMI and 71 with AIS as well as 50 age-matched healthy volunteers. Compared with the control group, plasma tissue factor (TF) and tissue factor pathway inhibitor (TFPI) activities and both TF and TFPI antigens were significantly higher in the AMI group; plasma TF activity and antigen in AIS group were significantly increased, but the activity and antigen of plasma TFPI were significantly decreased in the AIS group. Plasma FVII coagulation (FVII:C) activity was markedly higher in patients with AIS, but not statistically different to the control in patients with AMI. FVIII coagulation (FVIII:C) activity was remarkably higher in patients with AMI but slightly lower than the control in patients with AIS. In the AMI and AIS groups, prothrombin activity and clottable fibrinogen were significantly higher and plasma antithrombin III activity was remarkably lower than the control. The results suggested that during the onset of AMI and AIS, the initiation of TF pathway would be associated with the thrombotic events and that the blood be in hypercoagulable state. But the changes of FVII:C, TFPI and FVIII:C in AMI are different from those in AIS.

Topics: Acute Disease; Aged; Aged, 80 and over; Biomarkers; Blood Coagulation; Case-Control Studies; Coronary Thrombosis; Female; Humans; Intracranial Thrombosis; Male; Middle Aged; Myocardial Infarction; Stroke; Thromboplastin

Topics: Animals; Anticoagulants; Arteriosclerosis; Aspirin; Fibrinolytic Agents; Heparin; Humans; Lipoproteins; Myocardial Infarction; Platelet Aggregation Inhibitors; Thrombolytic Therapy; Thromboplastin; Thrombosis

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

In acute myocardial infarction (AMI), monocyte procoagulant activity is increased and may contribute to the risk for recurrence and other thrombotic events. This study sought to investigate the role tissue factor (TF) and tissue factor pathway inhibitor-1 (TFPI-1) in the regulation of monocyte procoagulant activity in AMI. Serial venous blood samples were obtained from 40 patients with AMI undergoing revascularization by stent placement. Twenty patients with elective stenting for stable angina served as control subjects. TF proteolytic activity was measured with spectrozyme factor Xa (FXa), TF and TFPI-1 surface expression on monocytes by flow cytometry, RNA expression in whole blood by reverse transcription-polymerase chain reaction, and concentrations of plasma prothrombin fragments F(1 + 2) by immunoassay. Forty-eight hours after AMI, an increase was found in TF RNA, followed by an increase in TF surface expression by 24% +/- 4% and in plasma concentration of F(1 + 2) by 103% +/- 17% (P <.05). These changes could not be attributed to the intervention because they did not occur in the control group. TFPI-1 RNA and binding to the monocyte surface remained unchanged. FXa generation by monocytes of patients with AMI increased 53.6% +/- 9% in the presence of polyclonal antibodies to TFPI-1, indicating that cell-associated TFPI-1 inhibits monocyte TF activity. The increased monocyte procoagulant activity in AMI was caused by an up-regulation of TF that was partially inhibited by surface-bound TFPI-1. Anticoagulant therapy by direct inhibition of TF activity may, thus, be particularly effective in AMI. (Blood. 2001;97:3721-3726)

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Binding Sites; Blood Coagulation Factors; Factor Xa; Female; Glycosylphosphatidylinositols; Hemostatics; Humans; Leukocyte Count; Lipoproteins; Male; Membrane Proteins; Middle Aged; Monocytes; Myocardial Infarction; Peptide Fragments; Prothrombin; RNA, Messenger; Thromboplastin

To evaluate the association between haemostatic parameters and increased risk of myocardial infarction (MI) at a young age, we measured fibrinogen, factor VII, antithrombin III, protein C, protein S, tissue factor (TF), free form tissue factor pathway inhibitor (TFPI), plasminogen, alpha2-antiplasmin, tissue plasminogen activator (tPA), plasminogen activator inhibitor-I (PAI-I), and lipoprotein (a) in 140 young men with MI before age 45 and 150 age-matched healthy men. TF, TF/TFPI ratio, PAI-I, PAI-I/tPA ratio, plasminogen, and lipoprotein (a) in young MI patients were all significantly higher than controls, while TFPI, antithrombin II, and tPA were significantly lower (P <0.001 of each). Significant determinants of MI risk were PAI-I/tPA ratio (R2 = 0.300, P <0.001), TF/TFPI ratio (R2 = 0.049, P <0.001), antithrombin III (R2 = 0.034, P <0.001), hyperlipidaemia (R2 = 0.019, P = 0.004), diabetes (R2 = 0.014, P = 0.015), lipoprotein (a) (R2 = 0.012, P = 0.023), alpha2-antiplasmin (R2= 0.014, P = 0.012), and protein C (R2= 0.012, P = 0.018). We conclude that the imbalances of PAI-I/tPA and TF/TFPI are significantly associated with MI at a young age, perhaps mediated via impaired fibrinolytic activity.

Topics: Adult; Blood Coagulation Factors; Case-Control Studies; Hemostasis; Homeostasis; Humans; Japan; Lipoproteins; Middle Aged; Myocardial Infarction; Plasminogen Activator Inhibitor 1; Risk Factors; Thromboplastin; Tissue Plasminogen Activator

Tissue factor (TF) is a transmembrane protein considered to be responsible for the initiation of coagulation. TF gene expression may be induced in monocytes and endothelial cells and is present in atherosclerotic plaque to initiate thrombus formation. To investigate whether individual differences in TF gene expression could predispose subjects to thrombosis, we sequenced the 5' domain of the gene up to nucleotide 2732 and found 6 different polymorphisms: 4 of them were completely concordant and defined 2 haplotypes with similar frequencies, designated as 1208 D and 1208 I. Genotyping of patients with myocardial infarction in a case-control study involving 2354 subjects showed no association between the polymorphisms and nonfatal coronary thrombosis. In another study involving 255 patients with venous thromboembolism and 1204 controls, allele D was less common in the cases (P=0.022). The odds ratio associated with the presence of at least 1 D allele was 0.72 (P=0. 031). Comparison of subgroups of control subjects who were homozygous for the D or I allele demonstrated a lower plasma TF concentration in DD homozygotes. These results indicate that the TF gene promoter exists in 2 major forms differing at 4 sites. The 1208 D haplotype is not associated with coronary thrombosis but is associated with reduced plasma TF levels and a lower risk of venous thrombosis.

Topics: 5' Untranslated Regions; Adult; Aged; Base Sequence; Case-Control Studies; DNA Primers; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Male; Middle Aged; Molecular Sequence Data; Myocardial Infarction; Polymorphism, Genetic; Prevalence; Promoter Regions, Genetic; Risk Factors; Thromboembolism; Thromboplastin; Venous Thrombosis

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

Oxygen free radicals induce de novo synthesis of tissue factor (TF), the initiator of the extrinsic pathway of coagulation, within the coronary vasculature during postischemic reperfusion. In the present study we wanted to assess whether TF expression might cause myocardial injury during postischemic reperfusion. Anesthetized rabbits underwent 30 min of coronary occlusion followed by 5.5 h of reperfusion. At reperfusion the animals received 1) saline (n = 8), 2) human recombinant, active site-blocked activated factor VII (FVIIai, 1 mg/kg, n = 8), or 3) human recombinant activated FVII (FVIIa, 1 mg/kg, n = 8). FVIIai binds to TF as native FVII, but with the active site blocked it inhibits TF procoagulant activity. The area at risk of infarction (AR), the infarct size (IS), and the no-reflow area (NR) were determined at the end of the experiment. FVIIai resulted in a significant reduction in IS and NR with respect to control animals (28.1 +/- 11.3 and 11.1 +/- 6.1% of AR vs. 59.8 +/- 12.8 and 24.4 +/- 2.7% of AR, respectively, P < 0.01), whereas FVIIa resulted in a significant increase in IS and NR to 80.1 +/- 13. 1 and 61.9 +/- 13.8% of AR, respectively (P < 0.01). In conclusion, TF-mediated activation of the extrinsic coagulation pathway makes an important contribution to myocardial injury during postischemic reperfusion.

Topics: Amino Acid Chloromethyl Ketones; Animals; Binding Sites; Blood Coagulation; Blood Platelets; Coronary Circulation; Factor VIIa; Fibrinogen; Hemodynamics; Hemostatics; Humans; Myocardial Infarction; Myocardial Reperfusion Injury; Rabbits; Recombinant Proteins; Thromboplastin

We examined plasma TF and free TFPI levels in 26 consecutive patients with AMI, 26 patients with stable exertional angina, and 25 patients with chest pain syndrome. In patients with AMI, blood samples were obtained immediately after admission and at 4, 8, 16, 24, and 48 h, and the third, fifth, seventh, and fourteenth day after initiation of reperfusion therapy. Plasma TF levels in patients with AMI on admission were significantly higher than in the chest pain syndrome and stable exertional angina groups (248.0+/-117. 4 vs. 179.5+/-29.2 vs. 189.5+/-29.6 pg/ml, P<0.01). In patients with AMI, the level subsequently decreased after heparin administration and was maintained at significantly lower levels compared to those on admission. Plasma free TFPI levels in patients with AMI on admission were significantly higher than in the chest pain syndrome and stable exertional angina groups [33.5+/-12.4 vs. 26.0+/-7.6 ng/ml (P<0.01) vs. 27.5+/-6.3 ng/ml, P<0.05]. In patients with AMI, it reached the maximum level at 4 h after the administration of heparin, and gradually decreased over the time course. These data indicated that continuous administration of a low dose of heparin was effective in decreasing TF levels without affecting TFPI levels. Our results elucidate one of the mechanisms by which the administration of heparin is beneficial in AMI patients undergoing percutaneous revascularization.

Topics: Aged; Angina Pectoris; Coronary Angiography; Female; Fibrinolytic Agents; Heparin; Humans; Lipoproteins; Male; Middle Aged; Myocardial Infarction; Thromboplastin

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

It is widely recognized that thrombosis is the major event in the evolution of stable vascular disease to unstable ischaemic syndromes including myocardial infarction and stroke. The purpose of this case-control study was to establish clinical and laboratory data on the possible relationship between specific components of the haemostatic system and coronary heart disease. The procoagulant activity (PCA) of peripheral monocytes and polymorphonuclear neutrophils was assessed in 21 males who had suffered a myocardial infarction (MI) and in age-matched controls. In addition, total factor VII activity, fibrinogen, tissue factor pathway inhibitor (TFPI). D-dimers, tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), tumour necrosis factor-alpha (TNF-alpha) and full blood counts were measured. Post MI patients had significantly higher monocyte PCA, higher plasma concentrations of TFPI, fibrinogen, t-PA, T/P100 and also higher total white blood cell and neutrophil counts compared to age-matched controls. This elevated procoagulant state in post MI patients could further exacerbate the disease process and increase the risk of subsequent acute ischaemic events.

Topics: Blood Cell Count; Blood Coagulation; Case-Control Studies; Factor VII; Fibrinogen; Homeostasis; Humans; Male; Middle Aged; Monocytes; Myocardial Infarction; Neutrophils; Plasminogen; Plasminogen Activators; Thromboplastin; Tumor Necrosis Factor-alpha

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

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

Thrombin activation of the soluble plasma protein fibrinogen is vital for successful haemostasis. Thrombin is generated from prothrombin by the prothrombinase complex which also includes factor Xa, factor Va, Ca2+ and a procoagulant membrane surface. Factor X activation is catalysed in a complex including either factor VIIa and tissue factor, or factor IXa and factor VIIIa. Factor IXa can be generated either by the factor VIIa/tissue factor complex or by factor XIa which is in turn produced by the contact phase reactions in vitro. Once activated, fibrinogen develops into the fibrin polymeric matrix at the site of injury. It is not known to what extent the properties of this haemostatic plug are sensitive to the pathway leading up to thrombin generation. Here static human plasma is studied in vitro using magnetically induced birefringence. It is shown that the contact phase/factor XIa pathway gives rise to linear fibrin assembly process curves whereas the factor VIIa/ tissue factor activation of factor X provokes largely sigmoid assembly. The latter pathway also causes the formation of significantly thicker fibres even though assembly is more rapid. This result is the inverse of that anticipated from the study of simple model systems. Whilst the streptokinase activated lysis both types of clot exhibits similar biphasic kinetics, an exponential main phase followed by a sigmoidal tailing off, the data suggest that clots produced by the contact phase/factor XIa pathway are more recalcitrant to lysis. These results demonstrate that the profile of thrombin generation not only determines the kinetics of assembly but also influences the rate of lysis and structure of the haemostatic plug.

Topics: Birefringence; Blood Coagulation; Blood Coagulation Factors; Blood Coagulation Tests; Enzyme Activation; Fibrin; Fibrinogen; Fibrinolysis; Gels; Hemophilia A; Humans; Myocardial Infarction; Plasma; Prothrombin; Thrombin; Thromboplastin

To investigate whether monocyte expression of tissue factor is increased in patients with acute coronary syndromes and chronic stable angina.. Cross sectional study of monocyte tissue factor expression in patients with ischaemic heart disease and control subjects.. Unstable angina and myocardial infarction are associated with enhanced mononuclear cell procoagulant activity. Procoagulant activity of blood monocytes is principally mediated by tissue factor expression. Tissue factor initiates the coagulation cascade and monocyte tissue factor expression may therefore be increased in these syndromes.. Monocyte tissue factor expression was measured cytometrically in whole blood flow using a polyclonal rabbit antihuman tissue factor antibody.. 30 patients with acute myocardial infarction, 17 with unstable angina, 13 with chronic stable angina, and 11 normal control subjects.. Increased proportions of monocytes expressing tissue factor (> 2.5%) were found in none of 11 (0%) normal subjects, five 13 (38%) patients with stable angina, 11 of 17 (64%) patients with unstable angina, and 16 of 30 (53%) patients with myocardial infarction (2P = 0.006). Blood from all subjects showed similar monocyte tissue factor expression similar monocyte tissue factor expression (46.1 (15.1)%) after lipopolysaccharide stimulation.. Hypercoagulability associated with acute myocardial infarction, unstable angina, and chronic stable angina may be induced by tissue factor expressed on circulating monocytes.

Topics: Acute Disease; Angina Pectoris; Cross-Sectional Studies; Female; Flow Cytometry; Fluorescent Antibody Technique; Humans; Male; Middle Aged; Monocytes; Myocardial Infarction; 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

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

Topics: Anticoagulants; Heart Valve Prosthesis; Humans; Multi-Institutional Systems; Myocardial Infarction; Prothrombin Time; Thromboplastin; Thrombosis; World Health Organization

Topics: Aged; Disseminated Intravascular Coagulation; Female; Humans; Male; Middle Aged; Myocardial Infarction; Thromboplastin

A total of 41 patients with ischaemic heart disease and 30 normal donors were subjected to examinations of the biochemical indices of the blood coagulation system in its coagulation and anticoagulation links, as well as to tests reflecting the fibrinolytic and inhibitory activity of the urine. In the presence of thromboembolic complications in myocardial infarction patients a sharp elevation of "residual fibrinogen" and antiplasmins is noted along with a reduction of the urokinase activity of the urine.

Topics: Adult; Blood Coagulation Tests; Chromatography, Paper; Factor XIII; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysin; Fibrinolysis; Humans; Middle Aged; Myocardial Infarction; Plasminogen Activators; Plasminogen Inactivators; Serum Globulins; Thromboembolism; Thromboplastin; Time Factors; Urokinase-Type Plasminogen Activator

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 case of a patient who, while being treated for an acute myocardial infarction, was found to have Fletcher factor deficiency with a Fletcher factor concentration of less than 1% of normal is described. Fletcher factor deficiency is associated with defects in several interrelated systems, including clotting, fibrinolysis and kinin generation, all of which play a role in the pathogenesis and evolution of infarction. The development of myocardial infarction in a patient who had severe Fletcher factor deficiency emphasizes the importance of alternate pathways for activation of these systems.

Topics: Adult; Blood Coagulation Disorders; Blood Coagulation Factors; Electrocardiography; Humans; Kallikreins; Male; Myocardial Infarction; Prekallikrein; Thromboplastin

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

The activated partial thromboplastin time is compared with the corresponding prothrombin ratio in 6378 samples of platelet-poor plasma from 446 patients treated for a total of more than 4500 patient/months with oral anticoagulatnts. A relative decrease in the activated partial thromboplastin time following deep vein thrombosis is described, which tends to become less obvious during the first year of treatment and is greater in older patients. Although this relative decrease is also found in patients treated after cerebrovascular accidents, it is not found in patients treated after myocardial infarction or in patients with mitral valve disease treated prophylactically with long-term oral anticoagulants. It is though possible that these changes following deep vein thrombosis might be useful in helping to determine the duration of oral anticoagulant treatment.

Topics: Adult; Blood Coagulation; Female; Heart Valve Diseases; Humans; Male; Middle Aged; Myocardial Infarction; Phenindione; Prothrombin Time; Thrombophlebitis; Thromboplastin; Warfarin

Topics: Animals; Brain; Drug Stability; Humans; Myocardial Infarction; Phenols; Prothrombin Time; Pulmonary Embolism; Rabbits; South Africa; Thrombophlebitis; Thromboplastin; Warfarin

Topics: Adult; Animals; Blood Coagulation; Blood Coagulation Tests; Electrophoresis, Polyacrylamide Gel; Factor VII; Factor X; Female; Humans; Immune Sera; Male; Menopause; Menstruation; Middle Aged; Myocardial Infarction; Neutralization Tests; Prothrombin Time; Rabbits; Sex Factors; Stimulation, Chemical; Thrombophlebitis; Thromboplastin; Time Factors; Warfarin

Topics: Adult; Antibody Formation; Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Complement Fixation Tests; Hemorrhage; Heparin; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Adhesiveness; Prothrombin Time; Thrombocytopenia; Thromboembolism; Thromboplastin; Thrombosis

Topics: Animals; Aorta; Blood Coagulation Factors; Blood Coagulation Tests; Endotoxins; Hemorrhage; Heparin; Infarction; Injections, Intra-Arterial; Injections, Intravenous; Kidney Cortex Necrosis; Leukocytes; Male; Myocardial Infarction; Peritoneum; Prothrombin Time; Pulmonary Embolism; Rabbits; Shwartzman Phenomenon; Thromboplastin; Thrombosis

Topics: Anticoagulants; Blood Coagulation Tests; Humans; Myocardial Infarction; Thrombophlebitis; Thromboplastin

Topics: Blood Coagulation; Blood Glucose; Blood Pressure; Body Constitution; Body Weight; Cholesterol; Factor VII; Factor VIII; Factor X; Fibrinogen; Fibrinolysis; Humans; Male; Middle Aged; Myocardial Infarction; Obesity; Plasminogen; Prothrombin; Sampling Studies; Skinfold Thickness; Smoking; Spirometry; Thromboplastin; Triglycerides; Vital Capacity

Topics: Adult; Animals; Blood Coagulation Tests; Dogs; Half-Life; Heparin; Humans; Injections, Intravenous; Kinetics; Male; Mathematics; Myocardial Infarction; Rabbits; Statistics as Topic; Thromboplastin; Thrombosis

Topics: Administration, Oral; Anticoagulants; Blood Coagulation Tests; Humans; Myocardial Infarction; Prothrombin Time; Thrombophlebitis; Thromboplastin

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: Anticoagulants; Blood Coagulation Tests; Humans; Methods; Myocardial Infarction; Thromboplastin

Topics: Anticoagulants; Blood Coagulation Tests; Cardiovascular Diseases; Embolism; Humans; Myocardial Infarction; Prothrombin; Thromboplastin; Thrombosis

Topics: Adult; Aged; Anticoagulants; Blood Coagulation Tests; Female; Heart Valve Diseases; Humans; Male; Middle Aged; Myocardial Infarction; Phenindione; Prothrombin Time; Pulmonary Embolism; Thrombophlebitis; Thromboplastin; Warfarin

Topics: Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Tests; Coronary Vessels; Factor VIII; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Prednisone; Shock; Spondylitis, Ankylosing; Thromboplastin

Topics: Animals; Blood Coagulation; Dogs; Fibrinolysis; Heparin; Methods; Myocardial Infarction; Prothrombin Time; Thrombelastography; Thromboplastin

Topics: Angina Pectoris; Blood Coagulation; Blood Coagulation Tests; Cholesterol; Diabetes Mellitus; Dietary Fats; Geriatrics; Humans; Linoleic Acid; Lipids; Myocardial Infarction; Palmitic Acid; Pharmacology; Stearic Acids; Thromboplastin; Triolein

Topics: Adult; Aged; Anticoagulants; Humans; Middle Aged; Myocardial Infarction; Thromboembolism; Thromboplastin; Thrombosis

Topics: Aged; Amputation, Surgical; Arteriosclerosis Obliterans; Blood Coagulation Disorders; Chronic Disease; Coumarins; Diabetes Mellitus; Follow-Up Studies; Humans; Hypercholesterolemia; Hypertension; Middle Aged; Myocardial Infarction; Thromboplastin

Topics: Arteriosclerosis; Hemorrhagic Disorders; Heparin; Lipoproteins; Myocardial Infarction; Oxalates; Thromboplastin

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: Hemorrhagic Disorders; Humans; Myocardial Infarction; Pulmonary Embolism; Thromboplastin; Thrombosis