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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue factor pathway of coagulation plays a dominant role during normal haemostasis. Tissue factor pathway inhibitor (TFPI), expressed primarily by the microvascular endothelium, appears to be the major physiologic inhibitor of TF-induced coagulation. TF-initiated coagulation also plays an important role in the pathophysiology of many diseases including coronary thrombosis, sepsis, disseminated intravascular coagulation, stroke, cancer, acute respiratory distress syndrome, and ischemia-reperfusion injury. Several animal studies have found a beneficial effect of anti-TF monoclonal antibodies and, recombinant TFPI in some of the above clinical conditions. rTFPI is presently being used in clinical trials in patients with sepsis and in those following microvascular surgery. This article discusses many of the animal studies addressing inhibition of TF-induced coagulation, as well as potential therapeutic uses of rTFPI in humans.
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PMID:Tissue factor pathway inhibitor: potential therapeutic applications. 919 99

To determine whether treatment with recombinant human tissue factor pathway inhibitor (TFPI), an inhibitor of the extrinsic coagulation pathway, can improve survival in a clinically relevant model of gram-negative sepsis, rabbits were given an intraperitoneal inoculation of a suspension containing hemoglobin (40 microg/mL), porcine mucin (150 microg/mL), and viable Escherichia coli O18:K1 (1.0 +/- 0.5 x 10(5) cfu/kg). Treatment with gentamicin (5 mg/kg every 12 h for five doses) was instituted 4 h after induction of peritonitis. At the same time point, rabbits were randomized to receive a 24-h infusion of vehicle or one of three different doses of TFPI. Treatment groups, 7-day survival rates, and significance versus control were as follows: control, 1 of 20; TFPI(LOW DOSE) (0.1 mg/kg, then 1 microg/kg/min), 3 of 12 (P = .14); TFPI(MID DOSE), (0.5 mg/kg, then 5 microg/kg/min), 7 of 12 (P = .002); TFPI(HIGH DOSE) (10 mg/kg, then 10 microg/kg/min), 4 of 13 (P = .04). Thus, delayed treatment with TFPI improves survival in septic rabbits.
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PMID:Delayed treatment with recombinant human tissue factor pathway inhibitor improves survival in rabbits with gram-negative peritonitis. 949 46

This study was designed to determine the effect of a delayed infusion (T+120 min) of alanyl tissue factor pathway inhibitor (ala-TFPI) on the response to LD100 E. coli. We hypothesized that baboons treated with a low dose of TFPI (5 mg/kg) which did not survive would exhibit thrombosis, infarction and hemorrhage of target tissues such as that seen in untreated animals infused with LD100 E. coli. Eight baboons were infused with 5 mg/kg of ala-TFPI over a 10 h period beginning immediately after a 2 h infusion of LD100 E. coli (experimental group). Four baboons were infused with E. coli followed by a 10 h infusion of saline (control group). Of the 12 baboons, the 11 non-survivors (TFPI = 7 out of 8; controls = 4 out of 4) were evaluated for the extent of thrombosis, necrosis, hemorrhage, and congestion of target tissues and for changes in clinical chemical parameters. We expected that failure to protect would correlate with failure to inhibit thrombosis of target tissue (8). Surprisingly ala-TFPI significantly inhibited thrombosis, hemorrhage and necrosis of adrenal and renal tissues and attenuated the rise in creatinine in the 7 treated non-survivors. The lungs of these non-survivors, however, exhibited intra-alveolar fibrin and a mild degree of hemorrhage and edema. We concluded that low doses of ala-TFPI begun as late as T+120 in minutes failed to protect against the lethal effects of LD100 E. coli in spite of completely preventing thrombosis and hemorrhage in target organs, and that thrombosis, infarction and hemorrhage of adrenal and renal tissue are not part of the lethal chain of events in this IV model of E. coli sepsis.
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PMID:Attenuation of tissue thrombosis and hemorrhage by ala-TFPI does not account for its protection against E. coli--a comparative study of treated and untreated non-surviving baboons challenged with LD100 E. coli. 960 45

TF (tissue factor) is a physiological inhibitor of blood coagulation in normal hemostasis and is a major initiator of clotting in thrombotic disease. TF functions as a protein cofactor for FVIIa. Coagulation at a site of injury is initiated by exposure of blood to cell-surface formation of TF/VIIa complex. The TF/VIIa complex then activates both factors IX and X leading to thrombin generation and fibrin formation. TFPI (tissue factor pathway inhibitor) appears to play a primary role in regulating TF-induced coagulation. Abnormal coagulation may contribute to the pathogenesis of many serious illnesses. In particular, induced expression of TF and TF-mediated coagulation occurs in atherosclerotic plaques, sepsis, malignancy, ARDS and glomerulonephritis. Several observations support the need for exogenous TFPI administration to effectively turn off the TF/VIIa complex in several clinical conditions with TF-induced coagulopathy. There are some reports about successful administration of rTFPI for antithrombotic therapy in humans.
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PMID:[The role of tissue factor and its inhibitor in hemostasis]. 969 46

This study tested the hypothesis that tissue factor pathway inhibitor (TFPI) would improve mortality and morbidity evoked by peritonitis-induced bacteremia in pigs. Secondarily, it sought to determine if TFPI treatment would attenuate cardiodynamic abnormalities produced by this septic model. 32 pigs were chronically instrumented with intracardiac transducers to measure left ventricular pressure and diameter, pulmonary and aortic pressures, and cardiac output. At least 5 days after surgery to implant transducers, basal cardiovascular readings and blood samples were obtained. Using a randomized, blinded study design, either purified, reconstituted TFPI (1 mg/kg bolus, 10 mg/kg/min for 48 h), placebo (arginine buffer), or saline was administered to pigs immediately after Escherichia coli 0111.B4 (3.0-11 x 10(9) colony-forming U/kg)-laden fibrin clots were implanted intraperitoneally, producing peritonitis and bacteremia. Pigs did not receive antibiotics or supportive therapy. No significant differences in primary or secondary endpoints were noted between the arginine and saline groups, so these data were combined into a control group (N = 20). 5 of 12 TFPI pigs survived (42%), while 5 of 20 control pigs survived (25%); this difference was not significant (p = .714, Fisher's exact test). TFPI treatment augmented cardiac output in surviving pigs, but did not affect any other cardiovascular performance variable (heart rate, % diameter shortening, or systemic and pulmonary vascular resistance). In controls, peritonitis induced rapid increase in plasma tumor necrosis factor-alpha (428 +/- 771 to 5,933 +/- 559 pg/mL at 2 h) and interleukin-8 (180 +/- 153 to 1,393 +/- 145 pg/mL at 2 h). TFPI treatment significantly attenuated cytokine responses to sepsis, reducing peak tumor necrosis factor-alpha to 2,103 +/- 813 pg/mL and reducing peak interleukin-8 levels to 534 +/- 211 pg/mL at 2 h (p < .05, Tukey test, two-way ANOVA). In conclusion, TFPI treatment attenuated important mediator components of the inflammatory response but did not provide significant survival benefit.
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PMID:Randomized, blinded, placebo-controlled trial of tissue factor pathway inhibitor in porcine septic shock. 978 57

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

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

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

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by intravascular fibrin formation occurring in the course of a variety of severe diseases. In gram-negative sepsis, endotoxin is the bacterial component eliciting a cascade of tissue factor dependent hypercoagulable reactions mediated by cytokines, including tumor necrosis factor-alpha and interleukin-6. Fibrinolysis is activated in this process by the action of tumor necrosis factor-alpha, but its activity is impaired by the predominant inhibitory effect of plasminogen activator inhibitor-1. Natural inhibitory mechanisms include antithrombin, the protein C system, and tissue factor pathway inhibitor. Each of these defense systems counteracts the harmful effects of DIC, and its acquired deficiency is associated with increased mortality in observational studies. The generation of several proteases in DIC, including factor Xa and thrombin, has potential interactions with inflammatory pathways that may potentiate the systemic inflammatory syndrome that often accompanies DIC. Experimental studies support the notion that defects in the protein C pathway modulate the inflammatory response, and illustrate that coagulation and inflammation are coupled systems in DIC.
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PMID:Pathophysiology of disseminated intravascular coagulation in sepsis. 1100 90

Tissue factor mediated pathways leading to microvascular thromboses and endothelial activation appear to play an important role in the development of multiple organ failure associated with severe sepsis. Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of tissue factor associated coagulation cascades. In experimental models of severe sepsis, treatment with TFPI results in significant reduction in mortality. Similarly, a recently completed Phase II 210-patient study comparing placebo and infusions of TFPI showed trends toward a relative reduction in day 28 all-cause mortality in TFPI treated patients. These data suggest that coagulation cascades involving tissue factor contribute to organ dysfunction in critically ill septic patients. TFPI may be a useful therapy in improving outcome of severe sepsis.
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PMID:Tissue factor inhibition and clinical trial results of tissue factor pathway inhibitor in sepsis. 1100 94


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