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)

Intravascular and extravascular fibrin formation are characteristic findings in patients with sepsis, suggesting that the activation of coagulation and the inhibiton of fibrinolysis are important in the pathogenesis of sepsis. Activation of coagulation during sepsis is primarily driven by the tissue factor (TF) pathway, while inhibition of fibrinolysis is primarily due to increases in plasminogen activator inhibitor -1(PAI-1). Downregulation of the anticoagulant Protein C pathway also plays an important role in the modulation of coagulation and inflammation in sepsis. Recent advances in the understanding of pathogenetic mechanisms of coagulation and fibrinolysis in sepsis may have therapeutic implications. Recombinant human activated protein C (rhAPC) is currently the only pharmacologic therapy that has been shown to reduce mortality in adults with severe sepsis, highlighting the importance of coagulation and fibrinolysis as a therapeutic target in sepsis. This review summarizes recent basic and clinical findings with regard to the role of the coagulation cascade in sepsis and explores potential therapeutic targets in the coagulation and fibrinolytic pathways in the management of sepsis.
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PMID:The coagulation cascade in sepsis. 1869 Oct 97

Evidence suggests that sepsis is a systemic inflammatory condition complicated by dysequilibrium in coagulation and fibrinolytic homeostasis, with a shift in the balance towards increased coagulation over fibrinolysis. Protein C is a natural anticoagulant consumed and inactivated during sepsis. We present the case of a 33-year-old female, postsplenectomy, with pneumococcal sepsis and purpura fulminans, successfully treated with activated protein C.
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PMID:Pneumococcal purpura fulminans successfully treated with activated protein C. 1879 6

Impairment of the protein C pathway plays a central role in the pathogenesis of sepsis. Treatment with recombinant human activated protein C (rhAPC) has been reported to increase survival from severe sepsis. Protein C levels also decrease markedly in acute lung injury, of both septic and nonseptic origin. Low levels of protein C in acute lung injury are associated with poor clinical outcome. The present article discusses the beneficial effects of rhAPC in oleic acid-induced lung injury as well as the controversies between different animal models and the timing of drug administration. The unique bronchial circulation in ovine models seems to be responsible for the beneficial effects of rhAPC when given simultaneously to the injury.
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PMID:Recombinant human activated protein C in acute lung injury: what is the role of bronchial circulation? 1902 14

Febrile Neutropenia (FN) is a complication of chemotherapy in childhood cancer and at the same time secondary deficit of Protein C (PC) is often present during sepsis in children with cancer. In this study we have compared the clinical outcome of two different groups. At the onset of FN during chemotherapy the first group (patients with a secondary deficit of PC) received Protein C Concentrate (PCC) replacement while the other group without PC deficiency received only symptomatic therapies. We report that PC replacement could shorten duration of FN and improve the clinical outcome. The administration of PCC was safe and without any complications.
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PMID:Successful treatment with Protein C of febrile neutropenia in pediatric patients during cancer therapy. 1923 36

Activated Protein C renders anti-apoptotic properties in neurons and endothelial cells. The aim of the present study was to evaluate the in vivo cytoprotective role of Protein C zymogen (PC) administration in septic rat brain. Male Wistar rats (n=60) were subjected to sepsis via Cecal Ligation and Puncture (CLP). Animals were randomly divided either to receive 100 IU/kg human PC concentrate at 1, 7 and 13 h post CLP (CLP+PC group) or placebo treatment (CLP group). At pre-specified time points (6, 12, 24, 36, 48 and 60 h post CLP) five animals from either group were euthanized and the brain tissue was removed. Apoptosis in both neurons (Neu-N+) and astroglia (GFAP+) was assessed by flow cytometry using 7-aminoactinomycin D (7AAD). Immunohistochemical detection of cleaved caspase 3, bax, bcl-2, cytochrome c and caspase 8 was also performed. PC treated animals had significantly reduced apoptosis in neurons at 6 and 24 h post CLP (p=0.04 and p=0.016 respectively) and necrosis at 6, 12 and 60 h post CLP (p=0.008, p=0.012 and p=0.032 respectively). Astrocyte necrosis was also decreased in septic rats receiving PC (6, 12 and 60 h post CLP p=0.008, p=0.016 and p=0.008 respectively). In addition, active caspase 3, bax, cytochrome c and caspase 8 expression was significantly decreased during early sepsis (6-36 h) while bcl-2 expression was increased (24 h p=0.001 and 60 h p=0.001) in the PC treated animals compared to placebo. PC concentrate administration in experimental sepsis produced a time dependent inhibition of apoptosis in rat neurons and astrocytes. The inhibition of sepsis related apoptosis concerned both the mitochondrial and caspase 8 dependent pathways.
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PMID:Administration of Human Protein-C concentrate prevents apoptotic brain cell death after experimental sepsis. 1936 19

In 2001, the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial demonstrated a 6.1% absolute decrease in mortality in patients with severe sepsis. Recombinant human activated protein C was subsequently licensed for use by both the US Food and Drug Administration and the European Medicines Evaluation Agency. There has been some controversy over aspects of the original study protocol, and subsequent trials have raised concerns about both the efficacy and the side effect profile of recombinant human activated protein C. Significant doubt remains as to the role of recombinant human activated protein C in the management of severe sepsis, and this review aims to summarize the evidence both for and against its use.
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PMID:Activated protein C for the treatment of severe sepsis. 1941 3

Protein C is a plasma serine protease that when activated plays a central role in modulating the function of the vascular endothelium and its interface with the innate immune system. Activated protein C (APC) has a dual mechanism of action via the feedback inhibition of thrombin generation, and as an agonist of protease activated receptor-1 (PAR-1). Through different cofactor interactions, this dual mechanism of antithrombotic and cytoprotective activity results in the ability of APC to modulate endothelial dysfunction by blocking cytokine signaling, functional cell adhesion expression, vascular permeability, apoptosis, and modulating leukocyte migration and adhesion. Deficiency in protein C, which occurs during systemic inflammatory activation, is highly associated with organ dysfunction. APC has shown efficacy in a number of preclinical models of thrombosis and ischemia, and the recombinant human APC drotrecogin alfa (activated), reduces mortality in patients with high-risk severe sepsis. The ability of APC to suppress pro-inflammatory pathways and enhance cellular survival suggests that APC plays a key role in the adaptive response to protect the vessel wall from insult and to enhance endothelial, cellular, and organ survival. The focus of this review will be to summarize the emerging data suggesting the potential therapeutic benefit of APC and related members of the pathway in the prevention and treatment of acute kidney injury.
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PMID:Activated protein C and acute kidney injury: Selective targeting of PAR-1. 1971 37

Protein C is a vitamin K-dependent anticoagulant serine protease zymogen in plasma which upon activation by the thrombin-thrombomodulin complex down-regulates the coagulation cascade by degrading cofactors Va and VIIIa by limited proteolysis. In addition to its anticoagulant function, activated protein C (APC) also binds to endothelial protein C receptor (EPCR) in lipid-rafts/caveolar compartments to activate protease- activated receptor 1 (PAR-1) thereby eliciting antiinflammatory and cytoprotective signaling responses in endothelial cells. These properties have led to FDA approval of recombinant APC as a therapeutic drug for severe sepsis. The mechanism by which APC selects its substrates in the anticoagulant and antiinflammatory pathways is not well understood. Recent structural and mutagenesis data have indicated that basic residues of three exposed surface loops known as 39-loop (Lys-37, Lys-38, and Lys-39), 60-loop (Lys-62, Lys- 63, and Arg-67), and 70-80-loop (Arg-74, Arg-75, and Lys-78) (chymotrypsin numbering) constitute an anion binding exosite in APC that interacts with the procoagulant cofactors Va and VIIIa in the anticoagulant pathway. Furthermore, two negatively charged residues on the opposite side of the active-site of APC on a helical structure have been demonstrated to determine the specificity of the PAR-1 recognition in the cytoprotective pathway. This article will review the mechanism by which APC exerts its proteolytic function in two physiologically inter-related pathways and how the structure- function insights into determinants of the specificity of APC interaction with its substrates in two pathways can be utilized to tinker with the structure of the molecule to obtain APC derivatives with potentially improved therapeutic profiles.
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PMID:Regulation of the protein C anticoagulant and antiinflammatory pathways. 2042 10

Protein C plays an important role in the coagulopathy associated with sepsis and probably also in the pathogenesis of sepsis-induced organ dysfunction. Plasma levels of protein C strongly correlate with clinical outcome in patients with severe sepsis. The RESPOND (Research Evaluating Serial Protein C Levels in Severe Sepsis Patients on Drotrecogin Alfa [Activated]) study shows that administration of recombinant human activated protein C in patients with severe sepsis with alternative dose regimens adjusted to plasma levels of protein C results in higher plasma levels of protein C. This may potentially translate to a better clinical outcome in patients with severe sepsis, although that was not directly shown in this trial.
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PMID:Treatment with recombinant human activated protein C: one size does not fit all. 2117 44

Sepsis is defined as a systemic response to infection, characterized by an intense inflammatory response linked to coagulation activation and fibrinolysis inhibition, two processes which are intimately associated. In a field where mortality remains very high, administration of activated protein C, a physiological coagulation inhibitor with cytoprotective properties, has demonstrated its effectiveness and was able to reduce mortality. Protein C belongs to a system that involves plasma proteins and endothelial cell receptors. In addition to well documented effects on coagulation and fibrinolysis, activated protein C exhibits anti-inflammatory, anti-apoptotic but also anti-histone activities. Indeed, a recent study focusing on the cytoprotective effects of activated protein C showed that extracellular histones are released during severe sepsis and may participate in the pathophysiology of severe sepsis. These histones appear to be new targets of activated protein C.
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PMID:[Activated protein C, a protein at the crossroads between coagulation and inflammation]. 2160 71


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