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)

Streptococcus pneumoniae is an important cause of upper and lower respiratory tract infections, meningitis, peritonitis, bacterial arthritis, and sepsis. Here we have studied a novel immune evasion mechanism of serotype 3 pneumococci, which are particularly resistant to phagocytosis. On their surfaces the bacteria express the factor H-binding inhibitor of complement (Hic), a protein of the pneumococcal surface protein C family. Using radioligand binding, microtiter plate assays, surface plasmon resonance analysis, and recombinant constructs of factor H, we located the binding site of Hic to short consensus repeats (SCRs) 8-11 in the middle part of factor H. This represents a novel microbial interaction region on factor H. The only other ligand known so far for SCRs 8-11 of factor H is C-reactive protein (CRP), an acute phase protein that binds to the pneumococcal C-polysaccharide. The binding sites of Hic and CRP within the SCR8-11 region were different, however, because CRP did not inhibit the binding of Hic and required calcium for binding. Binding of factor H to Hic-expressing pneumococci promoted factor I-mediated cleavage of C3b and restricted phagocytosis of pneumococci. Thus, virulent pneumococci avoid complement attack and opsonophagocytosis by recruiting functionally active factor H with the Hic surface protein. Hic binds to a previously unrecognized microbial interaction site in the middle part of factor H.
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PMID:Streptococcus pneumoniae evades complement attack and opsonophagocytosis by expressing the pspC locus-encoded Hic protein that binds to short consensus repeats 8-11 of factor H. 1182 23

Beriplex, a prothrombin complex concentrate (PCC), was administered to 42 patients requiring immediate reversal of their oral anticoagulant therapy. The dose administered was determined using the pretreatment International Normalized Ratio (INR). Blood samples were obtained before treatment and at 20, 60 and 120 min after treatment. The following investigations were performed on all samples - INR, clotting factors II, VII, IX and X, coagulation inhibitors protein C (PC) and antithrombin (AT), and other markers of disseminated intravascular coagulation, plasma fibrinogen, D-dimer and platelet count. Immediate reversal of the INR, the vitamin K-dependent clotting factors and PC was achieved in virtually all patients. Reduced AT levels were present in 18 patients before treatment. Further slight AT reductions occurred in four patients, but other associated abnormalities of haemostasis were observed in only one of the four patients. One patient with severe peripheral vascular disease, sepsis and renal and cardiac failure died of a thrombotic stroke following leg amputation, 48 h after receiving Beriplex. No other arterial and no venous thromboembolic events occurred within 7 d of treatment. Beriplex is effective in rapidly reversing the anticoagulant effects of warfarin, including PC deficiency, without inducing coagulation activation. Caution should continue to be exercised in the use of these products in patients with disseminated intravascular coagulation, sepsis or liver disease.
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PMID:Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. 1184 21

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

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 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

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

The coagulant and inflammatory exacerbation in sepsis is counterbalanced by the protective protein C (PC) pathway. Activated PC (APC) was shown to use the endothelial cell PC receptor (EPCR) as a coreceptor for cleavage of protease activated receptor 1 (PAR1) on endothelial cells. Gene profiling demonstrated that PAR1 signaling could account for all APC-induced protective genes, including the immunomodulatory monocyte chemoattractant protein-1 (MCP-1), which was selectively induced by activation of PAR1, but not PAR2. Thus, the prototypical thrombin receptor is the target for EPCR-dependent APC signaling, suggesting a role for this receptor cascade in protection from sepsis.
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PMID:Activation of endothelial cell protease activated receptor 1 by the protein C pathway. 1205 63

Activated protein C (APC) reduced all-cause 28-day mortality by 19% in patients with severe sepsis (sepsis associated with acute organ dysfunction) in the Protein C Evaluation in Severe Sepsis (PROWESS) trial, leading to recent approval of recombinant APC for treatment of this condition in adults. This review summarizes current knowledge derived from studies of a variety of animal models in which infused human APC demonstrated beneficial activities. Based on in vivo and also in vitro data, APC manifests antithrombotic, profibrinolytic, anti-inflammatory, and antiapoptotic activities. APC is a normal circulating component of plasma, derived from the protein C zymogen, and is thus a natural endogenous protective homeostatic factor. Because of its multiple activities, APC has a potential role in the treatment of complex and challenging medical disorders, including thrombosis and stroke.
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PMID:Activated protein C: potential therapy for severe sepsis, thrombosis, and stroke. 1212 82


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