thromboplastin and Systemic-Inflammatory-Response-Syndrome

Tissue factor (TF) is a major initiator of extrinsic pathway of blood coagulation. A dual role of TF in the extensive crosstalk between blood coagulation and inflammation has recently become apparent. The majority of the cases of systemic inflammatory response syndrome, disseminated intravascular coagulation, and sepsis are accompanied by hyperactivation of TF in circulating monocytes and damaged tissue. Systemic Gram-negative infection induces expression of TF by vascular cells. In addition to extrinsic coagulation pathway, TF induces proinflammatory signaling cascade originating from activation of protease-activated receptors. Because TF-activated proteolytic cascade is placed in a nexus between coagulation and inflammation, early modulation of TF activity presently becomes a tempting experimental therapeutic strategy in systemic inflammatory response syndrome patients.

Topics: Anti-Bacterial Agents; Blood Coagulation; Disseminated Intravascular Coagulation; Gram-Negative Bacteria; Humans; Lipopolysaccharides; Monocytes; Sepsis; Signal Transduction; Systemic Inflammatory Response Syndrome; Thromboplastin

Cellular signaling by proteases of the blood coagulation cascade through members of the protease-activated receptor (PAR) family can profoundly impact on the inflammatory balance in sepsis. The coagulation initiation reaction on tissue factor expressing cells signals through PAR1 and PAR2, leading to enhanced inflammation. The anticoagulant protein C pathway has potent anti-inflammatory effects, and activated protein C signals through PAR1 upon binding to the endothelial protein C receptor. Activation of the coagulation cascade and the downstream endothelial cell localized anticoagulant pathway thus have opposing effects on systemic inflammation. This dichotomy is of relevance for the interpretation of preclinical and clinical data that document nonuniform responses to anticoagulant strategies in sepsis therapy.

Topics: Anticoagulants; Blood Coagulation; Endopeptidases; Endothelium, Vascular; Humans; Inflammation; Protein C; Signal Transduction; Systemic Inflammatory Response Syndrome; Thromboplastin

To evaluate the pathogenetic role of tissue factor (TF), tissue factor pathway inhibitor (TFPI), and neutrophil elastase in acute respiratory distress syndrome (ARDS), as well as to test the hypothesis that TFPI levels modified by neutrophil activation are not sufficient to prevent TF-dependent intravascular coagulation, leading to sustained systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS), which determine the prognosis of these patients.. The study subjects consisted of 55 patients with trauma and sepsis who were divided into three groups according to the Lung Injury Score. Ten normal healthy volunteers served as control. Plasma levels of TF, TFPI, and neutrophil elastase were measured on the day of injury or the day of diagnosis of sepsis (day 0) and days 1 through 4. The number of SIRS criteria that the patient met and the disseminated intravascular coagulation (DIC) score is determined daily.. Patients (15) developed ARDS, 23 were at risk for but did not develop the syndrome, and 17 patients were without risk for ARDS. TF and neutrophil elastase levels in ARDS patients were persistently higher than those in other two groups and control subjects. However, the TFPI levels showed no difference among the three groups, which retained normal or slightly elevated levels compared to the control subjects. DIC scores did not improve and SIRS continued during the study period in patients with ARDS. The ARDS patients showed higher numbers of dysfunctioning organs and associated with poorer outcome than the other two groups.. Systemic activation of the TF-dependent pathway not adequately balanced by TFPI is one of the aggravating factors of ARDS. High levels of neutrophil elastase released from activated neutrophils may explain the imbalance of TF and TFPI. Persistent DIC and sustained SIRS contribute to MODS, determining the prognosis of ARDS patients.

Topics: Disseminated Intravascular Coagulation; Female; Humans; Leukocyte Elastase; Lipoproteins; Male; Middle Aged; Multiple Organ Failure; Respiratory Distress Syndrome; Risk Assessment; Statistics as Topic; Systemic Inflammatory Response Syndrome; Thromboplastin

Systemic inflammatory response, as observed in sepsis and severe COVID-19, may lead to endothelial damage. Therefore, we aim to compare the extent of endothelial injury and its relationship to inflammation in both diseases. We included patients diagnosed with sepsis (SEPSIS group, n = 21), mild COVID-19 (MILD group, n = 31), and severe COVID-19 (SEVERE group, n = 24). Clinical and routine laboratory data were obtained, circulating cytokines (INF-γ, TNF-α, and IL-10) and endothelial injury markers (E-Selectin, Tissue Factor (TF) and von Willebrand factor (vWF)) were measured. Compared to the SEPSIS group, patients with severe COVID-19 present similar clinical and laboratory data, except for lower circulating IL-10 and E-Selectin levels. Compared to the MILD group, patients in the SEVERE group showed higher levels of TNF-α, IL-10, and TF. There was no clear relationship between cytokines and endothelial injury markers among the three studied groups; however, in SEVERE COVID-19 patients, there is a positive relationship between INF-γ with TF and a negative relationship between IL-10 and vWF. In conclusion, COVID-19 and septic patients have a similar pattern of cytokines and endothelial dysfunction markers. These findings highlight the importance of endothelium dysfunction in COVID-19 and suggest that endothelium should be better evaluated as a therapeutic target for the disease.

Topics: Aged; Aged, 80 and over; Biomarkers; Blood Cell Count; C-Reactive Protein; COVID-19; E-Selectin; Endothelium, Vascular; Female; Humans; Interferon-gamma; Interleukin-10; Male; Middle Aged; Retrospective Studies; SARS-CoV-2; Sepsis; Severity of Illness Index; Systemic Inflammatory Response Syndrome; Thromboplastin; Tumor Necrosis Factor-alpha; von Willebrand Factor

Activated immune cells such as monocytes are key factors in systemic inflammatory response syndrome (SIRS) following trauma and sepsis. Activated monocytes induce almost all tissue factor (TF) expression contributing to inflammation and coagulation. TF and CD13 double-positive microparticles (TF/CD13MPs) are predominantly released from these activated monocytes. This study aimed to evaluate TF/CD13MPs and assess their usefulness as a biomarker of pathogenesis in early SIRS following trauma and sepsis. This prospective study comprising 24 trauma patients, 25 severe sepsis patients, and 23 healthy controls was conducted from November 2012 to February 2015. Blood samples were collected from patients within 24 h after injury and diagnosis of severe sepsis and from healthy controls. Numbers of TF/CD13MPs were measured by flow cytometry immediately thereafter. Injury Severity Score (ISS) and Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores were calculated at patient enrollment. APACHE II and SOFA scores and International Society of Thrombosis and Haemostasis (ISTH) overt disseminated intravascular coagulation (DIC) diagnostic criteria algorithm were calculated at the time of enrollment of severe sepsis patients. Numbers of TF/CD13MPs were significantly increased in both trauma and severe sepsis patients versus controls and correlated significantly with ISS and APACHE II score in trauma patients and with APACHE II and ISTH DIC scores in severe sepsis patients. Increased numbers of TF/CD13MPs correlated significantly with severities in the acute phase in trauma and severe sepsis patients, suggesting that TF/CD13MPs are important in the pathogenesis of early SIRS following trauma and sepsis.

Topics: Adult; Aged; APACHE; Biomarkers; CD13 Antigens; Cell-Derived Microparticles; Female; Humans; Injury Severity Score; Male; Middle Aged; Prospective Studies; Sepsis; Systemic Inflammatory Response Syndrome; Thromboplastin; Wounds and Injuries

There are no any systemized studies of relationship between the coagulative haemostasis' disorders and metabolic and cytokine status in patients with septic tuboovarial formations.. The aim of the present work was to study the mechanisms of blood coagulation disorders and their relationships with changes of cytokine status and acute phase of inflammatory response in septic tubo-ovarian formations in women.. 32 patients with purulent tubovarial formations and 30 healthy women were examined.. Shortening of activated partial thromboplastin, prothrombin and thrombin clotting time, increasing the duration of XIIa-kallikrehin-dependent fibrinolysis, as well as the elevation of paracoagulation products in blood plasma were observed. IL-1β (p =0.000023), TNF-α (p <0.001), C-reactive protein (p <0.001), haptoglobin (p <0.001) and fibrinogen (p <0.001) levels were higher in peripheral blood of patients in comparison with healthy women. Accumulation of lipid hydroperoxides (p <0. 001) and malonic dialdehyde (p <0.001) occurred in the blood plasma of patients. Serum albumin (p <0.001) and transferring (p <0.001) levels were lesser in patients with purulent tubo ovarial formations in comparison with healthy women.. The obtained results showing an initiating role of cytokine and oxidative metabolic status changes in blood coagulation potential's and fibrinolysis activity's disorders developing. This biochemical signs may be used as objective criteria which may serve to determine the risk of thrombosis in case of acute inflammatory response in women with purulent inflammation.

Topics: Adult; Blood Coagulation; Cytokines; Female; Fibrinogen; Humans; Oxidative Stress; Prospective Studies; Reproductive Tract Infections; Suppuration; Systemic Inflammatory Response Syndrome; Thromboplastin; Thrombosis

Microparticles (MPs), membrane fragments of 0.1-1.0 μm, are derived from many cell types in response to systemic inflammation. Acute liver failure (ALF) is a prototypical syndrome of systemic inflammatory response syndrome (SIRS) associated with a procoagulant state. We hypothesized that patients with ALF develop increased procoagulant MPs in proportion to the severity of systemic complications and adverse outcome. Fifty patients with acute liver injury (ALI), 78% of whom also had hepatic encephalopathy (HE; ALF), were followed until day 21 after admission. MPs were characterized by Invitrox Sizing, Antigen Detection and Enumeration, a light-scattering technology that can enumerate MPs as small as 0.15 μm, and by flow cytometry. Procoagulant activity was assessed by a functional MP-tissue factor (MP-TF) assay. Sixteen patients (32%) died and 27 (54%) recovered without liver transplantation (LT). Total MPs (0.15-1.0 μm) were present in nearly 19-fold higher concentrations in ALI/ALF patients, compared to healthy controls (P < 0.0001). MP-TF assays revealed high procoagulant activity (9.05 ± 8.82 versus 0.24 ± 0.14 pg/mL in controls; P = 0.0008). MP concentrations (0.28-0.64 μm) were higher in patients with the SIRS and high-grade HE, and MPs in the 0.36-0.64-μm size range increased in direct proportion to SIRS severity (P < 0.001) and grade of HE (P < 0.002). Day 1 MPs (0.28-0.64 μm) correlated with laboratory predictors of death/LT (higher phosphate and creatinine; lower bicarbonate), and day 1 and 3 MPs were higher in patients who died or underwent LT, compared to spontaneous survivors (P ≤ 0.01). By flow cytometry, 87% of patients had circulating CD41(+) MPs, indicating platelet origin.. Highly procoagulant MPs of specific size ranges are associated with the SIRS, systemic complications, and adverse outcome of ALI/ALF. MPs may contribute to the multiorgan system failure and high mortality of ALF.

Topics: Adult; Cell-Derived Microparticles; Female; Hepatic Encephalopathy; Humans; Liver Failure, Acute; Male; Middle Aged; Platelet Membrane Glycoprotein IIb; Systemic Inflammatory Response Syndrome; Thromboplastin

Protease activated receptor 1 (PAR1) signaling can play opposing roles in sepsis, either promoting dendritic cell (DC)-dependent coagulation and inflammation or reducing sepsis lethality due to activated protein C (aPC) therapy. To further define this PAR1 paradox, we focused on the vascular effects of PAR1 signaling. Pharmacological perturbations of the intravascular coagulant balance were combined with genetic mouse models to dissect the roles of endogenously generated thrombin and aPC during escalating systemic inflammation. Acute blockade of the aPC pathway with a potent inhibitory antibody revealed that thrombin-PAR1 signaling increases inflammation-induced vascular hyperpermeability. Conversely, aPC-PAR1 signaling and the endothelial cell PC receptor (EPCR) prevented vascular leakage, and pharmacologic or genetic blockade of this pathway sensitized mice to LPS-induced lethality. Signaling-selective aPC variants rescued mice with defective PC activation from vascular leakage and lethality. Defects in the aPC pathway were fully compensated by sphingosine 1 phosphate receptor 3 (S1P3) deficiency or by selective agonists of the S1P receptor 1 (S1P1), indicating that PAR1 signaling contributes to setting the tone for the vascular S1P1/S1P3 balance. Thus, the activating proteases and selectivity in coupling to S1P receptor subtypes determine vascular PAR1 signaling specificity in systemic inflammatory response syndromes in vivo.

Topics: Animals; beta-Alanine; Capillary Leak Syndrome; Capillary Permeability; Disseminated Intravascular Coagulation; Endothelial Protein C Receptor; Endothelium, Vascular; Endotoxins; Enzyme Activation; Glycoproteins; Hirudins; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Protein C; Receptor, PAR-1; Receptors, Cell Surface; Receptors, Lysosphingolipid; Signal Transduction; Specific Pathogen-Free Organisms; Sphingosine-1-Phosphate Receptors; Systemic Inflammatory Response Syndrome; Thiophenes; Thrombin; Thromboplastin

Topics: Animals; Antithrombin III; Blood Coagulation; Blood Coagulation Disorders; Factor VIIa; Humans; Mice; Peptide Hydrolases; Prognosis; Systemic Inflammatory Response Syndrome; Thromboplastin

Haemostatic changes in septic patients are complex, with both procoagulant and anticoagulant changes. Thirty-eight patients with severe sepsis and 32 controls were investigated by coagulation screens, individual factor assays, calibrated automated thrombography (CAT), whole blood low-dose-tissue factor activated (LD-TFA) Rotem and LD-TFA waveform analysis. Thirty-six of 38 patients had an abnormal coagulation screen. The mean levels of factors II, V (P < 0.05), VII, X, XI and XII, antithrombin and protein C (P < 0.01) was decreased in sepsis compared with controls. The mean factor VIII and fibrinogen level (P < 0.001) was increased. CAT in platelet rich and poor plasma showed a prolonged lag time (P < 0.02), decreased peak thrombin (P < 0.02) and delayed time to peak thrombin (P < 0.001) in sepsis patients, however, the endogenous thrombin potential was equivalent in sepsis and controls. In LD-TFA Rotem, septic patients had delayed clot times (P = 0.04) but an increased maximum velocity of clot formation (P < 0.01) and area under the clot elasticity curve (P < 0.01). LD-TFA waveform analysis showed a delayed onset time but an increased rate of clot formation (P < 0.005). In conclusion, global tests of haemostasis suggest that in this patient group, activation of haemostasis is delayed but once initiated thrombin generation and clot formation are normal or enhanced.

Topics: Adult; Aged; Aged, 80 and over; Blood Coagulation Factors; Blood Coagulation Tests; C-Reactive Protein; Hemostasis; Humans; Middle Aged; Protein C; Systemic Inflammatory Response Syndrome; Thrombelastography; Thrombin; Thromboplastin

To compare indicators of systemic inflammatory response in the second trimester in women who developed pre-eclampsia with normal pregnancies.. Prospective nested case control study derived from a cohort of 2190 pregnant women. Blood samples were obtained at 18 weeks of gestation. The following inflammatory parameters were measured: tumour necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor-1 (PAI-1), interleukin-1beta (IL-1beta), IL-6, IL-10, microCRP and tissue factor (TF).. Institute of Medical Genetics, University of Oslo, and Department of Medical Genetics, Ullevål University Hospital and Departments of Obstetrics and Gynecology, Aker University Hospital, Oslo, Norway.. The cases were 71 women who subsequently developed pre-eclampsia. The controls were 71 healthy, pregnant women matched for age, parity and first trimester body mass index (BMI).. Venous blood was drawn from fasting subjects into 5 mL test tubes containing EDTA. Samples were analysed for inflammatory parameters: IL-1-beta, IL-6, IL-10, TNF-alpha, PAI-1, TF (ELISA-technique) and CRP (latex-enhanced immunonephelometric assay), strictly according to the manufacturer's recommendation.. The matched case and control subjects were compared by the paired two-tailed Wilcoxon signed rank test. All P values were two-tailed and P < 0.05 was deemed statistically significant.. We found no differences in plasma concentrations of PAI-1, IL-1beta, IL-6,IL-10, microCRP, TNF-alpha or TF at 18 weeks of gestation between women who subsequently developed pre-eclampsia and matched control women.. In contrast to findings from women with overt pre-eclampsia, the present study indicates that there are no indications of intensified systemic inflammatory response at 18 weeks of gestation in women who later develop pre-eclampsia.

Topics: C-Reactive Protein; Case-Control Studies; Cohort Studies; Female; Humans; Interleukins; Plasminogen Activator Inhibitor 1; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies; Systemic Inflammatory Response Syndrome; Thromboplastin; Tumor Necrosis Factor-alpha

Sepsis and septic shock are very complex and dynamic clinical syndromes. A systemic response to an infection or other triggers can induce a cascade consisting of toxins--leukocytes--cytokines--mediators of inflammation--endothelial cell dysfunction--activation of blood coagulation--intravascular fibrin deposition--alteration of microcirculation, resulting in a damage of organs. Multi organ failure and sepsis are therefore tightly connected. The associated disturbances of blood coagulation range between a simple activation of coagulation with a transient increase of activation markers (i.e. D-dimer), similar to an acute-phase reaction and full blown disseminated intravascular coagulation with consumption coagulopathy. This article summarizes these pathophysiological mechanisms, shows available diagnostic tools and differential diagnoses, and discusses therapeutic options for sepsis and multi organ failure.

Topics: Animals; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Endothelium, Vascular; Fibrinolysis; Humans; Inflammation Mediators; Multiple Organ Failure; Platelet Activation; Shock, Septic; Systemic Inflammatory Response Syndrome; Thromboplastin

To determine the precise relationship between tissue factor and tissue factor pathway inhibitor (TFPI) after trauma, as well as to test the hypothesis that low TFPI levels are not sufficient to prevent tissue factor-dependent intravascular coagulation, leading to multiple organ dysfunction syndrome (MODS).. Prospective, observational cohort study.. Emergency room and intensive care unit in a university hospital.. Thirty-three trauma patients, 18 with disseminated intravascular coagulation (DIC) and 15 without DIC were studied. Ten normal, healthy volunteers served as control subjects.. None.. Antigen concentration of tissue factor and TFPI, and global parameters of coagulation and fibrinolysis were measured on the day of admission, and on days 1-4 after admission. The number of systemic inflammatory response syndrome (SIRS) criteria that patients met and the DIC score were determined, simultaneously. The results of these measurements, incidence of MODS, and outcome were compared between the DIC patients and those without DIC. In the DIC patients, significantly higher tissue factor levels (p =.0049) and lower platelet counts (p =.0016) were found compared with the non-DIC patients and control subjects. However, the TFPI values remained at normal levels during the study period. No correlation was found between the peak levels of tissue factor and TFPI. The mean duration of SIRS and the maximum number of the SIRS criteria being met by the patients in the DIC group were statistically longer and higher than those in the non-DIC patients. The incidence of MODS and the number of the dysfunctioning organs were higher in the DIC patients compared with those in the non-DIC patients, and the DIC patients had a poor outcome.. We systematically elucidated the relationship between tissue factor and TFPI in post-trauma patients. Highly activated tissue factor-dependent coagulation pathway is not sufficiently prevented by the normal TFPI levels in patients with DIC. The DIC associated with thrombotic and inflammatory responses causes MODS, and leads to poor outcome in post-trauma patients.

Topics: Analysis of Variance; APACHE; Case-Control Studies; Disseminated Intravascular Coagulation; Female; Humans; Incidence; Inflammation; Lipoproteins; Male; Middle Aged; Multiple Organ Failure; Multiple Trauma; Platelet Count; Prognosis; Prospective Studies; Systemic Inflammatory Response Syndrome; Thromboplastin; Time Factors; Treatment Outcome

Topics: Disseminated Intravascular Coagulation; Humans; Systemic Inflammatory Response Syndrome; Thrombin; Thromboplastin

To determine the roles of tissue factor and thrombin on the systemic inflammatory response syndrome (SIRS) in posttrauma patients, as well as to investigate the relationship between SIRS and sepsis.. Prospective, cohort study.. General intensive care unit of a tertiary care emergency department.. Forty trauma patients were classified into subgroups, according to the duration of SIRS: non-SIRS patients (n = 9); patients with SIRS for < 2 days (n = 15); and patients with SIRS for > 3 days (n = 16).. None.. Tissue factor antigen concentration, prothrombin fragment F1+2, thrombin antithrombin complex, fibrinopeptide A, and cross-linked fibrin degradation products (D-dimer) were measured on the day of admission, and on days 1 through 4 after admission. Simultaneously, the number of SIRS criteria that the patients met and the disseminated intravascular coagulation score were determined. The results of these measurements, frequency of acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome, sepsis, and outcome were compared among the groups. The values of all five hemostatic molecular markers in the patients with SIRS for > 3 days were significantly more increased than those molecular marker values measured in the other groups on the day of admission. These values continued to be markedly high up to day 4 of admission. The occurrence rates of disseminated intravascular coagulation in these patient groups were significantly higher than those rates in the other two groups (p = .0001), and the disseminated intravascular coagulation scores did not improve during the study period. The occurrence rates of ARDS (p < .05) and multiple organ dysfunction syndrome (p < .01) were higher in patients with SIRS for > 3 days compared with those rates in the other groups, and the patients with SIRS for > 3 days had a poor outcome. No significant difference was noted in the frequency of sepsis among the groups.. Sustained SIRS is the main determinant for ARDS, multiple organ dysfunction syndrome, and outcome in posttrauma patients. Disseminated intravascular coagulation associated with massive thrombin generation and its activation is involved in the pathogenesis of sustained SIRS. Sepsis has a small role in early posttrauma multiple organ dysfunction syndrome.

Topics: Abbreviated Injury Scale; Adult; Analysis of Variance; Anticoagulants; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Female; Humans; Male; Middle Aged; Multiple Organ Failure; Prospective Studies; Respiratory Distress Syndrome; Systemic Inflammatory Response Syndrome; Thrombin; Thromboplastin; Wounds and Injuries