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)

Plasma concentrations of endothelin-1 (ET-1) and thrombomodulin (TM) were determined in patients with burns to examine their relation to the severity of illness. Tumor necrosis factor-alpha (TNF-alpha) was also measured, and its relationship to ET-1 and TM determined. Twenty-three burn patients were evaluated, who had a total burn surface area (TBSA) of at least 20 per cent. ET-1 was measured by radioimmunoassay (RIA). TM and TNF-alpha were measured by enzyme-linked immunosorbent assay (ELISA). Both the ET-1 and TM concentrations were significantly higher in the patients who developed sepsis than in those who did not and in the patients who eventually died than in those who survived. Maximum plasma concentrations of ET-1 and TM were significantly correlated with the acute physiological and chronic health evaluation II score. There was also a significant correlation between the plasma levels of TNF-alpha and both ET-1 and TM. ET-1 and TM closely reflect the severity of illness in patients with burns in the infectious stage; TNF-alpha may be involved in the production of ET-1 and TM.
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PMID:Plasma levels of endothelin-1 and thrombomodulin in burn patients. 898 35

Adult respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC) are serious complications of sepsis. Thrombomodulin, an important endothelial anticoagulant, binds thrombin to generate activated protein C (APC). To determine whether thrombomodulin purified from human urine (urinary thrombomodulin, UTM) is useful for the treatment of DIC and ARDS in sepsis, we examined the effect of UTM on endotoxin (ET)-induced coagulation abnormalities and pulmonary vascular injury in rats. Intravenous administration of UTM prevented the ET-induced pulmonary accumulation of leukocytes and the increase in pulmonary vascular permeability, as well as ET-induced histological changes such as leukocyte infiltration and pulmonary interstitial edema. On the other hand, dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, did not prevent these effects of ET. UTM did not prevent ET-induced pulmonary accumulation of leukocytes and pulmonary vascular injury in rats pretreated with DEGR-Xa. Our findings suggest that UTM attenuates ET-induced coagulation abnormalities and pulmonary vascular injury. Furthermore, the latter effect may be dependent on the capacity of UTM to activate protein C.
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PMID:Effect of human urinary thrombomodulin on endotoxin-induced intravascular coagulation and pulmonary vascular injury in rats. 903 85

Multiple transplant-related complications (MTRC) represent a severe condition after bone marrow transplantation (BMT) and are supposed to reflect systemic endothelial damage. Soluble thrombomodulin (sTM) and plasminogen activator inhibitor type-1 (PAI-1) were investigated as markers of endothelial dysfunction in 35 patients after autologous or allogeneic BMT and compared with the occurrence of the typical complications sepsis, veno-occlusive disease of the liver (VOD), graft-versus-host disease (GVHD), and capillary leakage syndrome (CLS). PAI-1 was assessed by an assay of functional activity and sTM by antigenic determination. In patients who had undergone allogeneic BMT and had no transplant-related complications (TRC), PAI-1 peaked on day +14 (20 +/- 5 units/ml), and sTM doubled in comparison to the starting range, to 60-80 ng/ml between days +14 and +49. In contrast, PAI-1 and sTM were unchanged following autologous BMT. PAI-1 was increased in sepsis, CLS, and VOD to 39-49 units/ml (p < 0.05, compared with patients without TRC), and in GVHD to 16-47 units/ml (not significant). Soluble TM increased to 63-309 ng/ml in patients with sepsis, VOD, or CLS (p < 0.05, compared with patients without TRC) and to 79-224 ng/ml in GVHD (not significant). The increase of sTM and PAI-1 was also positively correlated to the number of complications, so that in patients with three complications PAI-1 was increased 2.8-fold and sTM 3.5-fold over patients with no complications at all. We conclude that endothelial dysfunction is a feature of VOD, sepsis, CLS, and to lesser extent of GVHD and is worse in patients with multiple complications.
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PMID:Endothelial dysfunction after bone marrow transplantation: increase of soluble thrombomodulin and PAI-1 in patients with multiple transplant-related complications. 954 Jul 59

Disseminated intravascular coagulation (DIC) can be caused by a variety of diseases. Experimental models of DIC have provided substantial insight into the pathogenesis of this disorder, which may ultimately result in improved treatment. Disseminated coagulation is the result of a complex imbalance of coagulation and fibrinolysis. Simultaneously occurring tissue factor-dependent activation of coagulation, depression of natural anticoagulant pathways and shutdown of endogenous fibrinolysis all contribute to the clinical picture of widespread thrombotic deposition in the microvasculature and subsequent multiple organ failure. Cornerstone for the treatment of DIC is the optimal management of the underlying disorder. At present, specific treatment of the coagulation disorders themselves is not based on firm evidence from controlled clinical trials. Plasma and platelet transfusion are used in patients with bleeding or at risk for bleeding and low levels of coagulation factors or thrombocytopenia. The role of heparin and low molecular weight heparin is controversial, but their use may be justified in patients with active DIC and clinical signs of extensive fibrin deposition such as those with meningococcal sepsis. There is some evidence to indicate that low molecular weight heparin is as effective as unfractionated heparin but may be associated with a decreased bleeding risk. Antithrombin III (AT III) replacement appears to be effective in decreasing the signs of DIC if high doses are administered, but effects on survival or other clinically significant parameters are at best uncertain. If AT III supplementation is used, the dosage should be selected to achieve normal or supranormal plasma levels of 100% or higher. Results of studies on protein C concentrate, thrombomodulin or inhibitors of tissue factor are promising, but the efficacy and safety of these novel strategies remains to be established in appropriate clinical trials.
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PMID:Current drug treatment strategies for disseminated intravascular coagulation. 961 92

Gram-negative septic shock is mediated in part by endotoxin (lipopolysaccharide; LPS), and animal models have shown that blockade of even single adhesion molecules considerably improves survival. Thus interference with the adhesion cascade may provide a useful therapeutic approach in human sepsis. Young healthy men (n = 30) each received a bolus of 4 ng/kg LPS intravenously to study the effects of endotoxemia on adhesion processes in humans and to identify potential targets for pharmacologic intervention. One third of subjects received pretreatment with 1,000 mg aspirin and 1,000 mg paracetamol to study potential antiinflammatory effects of aspirin or effects of antipyresis. Circulating neutrophils dropped by -80% at 67 min after LPS, monocytes by -96% at 90 min, and lymphocytes by -85% at 240 min. L-selectin expression decreased, particularly on monocytes. Circulating (c)E-selectin levels increased by 820%, von Willebrand factor-Ag (vWF), soluble thrombomodulin, circulating (c)P-selectin, circulating intercellular adhesion molecule-1 (cICAM-1), and circulating vascular cell adhesion molecule-1 (cVCAM-1) by a mean of 65 to 98% (p < 0.001 for all), but cL-selectin by only 15%. Urinary excretion of soluble adhesion molecules was negligible. Aspirin had no influence on the LPS-induced changes of adhesion parameters, but paracetamol blunted the relative increase in vWF while having no effects on the other parameters measured. The consistent, profound, and early upregulation of cE-selectin during endotoxemia indicates that cE-selectin may be a better surrogate marker to monitor the activation status of endothelial cells in systemic inflammation than the other markers measured. Although aspirin did not have any antiinflammatory effects in this model, paracetamol lowered the relative increase in vWF.
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PMID:Regulation of adhesion molecules during human endotoxemia. No acute effects of aspirin. 1005 Dec 63

In order to determine the effect of bacterial proteinases on activation of the protein C system, a negative regulator of blood coagulation, two arginine-specific cysteine proteinases (gingipains R) from Porphyromonas gingivalis, a causative bacterium of adult periodontitis, were examined. Each enzyme activated human protein C in a dose- and incubation time-dependent manner. Interestingly, the form of enzyme being composed of a non-covalent complex containing both catalytic and adhesion domains (RgpA) produced activated protein C 14-fold more efficiently than RgpB which contained the catalytic domain alone. The kcat/Km value of RgpA was 18-fold higher than that of RgpB and comparable to that of the thrombin-thrombomodulin complex, the physiological activator of protein C. RgpA catalyzed protein C activation was augmented 1.4-fold by phospholipids, ubiquitous cell membrane components. Furthermore, RgpA, but not RgpB, could activate protein C in plasma and this resulted in a decrease of the protein C concentration in plasma, which is often observed in patients with sepsis during the development of disseminated intravascular coagulation (DIC). These data indicate that RgpA is a more potent activator of protein C than RgpB and suggest that only the former enzyme can cause protein C activation in vivo. The present study further suggests that bacterial proteinases may possibly contribute to the consumption of plasma protein C which predisposes to DIC and/or promotes a thrombotic tendency towards DIC in sepsis.
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PMID:Activation of protein C by arginine-specific cysteine proteinases (gingipains-R) from Porphyromonas gingivalis. 1006 39

The protein C pathway plays a critical role in the negative regulation of the blood clotting process. We recently identified an endothelial cell receptor for protein C/activated protein C (APC). The receptor is localized almost exclusively on endothelial cells of large vessels and is present at only trace levels or indeed absent from capillaries in most tissues. Patients with sepsis or lupus erythematosus exhibit elevated levels of plasma EPCR which migrates on gels as a single band and is fully capable of binding protein C/APC. There is no correlation with thrombomodulin levels, probably due to different vascular localizations and/or cellular release mechanisms. To understand the mechanisms by which EPCR plasma levels are elevated, we examined EPCR mRNA expression in a rat endotoxin shock model. The EPCR mRNA gene exhibited an early immediate gene response to endotoxin with the mRNA levels increasing nearly 4 fold in the first 3-6 hrs, before returning toward baseline. Plasma levels of EPCR also rose about 4 fold with little change in tissue EPCR levels. Both processes were markedly attenuated by hirudin suggesting that thrombin was responsible for increases in mRNA and plasma EPCR levels. At the level of mRNA, the induction is mediated by a thrombin response element in the 5' flanking region of the gene. Direct thrombin infusion and cell culture experiments support this contention. On endothelium, thrombin is capable of releasing cell surface EPCR and this process is blocked by the metalloproteinase inhibitor orthophenanthroline. Taken together these studies indicate that elevation in soluble plasma EPCR reflects endothelial cell activation in the larger vessels and is likely to be an indication of local thrombin generation near these vessel surfaces.
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PMID:Regulation and functions of the protein C anticoagulant pathway. 1019 Sep 52

Sepsis is commonly associated with disturbances of the hemostatic balance. Most of the pathophysiological changes in sepsis are caused by endotoxin acting directly through endothelial injury or indirectly through release of cytokines with procoagulant effects. The relation between cytokines and hemostatic parameters was assessed in 32 patients with sepsis. Prothrombin fragment 1+2 (F1+2), thrombin-antithrombin III complexes (TAT), tissue type plasminogen activator (t-PA) functional and antigen, plasminogen activator inhibitor-1 (PAI-1), plasminalpha2-antiplasmin complexes (PAP), D-Dimer, thrombomodulin (TM) and von Willebrand factor (vWF) were measured in patients and in 30 healthy subjects. The levels of cytokines TNF-alpha and interleukin-6 (IL-6) also were determined. A significant increase of F1+2, TAT, PAI-1, PAP, and D-Dimer was observed in septic patients as compared with controls (p<0.0001), whereas t-PA activity was significantly reduced (p<0.01). The markers of endothelial cell activation TM, vWF, and t-PA antigen also were elevated significantly as compared with the control group (p<0.01). Finally, we found a marked increase of TNF-alpha and IL-6 (p<0.0001). Whereas the increase of cytokine levels could be partially responsible for the hemostatic activation, it did not correlate with markers of endothelial activation in patients with sepsis.
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PMID:Endothelial cell and hemostatic activation in relation to cytokines in patients with sepsis. 1023 Aug 94

We measured the plasma levels of adrenomedullin (AM), a novel vasodilating peptide, in 89 patients with various forms of systemic inflammatory response syndrome (SIRS) and 13 healthy volunteers serving as controls. Plasma levels of AM in SIRS (burns: 20.5 +/- 3. 2 fmol/ml [mean +/- SEM]; pancreatitis: 13.8 +/- 3.8 fmol/ml; trauma: 14.9 +/- 2.5 fmol/ml; traumatic shock: 41.1 +/- 7.8 fmol/ml; severe sepsis: 59.9 +/- 11.2 fmol/ml; septic shock: 193.5 +/- 30.1 fmol/ml) were significantly increased over those of controls (5.1 +/- 0.2 fmol/ml). The patients with traumatic shock or septic shock especially had higher levels of plasma AM than those with trauma or severe sepsis, respectively. These data showed that in patients with SIRS, plasma AM levels increased in proportion to the severity of illness. Subsequently, we measured the plasma levels of mediators such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, plasminogen activator inhibitor (PAI)-1, and thrombomodulin (TM) in patients with traumatic shock and septic shock. A significant correlation was observed between plasma AM and TNF-alpha levels in patients with septic shock, suggesting an important role for AM as well as of TNF-alpha in the pathophysiology of inflammation. Plasma AM and IL-8 levels correlated positively with Acute Physiology and Chronic Health Evaluation (APACHE) II score, peak multiple organ failure (MOF) score during the first month and prognosis in patients with septic shock, as did plasma IL-6 levels in patients with traumatic shock. The plasma AM level might serve as a useful marker for evaluating the severity of disease and as an early predictor of subsequent organ failure and outcome in septic shock.
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PMID:Increased plasma levels of adrenomedullin in patients with systemic inflammatory response syndrome. 1039 Mar 90

The protein C anticoagulant pathway converts the coagulation signal generated by thrombin into an anticoagulant response through the activation of protein C by the thrombin-thrombomodulin (TM) complex. The activated protein C (APC) thus formed interacts with protein S to inactivate two critical coagulation cofactors, factors Va and VIIIa, thereby dampening further thrombin generation. The proposed mechanisms by which TM switches the specificity of thrombin include conformational changes in thrombin, blocking access of normal substrates to thrombin and providing a binding site for protein C. The function of protein S appears to be to alter the cleavage site preferences of APC in factor Va, probably by changing the distance of the active site of APC relative to the membrane surface. The clinical relevance of this pathway is now established through the identification of deficient individuals with severe thrombotic complications and through the analysis of families with partial deficiencies in these components and an increased thrombotic tendency. One possible reason that even partial deficiencies are a thrombotic risk is that the function of the pathway can be down-regulated by inflammatory mediators. For instance, clinical studies have shown that the extent to which protein C levels decrease in patients with septic shock is predictive of a negative outcome. Initial clinical studies suggest that supplementation with protein C may be useful in the treatment of acute inflammatory diseases such as sepsis.
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PMID:Regulation of blood coagulation. 1070 69


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