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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of activated protein C (APC) in coagulation, inflammation, and fibrinolysis and the pharmacology, pharmacokinetics, and trials of recombinant human activated protein C (rhAPC), or drotrecogin alfa (activated), in sepsis are described. Protein C, a naturally occurring vitamin K-dependent serine protease in the blood, remains inactive until exposed to the thrombin-thrombomodulin complex. This change between the inactive and active forms occurs constantly in humans and serves to balance the coagulation cascade. APC functions in concert with protein S as an anticoagulant, a fibrinolytic agent, and an antiinflammatory agent. In response to serious infection, a procoagulant process is activated leading to thrombin and fibrin deposition in small vessels that results in decreased blood flow, decreased oxygen delivery, and organ failure. The body's natural defense during severe sepsis is to activate protein C through the thrombin-thrombomodulin complex in an attempt to restore the imbalance of the hemostatic systems. However, APC has a short half-life, and the pool of circulating protein C is rapidly depleted in severe sepsis. Low protein C levels have been correlated with poor outcome in patients with severe sepsis and in animal models. These observations led to a Phase III safety and efficacy trial of drotrecogin alfa (activated) that demonstrated a significant improvement in mortality compared with placebo (24.7% versus 30.8%). This 6.1% absolute difference in mortality translates to a 19.4% reduction in relative risk of death in the treated patients. The proper use of drotrecogin alfa (activated) will require careful consideration of appropriate patients to treat and further studies in patient populations that were excluded from the Phase III trial, as well as possible modification of dosing schemes on the basis of patient response.
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PMID:Recombinant human activated protein C in severe sepsis. 1188 9

The roles of inflammation and coagulation in the pathophysiology of sepsis are described. Sepsis results when an infectious insult triggers a localized inflammatory reaction that then spills over to cause systemic symptoms of fever or hypothermia, tachycardia, tachypnea, and either leukocytosis or leukopenia. These clinical symptoms are called the systemic inflammatory response syndrome. Severe sepsis is defined by dysfunction of one of the major organ systems or unexplained metabolic acidosis. The inflammatory reaction is mediated by the release of cytokines, including tumor necrosis factor-alpha, interleukins, and prostaglandins, from neutrophils and macrophages. The cytokines activate the extrinsic coagulation cascade and inhibit fibrinolysis. These overlapping processes result in microvascular thrombosis; thrombosis is one potential factor producing organ dysfunction. Activation of the coagulation system leads to consumption of endogenous anticoagulants (e.g., protein C and antithrombin); this may be an important factor in the development of microvascular coagulation. Antiinflammatory mediators as well as inflammatory mediators have a role in sepsis, and an excess of either can result in poor patient outcomes. Sepsis is a complex syndrome involving activation of a variety of systems.
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PMID:Pathophysiology of sepsis. 1188 12

Severe bacterial sepsis, particularly secondary to meningococcaemia, is a well-recognized cause of purpura fulminans resulting from severe acquired protein C (PC) deficiency. Recently, PC and activated protein C (APC) concentrate replacement therapy has been shown to improve outcome in patients with meningococcaemia- associated purpura fulminans and severe sepsis respectively. Despite these impressive findings, PC and APC concentrates are not currently widely available. We describe a 31-year-old patient with pneumococcal septic shock, purpura fulminans (PF) and severe acquired PC deficiency, whom we successfully treated with conventional therapy and high-volume plasma exchange as a source of PC.
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PMID:Plasma exchange as a source of protein C for acute onset protein C pathway failure. 1249 94

Drotrecogin alfa (activated), recombinant human activated protein C, inhibits coagulation and inflammation and promotes fibrinolysis in patients with severe sepsis. 850 patients with severe sepsis treated with intravenous drotrecogin alfa (activated) 24 microg/kg/h for 96 hours had a significantly greater reduction in 28-day all-cause mortality (24.7%) than 840 placebo recipients (30.8%) in a randomised, double-blind, placebo-controlled study. The drug was associated with a 19.4% reduction in the relative risk of death at 28 days compared with placebo. Baseline characteristics of and pre-existing conditions in patients with sepsis appeared to have no effect on the efficacy of drotrecogin alfa (activated). A significantly greater reduction in median percentage change from baseline plasma D-dimer levels (a coagulation marker) was seen with drotrecogin alfa (activated) treatment than with placebo on study days 1 to 7 in patients with severe sepsis. On study days 1, 4, 5, 6 and 7, a significantly greater median reduction in interleukin-6 levels (an inflammation marker) from baseline was seen with drotrecogin alfa (activated) treatment than placebo. Drotrecogin alfa (activated) was associated with an increased incidence of serious bleeding events during the infusion period [2.4% vs 1.0% with placebo; p = 0.024] and the 28-day study period (3.5 vs 2.0%; p = 0.06) of the efficacy trial. This increase was primarily related to procedure-related events; there were no significant differences between the treatment groups in nonprocedure-related serious bleeding events. The most frequent site of bleeding was the gastrointestinal tract. With the exception of bleeding events, there were no clinically significant differences between treatment groups in the efficacy trial in the incidence of adverse events. Of the 210 deaths in patients with severe sepsis treated with drotrecogin alfa (activated) 24 microg/kg/h in the efficacy trial, four deaths due to haemorrhage and one due to cerebral oedema were possibly related to the study drug.
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PMID:Drotrecogin alfa (activated). 1189 30

Protein C is a vitamin-K dependent zymogen of the anti-coagulant serine protease activated protein C (APC). In this paper, we report four lines of evidence that APC can activate protein C in pooled normal plasma, and purified protein C. First, the addition of APC to protein C-deficient plasma supplemented with protein C produces a prolongation of the clotting time of plasma that is proportional to the amount of protein C. This behavior was observed with APC from the Chromogenix APC resistance kit (Dia Pharm, Franklin, OH, USA) and from APC derived from the thrombin activation of human protein C (Enzyme Research Laboratories, South Bend, IN, USA). Secondly, using immunoblotting after gel electrophoresis, the disappearance of epitopes for monoclonal antibodies that recognize protein C but not APC indicates a time course for the activation by APC of protein C in pooled normal plasma and protein C purified from plasma. Thirdly, the same time course for the disappearance of protein C specific epitope can be followed using ELISA. Finally, protein C can be activated by APC as indicated by the increase in APC specific synthetic substrate Tryp-Arg-Arg-p nitroaniline hydrolysis. Kinetic data indicate a value of 4.7+/-0.4 mM(-1) s(-1) for the activation of protein C by APC under physiological conditions and in the presence of calcium. These observations document that APC must function not only in the inactivation of activated factors V and VIII, but also in the activation of protein C. This additional action of APC may be important to consider more broadly because of APC in the treatment of sepsis.
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PMID:Proteolysis of protein C in pooled normal plasma and purified protein C by activated protein C (APC). 1189 50

The dendritic cell (DC) is the most potent APC of the immune system, capable of stimulating naive T cells to proliferate and differentiate into effector T cells. Recombinant adenovirus (Adv) readily transduces DCs in vitro allowing directed delivery of transgenes that modify DC function and immune responses. In this study we demonstrate that footpad injection of a recombinant Adv readily targets transduction of myeloid and lymphoid DCs in the draining popliteal lymph node, but not in other lymphoid organs. Popliteal DCs transduced with an empty recombinant Adv undergo maturation, as determined by high MHC class II and CD86 expression. However, transduction with vectors expressing human IL-10 limit DC maturation and associated T cell activation in the draining lymph node. The extent of IL-10 expression is dose dependent; transduction with low particle numbers (10(5)) yields only local expression, while transduction with higher particle numbers (10(7) and 10(10)) leads additionally to IL-10 appearance in the circulation. Furthermore, local DC expression of human IL-10 following in vivo transduction with low particle numbers (10(5)) significantly improves survival following cecal ligation and puncture, suggesting that compartmental modulation of DC function profoundly alters the sepsis-induced immune response.
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PMID:Increased survival in sepsis by in vivo adenovirus-induced expression of IL-10 in dendritic cells. 1190 99

Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) are critically involved in activation of the coagulation system in sepsis, leading to disseminated intravascular coagulation (DIC). Natural anticoagulants such as antithrombin (AT) and activated protein C (APC) regulate the coagulation system by inhibiting thrombin generation. In addition to these anticoagulant effects, both AT and APC have been shown to attenuate inflammatory responses induced by various noxious stimuli in rats such as lipopolysaccharide (LPS) challenge. AT promotes the endothelial release of prostacyclin, a potent anti-inflammatory prostaglandin that inhibits the monocytic production of TNF-alpha, by interacting with cell-surface heparin-like substances. APC directly inhibits the production of TNF-alpha by inhibiting the activation of both nudear factor kappaB (NFkappaB) and activator protein-1 in monocytes stimulated with LPS. Thrombomodulin, an endothelial membranous integral protein that binds thrombin, exerts anti-inflammatory effects by generating APC. Furthermore, tissue factor pathway inhibitor, a natural anticoagulant for the extrinsic pathway of the coagulation system, also attenuates LPS-induced inflammatory responses in rats by inhibiting TNF-alpha production by monocytes. These findings strongly suggest that natural anticoagulants could regulate inflammatory responses as well as the coagulation system in rats by inhibiting the monocytic production of TNF-alpha. Such anti-inflammatory properties of natural anticoagulants are potentially important for their replacement in patients with sepsis who frequently develop DIC and organ failure as inflammatory responses.
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PMID:Regulation of inflammatory responses by natural anticoagulants. 1191 84

The treatment of sepsis consists of focus control as well as supportive and adjuvant therapy. Especially the last option has been investigated during the last years. Different approaches showed promising results in animal experiments and phase-I trials but did not prove to be successful in large multicenter studies. The application of TNF-receptors or interleukin-1 receptor antagonists did not lead to an improvement of outcome in patients with sepsis. Most studies with TNF-antibodies also presented negative results. However, a recent large study with a monoclonal antibody against TNFalpha demonstrated a significant survival benefit. The recently published PROWESS study is the first investigation demonstrating the decrease of mortality in patients with sepsis after administration of protein C. Additionally, current data support the low-dose hydrocortisone therapy in patients with vasopressor dependent septic shock.
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PMID:[New treatment approaches in sepsis]. 1193 79

Severe sepsis is a systemic inflammatory response to infection involving organ dysfunction. Severe sepsis is a common cause of death and is associated with a 20% to 56% mortality rate. Drotrecogin alpha (activated) is a recombinant human activated protein C(rhAPC) approved in the U.S. for the reduction of mortality in adult patients with severe sepsis who have a high risk of death. Drotrecogin alpha (activated), when administered to adult patients with clinically defined severe sepsis, demonstrated a 6.1% absolute reduction (p=0.005) in 28-day all-cause mortality in one published, randomized, double-blind study of 1,690 patients (PROWESS). Drotrecogin alpha (activated) is used as an adjunct to standard therapy and is therefore and "add-on" cost. Close attention must be paid to proper patient selection for treatment with drotrecogin alpha (activated). Certain individuals, such as those at a greater risk of bleeding, could be harmed from therapy. The benefit or harm in individuals not meeting the trial selection criteria is uncertain.
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PMID:Activated protein C for severe sepsis. 1198 65

Lipopolysaccharides in the outer membrane of Neisseria meningitidis are key molecules that induce inflammation and cause meningitis and shock. Mutant strains, with altered lipid A, the toxic moiety of lipopolysaccharide, or completely lacking lipopolysaccharide, induce significantly less inflammation than wild-type strains. Polymorphism of the Fc gamma receptors and interleukin-10 gene but not of the Toll-like receptor 4 may influence the development of meningococcal infection. Mannan-binding lectin is involved in complement activation, the regulation of adhesion molecules and cytokine production induced by meningococci. The activation of protein C by the thrombomodulin protein C receptor complex on the endothelial cell surface appears to be reduced in meningococcal sepsis but is still sufficient to convert protein C to activated protein C in patients treated with concentrated protein C.
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PMID:Current concepts in the role of the host response in Neisseria meningitidis septic shock. 1201 58


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