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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of tissue factor (TF) by monocytes/macrophages leads to thrombin generation and contributes to their physiological and pathophysiological roles in wound repair, disseminated intravascular coagulation linked to sepsis, postoperative thrombosis, unstable angina, atherosclerosis, chronic inflammation and cancer. Regulation of TF expression in monocytes is controlled by the transcription factors NF-kappaB and AP-1. In whole blood, the activation of the transcription factors is mediated through the phospholipase A2 pathway. Platelets play a crucial role in the expression of TF activity in monocytes, and granulocytes are mandatory in provoking the platelet effect in a P-selectin-dependent reaction. Although all induced or constitutive TF is expressed on the surface of monocytes, its catalytic activity is only about 10% compared to the activity of lysed cells. This phenomenon has been attributed to the increased availability of anionic phospholipid (phosphatidylserine) after cell lysis. At the surface of viable cells, the transmembrane phospholipid distribution and its regulation may be important for the expression of the catalytic activity of the complex of TF and activated factor VII. Phosphatidylserine pathophysiologically exposed at the outer surface of monocytes may, similar to that for platelet membranes, provide a strong stimulus for thrombin generation.
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PMID:Tissue factor expression by monocytes: regulation and pathophysiological roles. 981 23

Tissue factor (TF) is the major activator of the coagulation protease cascade and contributes to lethality in sepsis. Despite several studies analyzing TF expression in animal models of endotoxemia, there remains debate about the cell types that are induced to express TF in different tissues. In this study, we performed a detailed analysis of the induction of TF mRNA and protein expression in two rabbit models of endotoxemia to better understand the cell types that may contribute to local fibrin deposition and disseminated intravascular coagulation. Northern blot analysis demonstrated that lipopolysaccharide (LPS) increased TF expression in the brain, lung, and kidney. In situ hybridization showed that TF mRNA expression was increased in cells identified morphologically as epithelial cells in the lung and as astrocytes in the brain. In the kidney, in situ hybridization experiments and immunohistochemical analysis showed that TF mRNA and protein expression was increased in renal glomeruli and induced in tubular epithelium. Dual staining for TF and vWF failed to demonstrate TF expression in endothelial cells in LPS-treated animals. These results demonstrate that TF expression is induced in many different cell types in LPS-treated rabbits, which may contribute to local fibrin deposition and tissue injury during endotoxemia.
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PMID:Lipopolysaccharide induction of tissue factor expression in rabbits. 1022 18

Sepsis is a frequent complication of critically ill patients and its incidence is increasing. Currently, septic shock is the most common cause of death in non-coronary intensive care units. Over the last 10 to 15 years, new antibiotics and increasingly sophisticated critical care have had little impact on the mortality rate of septic shock. The Italian SEPSIS Study, carried out in 99 intensive care units in 1994, reported mortality rates of 52% and 82% for severe sepsis and septic shock respectively. New therapeutic approaches aimed at neutralizing microbial toxins and modulating host mediators have shown some efficacy in large clinical trials and/or in animal models, but to date, no therapy of sepsis aimed at reversing the effects of bacterial toxins or of harmful endogenous mediators of inflammation has gained widespread clinical acceptance. Because of the strong association of severe sepsis with a state of activation of blood coagulation and of the potential role of capillary thrombosis in the development of the multiple organ dysfunction syndrome, anticoagulant agents have been tested in the setting of septic shock. However, neither administration of heparin nor of active site-blocked factor Xa or of anti-tissue factor antibodies have proven effective in preventing deaths due to septic shock in animal models. In contrast, infusion of antithrombin, protein C, or tissue factor pathway inhibitor all resulted in a significant survival advantage in animals receiving lethal doses of E. Coli. Antithrombin concentrates have been used in a significant number of critically ill patients. A double-blind, placebo controlled study carried out in 3 italian intensive care units has recently shown that the administration of antithrombin aimed to normalize plasma antithrombin activity had a net beneficial effect on 30-day survival of patients requiring respiratory and/or hemodynamic support because of severe sepsis and/or post-surgery complications.
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PMID:Antithrombin replacement in patients with sepsis and septic shock. 1032 25

Induction of tissue factor (TF) activity by endotoxin and cytokines is an important mechanism for initiation of disseminated intravascular coagulation (DIC) seen in patients with gram-negative sepsis. Based on data from an in vitro study in which dithiocarbamates abrogated endothelial cell TF activity by inhibition of the NF-kappaB pathway, we investigated whether dithiocarbamates had in vivo activity in an animal model of DIC. Dithiocarbamates ameliorated the adverse clinical and histological effects of endotoxin-induced DIC, including morbidity, hypofibrinogenemia, and target organ damage, especially in the liver and kidney, even when given up to 1 hour after administration of endotoxin. This pilot study confirms the key role of the nuclear factor-kappa beta (NF-kappaB) pathway in induction of TF activity in initiating sepsis-associated DIC and suggests that dithiocarbamates may be useful in treatment of DIC associated with excessive TF expression because of gram-negative sepsis. Additional studies of dithiocarbamates in DIC models are warranted.
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PMID:Dithiocarbamates ameliorate the effects of endotoxin in a rabbit model of disseminated intravascular coagulation. 1054 75

Tissue factor pathway inhibitor (TFPI), the major downregulator of the procoagulant activity of tissue factor (TF), is synthesised by endothelial cells (EC) and acutely released in vitro after thrombin stimulation. Expression of TF on EC and subsequent thrombin generation occurs in vivo during sepsis or malignancy, inducing disseminated intravascular coagulation (DIC). The present study investigates the changes in plasma TFPI in relation to markers of in vivo thrombin generation induced by injection of factor Xa (FXa)/phospholipids in baboons at dosages leading to partial (48%) or complete fibrinogen depletion. The plasma concentrations of thrombin-antithrombin III (TAT) and fibrinopeptide A (FpA), as markers of in vivo generation of thrombin, were strongly enhanced after injection of FXa/phospholipids. TFPI levels, whether measured as antigen or activity, increased significantly in both treatment groups within few minutes, and were dependent on the dose of FXa/phospholipids. Significant positive correlations between plasma levels of TFPI and of TAT or FpA were observed. Altogether, our results indicate that experimentally induced in vivo generation of thrombin causes the acute release of TFPI, high-lighting a possible novel function of thrombin in downregulation of the coagulation process, potentially relevant for the outcome of DIC.
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PMID:Acute release of tissue factor pathway inhibitor after in vivo thrombin generation in baboons. 1061 51

Patients with meningococcal sepsis generally suffer from disseminated intravascular coagulation (DIC). The aim of this study was to address whether these patients have elevated numbers of circulating microparticles that contribute to the development of DIC. Plasma samples from 5 survivors, 2 nonsurvivors, and 5 healthy volunteers were analyzed for the presence of microparticles by flow cytometry. Ongoing coagulation activation in vivo was quantified by enzyme-linked immunosorbent assay of plasma prothrombin fragment F(1 + 2), and procoagulant properties of microparticles in vitro were estimated by thrombin-generation assay. On admission, all patients had increased numbers of microparticles originating from platelets or granulocytes when compared with controls (P =.004 and P =.008, respectively). Patients had elevated levels of F(1 + 2) (P =.004), and their microparticles supported thrombin generation more strongly in vitro (P =.003) than those of controls. Plasma from the patient with the most fulminant disease course and severe DIC contained microparticles that expressed both CD14 and tissue factor, and these microparticles demonstrated extreme thrombin generation in vitro. We conclude that patients with meningococcal sepsis have elevated numbers of circulating microparticles that are procoagulant. These findings may suggest a novel therapeutic approach to combat clinical conditions with excessive coagulation activation.
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PMID:Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. 1064 5

Inhibition of the tissue factor pathway has been shown to attenuate the activation of coagulation and to prevent death in a gram-negative bacteremia primate model of sepsis. It has been suggested that tissue factor influences inflammatory cascades other than the coagulation system. The authors sought to determine the effects of 2 different doses of recombinant tissue factor pathway inhibitor (TFPI) on endotoxin-induced coagulant, fibrinolytic, and cytokine responses in healthy humans. Two groups, each consisting of 8 healthy men, were studied in a double-blind, randomized, placebo-controlled crossover study. Subjects were studied on 2 different occasions. They received a bolus intravenous injection of 4 ng/kg endotoxin, which was followed by a 6-hour continuous infusion of TFPI or placebo. Eight subjects received 0.05 mg/kg per hour TFPI after a bolus of 0.0125 mg/kg (low-dose group), and 8 subjects received 0.2 mg/kg per hour after a bolus of 0.05 mg/kg (high-dose group). Endotoxin injection induced the activation of coagulation, the activation and subsequent inhibition of fibrinolysis, and the release of proinflammatory and antiinflammatory cytokines. TFPI infusion induced a dose-dependent attenuation of thrombin generation, as measured by plasma F1 + 2 and thrombin-antithrombin complexes, with a complete blockade of coagulation activation after high-dose TFPI. Endotoxin-induced changes in the fibrinolytic system and cytokine levels were not altered by either low-dose or high-dose TFPI. The authors concluded that TFPI effectively and dose-dependently attenuates the endotoxin-induced coagulation activation in humans without influencing the fibrinolytic and cytokine response. (Blood. 2000;95:1124-1129)
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PMID:Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. 1066 80

During sepsis, lipopolysaccharide (LPS) triggers the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation resulting in massive thrombin generation and fibrin polymerization. Recently, animal studies demonstrated that hirudin reduced fibrin deposition in liver and kidney and decreased mortality in LPS-induced DIC. Accordingly, the effects of recombinant hirudin (lepirudin) was compared with those caused by placebo on LPS-induced coagulation in humans. Twenty-four healthy male subjects participated in this randomized, double-blind, placebo-controlled, parallel group study. Volunteers received 2 ng/kg LPS intravenously, followed by a bolus-primed continuous infusion of placebo or lepirudin (Refludan, bolus: 0.1 mg/kg, infusion: 0.1 mg/kg/h for 5 hours) to achieve a 2-fold prolongation of the activated partial thromboplastin time (aPTT). LPS infusion enhanced thrombin activity as evidenced by a 20-fold increase of thrombin-antithrombin complexes (TAT), a 6-fold increase of polymerized soluble fibrin, termed thrombus precursor protein (TpP), and a 4-fold increase in D-dimer. In the lepirudin group, TAT increased only 5-fold, TpP increased by only 50%, and D-dimer only slightly exceeded baseline values (P <.01 versus placebo). Concomitantly, lepirudin also blunted thrombin generation evidenced by an attenuated rise in prothrombin fragment levels (F(1 + 2), P <. 01 versus placebo) and blunted the expression of tissue factor on circulating monocytes. This experimental model proved the anticoagulatory potency of lepirudin in LPS-induced coagulation activation. Results from this trial provide a rationale for a randomized clinical trial on the efficacy of lepirudin in DIC. (Blood. 2000;95:1729-1734)
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PMID:Lepirudin blunts endotoxin-induced coagulation activation. 1068 31

High circulating levels of the procoagulant molecule tissue factor (TF) are associated with thrombosis in a variety of diseases including unstable angina, cancer, and sepsis. Currently, there are no clinical assays to measure the level of TF activity in whole blood. We present an assay called Tissue Factor Clotting Time ("TiFaCT") that detects fibrin formation in human blood. The mean baseline clotting time in a healthy population was 472 +/- 94 s (mean +/- SD, n = 150). Bacterial lipopolysaccharide (LPS or endotoxin) shortened the clotting time in a time-dependent manner. Inhibitory anti-TF antibodies prolonged the clotting time of LPS-stimulated blood, indicating that the shortened clotting time was due to induction of TF expression. Patients with unstable angina had shortened mean baseline clotting time (284 +/- 86, n = 13) compared with healthy volunteers (474 +/- 98, n = 30), suggesting that these patients had elevated levels of circulating TF. The TiFaCT assay should prove clinically useful in quantifying the levels of circulating TF in patients at risk of thrombosis.
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PMID:Measurement of tissue factor activity in whole blood. 1074 52

Endothelial cells have two important anticoagulant systems, heparan sulfate-antithrombin system and thrombomodulin-protein C system. Under physiological conditions, these two systems inhibit activation of coagulation on endothelial cells. However, under inflammatory conditions, tumor necrosis factor(TNF)-alpha or other cytokines produced by monocytes reduce the anticoagulant properties of endothelial cell by downregulating expression of heparan sulfate and thrombomodulin on endothelial cells. Antithrombin stimulates prostacyclin generation from endothelial cells by interacting with heparan sulfate of endothelial cells and generated prostacyclin inhibits TNF-alpha production by monocytes. Activated protein C inhibits TNF-alpha production by monocyte dependent of its protease activity. Thus, antithrombin and activated protein C might inhibit the endothelial perturbation induced by cytokines. Antithrombin regulates TNF-alpha induced tissue factor expression on endothelial cells by an unknown mechanism. Thus, antithrombin and activated protein C might be useful agents for treating coagulation abnormalities associated with sepsis or other inflammation because these agents inhibit not only coagulation but also downregulation of anticoagulant activities of endothelial cells.
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PMID:[Endothelial cells and coagulation abnormalities]. 1081 Aug 75


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