Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endotoxemia was evoked by bolus injection of Escherichia coli endotoxin (2 ng/kg body weight) in six healthy subjects to investigate the early kinetics of cytokine release in relation to the development of clinical and hematologic abnormalities frequently seen in gram-negative septicemia. The plasma concentration of tumor necrosis factor (TNF) increased markedly after 30 to 45 minutes, and reached a maximal level after 60 to 90 minutes. In each volunteer, the initial increase of plasma interleukin 6 (IL-6) concentrations occurred 15 minutes after the initial TNF increase, and maximal IL-6 concentrations were reached at 120 to 150 minutes. A transient increase in body temperature and pulse rate occurred simultaneously with the initial TNF and IL-6 increases, whereas a significant decrease in blood pressure occurred after 120 minutes. These changes were proportional to the changes in TNF and IL-6 concentrations. Coagulation activation, as assessed by a rise of prothrombin fragments and thrombin-antithrombin III complexes, was noted after 120 minutes, in the absence of activation of the contact system. A two- to sixfold increase in the concentrations of tissue plasminogen activator (t-PA) and von Willebrand factor antigen indicated endothelial cell activation. This increase started at 120 and 90 minutes, respectively. The release of t-PA coincided with activation of the fibrinolytic pathway, as measured by plasmin-alpha 2-antiplasmin complexes. The fibrinolytic activity of t-PA was subsequently offset by release of plasminogen activator inhibitor, observed 150 minutes after the endotoxin injection, and reaching a peak at 240 minutes. No complement activation was detected. These results show that in humans endotoxin induces an early, rapidly counteracted fibrinolytic response, and a more long-lasting activation of thrombin by a mechanism other than contact system activation. In addition, our data suggest that endotoxin-induced leukopenia and endothelial cell activation are mediated by TNF.
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PMID:Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. 212 34

Fatal multiple organ failure after severe infection may be related to an early activation of protease cascade systems. This study aimed to relate changes in coagulation, fibrinolysis, and kallikrein to shock and outcome. Of 53 patients with severe infection, 30 did not develop shock, 12 survived septic shock, and 11 died from organ failure after septic shock. No patient had overt disseminated intravascular coagulation. We measured 17 components of the coagulation/fibrinolysis/kallikrein pathways on admission and on the next 2 days. High values for fibrinogen, factor VIII:C, von Willebrand factor antigen, and D-dimer were seen in all patients; factor XII, prekallikrein, factor VII, antithrombin, protein C, and fibronectin were low. The patients thus appeared to be hypercoagulable. These disturbances were more pronounced in septic shock survivors, who also had low plasminogen and antiplasmin, indicating ongoing fibrinolysis. Nonsurvivors of sepsis were distinguished mainly by high plasminogen activator inhibitor values; this suggests an impaired functional fibrinolysis in fatal sepsis, with possible therapeutic implications. Cryoprecipitate infusion increased the fibronectin concentration, but did not influence the other factors studied.
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PMID:Coagulation, fibrinolysis, and kallikrein systems in sepsis: relation to outcome. 250 62

von Willebrand factor (vWF), a large adhesive glycoprotein, is synthesized by vascular endothelial cells (EC). Plasma levels of vWF manifest a broad normal range, and are elevated during sepsis and in inflammatory states. Since the inflammatory mediator, interleukin 1 (IL1) and bacterial endotoxin (LPS) both initiate procoagulant changes in vascular endothelium, we investigated the effect of these substances on endothelial cell release and residual endothelial cell content of vWF-antigen (vWFAg). Cultured human EC exposed to either IL1 or LPS released greater amounts of vWFAg compared to control EC. The augmented release could be detected within 1-2 h after exposure to IL1 or LPS and was not inhibited by cycloheximide, suggesting that de novo protein synthesis was not required for release to occur. Residual cellular vWFAg was reciprocally lower in IL1- or LPS-treated EC at 24 and 48 h, indicating that compensatory increase in synthesis of vWFAg did not occur during this time interval. Released vWF contained the higher molecular weight multimers observed in normal endothelial cells, and it possessed ristocetin cofactor activity. We propose that release of functional vWF from EC exposed to inflammatory mediators may be at a mechanism for localization of platelets and enhanced thrombogenicity at inflammatory foci.
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PMID:Interleukin 1 or endotoxin increases the release of von Willebrand factor from human endothelial cells. 349 29

In patients with nonpulmonary sepsis, von Willebrand factor antigen (vWF:Ag or Factor VIIR:Ag) levels have been reported to be predictive for the development of the adult respiratory distress syndrome (ARDS). We addressed the ability to generalize these results by measuring serial Factor vWF:Ag levels in 96 patients at risk for the development of ARDS. Patients with sepsis, pancreatitis, hypertransfusion, witnessed aspiration of gastric contents, abdominal trauma, chest trauma, and multiple fractures were studied. Sequential measurements were obtained at enrollment into the study (T = 0), and T = 6, 12, 24, and 48 h. Subjects were grouped into sepsis and nonsepsis categories and analyzed according to the following outcome definitions: ARDS and non-ARDS. The mean values for the sepsis and nonsepsis groups were elevated above normal at all time points. A statistically significant difference occurred in the mean vWF:Ag level for the ARDS and non-ARDS patients in the nonsepsis group at T = 0 (p = 0.05). To assess the clinical utility of these results, ROC (receiver operating characteristics) curves were plotted at T = 0, and optimal cutoff values of vWF:Ag were determined. In the sepsis group, the best value for vWF:Ag above which patients would actually develop ARDS was 399%, resulting in a 70% sensitivity and a 47% specificity. For the non-sepsis patients, the optimal value was 273%, yielding a sensitivity of 64% and a specificity of 52%. We conclude that measuring vWF:Ag levels are not helpful in predicting the progression to ARDS in multiple at-risk patients.
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PMID:von Willebrand factor antigen levels are not predictive for the adult respiratory distress syndrome. 781 45

Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein primarily synthesized by the endothelium. A major fraction (approximately 85%) of TFPI remains associated with the endothelium, whereas a small fraction (approximately 15%) is secreted into the blood. In our attempts to search for a marker(s) of endothelial injury in the setting of adult respiratory distress syndrome (ARDS), we retrospectively measured plasma TFPI levels in patients at risk for and with ARDS caused by several etiologic factors. Plasma von Willebrand factor antigen (vWF-Ag), another endothelial-specific protein, was also measured in these patients. The mean plasma TFPI levels were slightly elevated (approximately 1.3-fold), whereas vWF-Ag levels were significantly elevated (approximately 3-fold) in the at-risk group as compared with those in the normal subjects. Both the TFPI (approximately 1.8-fold) and the vWF-Ag (approximately 4-fold) levels were further elevated in the ARDS group. Moreover, the sequential plasma samples from patients with ARDS had progressively increased levels of vWF-Ag and TFPI up to Days 4 and 8, respectively. Neither plasma vWF-Ag nor TFPI levels correlated with mortality in the at-risk group or the ARDS group. TFPI levels were also measured in bronchoalveolar lavage fluids (BALF). The levels (ng/ml) were: normal subjects, 0.05 +/- 0.02 SE; at-risk group, 0.35 +/- 0.16 SE; ARDS group, 0.99 +/- 0.28 SE. Thus, the BALF TFPI levels were increased approximately 7-fold in the at-risk group and approximately 20-fold in the ARDS group relative to the value in the normal subjects. These findings indicate increased local synthesis of TFPI in the alveolar space both in the at-risk patients and in those with ARDS. In additional studies in a primate model of sepsis, lethal doses (LD100) of E. coli administered to baboons resulted in a progressive increase in TFPI levels (approximately 2-fold at 6 h), whereas sublethal doses caused only minimal increase (approximately 1.2-fold). The vWF-Ag levels were elevated approximately 5-fold after infusion of LD100 concentrations of E. coli at 6 h and 4-fold after infusion of sublethal concentrations of E. coli at 24 h. Autopsies on animals in the LD100 group revealed pulmonary congestion, leukocyte infiltration, edema, and hemorrhage, all suggestive of acute lung injury. Thus, in the setting of acute lung injury plasma vWF-Ag appears to be considerably increased prior to significant damage to the endothelium, whereas increased plasma TFPI occurs only after severe injury.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Tissue factor pathway inhibitor and von Willebrand factor antigen levels in adult respiratory distress syndrome and in a primate model of sepsis. 788 67

The aim of this study was to investigate a possible activation of human endothelial cells in monolayer culture by a purified neutrophil-derived proteinase, i.e. elastase. Cells were isolated from human umbilical cord veins, and incubated either in primary culture or after two passages, in the presence of various concentrations of this proteinase. Although a lack of prostacyclin formation was noted, elastase induced a large release of von Willebrand factor (vWf) in a concentration-dependent manner. Thus, upon incubation with 1 microgram.ml-1 elastase for 30 min, 70 mU.ml-1 vWf were detected in the incubation medium, as compared to 5 mU.ml-1 for control. Using cells in primary culture, a fivefold higher concentration of vWf was recovered following incubation with 10 micrograms.ml-1 elastase than with 0.5 IU.ml-1 thrombin. This effect was linked to the enzymatic activity of elastase and not to its cationic charge, as deduced from the inhibition by eglin C, and the lack of effect of the phenylmethylsulphonyl fluoride (PMSF) treated proteinase. We conclude that vWf release was not due to cell activation, since cytoplasmic calcium mobilization was absent, and inhibition of protein kinase C did not modify the response. In fact, this release was the consequence of cell damage, since concentrations of vWf recovered correlated with cell lysis. These results support the hypothesis that the high level of plasma vWf in patients with sepsis or adult respiratory distress syndrome could result from damage to the endothelial cells by elastase released from activated neutrophils.
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PMID:Leucocyte elastase-mediated release of von Willebrand factor from cultured endothelial cells. 833 96

We investigated the relationships between the angiographic severity of peripheral arterial occlusive disease (PAOD) and haemostasis, fibrinolytic, and rheological variables in 219 patients with symptomatic peripheral arterial occlusive disease (PAOD). White cell count, fibrinogen, cross-linked fibrin degradation products (FDP), von Willebrand factor, and plasminogen activator inhibitor levels were all elevated in comparison with age-matched population controls (all p < 0.0001, Mann-Whitney U test), while fibrinogen (Spearman r = 0.30), von Willebrand factor (r = 0.40), and log (FDP) (r = 0.56), (all p < 0.0001) showed a strong correlation with the angiographic extent of PAOD. Multivariate analysis indicated that log (FDP) was a strong independent predictor of the angiographic severity of PAOD (p < 0.0001), in addition to increasing age (p < 0.0001), presence of tissue sepsis (p < 0.02), prior vascular surgery (p = 0.007), and other vascular pathology (p = 0.007). These results confirm that increase in fibrinogen, von Willebrand factor, plasminogen activator inhibitor and fibrin turnover, are strongly associated with the presence of symptomatic peripheral arterial disease, and suggest that there may be a causal link between fibrin turnover, as determined by FDP levels, and the extent of peripheral arterial occlusive disease.
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PMID:Relation of haemostatic, fibrinolytic, and rheological variables to the angiographic extent of peripheral arterial occlusive disease. 870 25

Tumor necrosis factor-alpha (TNF alpha) is a central mediator in the pathogenesis of sepsis. It also interferes with the hemostatic system and exerts and a net procoagulant effect. Since TNF alpha may contribute to thrombotic complications in sepsis patients, we determined markers of thrombin activation, parameters of the fibrinolytic system (D-dimer, tissue plasminogen activator antigen (tPA) urinary type plasminogen activator antigen (uPA), plasminogen activator inhibitor antigen (PAI-1) and von Willebrand factor antigen (vWF) in 30 patients with sepsis or septic shock. All patients were treated with standard therapy, but 14 patients were treated additionally with an anti-TNF alpha monoclonal antibody (MAK 195F); 16 patients served as historical controls. No significant effect of the antibody on the parameters of the hemostatic system could be determined. Our data speak against a modulation of coagulation or the fibrinolytic system by the monoclonal anti-TNF alpha antibody MAK 195F in this cohort of sepsis patients.
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PMID:Hemostatic parameters in sepsis patients treated with anti-TNF alpha-monoclonal antibodies. 890 37

We investigated the relationships between the angiographic severity of peripheral arterial occlusive disease (PAOD) and haemostasis, fibrinolytic, and rheological variables in 219 patients with symptomatic peripheral arterial occlusive disease (PAOD). White cell count, fibrinogen, cross-linked fibrin degradation products (FDP), von Willebrand factor, and plasminogen activator inhibitor levels were all elevated in comparison with age-matched population controls (all p < 0.0001, Mann-Whitney U test), while fibrinogen (Spearman r = 0.30), von Willebrand factor (r = 0.40), and log (FDP) (r = 0.56), (all p < 0.0001) showed a strong correlation with the angiographic extent of PAOD. Multivariate analysis indicated that log (FDP) was a strong independent predictor of the angiographic severity of PAOD (p < 0.0001), in addition to increasing age (p < 0.0001), presence of tissue sepsis (p < 0.02), prior vascular surgery (p = 0.007), and other vascular pathology (p = 0.007). These results confirm that increases in fibrinogen, von Willebrand factor, plasminogen activator inhibitor and fibrin turnover, are strongly associated with the presence of symptomatic peripheral arterial disease, and suggest that there may be causal link between fibrin turnover, as determined by FDP levels, and the extent of peripheral arterial occlusive disease.
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PMID:Relation of haemostatic, fibrinolytic, and rheological variables to the angiographic extent of peripheral arterial occlusive disease. 891 37

To investigate interactions between the endothelium and leukocytes in patients with sepsis, we measured soluble adhesion molecules (sE-selectin and sICAM-1), von Willebrand factor antigen (vWf:Ag), myeloperoxidase (MPO), and lactoferrin (Lacto-f) as plasma markers of endothelial and neutrophil activation. We tested whether the five proteins were predictors of clinical severity, which was evaluated by simplified acute physiological score (SAPS), number of organ failures (MOF), acute lung injury (ALI), and subsequent final outcome. Levels of the five plasma markers were higher in patients with severe infection (n = 25) than in patients without sepsis (n = 7) and healthy volunteers (n = 9). In the study population, levels of sE-selectin, sICAM-1, and vWf:Ag were higher for nonsurvivors as well as for patients with septic shock or with bacteremia, and they were correlated with SAPS and MOF. Survival outcome was predicted with high sensitivity and specificity by initial plasma levels of sICAM-1 and vWf:Ag. The initial sICAM-1 level appeared to be an independent prognostic variable, based on a logistic regression analysis. Unlike sE-selectin, sICAM-1 remained at high levels indefinitely in nonsurvivors. We conclude that, unlike neutrophil activation markers, levels of endothelium-derived soluble adhesion molecules and vWf:Ag in severe sepsis syndrome are correlated with the severity of illness and may be considered as predictors of survival outcome.
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PMID:Elevated circulating E-selectin, intercellular adhesion molecule 1, and von Willebrand factor in patients with severe infection. 951 90


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