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

Severe sepsis with multiple organ failure after hematopoietic stem cell transplantation (HSCT) results in extremely high morbidity and mortality. Recent studies have highlighted the importance of sepsis-induced activation of the coagulation system in the pathophysiology of severe sepsis. Activated protein C is an important modulator of coagulation and inflammatory derangements during severe sepsis. Low levels of protein C occur in severe sepsis and are predictive of poor outcome. Recombinant human activated protein C (drotrecogin alfa (activated)) was recently approved by the Food and Drug Administration (FDA) for severe sepsis. The phase III trial that resulted in the approval of this agent, however, enrolled a general sepsis population and excluded patients undergoing HSCT. We report a case of fulminant septic shock and multiple organ failure after HSCT that was treated with drotrecogin alfa (activated) in addition to standard therapy, and recovered. The high mortality rates of patients who develop severe sepsis after HSCT demand that new avenues of treatment be considered for this very high-risk patient population. This case illustrates the potential application of a novel therapeutic approach. Clinical trials are warranted to further investigate the safety and efficacy of drotrecogin alfa (activated) in patients with severe sepsis after HSCT.
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PMID:Septic shock and multiple organ failure after hematopoietic stem cell transplantation: treatment with recombinant human activated protein C. 1213 53

Activated protein C (APC), an important natural anticoagulant, inhibits tumor necrosis factor-alpha (TNF-alpha) production and attenuates various deleterious events induced by lipopolysaccharide (LPS), contributing thereby to a significant reduction of mortality in patients with severe sepsis. In this study, we investigated the mechanism(s) by which APC inhibits TNF-alpha production by LPS-stimulated human monocytes in vitro. Although APC inhibited LPS-induced TNF-alpha production in a concentration-dependent fashion, diisopropyl fluorophosphate-treated APC, an active-site-blocked APC, had no effect. APC inhibited both the binding of nuclear factor-kappa B (NF-kappa B) to target sites and the degradation of I kappa B alpha. APC also inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase pathways. These observations strongly suggest that APC inhibited LPS-induced TNF-alpha production by inhibiting the activation of both NF-kappa B and AP-1 and that the inhibitory activity of APC might depend on its serine protease activity. These results would at least partly explain the mechanism(s) by which APC reduces the tissue injury seen in animal models of sepsis and in patients with sepsis.
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PMID:Activated protein C inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production by inhibiting activation of both nuclear factor-kappa B and activator protein-1 in human monocytes. 2213 Oct 84

An impaired function of the protein C pathway plays a central role in the pathogenesis of sepsis. Administration of human recombinant activated protein C (Xigris) may restore the dysfunctional anticoagulant mechanism and prevent amplification and propagation of thrombin generation and formation of microvascular thrombosis but may simultaneously modulate the systemic pro-inflammatory response. Experimental studies indicated that the administration of activated protein C could block the derangement of coagulation, inhibit inflammatory effects and preserve organ function. Randomised controlled clinical studies in patients with severe sepsis confirmed these beneficial effects and demonstrated that administration of recombinant human activated protein C resulted in a reduction of mortality in patients with severe sepsis.
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PMID:Recombinant human activated protein C (Xigris). 1229 18

Hyperthrombinogenesis due to bacterial septicemia may aggravate the risk of irreversible septic shock. In 22 patients with septicemia complicating urinary or alimentary infections, daily assessment of hemostasis was performed throughout 1 week. Standard screening of hemostasis revealed significantly increased mean values of prothrombin time, fibrinogen, and fibrinogen degradation product (FDP) concentration. However, platelet counts, activated partial thromboplastin times (APTT), thrombin times, ethanol gelation tests, and antithrombin activity remained within the normal range. By contrast, except for insignificant changes in protein C activity and activated factor VII content, specific markers of plasma hypercoagulability, that is, thrombin-antithrombin (TAT) complexes, prothrombin activating factor F 1+2, activated factor XII (XIIa), and dimer D were all markedly increased. Pathologic levels of TAT and Xlla were found in 82% and 73% of all plasma samples, respectively. The augmentation of TAT correlated with prolongation of thrombin time and increases in F 1+2 levels. The increase in XIIa correlated with thrombocytopenia, prolongation of APTT, exhaustion of antithrombin, and accumulation of F 1+2 and FDP in the plasma. Moreover, a significant increase in XIIa, stronger positivity of the ethanol gelation test, a greater increase in FDP, and a more pronounced decrease in protein C activity were observed in 8 patients with fatal septic shock. This study suggests the usefulness of TAT and XIIa measurements in the early recognition of plasma hypercoagulation in serious infections.
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PMID:Plasma markers of hypercoagulability in patients with serious infections and risk of septic shock. 1236 Nov 99

In patients with severe sepsis, thrombin has been implicated in the interrelationship between the coagulation and inflammation pathways. Thrombin is responsible for conversion of fibrinogen to fibrin (thrombus formation). Thrombin also activates endothelial cells, white blood cells and platelets. Regulation of both the coagulation and inflammation pathways is in part through the interaction of thrombin and activated protein C. Activated protein C has particular attributes that may inhibit microvascular thrombi, promote fibrinolysis and directly dampen the pro-inflammatory aspect of infection. In patients with severe sepsis, many investigators have demonstrated an active coagulopathic state, with low protein C levels. A phase III clinical trial has now demonstrated reduced mortality in patients with severe sepsis receiving activated protein C.
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PMID:Relationship between the inflammation and coagulation pathways in patients with severe sepsis: implications for therapy with activated protein C. 1246 64

The protein C pathway, which plays an important role in maintaining normal hemostasis and is a critical link between the inflammatory and procoagulant host responses to infection, is involved in modulating the coagulation and inflammation associated with severe sepsis. Recombinant human activated protein C (APC), or drotrecogin alfa (activated), shares the intrinsic pharmacologic activity of endogenous APC. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, drotrecogin alfa (activated) decreased absolute mortality by 6% and relative risk of mortality by 19% compared with placebo. Drotrecogin alfa (activated) is an important advancement in the treatment of adult patients with severe sepsis.
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PMID:Pharmacology, clinical efficacy, and safety of drotrecogin alfa (activated). 1249 25

Sepsis with organ failure (severe sepsis) remains an important cause of morbidity and mortality among children. The clinical pathophysiology of severe sepsis reflects a coordinated activation of the innate immune response, including elaboration of proinflammatory cytokines and the induction of the extrinsic pathway of coagulation (sepsis-induced coagulopathy). These proinflammatory and procoagulant pathways are linked, and are similarly coregulated by a number of proteins and factors, including protein C. However, at least 80% of children and adults with severe sepsis develop acquired deficiency of protein C because of factor consumption. This deficiency is associated with poor outcomes, including multiple organ failure and mortality. Recently, recombinant activated protein C was shown to reduce the mortality of adults with severe sepsis, and is now approved for such use in the United States and Europe. The rationale for pediatric applications of protein C and ongoing clinical trials in children are reviewed.
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PMID:Recombinant human activated protein C for the treatment of severe sepsis: is there a role in pediatrics? 1254 78

The goals of this chapter are to provide a brief review of the biology of the protein C pathway and some of the features of the pathway that make it uniquely positioned to control microvascular coagulation and control the acute inflammatory response. Activated protein C works as an antithrombotic agent by inactivating factors Va and VIIIa. It is particularly effective at preventing microvascular thrombosis. Platelets may provide a margin of safety for activated protein C as an antithrombotic. Approximately 25% of the factor V/Va in plasma is contained within the platelet and hence resistant to time dependent inactivation by activated protein C. In addition, factor Va bound to the platelet surface is relatively resistant to inactivation by activated protein C. Activated protein C also facilitates clot lysis by inhibiting plasminogen activator inhibitor 1, a process that is accelerated markedly by vitronectin. Inflammatory cytokines like tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) downregulate two key components of the protein C activation complex, thrombomodulin and the endothelial cell protein C receptor resulting in decreased protein C activation. Activated protein C in turn has been shown in several animal models and in vitro to inhibit TNF elaboration in response to endotoxin. This inhibition appears to be due to diminished nuclear factor kappaB (NF kappaB) expression and nuclear translocation. Activated protein C has been shown to reduce the rate of death due to severe sepsis. This reduction may be due to both the anticoagulant effects as demonstrated by a reduction in D-dimer and inflammatory effects as demonstrated by a reduction in interleukin 6.
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PMID:Protein C pathway in sepsis. 1255

Activated protein C (APC) is a systemic anti-coagulant and anti-inflammatory factor. It reduces organ damage in animal models of sepsis, ischemic injury and stroke and substantially reduces mortality in patients with severe sepsis. It was not known whether APC acts as a direct cell survival factor or whether its neuroprotective effect is secondary to its anti-coagulant and anti-inflammatory effects. We report that APC directly prevents apoptosis in hypoxic human brain endothelium through transcriptionally dependent inhibition of tumor suppressor protein p53, normalization of the pro-apoptotic Bax/Bcl-2 ratio and reduction of caspase-3 signaling. These mechanisms are distinct from those involving upregulation of the genes encoding the anti-apoptotic Bcl-2 homolog A1 and inhibitor of apoptosis protein-1 (IAP-1) by APC in umbilical vein endothelial cells. Cytoprotection of brain endothelium by APC in vitro required endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1), as did its in vivo neuroprotective activity in a stroke model of mice with a severe deficiency of EPCR. This is consistent with work showing the direct effects of APC on cultured cells via EPCR and PAR-1 (ref. 9). Moreover, the in vivo neuroprotective effects of low-dose mouse APC seemed to be independent of its anti-coagulant activity. Thus, APC protects the brain from ischemic injury by acting directly on brain cells.
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PMID:Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. 1261 68

Recent studies have highlighted the close link between activation of the coagulation system and the inflammatory response in the pathophysiology of severe sepsis. The protein C anticoagulant pathway plays an integral part in modulating the coagulation and inflammatory responses to infection. In patients with sepsis, endogenous protein C levels are decreased, shifting the balance toward greater systemic inflammation, coagulation, and cell death. On the basis of a single large randomised phase 3 trial, drotrecogin alfa (activated), a recombinant form of human activated protein C, was recently approved for the treatment of adult patients with severe sepsis and a high risk of death. Since its approval, several questions have been raised regarding the appropriate use of this agent. Given the increased risk of serious bleeding and the high cost of treatment, drotrecogin alfa (activated) should be reserved at this time for the most acutely ill patients with severe sepsis who meet the criteria that were used in the phase 3 trial.
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PMID:Drotrecogin alfa (activated): a novel therapeutic strategy for severe sepsis. 1256 44


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