thromboplastin and Acute-Disease

The evidence gathered in clinical trials of low molecular weight heparins (LMWHs) or with unfractionated heparin (UH) given subcutaneously at low or medium doses to patients with acute stroke cannot be extrapolated to the insufficiently tested effects of intravenous, weight-adjusted UH. Recent small studies have provided encouraging results but are potentially confounded and deserve confirmation in larger randomized controlled trials. In accordance with the current understanding of the biology of acute ischemic stroke and the pharmacology of UH, the new randomized controlled trials on heparin should give appropriate credit to the importance of a short therapeutic window, adequate dose adjustment of the drug, intravenous administration, and close monitoring of biological effects. UH is an orphan drug and only an academic driven trial would be able to face such an enterprise. Meanwhile, recommendations against the value of "early" anticoagulation with full dose of weight adjusted UH in the setting of acute ischemic stroke are not based on direct evidence but on extrapolations.

Topics: Acute Disease; Anticoagulants; Brain Ischemia; Fibrinolytic Agents; Heparin; Humans; Stroke; Thromboplastin

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

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

Crucial advances in our understanding of the pathogenesis of atherothrombosis, defined as atherosclerosis and its thrombotic complications, have been achieved during the past two decades. The historical hypothesis of pathogenesis ("lipid accumulation") has evolved to integrate several factors contributing to the initiation and evolution of this complex disease. Endothelial dysfunction is considered to be the earliest event in atherogenesis. Inflammation and apoptosis play critical roles in its progression and onset. Tissue factor is postulated to be a central actor in determining plaque thrombogenicity. A hyperreactive state of the blood ("vulnerable blood") may be responsible for one-third of all the acute coronary syndromes. This review will discuss emerging concepts in the pathogenesis of and therapeutic approaches to atherothrombotic disease.

Topics: Acute Disease; Apoptosis; Arteriosclerosis; Endothelium; Humans; Inflammation; Risk Factors; Thromboplastin; Thrombosis

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

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

Recent advances in basic science have linked some systemic risk factors to endothelial dysfunction which gives rise to atherosclerotic disease and triggers the progression of thrombotic complications. Superficial erosion of the stenotic plaque can be observed in one-third of acute coronary syndromes (ACS). In these cases the presence of classic risk factors such as diabetes mellitus, hypercholesterolemia and smoking favor a state of "vulnerable blood" or high risk. Increased thrombogenicity can exacerbate thrombus formation and is able to trigger an ACS. The vessel endothelium regulates contractile, mitogenic and thrombotic activities of the vessel wall. Risk factors impair both homeostasis and hemostasis of the vessel wall and promote inflammatory signals. Platelet and monocyte activation favors the expression of tissue factor (TF), thus triggering the coagulation cascade with thrombin generation and clot formation. Increased blood thrombogenicity linked to classic risk factors may be associated with circulating TF levels which are much higher than those observed in healthy subjects without risk factors. These observations not only emphasize the usefulness of aggressive management of risk factors but open a new avenue for future studies to devise therapeutic strategies to treat ACS by inhibiting TF expression.

Topics: Acute Disease; Coronary Artery Disease; Coronary Thrombosis; Diabetes Complications; Humans; Hypercholesterolemia; Risk Factors; Smoking; Syndrome; Thromboplastin

Plaque disruption with superimposed thrombosis is the main cause of acute coronary events such as acute myocardial infarction and unstable angina. Among other factors, tissue factor seems to play an important role determining plaque thrombogenicity. Tissue factor is a potent initiator of the coagulation cascade situated within the vessel wall and is highly exposed to the blood after plaque rupture. Several mediators involved in the process of atherosclerotic plaque formation are capable of inducing tissue factor expression in cells such as monocytes, macrophages and endothelial cells, which under normal conditions do not express tissue factor or to a limited extent only. The increased expression of tissue factor is not limited to the plaque but is also found in circulating monocytes in patients with acute coronary syndromes. In addition, studies have shown an important contribution of tissue factor in the pathogenesis of thrombosis and restenosis after balloon angioplasty. Recent basic studies focus on the therapeutic inhibition of tissue factor. Specific and non-specific inhibitors of tissue factor or the tissue factor/factor VIIa complex have been developed or identified, and have been tested in experimental studies. Clinical studies are currently being initiated. In this review, we present the current knowledge on the role of tissue factor in atherosclerosis, arterial intervention and potential pharmacological approaches, with focus on acute coronary syndromes.

Topics: Acute Disease; Angioplasty, Balloon, Coronary; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Anticoagulants; Arginine; Aspirin; Coronary Artery Disease; Coronary Thrombosis; Cyclosporine; Endothelium, Vascular; Factor VIIa; Heparin, Low-Molecular-Weight; Hirudin Therapy; Humans; Hypolipidemic Agents; Leukocytes, Mononuclear; Muscle, Smooth, Vascular; Recombinant Proteins; Thrombin; Thromboplastin

Topics: Acute Disease; Anticoagulants; Brain Ischemia; Drug Administration Schedule; Heparin; Humans; Injections, Subcutaneous; Randomized Controlled Trials as Topic; Thromboplastin; Time Factors; Vascular Cell Adhesion Molecule-1

Human tissue factor pathway inhibitor (TFPI) is a modular protein comprised of three Kunitz type domains flanked by peptide segments that are less structured. The sequential order of the elements are: an N-terminal acidic region followed by the first Kunitz domain (K1), a linker region, a second Kunitz domain (K2), a second linker region, the third Kunitz domain (K3), and the C-terminal basic region. The K1 domain inhibits factor VIIa complexed to tissue factor (TF) while the K2 domain inhibits factor Xa. No direct protease inhibiting functions have been demonstrated for the K3 domain. Importantly, the Xa-TFPI complex is a much more potent inhibitor of the VIIa-TF than TFPI by itself. Furthermore, the C-terminal basic region of TFPI is required for rapid physiologic inhibition of coagulation and is needed for the inhibition of smooth muscle cell proliferation. Although a number of additional targets for attachment have been reported, the C-terminal basic region appears to play an important role in binding of TFPI to cell surfaces. A primary site of TFPI synthesis is endothelium and the endothelium-bound TFPI contributes to the antithrombotic potential of the vascular endothelium. Further, increased levels of plasma TFPI under septic conditions may represent endothelial dysfunction. We have proposed that the extravascular cells that synthesize TF also synthesize TFPI providing dual components necessary for the regulation of clotting in their microenvironment. Like the TF synthesis in these cells is augmented by serum, so is the case with the TFPI gene expression. TFPI gene knock out mice reveal embryonic lethality suggesting a possible role of this protein in early development. Since TF-induced coagulation is thought to play a significant role in many disease states, including disseminated intravascular clotting, sepsis, acute lung injury and cancer, recombinant TFPI may be a beneficial therapeutic agent in these disease states to attenuate pathologic clotting. The purpose of this review is to outline recent developments in the field related to the structural specificity and biology of TFPI.

Topics: Acute Disease; Amino Acid Sequence; Amino Acids; Antiphospholipid Syndrome; Blood Coagulation; Cardiovascular Diseases; Endothelium, Vascular; Humans; Lipoproteins; Lung Diseases; Models, Biological; Models, Molecular; Molecular Sequence Data; Neoplasm Metastasis; Neoplasms; Protein Conformation; Protein Structure, Tertiary; Sepsis; Sequence Alignment; Sequence Homology, Amino Acid; Structure-Activity Relationship; Thrombophilia; Thromboplastin

Tissue factor (TF) is the essential cofactor for the coagulation protease factor VIIa (FVIIa), initiating the coagulation cascade. The role of TF in thrombotic diseases is becoming increasingly evident. Recent findings suggest that inhibition of TF/FVIIa activity could be important in the prevention of clinical sequelae associated with plaque rupture or vessel damage that exposes TF to blood. Furthermore, selective inhibitors of TF/FVIIa may be associated with less bleeding risk than other antithrombotic agents. Several TF/FVIIa inhibitors are in development, including the protein-based inhibitors (such as NAPc2, Corsevin M, FFR-FVIIa, and Tifacogin). Research into the development of small molecule inhibitors is on-going, but is at a less advanced stage.

Topics: Acute Disease; Animals; Antibodies, Monoclonal; Anticoagulants; Clinical Trials as Topic; Coronary Thrombosis; Factor VII; Factor VIIa; Fibrinolytic Agents; Helminth Proteins; Humans; Proteins; Thromboplastin

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

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

Tissue factor (TF) exists in a cryptic form [i.e. without procoagulant activity (PCA)] in peripheral blood monocytes and quiescent tissue macrophages but is expressed constitutively in most human tumor cells. Induction and cell surface expression of TF in these cells in vivo is associated with activation of intravascular and extravascular coagulation in patients with a variety of inflammatory or malignant diseases. The regulation of TF synthesis in cells is complex and new information from transfection studies suggests that changes in cellular glycosylation pathways impair cell surface expression of functional TF. Such dysregulation may also characterize the lineage-unfaithful expression of TF in leukemic cells and perhaps explain some of the thrombohemorrhagic complications in patients with acute progranulocytic leukemia. The importance of carbohydrate modification of TF is reviewed.

Topics: Acute Disease; Animals; Blood Coagulation Disorders; Carbohydrate Sequence; Cell Differentiation; CHO Cells; Cricetinae; Cricetulus; Cysteine Endopeptidases; Glycosylation; HL-60 Cells; Humans; Leukemia; Leukocytes; Molecular Sequence Data; Neoplasm Proteins; Neoplasms; Neoplastic Stem Cells; Thromboplastin

Topics: Acute Disease; Animals; Disseminated Intravascular Coagulation; Hematologic Diseases; Heparin; Humans; Leukemia; Rabbits; Thromboplastin

Studies on the association between microparticle expressing tissue factor (MP-TF) activity, FVIII activity (. C) and recurrent VTE yielded inconclusive results. We studied these associations in patients diagnosed with acute pulmonary embolism. Plasma levels of MP-TF and FVIII activity were measured in 277 patients with a first and 72 patients with a recurrent VTE. All patients were categorized based on the quintiles of MP-TF and FVIII activity in those with a single VTE. For both markers, odds ratios (ORs) for recurrent VTE were computed using patients in the lowest quintile as a reference group. No association was observed between MP-TF activity and recurrent VTE, with an OR of 1.4 (95 % CI 0.7-2.9) in the highest quintile of MP-TF activity. Compared with the reference group, patients in the highest quintile of. C were at increased risk of recurrent VTE, OR 4.2 (95 % CI 1.4-12.2). MP-TF activity was not associated with recurrent VTE whereas high. C levels were associated with a 4-fold increased risk of VTE recurrence. Future prospective studies are necessary to explore the potential of. C as a tool for risk stratification, either by itself or in combination with other pro-thrombotic markers.

Topics: Acute Disease; Adult; Aged; Cell-Derived Microparticles; Factor VIII; Female; Humans; Male; Middle Aged; Pulmonary Embolism; Thromboplastin; Venous Thromboembolism

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

Membrane-dependent coagulation processes play a key role in acute coronary syndromes (ACS), where the generation of thrombin depends on the complex of activated factors X and V (prothrombinase complex) assembled on activated platelets. The aim of the present study was to evaluate prothrombinase activity in patients with ACS and to examine the effect of treatment with 80 mg/day atorvastatin on prothrombinase activity. Blood samples were obtained at admission from 22 patients with ACS, and then again at 2 weeks and at 16 weeks after double-blind randomization to either placebo or atorvastatin. Prothrombinase activity was evaluated by measuring the generation of thrombin by in vitro reconstructed thrombi, and also by measuring plasma levels of prothrombin fragment F1 + 2. Twenty age-matched subjects with stable angina and 11 without coronary disease were used as controls. At admission, prothrombinase activity and F1 + 2 were significantly higher in ACS patients than in controls. Prothrombinase activity was still high at 2 weeks while it returned to normal levels at 16 weeks. F1 + 2 remained high both at 2 and at 16 weeks. Our data indicate that prothrombinase activity is high in patients with ACS, and that it is not affected by high-dose atorvastatin.

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

Topics: Acute Disease; Child; Clinical Trials as Topic; Factor VIII; Hemarthrosis; Hemophilia A; Hemophilia B; Humans; Male; Placebos; Prednisone; Thromboplastin

To detect the expressions of tumor necrosis factor-α-induced protein-8-like 2 (TIPE2) and tissue factor (TF) in peripheral blood mononuclear cells (PBMCs) of patients with acute exacerbation of bronchial asthma (BA), and to analyze their associations with changes in inflammatory factors and T lymphocytes.. A total of 59 patients with BA treated in our hospital from February 2018 to April 2019 were selected as objects, including 30 cases in the acute exacerbation phase (BA group) and 29 in the remission phase (RE group). During the same period, 28 people receiving physical examinations were selected as healthy controls (Control group). The proportion of eosinophils in the sputum and the fractional exhaled nitric oxide (FeNO) level were detected in each subject. Blood samples were collected in patients of BA group and Control group, aiming to isolate PBMCs. Then, the messenger RNA (mRNA) expressions of TIPE2 and TF in PBMCs were determined via reverse transcription-polymerase chain reaction (RT-PCR). Serum levels of interleukin-1β (IL-1β) and IL-6 in BA group and Control group were determined via enzyme-linked immunosorbent assay (ELISA), and protein expressions of serum T helper 1 (Th1) and Th2 cells in BA group and Control group were detected using Western blotting.. Compared with those in Control group, the proportion of eosinophils and FeNO level increased in BA and RE group, which were more pronounced in BA group. Downregulated mRNA level of TIPE2, and upregulated TF were detected in BA and RE groups compared to those of Control group, and the expression changes were more significant in the former group. Enzyme-linked immunosorbent assay (ELISA) data showed that serum levels of IL-1β and IL-6 were significantly elevated in BA and RE groups in comparison to Control group, especially BA group. In addition, protein level of Th1 cells was downregulated, while that of Th2 was upregulated in BA group and RE group compared to those of Control group, and a more significant change was observed in BA group compared to that of RE group.. In patients with acute exacerbation of BA, the expression of TIPE2 in PBMCs declined, while that of TF rose, which were negatively correlated with each other. Moreover, the proportion of Th1 cells declined in patients with acute exacerbation of BA, indicating that it is associated with the lung function, inflammatory level and proportion of eosinophils.

Topics: Acute Disease; Adult; Aged; Asthma; Female; Humans; Interleukin-1beta; Interleukin-6; Intracellular Signaling Peptides and Proteins; Leukocytes, Mononuclear; Male; Middle Aged; Th1 Cells; Thromboplastin

To study the change in endogenous hydrogen sulfide (H2S) in patients with acute pancreatitis and its relationship to coagulation function.. A prospective case control study was conducted. Forty patients with mild acute pancreatitis (MAP group) and 40 with severe acute pancreatitis (SAP group) admitted to Yiwu Central Hospital in Zhejiang Province from December 2002 to March 2015 were enrolled. Forty healthy persons served as control (healthy control group). Blood was collected to determine the levels of H2S, blood coagulation factor Ⅷ (FⅧ), von Willebrand factor (vWF), plasminogen (PLG), antithrombin (AT), platelet count (PLT), tissue factor (TF), tumor necrosis factor-α (TNF-α), and protease activated receptor-1 (PAR-1). The correlations among the above parameters were analyzed.. There was no statistical significance in sex, age, body weight and time of disease among three groups, indicating it was comparable among the groups. Compared with healthy control group, the levels of H2S, FⅧ, vWF, TF, TNF-α, and PAR-1 in MAP and SAP groups were significantly elevated [H2S (μmol/L): 67.42±6.34, 112.47±12.69 vs. 42.57±4.18, FⅧ: (67.5±5.8)%, (82.3±4.7)% vs. (57.2±6.4)%, vWF: (112.6±9.7)%, (142.5±12.5)% vs. (76.4±8.2)%, TF (ng/L): 45.27±4.34, 64.76±6.25 vs. 18.15±1.89, TNF-α (ng/L): 197.67±13.62, 324.72±25.54 vs. 20.08±2.57, PAR-1 (fluorescence intensity): 32.16±4.43, 56.12±7.07 vs. 12.27±2.12, all P < 0.01], and PLG and AT activity were significantly decreased [PLG: (52.4±4.7)%, (36.7±3.2)% vs. (62.1±5.6)%, AT: (43.2±6.9)%, (35.5±5.4)% vs. (53.6±6.1)%, all P < 0.01]. The changes in the parameters in SAP group were more remarkable than those in MAP group (all P < 0.01). PLT in SAP group was significantly lower than that in healthy control and MAP groups (×109/L: 8.5±1.1 vs. 15.7±2.8, 12.4±1.9, both P < 0.01). H2S was positively correlated with FⅧ, vWF, TF, TNF-α, and PAR-1 (r value was 0.56, 0.61, 0.72, 0.66, 0.64, respectively, all P < 0.01), and it was negatively correlated with PLG and AT (r value was -0.64, -0.57, both P < 0.01).. As an inflammatory factor, endogenous H2S deteriorates coagulation function in patients with acute pancreatitis by up-regulating TF, TNF-α, and PAR-1.

Topics: Acute Disease; Antithrombin III; Blood Coagulation; Case-Control Studies; Factor VIII; Humans; Hydrogen Sulfide; Pancreatitis; Prospective Studies; Thromboplastin; Tumor Necrosis Factor-alpha; Up-Regulation; von Willebrand Factor

This study was conducted to investigate the variation of monocyte chemoattrant protein-1 (MCP-1) and tissue factor (TF) in elderly patients with acutely exacerbated chronic obstructive pulmonary disease (AECOPD) and their clinical significance.. Serum specimens were obtained from 49 AECOPD. Patients and 30 health controls, with mean age of 76.1 ± 10.2 and 62.8 ± 6.5 years. Patients in AECOPD group were further grouped into two subgroups, with high or normal procaletonin (PCT) levels. Plasma TE, MCP-1 and PCT were qualified by enzyme-linked immunosorbent assay (ELISA).. TF and MCP-1 were found to be higher in AECOPD patients than in health people (p < 0.01), and TF was linearly and positively related to MCP-1. In the subgroups TF was significantly higher in patients with higher PCT than those with normal PCT (p < 0.05).. In AECOPD patients blood cells are activated to hypercoagulation state, particularly when their PCT level is high. Extrinsic pathway activated by TE plays important role in development of the hypercoagulation state. Our results indicate that plasma TF level was positively correlated to the level of MCP-1. This suggests that monitoring of plasma TF and MCP-1 levels in AECOPD patients could be a very useful way to prevent and cure blood hypercoagulability, cardiovascular and cerebrovascular thrombotic diseases.

Topics: Acute Disease; Age Factors; Aged; Aged, 80 and over; Case-Control Studies; Chemokine CCL2; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Thromboplastin

The two sides of trauma-induced coagulopathy, the hypocoagulable and the hypercoagulable states, are poorly understood. To identify potential mechanisms for venous thromboembolism and bleeding after acute trauma, we estimated changes in circulating procoagulant microparticles (MPs) and thrombin activity during hospitalization for trauma.. Whole blood was collected by venipuncture into 3.2% trisodium citrate at 0, 6, 12, 24, and 72 hours after injury and discharge. Platelet-poor plasma was harvested and stored at -80°C until analysis. Thrombin generation was determined using the calibrated automated thrombogram (CAT), reported as lag time (minutes), peak height (nM thrombin), and time to reach peak height (ttPeak, minutes). The concentration of total procoagulant MPs (number/μL) was measured by flow cytometry. Data are presented as median (interquartile range [IQR]).. Among 443 trauma patients (1,734 samples; Injury Severity Score [ISS], 13.0 [IQR, 6.0-22.0]; hospital length of stay, 4.0 days [IQR, 2.0-10.0]; age, 48 years [IQR, 28-65]; 70.7% male; 95% with blunt mechanism; mortality, 3.2%), no discernable patterns in thrombin generation or MP concentration were observed over time. The peak height and MPs were significantly different from healthy volunteers and were 337 nM (IQR, 285-395) and 400/μL plasma (IQR, 211-772), respectively. Extreme (defined as highest or lowest 5%) values reflecting a possible "hypercoagulable state" (lag time ≤ 1.98, peak height ≥ 486.2, ttPeak ≤ 3.61, and total procoagulant MP ≥ 2,278) were reached within 12 hours after acute trauma, while extreme values representing a possible "hypocoagulable state" (lag time ≥ 18.6, peak height ≤ 17.8, and ttPeak ≥ 29.45) were not reached until 1 day to 3 days.. Although there was no predictable pattern of coagulopathy observed in each patient after trauma, those who reached extreme values did so relatively early after injury. These findings should be taken into account when designing risk model tools involving coagulation laboratory parameters.. Epidemiologic study, level III.

Topics: Acute Disease; Adult; Aged; Biomarkers; Blood Coagulation Tests; Blood Transfusion; Cell-Derived Microparticles; Cohort Studies; Emergency Service, Hospital; Female; Flow Cytometry; Follow-Up Studies; Humans; Injury Severity Score; Male; Middle Aged; Prospective Studies; Risk Assessment; Survival Analysis; Thrombin; Thromboplastin; Treatment Outcome; Wounds and Injuries

Tissue factor (TF) is the main in-vivo initiator of blood coagulation. Microparticles (MPs) are small procoagulant membrane vesicles. Elevated TF-bearing MPs have been found in different prothrombotic conditions and MP-associated TF activity may contribute to the pathogenesis of unprovoked deep vein thrombosis (DVT).. To determine MP-TF activity levels at diagnosis of DVT and at four additional time points during the course of one year in a well-defined group of patients with unprovoked DVT of the lower limb.. In this study, 41 patients with acute unilateral symptomatic and unprovoked DVT of the lower limb were included and followed for 1 year. Venous blood samples for determination of MP-TF activity were drawn at diagnosis of acute DVT, and 1-, 3-, 6-, and 12 months later. In addition, 10 young and healthy control subjects were included.. The median MP-TF activity was 0.06 pg/mL (25th-75th percentile: 0.0-0.53) in patients with acute DVT and 0.18 pg/mL (0.07-0.33) in healthy controls, and did not differ significantly (p=0.35). No significant changes in MP-TF activity were found in the follow-up measurements. MP-TF activity did also not differ significantly between patients with proximal- or distal DVT and between those with- or without residual DVT after 6 months.. MP-TF activity is low at the acute event in patients with unprovoked DVT of the lower limb and remains unchanged during the course of the disease. Our data do not support the hypothesis that TF-bearing MPs play a determining role in the pathogenesis of unprovoked DVT.

Topics: Acute Disease; Adult; Blood Coagulation; Cell-Derived Microparticles; Female; Humans; Male; Middle Aged; Prospective Studies; Thromboplastin; Venous Thrombosis

This study was performed to gain further insight in pro- and anticoagulant characteristics of leukocytes in acute coronary syndrome (ACS). For this purpose, patients presenting on the emergency department (ED) with anginal chest pain were included in this study. In peripheral blood, procoagulant tissue factor (TF) expression was measured in the different blood-borne phagocytes, i.e. neutrophilic granulocytes and the three different monocyte subsets based on expression of CD14 and CD16. Simultaneously, intracellular presence of platelet-(CD41) and/or endothelial cell-remnants (CD62e) was analysed in these different leukocyte subsets. Neutrophils showed a weak intracellular staining of CD62e and CD41 that increased with severity of ACS. Monocytes, and especially the classical (CD14++CD16-) and intermediate monocytes (CD14++CD16+) showed a clear and significant increase in intracellular CD41-staining after coronary damage. The different monocyte subsets showed an increase in expression of TF in severe ACS. Finally, it appeared that also neutrophils showed a significant increase in expression of TF on their membrane. In conclusion, this study showed an increased intracellular staining in blood-borne phagocytes for CD62e and CD41 in patients with ACS compared to non-cardiac related control patients. This indicates that at least in the acute phase of ACS phagocytosis of platelet and endothelial cell-remnants is increased. These data support the recent hypothesis that neutrophils protect against further thrombotic processes by clearing platelet and endothelial cell-remnants. In addition, this study shows that the different monocyte subsets are also involved in this process. Furthermore, both monocytes and neutrophils show increased TF expression in ACS.

Topics: Acute Coronary Syndrome; Acute Disease; Adult; Aged; Aged, 80 and over; Antigens, CD; Apoptosis; Blood Cells; Blood Coagulation; Cells, Cultured; Endothelial Cells; Female; Humans; Male; Middle Aged; Phagocytes; Phagocytosis; Thromboplastin; Young Adult

We tested the hypotheses that an increase in systemic thrombin activity occurs in both disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype and in acute coagulopathy of trauma shock (ACoTS), and that the patients diagnosed as having ACoTS overlap or are identical with those diagnosed as having DIC.. We made a prospective study of 57 trauma patients, including 30 patients with DIC and 27 patients without DIC. Patients with ACoTS, defined as a prothrombin time ratio >1.2, were also investigated. We included 12 healthy volunteers as controls. The levels of soluble fibrin, antithrombin, prothrombinase activity, soluble thrombomodulin, and markers of fibrin(ogen)olysis were measured on days 1 and 3 after the trauma. The systemic inflammatory response syndrome and the Sequential Organ Failure Assessment were scored to evaluate the extent of inflammation and organ dysfunction.. Patients with DIC showed more systemic inflammation and greater Sequential Organ Failure Assessment scores and were transfused with more blood products than the patients without DIC. On day 1, normal prothrombinase activity, increased soluble fibrin, lesser levels of antithrombin, and increased soluble thrombomodulin were observed in patients with DIC in comparison with controls and non-DIC patients. These changes were more prominent in patients with DIC who met the overt criteria for DIC established by the International Society on Thrombosis and Haemostasis. Multiple regression analysis showed that antithrombin is an independent predictor of high soluble fibrin in DIC patients. Greater levels of fibrin and fibrinogen degradation products, D-dimer, and the fibrin and fibrinogen degradation products/D-dimer ratio indicated increased fibrin(ogen)olysis in DIC patients. Almost all ACoTS patients overlapped with the DIC patients. The changes in the measured variables in ACoTS patients coincided with those in DIC patients.. Normal prothrombinase activity and insufficient control of coagulation give rise to systemic increase in thrombin generation and its activity in patients with DIC with the fibrinolytic phenotype at an early phase of trauma. The same is true in patients with ACoTS, and shutoff of thrombin generation was not observed.

Topics: Acute Disease; Adult; Antithrombins; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Female; Humans; Male; Middle Aged; Peptide Fragments; Prospective Studies; Prothrombin; Shock, Traumatic; Thrombin; Thromboplastin

Circulating tissue factor positive microparticles (MPTF) were reported in a wide range of diseases with thrombotic tendency. Though D-dimer assay had a high negative predictive value for deep venous thrombosis (DVT) recurrence, there are currently no reliable positive predictors for recurrent DVT. We therefore quantified MPTF in patients with acute recurrent DVT to determine whether MPTF levels could be used to predict recurrent DVT.. Microparticles (MPs) were isolated from plasma of initial DVT patients (n=25), recurrent DVT patients (n=25) and sex- and age-matched healthy individuals (n=25), stained with annexin V, cell-specific monoclonal antibodies (MoAbs) and a MoAb directed against tissue factor (TF), and analyzed by flow cytometry. We also determined the plasma procoagulant activity with a Human TF Chromogenic Activity Assay Kit.. We found total MPTF to be elevated in recurrent DVT patients versus normal individuals (P=0.001). The number of monocyte-derived MPTF in both initial and recurrent DVT was higher than in normal individuals (P<0.01, respectively). The platelet and endothelial cell derived MPTF in recurrent DVT were significantly increased relative to other MPTF (P<0.05), although there was no difference between initial DVT patients and normal individuals. We demonstrated elevated procoagulant activity of platelet-free plasma in DVT patients relative to normal individuals, and a positive correlation with MPTF.. The elevated MPTF could be a potentially predictor for DVT recurrence. Further studies are needed to validate its sensitivity and specificity.

Topics: Acute Disease; Adult; Blood Cells; Cell-Derived Microparticles; Coagulants; Female; Humans; Male; Middle Aged; Prognosis; Thromboplastin; Venous Thrombosis

Severe acute pancreatitis (SAP)-associated liver injury is systematically one of main pathophysiological events due to SAP development. The aim of the study was to investigate whether fgl2 prothrombinase is involved in SAP-associated liver injury.. Microthrombosis in the liver of rats with SAP was observed by Masson staining. Fgl2 prothrombinase expression in the liver of rats with SAP was analyzed by real-time PCR and immunohistochemistry methods.. Fgl2 prothrombinase gene and protein expression in SAP group were significantly up-regulated compared to sham-operation (SO) group. Immunohistochemistry staining showed that fgl2 prothrombinase was localized speci?cally to the endothelial cells of intrahepatic veins and hepatic sinusoids. Furthermore, Masson staining demonstrated that the proportion of hepatic microthrombotic capillaries in SAP group were evidently increasing in comparison to SO group and closely correlated with fgl2 expression (r=0.948, p<0.01 ). In addition, there was a positive correlation between fgl2 expression and the severity of hepatocellular injury as indicated by hepatic pathological grade (r=0.704, p<0.01).. Fgl2 prothrombinase may contribute to microthrombosis in SAP-associated liver injury, thus resulting in hepatic microcirculatory disturbance and measurement of fgl2 may be used as a helpful biomarker in the prognosis of the severity of hepatic pathological injury in SAP.

Topics: Acute Disease; Alanine Transaminase; Animals; Aspartate Aminotransferases; Immunohistochemistry; Liver; Liver Diseases; Male; Pancreatitis; Rats; Rats, Sprague-Dawley; Thromboplastin; Thrombosis

Antipsychotic treatment has been repeatedly found to be associated with an increased risk for venous thromboembolism in schizophrenia. The extent to which the propensity for venous thromboembolism is linked to antipsychotic medication alone or psychosis itself is unclear. The objective of this study was to determine whether markers of thrombogenesis are increased in psychotic patients who have not yet been treated with antipsychotic medication.. We investigated the plasma levels of markers indicating activation of coagulation (D-dimers and Factor VIII) and platelets (soluble P-selectin, sP-selectin) in an antipsychotic-naive group of fourteen men and eleven women with acute psychosis (age 29.1 ± 8.3 years, body mass index 23.6 ± 4.7), and twenty-five healthy volunteers were matched for age, gender and body mass index.. D-dimers (median 0.38 versus 0.19 mg/l, mean 1.12 ± 2.38 versus 0.28 ± 0.3 mg/l; P = 0.003) and sP-selectin (median 204.1 versus 112.4 ng/ml, mean 209.9 ± 124 versus 124.1 ± 32; P = 0.0005) plasma levels were significantly increased in the group of patients with acute psychosis as compared with healthy volunteers. We found a trend (median 148% versus 110%, mean 160 ± 72.5 versus 123 ± 62.5; P = 0.062) of increased plasma levels of factor VIII in psychotic patients as compared with healthy volunteers.. The results suggest that at least a part of venous thromboembolic events in patients with acute psychosis may be induced by pathogenic mechanisms related to psychosis rather than by antipsychotic treatment. Finding an exact cause for venous thromboembolism in psychotic patients is necessary for its effective treatment and prevention.

Topics: Acute Disease; Adolescent; Adult; Antipsychotic Agents; Biomarkers; Case-Control Studies; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; P-Selectin; Psychotic Disorders; Schizophrenia; Thromboplastin; Venous Thromboembolism

Recent studies have suggested that circulating inflammatory cells augment the growth of thrombus in acute coronary syndrome (ACS). We therefore immunohistochemically analyzed thrombi in aspirates obtained from patients immediately after the onset of ACS.. Two hundred twenty samples were studied. Total thrombus area, white thrombus area, and red thrombus area were measured. As antibodies in immunohistochemical staining, myeloperoxidase (MPO), CD66b, CD68, p-selectin, tissue factor (TF) and PAI-1 were employed respectively.. The ratios of areas of red and white thrombi correlated with whole sample areas of enlarged thrombi (r = 0.48, p < 0.001). The immunohistochemical findings revealed granulocytes and macrophages aggregated around p-selectin-positive platelets that shared the boundary between white and red thrombi, a region where MPO and CD66b expression was abundant in neutrophils. The ratios (%) of MPO- and CD66b-positive cells significantly correlated with whole sample areas (r = 0.50; p < 0.001 and r = 0.49; p < 0.001, respectively). Neutrophils and macrophages within thrombi were positive for TF and PAI-1. Along the boundary between red and white thrombi, TF and PAI-1 positivity coincided with MPO-, CD66b- and CD68-positive cells. The ratios of cells positive for both TF and PAI-1 in this area significantly correlated with the whole sample area (r = 0.43, p < 0.001 and r = 0.60, p < 0.001, respectively).. These results suggested that enhanced activation of peripheral neutrophils together with increased TF and PAI-1 expression might comprise a considerable portion of thrombus enlargement.

Topics: Acute Coronary Syndrome; Acute Disease; Adult; Aged; Aged, 80 and over; Female; Humans; Immunohistochemistry; Inflammation Mediators; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Thromboplastin; Thrombosis

The patient was a 36-year-old man who had been aware of a mild bleeding tendency since childhood, but did not show any history of severe bleeding. After lumbar epidural block was performed for pain caused by lumbar disc herniation, the patient developed paraplegia due to an acute epidural hematoma, and rectovesical disorder. He was admitted to our hospital, and wide fenestration and hematoma evacuation were performed. Because of persistent bleeding, reoperation was performed to achieve hemostasis. Although factor VIII antigen was 138%, its activity was decreased to 18% of normal. A diagnosis of cross-reacting material positive mild hemophilia A was made. Postoperative injection of a factor VIII preparation resulted in complete hemostasis. The activated partial thromboplastin time was within normal range. A thrombin generation test showed reduced endogenous thrombin potential, peak thrombin levels, and prolonged time-to-peak levels. The thrombin generation test, which allows comprehensive assessment of the coagulation profile, was useful for diagnosis and treatment of this case.

Topics: Acute Disease; Adult; Analgesia, Epidural; Biomarkers; Blood Coagulation Tests; Hematoma, Epidural, Spinal; Hemophilia A; Humans; Male; Thrombin; Thromboplastin

Ischemic renal injury is a formidable clinical problem, the pathophysiology of which is incompletely understood. As the Na/H exchanger-3 (NHE3) mediates the bulk of apical sodium transport and a significant fraction of oxygen consumption in the proximal tubule, we examined mechanisms by which ischemia-reperfusion affects the expression of NHE3. Ischemia-reperfusion dramatically decreased NHE3 protein and mRNA (immunohistochemistry, immunoblot, and RNA blot) in rat kidney cortex and medulla. The decrease in NHE3 protein was uniform throughout all tubules, including those appearing morphologically intact. In the kidney cortex, a decrease in NHE3 surface protein preceded that of NHE3 total protein and mRNA. Kidney homogenates from rats exposed to mild renal ischemia-reduced cell surface NHE3 protein expression in opossum kidney cells in vitro, whereas homogenates from animals with moderate-to-severe ischemia reduced both total NHE3 protein and mRNA. The decrease in total NHE3 protein was dependent on the proteasomal degradation associated with NHE3 ubiquitylation measured by coimmunoprecipitation. The transferable factor(s) from the ischemic homogenate that reduce NHE3 expression were found to be heat sensitive and to be associated with a lipid-enriched fraction, and did not include regulatory RNAs. Thus, transferable factor(s) mediate the ischemia-reperfusion injury-induced decrease in NHE3 of the kidney.

Topics: Acute Disease; Animals; Cells, Cultured; Immunohistochemistry; Opossums; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Thromboplastin

Atrial fibrillation (AF) is associated with a prothrombotic state. The aim of this study was to analyze platelet activation and tissue factor (TF) induction in mononuclear cells (MNCs) and granulocytes downstream of cell-cell interactions in AF patients.. Blood samples were obtained from patients with paroxysmal AF (n=14) at sinus rhythm and at 15 min after induction of AF during an electrophysiological study, and from control subjects (n=13) and patients with chronic AF (n=14) in the outpatient clinic. The expression of CD41a, CD42b, P-selectin, and P-selectin glycoprotein ligand-1 (PSGL-1) on platelets and microparticles in platelet-rich plasma (PRP), and on MNCs and granulocytes in whole blood were examined by flow cytometry. MNC-platelet interaction was investigated ex vivo.. The expression of CD41a and CD42b on platelets and microparticles was comparable between the control and chronic AF groups, and unchanged after AF induction. Acute induction of AF significantly increased the expression of P-selectin on platelets and microparticles, and to a similar extent, P-selectin-positive MNCs and granulocytes and P-selectin/PSGL-1-double positive MNCs. However, AF induction had no effect on platelet-MNC interactions ex vivo or TF expression on MNCs and granulocytes. Only patients with chronic AF showed platelet-MNC interaction ex vivo and TF overexpression on MNCs.. Acute-onset AF activates platelets within minutes to initiate platelet-MNC interaction. The subsequent platelet binding induced TF expression in patients with chronic AF. These findings support the efficacy of anticoagulant therapeutics in chronic AF and suggest the underlying utility of antiplatelet therapeutics in early phase of AF occurrence.

Topics: Acute Disease; Atrial Fibrillation; Blood Platelets; Case-Control Studies; Cell Communication; Chronic Disease; Female; Flow Cytometry; Granulocytes; Humans; Leukocytes, Mononuclear; Male; Middle Aged; P-Selectin; Platelet Activation; Platelet Glycoprotein GPIb-IX Complex; Platelet Membrane Glycoprotein IIb; Thromboplastin

To explore the changes and clinical significances of plasma D-dimer, factor X and tissue factor in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and analyze the in-depth changes of these indicators in AECOPD with co-current deep venous thrombosis (DVT).. A total of 56 AECOPD patients were divided into the DVT and non-DVT subgroups (n = 28 each). And 60 normal control subjects were recruited according to age and gender. For each subject, 2.7 ml whole blood was drawn and then the plasma levels of D-dimer, factor X and tissue factor were detected. The results were statistically analyzed with the software SPSS 13.0. And the analysis of variance was performed between the groups.. There was no significant difference between the distribution of the AECOPD group and the control group by gender and age. Therefore two groups were comparable. And in the AECOPD group, there was no significant difference between the distribution of DVT and non-DVT subgroups by gender and age. Therefore these two subgroups were comparable as well. The value of D-dimer in the AECOPD patients was significantly higher than that in the normal control [(0.76 ± 0.30) vs (0.29 ± 0.11) mg/L, P < 0.01]; and in the AECOPD group, the value of D-dimer in the DVT subgroup was significantly higher than that in the non-DVT subgroup [(0.85 ± 0.29) vs (0.67 ± 0.28) mg/L, P < 0.05]. In the AECOPD group, the value of tissue factor was (238 ± 68) mg/L and the value of factor X (1181 ± 337) mg/L. While in the normal control group, the values were (124 ± 30) and (998 ± 260) mg/L respectively. As for tissue factor and factor X, there were significant differences between two groups (all P < 0.01). Yet in AECOPD patients, neither indicator had significant differences between the DVT and non-DVT subgroups (all P > 0.05).. The blood of AECOPD patients is in a hypercoagulatory state. And an obvious rise in their plasma level of D-dimer suggests that it may be complicated with DVT.

Topics: Acute Disease; Aged; Aged, 80 and over; Blood Coagulation; Case-Control Studies; Factor X; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Thromboplastin; Venous Thrombosis

Being a central link between inflammation and coagulation, tissue factor (TF) and its inhibitor (TFPI) might be associated with the severity of acute pancreatitis (AP) and the development of organ failure (OF).. The study comprises 9 severe AP patients with OF and 24 reference patients (11 mild AP and 13 severe AP without OF). Plasma samples were collected on admission. TF-induced thrombin generation in plasma samples was studied using the thrombogram method. In vivo thrombin generation was estimated by prothrombin fragment F1+2. Free and total TFPI levels were measured. To evaluate coagulation status the activated partial thromboplastin time, prothrombin time, platelet count, D-dimer, fibrinogen, antithrombin (AT) 3 and protein C (PC) were determined.. There was no significant difference in F1+2 levels between the patient groups. Patients with severe AP tended to show low platelet counts, PC and AT3 levels, and high D-dimer levels. In 11 patients the standard TF stimulation did not trigger thrombin generation in the thrombogram. All deaths occurred in these patients. Free TFPI levels and free/total TFPI ratios were significantly higher in these patients and in non-survivors.. Failure of TF-initiated thrombin generation in the thrombogram assay explained by high levels of circulating free TFPI may be associated with OF and mortality in AP. and IAP.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Coagulation; Blood Coagulation Tests; Cells, Cultured; Female; Finland; Humans; Lipoproteins; Male; Middle Aged; Multiple Organ Failure; Pancreatitis; Platelet Count; Survival Rate; Thrombin; Thromboplastin

The International Normalised Ratio (INR)/International Sensitivity Index (ISI) system was developed as a way to standardise the prothrombin time during the monitoring of patients undergoing oral anti-coagulant therapy with vitamin K antagonists. The wide acceptance of the INR has led to its use as one of three parameters used in the Model for End stage Liver disease (MELD) scoring system to aid the prioritisation of patients for liver transplant. Literature published recently has highlighted the potential inadequacy of the INR system in this context. Our aim was to investigate the degree of difference between INR values calculated using an ISI derived from warfarinised patients and those calculated using an ISI derived from patients with liver disease. Prothrombin times from 60 patients with liver disease were determined using three working thromboplastin reagents; Innovin, Thromborel S and Thromboplastin C and two reference thromboplastins; rTF/95 and RBT/05. All thromboplastin reagents tested had standard international sensitivity indices (ISIs) assigned following calibration with patients on oral anticoagulant therapy (ISIvka). As a result of the new calibration each of the working thromboplastin reagents was assigned a specific "liver patient" ISI. Two INR values were calculated for each thromboplastin patient involved in the calibration. A comparison of the mean INRliver with INRvka showed a statistically significant difference between the two values (p<0.0001). A similar relationship existed for INRs on a further 20 patients with liver disease whose plasmas were not used to derive the ISIliver. This difference led to a change in the final MELD score and could therefore affect the prioritisation and management of these patients.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Blood Coagulation; Calibration; Chronic Disease; Humans; International Normalized Ratio; Liver; Liver Diseases; Liver Transplantation; Predictive Value of Tests; Prothrombin Time; Recombinant Proteins; Severity of Illness Index; Thromboplastin; Warfarin

to study tissue factor (TF) in acute pancreatitis and evaluate the role of TF as a predictive marker of severity.. forty-nine consecutive patients admitted to Lund University Hospital, fulfilling the criteria of predicted severe acute pancreatitis (AP), were recruited prospectively between 2002 and 2004. Blood samples for TF analyses were drawn at inclusion in the study and 12 h, 1 d and 3 d later.. twenty-seven patients developed mild AP, and 22 patients severe AP. At inclusion in the study, the groups were comparable with respect to gender, aetiology, Acute Physiology and Chronic Health Evaluation II score, and duration of pain. At inclusion in the study and at 12 h, TF was higher in the severe AP group (P = 0.035 and P = 0.049, respectively). After 1 and 3 d, no differences in TF levels were noted. Interleukin (IL)-6 was significantly higher in the severe AP group at all of the studied time points. C-reactive protein (CRP) was significantly higher in the AP group at 1 and 3 d. In receiver operating characteristic-curves, the area under the curve (AUC) for TF was 0.679 (P = 0.035) at inclusion in the study, and a cut off level for TF of 40 pg/mL showed a sensitivity of 71% and a specificity of 67%, whereas corresponding AUC for IL-6 was 0.775, P = 0.001, and for CRP was 0.653. IL-6 showed better AUC-values than TF at all time points studied.. TF-levels are raised early in severe AP. TF as an early predictive marker of severe AP is superior to CRP, but inferior to IL-6.

Topics: Acute Disease; Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Female; Humans; Male; Middle Aged; Pancreatitis; ROC Curve; Thromboplastin

In acute pancreatitis (AP), disorders of the coagulation-fibrinolysis system are closely related to the severity of the AP and to organ dysfunctions. We previously reported that plasma tissue factor (TF) levels were elevated in patients with AP, particularly in cases of alcoholic AP with pancreatic necrosis. Tissue factor pathway inhibitor (TFPI) is a key regulator of the extrinsic coagulation pathway, but plasma TFPI levels in AP have not yet been determined.. Plasma TFPI concentrations were measured by enzyme-linked immunosorbent assay in 44 patients with AP on admission. The relationships between AP severity, pancreatic necrosis, organ dysfunction, infection, and prognosis were analyzed.. Plasma TFPI levels were increased in AP patients compared with healthy volunteers. Plasma TFPI levels in severe AP were greater than those in mild AP. Plasma TFPI levels significantly correlated with Ranson score, APACHE II score, and Japanese severity score. Plasma TFPI levels in patients with pancreatic necrosis were greater than those in patients without pancreatic necrosis. Plasma TFPI levels in patients with organ dysfunction were greater than those in patients without organ dysfunction. In patients with pancreatic necrosis, the TF/TFPI ratios in non-survivors were lower than those in survivors. Moreover, the mortality rates in patients with TF/TFPI ratios > or = 2.0 were lower than those in patients with TF/TFPI ratios < 2.0.. Plasma TFPI levels were significantly increased in patients with AP, and the elevation was markedly related to the severity, pancreatic necrosis and organ dysfunctions. The imbalance of TF and TFPI may influence the disease state and thereby the prognosis in AP.

Topics: Acute Disease; APACHE; Biomarkers; Blood Coagulation; Case-Control Studies; Female; Humans; Lipoproteins; Male; Middle Aged; Multiple Organ Failure; Necrosis; Pancreatitis; Prognosis; Severity of Illness Index; Thromboplastin

This study examined the expressions of human serum tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their clinical significance. The serum TF and TFPI levels were detected by ELISA in 28 allo-HSCT recipients before and after the transplantation and the changes of TF and TFPI levels were dynamically monitored at different phases of the disease. No significant differences in the serum TF and TFPI levels were found in allo-HSCT recipients in the absence of aGVHD or with grade I aGVHD before and after the transplantation. The levels of serum TF and TFPI were substantially increased in the patients with gradeII aGVHD at the peak of aGVHD (P<0.05) and they were even higher in the patients with grade III-IV aGVHD (P<0.01). When the conditions became stable after treatment with immunosuppressive agents, the serum TFPI level was decreased to the baseline level (P>0.05) and the TF level was lowered but still higher than the baseline level (P<0.05). It was concluded that the levels of serum TF and TFPI were increased significantly in the patients with grade II-IV aGVHD after allo-HSCT and decreased markedly after the treatment. Monitoring the levels of serum TF and TFPI in the patients with allo-HSCT is important to predict the occurrence, outcome and prognosis of aGVHD.

Topics: Acute Disease; Adolescent; Adult; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Lipoproteins; Male; Middle Aged; Prognosis; Thromboplastin; Transplantation, Homologous; Young Adult

This study was purposed to explore the significance of tissue factor (TF), tissue factor pathway inhibitor (IFPI) and interleukin-1beta (IL-1beta) in the evaluation of development, curative effect and prognosis of AL patients. ELISA was used to detect the levels of TF, TFPI and IL-1beta in plasma of 20 healthy individuals and 24 newly diagnosed AL patients. All the three indications of patients were measured in different stages including pre-chemotherapy phase, at 72 hours after chemotherapy, complete remission phase. The results showed that as compared with normal control, levels of TF, TFPI and IL-1beta in plasma of AL patients during pre-chemotherapy phase were higher (p < 0.01); as compared with pre-chemotherapy phase, levels of TF, IL-1beta were elevated at 72 hours after -chemotherapy (p < 0.05). However, the levels of TFPI was much lower than that of 72 hours after chemotherapy (p < 0.01). 16 out of 24 patients got complete remission, there was no difference of TF, TFPI and IL-1beta between complete remission group and normal control group. It is concluded that the levels of TF, TFPI and IL-1beta in plasma can be used as the indicators for understanding clinical features, evaluating disease status and predicting prognosis in acute leukemia patients.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Child; Female; Humans; Interleukin-1beta; Leukemia; Lipoproteins; Male; Middle Aged; Thromboplastin; Young Adult

Circulating procoagulant microparticles are reliable markers of vascular damage. The microparticle phenotypes provide additional information reflecting the nature of cell injury. This study assessed procoagulant microparticle levels and phenotypes in the diagnosis of acute allograft rejection after heart transplantation.. Microparticles were prospectively investigated in the venous blood of 64 heart transplant patients, 23 with allograft rejection mainly of low score, and 41 without a rejection episode. Plasma concentrations of cytokines, cytoadhesins, and platelet activation markers were determined.. By univariate analysis, the mean time elapsed from heart transplant, cold ischemia time, E-selectin-, Fas- and tissue factor-bearing microparticles were associated with allograft rejection. By multivariate analysis, E-selectin-microparticle levels appeared independently associated with allograft rejection, even when other significant variables were included in the model (odds ratio, 9.8; 95% confidence interval, 1.36-71.4; p = 0.023).. The pattern of procoagulant microparticles released during acute allograft rejection suggests endothelial cell activation and Fas-mediated apoptosis. E-selectin-bearing microparticles appeared as an independent marker of acute allograft rejection that was still informative after adjustment for graft characteristics.

Topics: Acute Disease; Apoptosis; Biomarkers; Biopsy; Cytokines; E-Selectin; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; fas Receptor; Female; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Male; Middle Aged; Platelet Activation; Prognosis; Prospective Studies; Receptors, Cytoadhesin; Thromboplastin; Transplantation, Homologous; Ultracentrifugation

Different signaling routes seem to be simultaneously triggered in leukemia, with distinct and overlapping activities. To analyze if altered signals are coordinated and to evaluate their effect on this disease, we have investigated in acute myeloid leukemia samples (AML) the expression and activation status of procoagulant/proangiogenic tissue factor receptor (TF), angiogenic protein VEGF, its cell surface receptor, KDR, and two intracellular proteins involved in their regulation: extracellular regulated kinase (ERK1/2) and nuclear factor kappa-B (NFkappaB). Significantly higher mRNA and protein levels of VEGF, KDR, and TF were found in the AML samples versus controls. Enhanced ERK phosphorylation and NFkappaB activation in most AML samples were also found. In vitro MEK/ERK and NFkappaB-binding activity blockade suppressed the constitutive expression of TF, VEGF, and KDR. Anti-TF antibody treatment significantly suppressed VEGF and KDR expression as well as ERK activation, suggesting that TF expressed by AML cells may be both a regulatory target and a mediator of tumor-associated angiogenesis. Patients showing parallel activation of the studied proteins trended to exhibit higher incidence of fatal outcome. Our results show a coordinated deregulation of cellular receptors, proangiogenic factors, and intracellular pathways in leukemia cells, which may help to design mechanism-based combinations of single transduction-related therapies.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Angiogenic Proteins; Case-Control Studies; Child, Preschool; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid; Male; Middle Aged; NF-kappa B; Prognosis; Receptors, Cell Surface; Signal Transduction; Thromboplastin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Several studies have indicated association between hematologic markers and increased risks of cerebrovascular disease, but few reports referred to their roles together. We studied plasma levels of 16 hematologic markers in 50 cases diagnosed as acute cerebral infarction (ACI) and 54 hospital control subjects. Plasma levels of thrombomodulin, fibrinogen, and activity of tissue factor (aTF) were significantly higher in cases than in control subjects (P < .001, P < .01, and P < .05, respectively). Multivariate logistic regression analysis showed that hypertension and high plasma levels of thrombomodulin, fibrinogen, and aTF were significantly associated with presence of ACI (odds ratio [OR], 143.74, P < .001; OR, 2.05, P < .05; OR, 2.09, P < .05; OR, 1.02, P < .05, respectively). Our findings indicate that hypertension and elevation of plasma thrombomodulin, fibrinogen, and aTF are independent risk factors for ACI.

Topics: Acute Disease; Adult; Aged; Cerebral Infarction; Cholesterol, HDL; Female; Fibrinogen; Humans; Male; Middle Aged; Protein C; Risk Factors; Thrombomodulin; Thromboplastin

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

There is no biological marker that can accurately predict the prognosis after an acute ischaemic stroke. The main objective of this study was to evaluate the prognostic value of tissue factor (thromboplastin) levels in first ischaemic stroke.. This was a prospective study of all patients with first ischaemic stroke conducted from October 2003 to February 2004. Plasma for tissue factor levels was kept at -80 degrees Celsius and was analysed at the end of the study period by an independent person. The activities of daily living (ADL) were assessed by using the Barthel index (BI) on admission and at one month after the stroke onset. Any death or recurrent events were recorded.. 50 patients were recruited into the study. The median tissue factor level was 184.5 +/- 97.3 pg/ml. Only age (p-value is 0.027) and middle cerebral artery (MCA) infarcts (p-value is 0.038) were found to be significant independent predictors for severe disability at one month with BI equal to or less than 9. There was no correlation of tissue factor level with BI at one month post-stroke (r equals -0.028, p-value is 0.846) and there was also no significant relationship between levels of tissue factor and recurrent events (p-value is 0.41).. There is no correlation between tissue factor levels with acute ischaemic stroke outcome.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Brain Ischemia; Female; Humans; Male; Middle Aged; Prognosis; Prospective Studies; Stroke; Thromboplastin

Coagulative disorders are known to occur in severe acute pancreatitis (SAP), and they are related to its severity and organ dysfunctions. Tissue factor (TF) is a transmembrane glycoprotein that activates the extrinsic pathway of the blood coagulation cascade. Plasma TF levels increase in patients with sepsis and acute coronary syndrome. However, plasma TF levels in SAP have not yet been reported.. We measured plasma TF antigen levels by enzyme-linked immunosorbent assay in 36 patients with acute pancreatitis at the time of admission. The relationships between their plasma TF levels and various factors (severity, etiology, pancreatic necrosis, organ dysfunction, and prognosis) were analyzed. The utility of plasma TF as a clinical marker was evaluated.. Plasma TF levels significantly increased in patients with SAP compared with healthy volunteers and drinkers, respectively. Plasma TF level in alcoholic SAP with pancreatic necrosis was significantly higher than that in alcoholic SAP without pancreatic necrosis or that in nonalcoholic SAP with pancreatic necrosis. The incidence of an abnormally high level of plasma TF was 63.6% in alcoholic SAP with pancreatic necrosis. The area under the ROC curve of plasma TF for detection of pancreatic necrosis in alcoholic SAP was 0.773 and was superior to those of Japanese severity score and lactate dehydrogenase.. Plasma TF levels were elevated in patients with SAP, particularly in those with alcoholic SAP with pancreatic necrosis, suggesting that TF may be closely related to the development of pancreatic necrosis in alcoholic SAP and that the plasma TF level may be a useful marker for it.

Topics: Acute Disease; Female; Humans; Male; Middle Aged; Pancreatitis; Pancreatitis, Acute Necrotizing; Severity of Illness Index; Thromboplastin

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

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

Chronometric hypocoagulation was observed in children, suffering an acute hematogenic ostheomyelitis, witnessed by processes of thrombin formation according to internal (the prolonged time of the blood plasm recalcification and activated partial thromboplastin time) and external (the thrombin time enhancement) ways of the blood coagulation process, as well as changes in fibrinogenesis mechanisms (the thrombin time prolongation). The lowering of anticoagulant capacity of the blood (the antithrombin III activity inhibition by 18.5%) was combined with significant increase of the thrombocytes functional activity (the rising of their adhesive and aggregational properties) in more than two times, which have occurred on the background of constant content of fibrinogen in the blood. Changes in the system of the plasm fibrinolysis in an acute hematogenic ostheomyelitis was characterized by inhibition of cofermental and, mainly, fermental fibrinolytic activity of the blood plasm, in conjunction with Hageman-dependent fibrinolysis intensification and was accompanied by accumulation of soluble complexes of fibrin-monomer in the blood. So far, chronometric hypocoagulation is secondary process, caused by the influence of soluble complexes of fibrin-monomer, which blocks fibrinogenesis. That's why the general potential of the blood coagulation system in children with an acute hematogenic ostheomyelitis must be regarded as a structural hypercoagulation.

Topics: Acute Disease; Adolescent; Blood Coagulation Disorders; Child; Child, Preschool; Female; Fibrinolytic Agents; Hemostatics; Humans; Male; Osteomyelitis; Thromboplastin

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

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

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

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

To observe the expressions of early growth response factor-1 (Egr-1) and tissue factor (TF) in rats with cerulein-induced acute pancreatitis and to explore its significance.. A large dose of cerulein was used to create the experimental acute pancreatitis model in rats. The changes of Egr-1 mRNA and protein in rats were observed during 30 min to 4 h after the treatment and immunohistochemical method was used to observe the localized expression of Egr-1 in tissues. In addition to the mRNA expression of Egr-1 target gene, TF was also observed. A blank control group, and a bombesin-administered group were used for comparison.. After the stimulation of a large dose of cerulein, the rats showed typical inflammatory changes of acute pancreatitis. Thirty minutes after the stimulation, the mRNA expression of Egr-1 in the pancreatic tissue reached its peak and then declined, while the expression of Egr-1 protein reached its peak 2 h after the stimulation. Histologically, 2 h after the stimulation, almost all pancreatic acinar cells had the expression of Egr-1 protein, which was focused in the nuclei. The mRNA expression of TF occurred 1 h after the stimulation and gradually increased within 4 h. However, a large dose of bombesin only stimulated the pancreatic tissue to produce a little mRNA expression of Egr-1 and no mRNA expression of Egr-1 protein and TF.. Egr-1 as a pro-inflammatory transcription factor may play an important role in the pathogenesis of acute pancreatitis by modulating the expression of TF.

Topics: Acute Disease; Animals; Ceruletide; Disease Models, Animal; DNA-Binding Proteins; Early Growth Response Protein 1; Gene Expression; Immediate-Early Proteins; Male; Pancreatitis; Rats; Rats, Wistar; Thromboplastin; Transcription Factors

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

Tissue factor (TF) has, among other factors, a prominent role in acute coronary syndrome (ACS). Our goal was to investigate whether single nucleotide polymorphisms (SNP) in the TF gene (F3) are associated with plasma TF, risk, and outcome in patients with ACS. Moreover, we wanted to investigate the impact of associated TF SNPs on mRNA production in human monocytes.. In 725 patients with ACS [Fragmin and Fast Revascularization during Instability in Coronary Artery Disease II (FRISC-II) study] and 376 controls, 13 SNPs were genotyped and plasma TF measured. Thereafter, the 5466 A>G and the -1812 C>T were genotyped among all of the FRISC-II participants (n=3143) and assessed concerning clinical outcome. Associated SNPs were genotyped in 92 healthy blood donors for comparison of TF activity and TF mRNA expression. None of the SNPs were associated with patient/control status. The 5466 A>G SNP was associated with cardiovascular death (odds ratio, 1.8; P=0.025). The CG haplotype by -1812 C>T and 5466 A>G was associated with a 3-fold increased risk of death (P<0.001). TF mRNA and basal TF activity was significantly lower among 5466 AG carriers, whereas the increase in monocyte TF activity on lipopolysaccharide stimulation was significantly stronger (P=0.04).. The 5466 AG genotype is a novel predictor of cardiovascular death in ACS and may act through a high TF response.

Topics: Acute Disease; Adult; Coronary Thrombosis; Female; Gene Expression; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Male; Middle Aged; Monocytes; Polymorphism, Single Nucleotide; Predictive Value of Tests; Risk Factors; RNA, Messenger; Thromboplastin

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

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

Deposition of fibrin in the form of fibrinoid necrosis is a common feature of severe acute renal allograft rejection. The role of the coagulation system and its initiator tissue factor (TF) during this process is, however, still poorly understood. In this study, we analyzed the expression of TF in 88 renal transplants afflicted with different forms of rejection and calcineurin inhibitor-induced nephrotoxicity, to see whether there was differential expression of this protein. TF immunoreactivity was evaluated semiquantitatively in six different renal structures: the podocytes, Bowman epithelium, the endothelium of the glomeruli, the brush border of tubular cells, the thin ascending loop of Henle, and small arteries/arterioles. The TF expression of normal renal tissue (n=6) was restricted to the glomerular podocytes and Bowman epithelium, and to some extent the ascending loop of Henle. Renal allografts undergoing acute rejection (AR) of grades I-III, (n=13, n=17 and n=12, respectively) did not show any altered TF expression in the glomeruli or vascular endothelium. In the ascending loop of Henle, a reduced expression could be seen (ARI, p=0.015; and ARII, p=0.043). TF staining of the brush border of renal transplants undergoing acute cyclosporin A (CsA) nephrotoxicity (n=18) was significantly higher than in normal kidneys (p=0.0003), as well as in transplants undergoing various degrees of acute rejection (ARI, p=0.027; ARII, p=0.0012; and ARIII, p=0.0001). Tubular brush border-expressed TF was also evident in 10 of 15 allografts suffering from chronic CsA nephrotoxicity, compared to 4 out of 13 cases with chronic allograft vasculopathy (CAV), but the increase was not statistically significant relative to normal kidneys. The majority of the grafts afflicted with either of the two chronic conditions displayed a TF-positive arterial endothelium (CAV, p=0.0034; and chronic CsA nephrotoxicity, p=0.0026) relative to controls. In conclusion, these results indicate that vascular TF expression is not altered during acute rejection, but may be of importance in chronic allograft nephropathy. Furthermore, TF immunoreactivity in the tubular brush border may be specific to acute CsA nephrotoxicity and might be used as a biomarker for this condition. Further studies are required to evaluate the possible role of brush border-expressed TF in the pathogenesis of CsA nephrotoxicity.

Topics: Acute Disease; Animals; Biomarkers; Blood Coagulation; Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Graft Rejection; Humans; Kidney; Kidney Glomerulus; Kidney Transplantation; Rabbits; Thromboplastin

Hyperacute rejection of vascularized discordant xenografts can now be effectively managed. However, acute vascular rejection (AVR) then ensues, resulting in graft destruction, coagulopathy, or both within weeks. The aim of this study was to determine associations between humoral responses to the xenograft and the induction of AVR, coagulopathy, or both.. In vitro, heat-inactivated, naive or sensitized baboon sera containing xenoreactive natural or elicited antibodies were used to activate porcine aortic endothelial cells (PAEC) in vitro. Tissue factor expression on PAEC was determined as an index of heightened procoagulant activity. In vivo, porcine renal xenografts were transplanted into immunosuppressed baboons, and at the time of rejection or the development of a consumptive coagulopathy, biopsy specimens were obtained for studies of xenoreactive antibody binding and tissue factor expression.. In vitro, incubation of PAEC with naive baboon sera containing natural anti-Galalpha1,3Gal (Gal) antibodies resulted in minimal tissue factor induction; the addition of complement boosted procoagulant responses. Elicited xenoreactive antibodies, and to non-Gal epitopes alone, induced high amounts of procoagulant activity on PAEC; the addition of complement resulted in overt cytotoxicity. In vivo, AVR was associated with xenoreactive antibody deposition in the graft. When vascular endothelial binding of xenoreactive antibody was combined with the expression of tissue factor, consumptive coagulopathy developed irrespective of histopathologic features of AVR.. Our in vitro results indicate that elicited antibodies, potentially to non-Gal epitopes, induce endothelial cell activation and tissue factor expression; in vivo, a consumptive coagulopathy occurred when there was xenoreactive antibody deposition and increase of tissue factor.

Topics: Acute Disease; Animals; Antibodies, Heterophile; Aorta; Blood; Blood Coagulation Disorders; Cells, Cultured; Endothelium, Vascular; Graft Rejection; Immunization; Kidney Transplantation; Papio; Plant Lectins; Swine; Thromboplastin; Transplantation, Heterologous

Previous studies have emphasized the role of ischemia in inducing vascular thrombosis.. Using a skin flap model of acute ischemia in the rat, we studied the effect of active-site inactivated factor VIIa (FVIIai), an inhibitor of tissue factor (TF), on tissue survival during acute ischemia.. Ribonuclease protection analysis revealed an increase in TF in ischemic parts of the flap, and in situ hybridization localized this increase mainly to perivascular cells. A decrease in vascular thrombosis, as determined by fibrin immunostaining, was observed in FVIIai-treated animals. Intravenous administration of FVIIai had a positive impact on survival of the flap. Laser Doppler flowmetry revealed an increase in blood flow in the FVIIai-treated group. In treated animals, prothrombin time (PT) was increased (P < 0.01), whereas partial thromboplastin time (APTT) was unaltered; no significant impairment in systemic hemostasis (peri- and postoperative bleeding) was observed.. These findings demonstrate that TF expression is increased in perivascular cells in ischemic skin flaps and that FVIIai, by inhibiting TF, increases flap survival.

Topics: Acute Disease; Animals; Blood Coagulation; Factor VIIa; Female; Ischemia; Necrosis; Rats; Rats, Wistar; Regional Blood Flow; Skin; Surgical Flaps; Thromboplastin; Thrombosis; Time Factors; Tissue Survival

Arterial thrombotic and thromboembolic complications are increased in congestive heart failure (CHF), and are a particular problem in acute decompensated heart failure, which carries a poor prognosis. As interleukin-6 (IL-6) has been shown to induce the potent procoagulant tissue factor (TF) in experimental models, we hypothesized that the pro-inflammatory IL-6 may be one mechanism contributing to thrombosis in heart failure, mediated via endothelial expression of TF on activated/damaged cells [indicated by plasma von Willebrand factor (vWF)]. Seventy-seven patients (67% men, New York Heart Association class III-IV, 87%) with acute CHF were recruited, and were compared with 53 chronic stable CHF patients in sinus rhythm (66% men, New York Heart Association class III-IV, 2%) and 37 healthy controls (68% men). Acute CHF patients in sinus rhythm had elevated baseline levels of IL-6 (P < 0.0001), TF (P = 0.041) and vWF (P < 0.0001) (all measured by enzyme-linked immunosorbent assay) compared with both chronic CHF and healthy control groups. A correlation exists in acute CHF between baseline TF and IL-6 (Spearman r = 0.64, P < 0.0001). After 3 months treatment, with control or alleviation of heart failure symptoms in 40 patients, there was a fall in levels of IL-6 (P < 0.0001) and vWF (P < 0.0001), but levels still remained significantly higher than healthy controls. Patients who died at 6 months follow-up also had higher baseline levels of IL-6 (P = 0.008), TF (P = 0.037) and vWF (P = 0.039) when compared with those who remained alive. Elevated IL-6 may contribute to the thrombotic and thromboembolic complications in acute heart failure, in a process mediated via increased TF and vWF. Improvement of symptoms and plasma markers after treatment of acute CHF and prediction of prognosis by the markers may be useful in the clinical setting.

Topics: Acute Disease; Aged; Biomarkers; Case-Control Studies; Female; Heart Failure; Humans; Interleukin-6; Male; Middle Aged; Prognosis; Risk Factors; Thromboplastin; Thrombosis; Treatment Outcome; von Willebrand Factor

To establish the possible relationship between some coagulation factors and the onset of acute cerebral infarction (ACI).. The study population consisted of 71 patients with ACI confirmed by CT and 50 age-matched healthy volunteers. Blood samples were obtained during the onset period of ACI. Tissue factor (TF) and tissue factor pathway inhibitor (TFPI) activity in plasma were assayed with the chromogenic assay. Plasma TF and TFPI antigen were measured with enzyme linked immunoadsorbent assay (ELISA). Plasma F VII coagulation activity (F VII: C) and F VIII coagulation activity (F VIII: C) were developed in the one-stage system. Plasma prothrombin (FII) was determined with Ecarin assay. Plasma fibrinogen (Fbg) was measured with thrombin assay. Plasma antithrombin III activity (ATIII) was determined using heparin cofactor activity assay.. Compared with the control, plasma TF activity and antigen in patients with ACI were significantly higher (both P<0.05). But plasma TFPI activity and antigen were remarkably lower in the ACI group (both P<0.05). Plasma F VII: C was significantly higher (P<0.01), and F VIII: C was markedly lower (P<0.05). Plasma FII was remarkably higher (P<0.01). Similarly the Fbg was significantly higher in the ACI than that in the control group (P<0.01), whereas ATIII was significantly lower (P<0.01).. The initiation of TF pathway is contributed to the onset of ACI and the blood is in hypercoagulable state during the early period of ACI.

Topics: Acute Disease; Aged; Aged, 80 and over; Blood Coagulation Factors; Cerebral Infarction; Female; Humans; Lipoproteins; Male; Middle Aged; Thromboplastin

A cascade of inflammatory reactions characterize acute vascular rejection after heart transplantation. This study was undertaken to test the hypothesis that acute vascular rejection is associated with up-regulation of vitronectin receptor (alphavbeta3), increased expression of tissue factor, and activation of the extracellular matrix metalloproteinase induction system.. Acute vascular rejection developed in 14 heart transplant recipients within 2 weeks of transplantation, confirmed by immunofluorescence (AVR group). We compared these patients with 10 transplant recipients who had no evidence of acute vascular rejection or peritransplant ischemic injury (control group). We evaluated endomyocardial biopsy specimens for alphavbeta3, tissue factor, and extracellular matrix metalloproteinase inducer (EMMPRIN).. Compared with the control group, the AVR group demonstrated evidence of significantly increased expression of alphavbeta3 (1.9-fold, p < 0.001), tissue factor (1.8-fold, p < 0.001), and EMMPRIN (1.5-fold, p < 0.001). All patients in the AVR group received plasmapheresis; 11 of 14 patients had evidence of ischemic necrosis on biopsy specimens, and 3 of 14 patients experienced hemodynamic compromise and graft dysfunction and died within 3 weeks of transplant. Another patient died at 10 months after transplant.. Acute vascular rejection is associated with up-regulation of alphavbeta3, tissue factor, and activation of the matrix metalloproteinase induction system, which may contribute to the lethal morbidity associated with this disease.

Topics: Acute Disease; Adult; Antigens, CD; Antigens, Neoplasm; Basigin; Endothelium, Vascular; Female; Graft Rejection; Heart Transplantation; Humans; Male; Membrane Glycoproteins; Myocardium; Necrosis; Receptors, Vitronectin; Thromboplastin; Up-Regulation

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

ADP plays a key role in hemostasis, acting through 2 platelet receptors: the P2Y(1) receptor and an unidentified P2 receptor, called P2cyc, coupled to adenylyl cyclase inhibition, which is the target of the antiplatelet drug clopidogrel. We showed that the P2Y(1) receptor is an essential cofactor in thrombotic states induced by intravenous infusion of collagen and epinephrine. The aim of the present study was to assess the role of this receptor in thrombin-dependent tissue factor-induced thromboembolism.. Human thromboplastin was injected intravenously into wild-type or P2Y(1)-deficient mice, and the effects on platelet count and mortality were determined and plasma thrombin-antithrombin III (TAT) complexes were quantified. P2Y(1)-deficient mice were resistant to the thromboembolism induced by injection of thromboplastin. Whereas the platelet count decreased sharply in wild-type mice, there was no significant drop in platelets in P2Y(1)-knockout mice. The platelet consumption in wild-type mice was probably due to thrombin generation, because it was abolished by hirudin. Thromboplastin also led to a rise in TAT complexes in plasma, again reflecting thrombin formation. This effect, however, was less important in P2Y(1)-knockout mice than in wild-type mice, indicating that less thrombin was generated in the absence of P2Y(1). Similar results were obtained after intravenous administration of N:(6)-methyl-2'-deoxyadenosine-3':5'-bisphosphate, a selective antagonist of the P2Y(1) receptor, to wild-type mice.. Our results demonstrate a role of the P2Y(1) receptor in thrombotic states involving thrombin generation and provide further evidence for the potential relevance of this receptor as a target for antithrombotic drugs.

Topics: Acute Disease; Adenosine Diphosphate; Animals; Antithrombin III; Disease Models, Animal; Fibrinolytic Agents; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Hydrolases; Platelet Count; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Receptors, Purinergic P2Y1; Thrombin; Thromboembolism; Thromboplastin

Activated monocytes may contribute to the pathogenesis of ischemic stroke. We tested the hypothesis that release products and procoagulant activity of monocytes are increased in acute ischemic stroke. In patients on days 1, 3 and 7 after ischemic stroke and in age- and sex-matched healthy control subjects, we assessed plasma levels of interleukin 8 (IL-8) and neopterin (enzyme linked immunosorbent assay, ELISA) and investigated superoxidanion release (ferricytochrome C reduction), procoagulant activity (one-stage clotting assay) and tissue factor (TF) gene transcription (reverse transcriptase polymerase chain reaction) by monocytes. As compared to control subjects (n=23), IL-8 levels were increased on day 1 after stroke (n=22; p=0.005) and remained elevated on days 3 and 7. Neopterin levels were elevated on days 3 and 7 (p<0.05, respectively) but not on day 1. Neopterin and IL-8 were not correlated with monocyte counts. Superoxid anion production by stimulated and unstimulated monocytes was not different between groups. TF mRNA could neither be detected in monocytes from patients investigated within 12 h after ischemia (n=12) nor in control subjects (n=10) and procoagulant activity of cells was similar in both groups. Our results indicate increased monocyte activation after ischemic stroke although not all activation parameters were elevated. We found no support for the hypothesis that circulating monocytes express TF and possess increased procoagulant activity. Elevated IL-8 may contribute to stroke pathophysiology by activating polymorphonuclear leukocyte (PMNL) activation early after ischemia.

Topics: Acute Disease; Aged; Blood Coagulation; Brain; Brain Ischemia; Female; Gene Expression; Humans; Interleukin-8; Leukocyte Count; Male; Middle Aged; Monocytes; Neopterin; RNA, Messenger; Stroke; Superoxides; Thromboplastin; Transcription, Genetic

Apoptotic microparticles are responsible for almost all tissue factor activity of the plaque lipid core. We hypothesized that elevated levels of procoagulant microparticles could also circulate in the peripheral blood of patients with recent clinical signs of plaque disruption and thrombosis.. We studied 39 patients with coronary heart disease, including 12 patients with stable angina and 27 patients with acute coronary syndromes (ACS), and 12 patients with noncoronary heart disease. We isolated the circulating microparticles by capture with annexin V and determined their procoagulant potential with a prothrombinase assay. The cell origins of microparticles were determined in an additional 22 patients by antigenic capture with specific antibodies. The level of procoagulant microparticles did not differ between stable angina patients and noncoronary patients (10.1+/-1.6 nmol/L phosphatidylserine [PS] equivalent versus 9.9+/-1.6 nmol/L PS equivalent, respectively). However, procoagulant microparticles were significantly elevated in patients with ACS (22.2+/-2.7 nmol/L PS equivalent) compared with other coronary (P<0.01) or noncoronary (P<0.01) patients. Microparticles of endothelial origin were significantly elevated in patients with ACS (P<0.01), which suggests an important role for endothelial injury in inducing the procoagulant potential.. High levels of procoagulant endothelial microparticles are present in the circulating blood of patients with ACS and may contribute to the generation and perpetuation of intracoronary thrombi.

Topics: Acute Disease; Angina Pectoris; Antigens, CD; Apoptosis; CD146 Antigen; Coronary Artery Disease; Coronary Thrombosis; Endothelium, Vascular; Female; Humans; Male; Membrane Glycoproteins; Middle Aged; Neural Cell Adhesion Molecules; Phosphatidylserines; Platelet Endothelial Cell Adhesion Molecule-1; Prospective Studies; Receptors, Cell Surface; Thrombophilia; Thromboplastin

Acute vascular rejection destroys vascularized xenografts over a period of hours to days and is now considered the major hurdle to the clinical application of xenotransplantation. The hallmark of acute vascular rejection is diffuse intravascular coagulation; however, the pathogenesis of coagulation is a matter of controversy. One line of evidence points to activated endothelial cells and another to activated inflammatory cells as a source of tissue factor and thus as a primary cause of this lesion. The distinction between the two mechanisms inducing coagulation in the xenograft provides an opportunity for specific intervention.. To explore these mechanisms, we studied the expression of tissue factor mRNA by in situ reverse transcriptase-polymerase chain reaction in relation to the histopathologic manifestations of acute vascular rejection in guinea pig hearts transplanted into rats treated by cobra venom factor to avoid the hyperacute rejection.. Three hours after transplantation and before the deposition of fibrin, tissue factor mRNA was expressed in the endothelial cells lining small and medium blood vessels and in smooth muscle cells of guinea pig cardiac xenografts. Sixteen hours after transplantation, while rat tissue factor mRNA was expressed only in occasional infiltrating cells, cardiac xenografts showed prominent deposits of fibrin in small vessels. Maximum expression of tissue factor on rat infiltrating cells was observed 48 hr after transplantation.. These results suggest that in acute vascular rejection, coagulation is initiated on the donor vascular system, while the procoagulant characteristics of infiltrating cells may reflect a response to tissue injury rather than a cause.

Topics: Acute Disease; Animals; Coronary Vessels; Endothelium, Vascular; Graft Rejection; Guinea Pigs; Heart Transplantation; Leukocyte Common Antigens; Leukocytes; Male; Rats; Rats, Inbred Lew; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thromboplastin; Time Factors; Transplantation, Heterologous; Treatment Outcome

Topics: Acute Disease; Animals; Antithrombin III; Blood Coagulation Disorders; Complement Activation; Cytokines; Disseminated Intravascular Coagulation; Endotoxemia; Fibrin; Gene Expression Regulation; Hemorrhage; Humans; Lipoproteins; Lung Injury; Primates; Protein C; Reactive Oxygen Species; Respiratory Distress Syndrome; Sepsis; Thromboplastin; Transcription, Genetic; Tumor Necrosis Factor-alpha

Topics: Acute Disease; Animals; Complement Inactivator Proteins; Elapid Venoms; Fibrin; Graft Rejection; Guinea Pigs; Heart Transplantation; Male; Rats; Rats, Inbred Lew; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thromboplastin; Transcription, Genetic

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

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

The specific role of apoptosis in human atherosclerosis remains unknown. During apoptotic cell death, phosphatidylserine exposure on the cell surface confers a high tissue-factor (TF)-dependent procoagulant activity.. In this study, we examined the role of apoptotic cell death in the promotion of plaque thrombogenicity. TF expression and its relation to apoptosis was analyzed in 16 human atherosclerotic plaques by the use of immunohistochemical techniques. The presence of shed membrane apoptotic microparticles was analyzed in extracts from 6 human atherosclerotic plaques and 3 underlying arterial walls. The microparticles were captured by annexin V and their amounts estimated with respect to their phospholipid content by use of a prothrombinase assay. The prothrombogenic potential of the microparticles was further assessed by the measurement of total and microparticle-dependent TF activity in the extracts. The cell origin of the microparticles was determined after capture by specific antibodies. We were able to detect marked TF expression in the plaques in close proximity to apoptotic cells and debris, suggesting a potential interaction between TF and the apoptotic cell surfaces. High levels of shed membrane apoptotic microparticles were detected in extracts from atherosclerotic plaques but not in the underlying arterial walls (29.5+/-3.7 nmol/L phosphatidylserine equivalent versus 1.3+/-0.4 nmol/L, respectively, P<0.02). The microparticles were mainly of monocytic and lymphocytic origin and retained 97+/-2% of total TF activity, indicating a direct causal relationship between shed membrane microparticles and procoagulant activity of plaque extracts.. These results indicate that shed membrane microparticles with procoagulant potential are produced in human atherosclerotic plaques. Apoptosis could be a critical determinant of plaque thrombogenicity after plaque rupture.

Topics: Acute Disease; Apoptosis; Arteriosclerosis; Carotid Arteries; Cell Membrane; Endothelium, Vascular; Humans; In Situ Nick-End Labeling; Microspheres; Phosphatidylserines; Thromboplastin; Thrombosis

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

Topics: Acute Disease; Adult; Aged; Chronic Disease; Female; Humans; Lipoproteins; Male; Middle Aged; Renal Insufficiency; Thromboplastin

Tissue factor (TF) and urokinase receptor (uPAR) are key cellular receptors triggering, respectively, coagulation and fibrinolysis. Bleeding complications among leukemic patients have been related to an abnormal expression of TF by blast cells and/or to an abnormal fibrinolytic response. In this study the expression of TF and uPAR has been assessed in 18 acute non-lymphoblastic and 8 lymphoblastic leukemic blast cells using several methodological approaches. TF mRNA was evaluated by in situ hybridization and TF and uPAR antigen were evaluated immunologically in cell lysates and on the cell surface by flow cytometry. In addition, TF-procoagulant activity was measured in coagulation-based assays. The reliability of these methods was corroborated in six leukemic cell lines of different lineages and states of maturation. Disseminated intravascular coagulation was detected in two M3 leukemia patients whose blast cells expressed high amounts of TF. Hyperfibrinolysis was detected in one M1 and two M2 patients, whose blast cells displayed a high content of uPAR antigen, but no TF. Furthermore, M5 leukemia blast cells expressed both TF and uPAR, although no hemostatic defects or bleeding complications were detected in these patients. Taken together, although a limited number of patients was included in this study, these data suggest that in leukemia patients exhibiting bleeding, either TF or uPAR are expressed by their blast cells. However, the presence of these receptors does not necessarily imply the existence of a hemostatic disorder.

Topics: Acute Disease; Blood Coagulation; Hemorrhage; Humans; Leukemia; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Thromboplastin; Tumor Cells, Cultured

The murine/human chimeric monoclonal antibody fragment (c7E3 Fab) blocks GPIIb/IIIa and alpha v beta 3 receptors, inhibits platelet aggregation, and decreases the frequency of ischemic events after coronary artery angioplasty in patients at high risk of suffering such events. Although inhibition of platelet aggregation is likely to be the major mechanism of c7E3 Fab's effects, since activated platelets facilitate thrombin generation, it is possible that c7E3 Fab also decreases thrombin generation. To test this hypothesis, the effects of c7E3 Fab and other antiplatelet agents were tested in a thrombin generation assay triggered by tissue factor. c7E3 Fab produced dose-dependent inhibition of thrombin generation, reaching a plateau of 45-50% inhibition at concentrations > or = 15 micrograms/ml. It also inhibited thrombin-antithrombin complex formation, prothrombin fragment F1-2 generation, platelet-derived growth factor and platelet factor 4 release, incorporation of thrombin into clots, and microparticle formation. Antibody 6D1, which blocks platelet GPIb binding of von Willebrand factor, had no effect on thrombin generation, whereas antibody 10E5, which blocks GPIIb/IIIa but not alpha v beta 3 receptors decreased thrombin generation by approximately 25%. Combining antibody LM609, which blocks alpha v beta 3 receptors, with 10E5 increased the inhibition of thrombin generation to approximately 32-41%. The platelets from three patients with Glanzmann thrombasthenia, who lacked GPIIb/IIIa receptors but had normal or increased alpha v beta 3 receptors, supported approximately 21% less thrombin generation than normal platelets. We conclude that thrombin generation initiated by tissue factor in the presence of platelets is significantly inhibited by c7E3 Fab, most likely in part through both GPIIb/IIIa and alpha v beta 3 blockade, and that this effect may contribute to its antithrombotic properties.

Topics: Acute Disease; Animals; Antibodies, Monoclonal; Blood Platelets; Calcimycin; Chromatography, Gel; Humans; Immunoglobulin Fab Fragments; Mice; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Fusion Proteins; Thrombin; Thromboplastin; Thrombosis

Acute obstructive cholangitis (AOC) is one of the most fatal outcomes in sepsis, and frequently complicates disseminated intravascular coagulation (DIC). Recently we found that the plasma tissue factor (TF) level increased and changed in parallel with plasma markers of DIC in patients with AOC. To elucidate the role of TF in the pathogenesis of coagulopathy in AOC, we investigated the plasma levels of TF and its localization by immunohistochemical staining in rabbit models of AOC. Plasma TF activity significantly increased 3 h after the insult (0.63 +/- 0.1¿9 U/ml; p < 0.01) compared with that beforehand (0.05 +/- 0.02 U/ml), then reached a maximum level at 6 h (0.94 +/- 0.16 U/ml). The fluctuations in plasma TF activity correlated with those of the coagulation parameters including platelet count, fibrinogen, prothrombin time, and antithrombin III activity. Immunohistochemically, enhanced expression of TF was mainly detected in macrophages and neutrophils that had infiltrated into the liver sinusoids and around the bile duct, but not in the sinusoidal endothelial cells. A double immunofluorescence study revealed the concomitant presence of TF and fibrin at sites where macrophages and neutrophils had conglomerated. However, we could not detect an apparent change in TF expression in the lung or kidney. These data suggest that macrophages and neutrophils infiltrating into the liver sinusoids and around the bile duct play a pivotal role in TF expression, leading to coagulopathy in the acute phase of obstructive cholangitis in rabbits.

Topics: Acute Disease; Animals; Blood Coagulation; Cell Movement; Cholangitis; Disease Models, Animal; Female; Immunohistochemistry; Liver; Macrophages; Neutrophils; Rabbits; Thromboplastin

Peritoneal fluid was collected aseptically from 30 healthy adult horses and 115 horses with acute gastrointestinal disease and supernatant was separated from cells by centrifugation followed by freezing until assayed for endotoxin and tumour necrosis factor activity. Peritoneal macrophages obtained from healthy horses were incubated in vitro for 3, 6, 12 or 24 h in the absence (media control) or presence of Escherichia coli 055:B5 endotoxin (final concentrations of 1, 10, 100 or 1000 ng/ml). Macrophages obtained from horses with acute gastrointestinal disease were incubated for 12 h in the absence (media control) or presence of 100 ng endotoxin/ml. At the conclusion of the incubation, macrophage supernatants were collected and frozen at -70 degrees C until analysed for tumour necrosis factor activity. Macrophage membranes were lysed and frozen at -70 degrees C until assayed for tissue factor and plasminogen activator inhibitor type 2 activity. Compared to cells incubated with media, incubation of macrophages, obtained from healthy horses, with endotoxin significantly increased tumour necrosis factor, tissue factor and plasminogen activator inhibitor type 2 activity. These increases were dependent on the endotoxin concentration and the duration of incubation. Compared to cells incubated with media alone, incubation of macrophages, obtained from horses with acute gastrointestinal disease with endotoxin, significantly increased tumour necrosis factor and tissue factor activity. Endotoxin induced tumour necrosis factor activity in vitro was significantly less for macrophages from horses with acute gastrointestinal disease, as compared to that produced by similarly treated cells obtained from healthy horses. For those horses with acute gastrointestinal disease, macrophages obtained from horses with either endotoxin or tumour necrosis factor activity in the peritoneal fluid supernatant had significantly less endotoxin induced tumour necrosis factor in vitro, as compared to similarly treated cells obtained from horses without endotoxin or tumour necrosis factor activity in the peritoneal fluid supernatant. The results of this study indicate that exposure of equine peritoneal macrophages to endotoxin results in a significant increase in tumour necrosis factor, tissue factor and plasminogen activator inhibitor type 2 activity. After in vitro exposure to endotoxin, there is significant down-regulation of inflammatory mediator production by peritoneal macrophages ob

Topics: Acute Disease; Animals; Ascitic Fluid; Cell Count; Endotoxins; Escherichia coli; Female; Gastrointestinal Diseases; Horse Diseases; Horses; Macrophages, Peritoneal; Male; Plasminogen Activator Inhibitor 2; Thromboplastin; Tumor Necrosis Factor-alpha

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

We report two cases of renal vein thrombosis, unusual because of acute expression, right renal vein localization, absence of the usual renal or perirenal causes, surgical management and a never before reported etiology. In one case the thrombosis was secondary to primary antiphospholipid syndrome, in the other it was secondary to heparin associated thrombocythemia. In this case surgical management was performed during prostacyclin infusion.

Topics: Acute Disease; Autoantibodies; Blood Coagulation Disorders; Combined Modality Therapy; Epoprostenol; Female; Heparin; Humans; Male; Middle Aged; Phospholipids; Renal Veins; Syndrome; Thrombocytopenia; Thromboplastin; Thrombosis

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

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

The procoagulant cellular activity (PCA) of intact and lysed leukaemic cells was evaluated at diagnosis in 23 patients with acute non-lymphoid leukaemia (ANLL). The leukaemic cells of all 13 patients having DIC feature (excess of fibrin monomers, serum FDP and plasma fibrino-peptide A) showed a significant (P less than 0.0001) increase of PCA, while a pattern similar to that of normal granulocytes and lymphomonocytes was observed in the remaining 10 patients without evidence of DIC. When the patients were subdivided according to the FAB cytological classification, features of DIC and increased PCA were demonstrated in 3/3 M3 patients, 5/6 M5 patients and only in 5/14 remaining patients. These findings indicate that in ANLL patients: (1) the increased PCA of leukaemic cells is closely related to the occurrence of DIC; (2) the increased PCA seems related to the differentiation line and maturation level of the leukaemic cells.

Topics: Acute Disease; Adolescent; Adult; Aged; Blood Coagulation Tests; Bone Marrow; Disseminated Intravascular Coagulation; Female; Granulocytes; Hematopoietic Stem Cells; Humans; Leukemia; Lymphocytes; Male; Middle Aged; Monocytes; Thromboplastin

Topics: Acute Disease; Adolescent; Adult; Aged; Blood Platelets; Clot Retraction; Female; Hematopoiesis; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Male; Megakaryocytes; Middle Aged; Platelet Count; Thromboplastin

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 possible association between acute respiratory failure and disseminated intravascular coagulation was examined in eight patients with severe acute respiratory failure--a condition characterized by tachypnea, right to left intrapulmonary shunting of blood greater than 30 per cent of cardiac output, increased pulmonary artery pressure with low or normal pulmonary artery wedge pressure and roentgenologic interstitial pulmonary edema. Treatment consisted of mechanical ventilation with positive end expiratory pressure sufficient to minimize intrapulmonary shunting. There was no abnormality in platelet concentration fibrin split product concentration, fibrinogen concentration, prothrombin time or activated partial thromboplastin time during the period of most severe respiratory failure in any patient. However, mean platelet concentration fell to 90,000+/-9,000 per cubic millimeter, less than 0.001, and mean fibrin split product levels rose to 60+/-10 micrograms per milliliter, p less than 0.05, the fourth day after the onset of acute respiratory failure. No significant change occurred in other coagulation parameters. Disseminated intravascular coagulation developed in none of the patients nor was there any correlation between coagulation abnormalities and severity of acute respiratory failure that would suggest a cause and effect relationship.

Topics: Acute Disease; Adult; Blood Cell Count; Blood Platelets; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Male; Middle Aged; Oxygen; Positive-Pressure Respiration; Prothrombin Time; Respiratory Insufficiency; 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

Topics: Acute Disease; Animals; Aprotinin; Blood Coagulation; Chromatography, Gel; Disseminated Intravascular Coagulation; Fibrinolysis; Heparin; Humans; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocytes; Rabbits; Thrombin; Thromboplastin; Tranexamic Acid; Trypsin Inhibitors

Evidence of disseminated intravascular coagulation (DIC) was dought in normal baboons infused with autologous hemolyzed whole blood, preceded or followed by infusion of dextran (molecular weight, 70,000). Mean peak plasma hemoglobin following a rapid single injection was 370 mg/100 ml in 2 animals and 1,236 mg/100 ml in 1 animal, while levels during continuous 5 hour infusion in 2 animals averaged 326 and 474 mg/100 ml, respectively. Dextran infusion immediately preceded hemoglobin injection in 2 baboons and followed hemoglobin injection by 1 1/2 and 2 1/2 hours, respectively, in 2 baboons. Coagulation studies showed a moderate although significant fall in platelet count with prolongation of the partial thromboplastin time following hemoglobin infusion, and shortening of the thrombin time after dextran. Fibrin degradation products developed in four of five experiments after hemolysate injection. The induction of acute experimental hemoglobinemia results, therefore, in the development of coagulation changes consistent with milk DIC. Preliminary infusion of dextran (molecular weight, 70,000) may facilitate this response by either initiating the development or impeding the clearance of fibrin degradation products.

Topics: Acute Disease; Animals; Blood Cell Count; Blood Coagulation; Blood Platelets; Dextrans; Disseminated Intravascular Coagulation; Fibrin; Fibrinogen; Haplorhini; Hemoglobins; Hemolysis; Molecular Weight; Papio; Prothrombin Time; Thrombin; Thromboplastin; Time Factors

Topics: Acute Disease; Adult; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Bilirubin; Blood Coagulation Tests; Cholangitis; Chronic Disease; Diagnosis, Differential; Female; Hepatitis A; Humans; Indicators and Reagents; Male; Methods; Middle Aged; Prothrombin Time; Thromboplastin

Topics: Acute Disease; Adolescent; Child; Child, Preschool; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphatic Diseases; Thromboplastin

Liver biopsy was performed in 38 patients with fulminant hepatitis and coma and repeated in 22. Stereological estimation of hepatocyte volume was correlated with levels of clotting factors. Early liver biopsy allowed prognosis in 55% of the cases. All patients with a hepatocyte volume of <35% and thromboplastin time /=35% and thromboplastin time >10% recovered consciousness (n = 9) or at least showed evidence of marked liver regeneration (n = 2). On serial liver biopsy a significant increase in hepatocyte volume and clotting factors was only observed in patients who recovered consciousness. The estimated liver cell mass after regeneration in patients who recovered consciousness was >/=45% and <45% in the patients who did not.

Topics: Acute Disease; Biopsy; Factor V; Hepatic Encephalopathy; Hepatitis; Hepatitis A; Humans; Liver; Liver Diseases; Prognosis; Thromboplastin; Time Factors

Topics: Acute Disease; Blood Coagulation Disorders; Blood Urea Nitrogen; Factor VIII; Fibrin; Fibrinolysin; Fibrinolysis; Glomerulonephritis; Humans; Thromboplastin; Time Factors

Topics: Acute Disease; Aspartate Aminotransferases; Blood Coagulation Factors; Blood Coagulation Tests; Chronic Disease; Hepatitis A; Humans; Indicators and Reagents; Thromboplastin

Topics: Acute Disease; Blood Coagulation; Blood Coagulation Disorders; Blood Platelets; Deafness; Dextrans; Ear, Inner; Evaluation Studies as Topic; Female; Hearing Disorders; Humans; Ischemia; Labyrinth Diseases; Male; Nicotinic Acids; Prothrombin Time; Theophylline; Thrombelastography; Thromboplastin; Time Factors

Topics: Acute Disease; Adolescent; Age Factors; Alanine Transaminase; Aspartate Aminotransferases; Bilirubin; Blood Protein Electrophoresis; Blood Proteins; Child; Child, Preschool; Cholesterol; Enzymes; Female; Haptoglobins; Hepatitis A; Humans; Lipids; Male; Thromboplastin

Topics: Acute Disease; Blood Platelets; Child; Humans; Infant; Leukemia; Thromboplastin