Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Purpura fulminans is associated with homozygous protein C and homozygous protein S deficiency or may follow bacterial or viral infections. We present 2 children from 2 unrelated Arab families with purpura fulminans who were double heterozygotes for factor V Leiden inherited from their fathers and protein S deficiency inherited from their mothers. No previous thrombotic events have occurred in either patient or their respective family members. In one patient sepsis accompanied by disseminated intravascular coagulation appeared to be the trigger of purpura fulminans. In the other patient varicella infection preceded purpura fulminans and was also associated with disseminated intravascular coagulation. This report emphasizes the need for evaluation of hereditary defects in the inhibitory mechanisms of blood coagulation in patients with purpura fulminans at any age.
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PMID:Purpura fulminans induced by disseminated intravascular coagulation following infection in 2 unrelated children with double heterozygosity for factor V Leiden and protein S deficiency. 924 37

Budd Chiari syndrome is a rare disorder resulting from occlusion of hepatic venous drainage by hepatic vein thrombosis or by a membranous web in the inferior vena cava. In western countries the commonest causes are myeloproliferative disorders and hypercoagulable states. Presentation may be acute with rapid accumulation of ascites and hepatic failure, or subacute with symptoms developing over a few months. A chronic progressive form has also been described. On presentation there is usually abdominal pain, ascites, and hepatosplenomegaly; hepatic encephalopathy is found in about a third. Noninvasive, ultrasound-Doppler is recommended in diagnosis, and has a high correlation with hepatic venography. Liver biopsy is required for therapeutic decisions. Those with advanced hepatic failure or severe fibrosis on liver biopsy are referred for hepatic transplantation. When biopsy shows only hepatic congestion and inflammatory infiltrates, portosystemic shunting is recommended. We present a 61-year-old woman with ascites and hepatosplenomegaly that had developed over the courses of a few months. Budd-Chiari syndrome with chronic myelofibrosis and congenital protein C deficiency were diagnosed. Portosystemic shunt was performed but death from sepsis followed shortly.
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PMID:[Budd-Chiari syndrome]. 933 72

In patients with sepsis and septic shock, both coagulation and fibrinolysis are activated frequently leading to the syndrome of diffuse intravascular coagulation (DIC). The different mechanisms leading to abnormalities in coagulation and fibrinolysis are discussed in detail. The coagulation and fibrinolytic system appear to be influenced by the septic process largely independently, leading to a procoagulant imbalance between these systems. Coagulation is initiated by mediator-induced expression of tissue factor and is associated with consumption of the natural coagulation inhibitors antithrombin III, protein C, and protein S. As a result, high plasma levels of thrombin-antithrombin complex (TAT) can be found. The effects on fibrinolysis are dominated by (highly) increased levels of plasminogen activator inhibitor type 1 (PAI-1), leading to inadequate fibrinolysis. Although levels of plasminogen activator antigen are increased, its activity is almost completely inhibited by PAI-1. The resulting effects predispose to a procoagulant state, with widespread fibrin deposition, which may be an important mechanism contributing to multiple organ failure. A thorough understanding of the pathophysiological mechanisms underlying the DIC-syndrome is a prerequisite for a rational approach and future therapy for this severe complication of sepsis.
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PMID:Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. 951 78

An 11-y-old girl who presented with cellulitis and clinical signs of deep vein thrombosis (DVT) is reported here. She developed staphylococcal sepsis, recurrent septic emboli and a large vegetation on the tricuspid valve. The patient was found to be heterozygous for the Arg506Gln mutation in factor Va and had low levels of protein C and protein S during the sepsis. The coexistence of the two thrombophilic states may explain the severe thromboembolic manifestations.
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PMID:Coexistence of acquired protein S and protein C deficiency and the Arg506Gln mutation in factor Va in a child with severe thromboembolic disease. 956 48

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

Antithrombin III (ATIII) and protein C (PC) are major inhibitors of the coagulation cascade and might regulate the cytokine network. We tested the possibility that a combined supplementation using these two inhibitors might have synergistic effects on sepsis-induced disseminated intravascular coagulation and shock. Hemodynamics, coagulation parameters, tumor necrosis factor (TNF) alpha, and interleukin 6 levels were measured in pigs submitted to a bolus infusion of Escherichia coli endotoxin (lipopolysaccharide). Four groups were studied: control lipopolysaccharide, ATIII (100 IU/kg), PC (50 IU/kg), and ATIII-PC (same doses). The endotoxin infusion resulted in a typical hypokinetic shock with disseminated intravascular coagulation in all animals. Compared with the control group, a significant improvement in mean arterial pressure and systemic vascular resistance was observed in the PC and ATIII-PC groups. The increase in lactate levels was almost completely blunted in the PC group. A significant lesser increase in TNFalpha levels was observed in the ATIII-PC group. No effects were seen on interleukin 6 levels. Coagulation and fibrinolysis parameters were not improved by ATIII and/or PC, except for a lesser decrease in prothrombin time in the ATIII-PC group. We conclude that in this acute endotoxic model, a combined supplementation using PC and ATIII concentrates has favorable effects on hemodynamic parameters and TNFalpha levels, independently from the anticoagulant actions of these inhibitors.
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PMID:Effects of a combined antithrombin III and protein C supplementation in porcine acute endotoxic shock. 984 Jun 53

During severe sepsis there is dramatic activation of both contact proteases and the coagulation pathway. These processes contribute to the development of shock and disseminated intravascular coagulation (DIC) respectively. The Pittsburgh mutant of antitrypsin (358Met-Arg) is a novel protease inhibitor with activity against both thrombin and the contact proteases and should therefore prove beneficial as a therapeutic agent in the management of septic shock. This hypothesis was supported by an earlier study in a pig model where recombinant antitrypsin Pittsburgh (rAT Pittsburgh) at a concentration of 1 microM alleviated some of the features of shock, but did not improve survival. In order to reduce the lethal effects of E. coli sepsis we postulated that a higher concentration of antitrypsin Pittsburgh would be necessary. To test this hypothesis we used rAT Pittsburgh in a primate model. This was chosen in preference to another species as E. coli sepsis in the primate has been well characterised and closely resembles the changes seen in man. Surprisingly this treatment did not alleviate the features of shock and unexpectedly appeared to exacerbate the associated coagulopathy. We propose two possible mechanisms for this unforeseen outcome. The first results from the broad spectrum of activity of antitrypsin Pittsburgh. As well as inhibiting thrombin and the contact proteases, the Pittsburgh mutant also inhibits activated protein C. Inhibition of the protein C system is known to exacerbate septic shock. Secondly, a significant quantity of inactive antitrypsin Pittsburgh, cleaved at the reactive centre, was detected in the plasma of the treated animals. Proteolytically altered serpins, including antitrypsin. have been shown to enhance the inflammatory process. Therefore the accumulation of cleaved rAT Pittsburgh might be expected to exacerbate septic shock.
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PMID:Recombinant antitrypsin Pittsburgh undergoes proteolytic cleavage during E. coli sepsis and fails to prevent the associated coagulopathy in a primate model. 984 77

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 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


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