Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the pathogenesis of sepsis and disseminated intravascular coagulation (DIC), dysfunctional anticoagulant pathways are important. The function of the protein C system in DIC is impaired because of low levels of protein C and down-regulation of thrombomodulin. The administration of (activated) protein C results in an improved outcome in experimental and clinical studies of DIC. It is unknown whether congenital deficiencies in the protein C system are associated with more severe DIC. The aim of the present study was to investigate the effect of a heterozygous deficiency of protein C on experimental DIC in mice. Mice with single-allele targeted disruption of the protein C gene (PC+/-) mice and wild-type littermates (PC+/+) were injected with Escherichia coli endotoxin (50 mg/kg) intraperitoneally. PC+/-mice had more severe DIC, as evidenced by a greater decrease in fibrinogen level and a larger drop in platelet count. Histologic examination showed more fibrin deposition in lungs, kidneys, and liver in mice with a heterozygous deficiency of protein C. Interestingly, PC+/- mice had significantly higher levels of proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta, indicating an interaction between the protein C system and the inflammatory response. Survival was lower at 12 and 24 hours after endotoxin in the PC+/- mice. These results confirm the important role of the protein C system in the coagulative-inflammatory response on endotoxemia and may suggest that congenital deficiencies in the protein C system are associated with more severe DIC and adverse outcome in sepsis.
 ...
PMID:Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice. 1260 41

Severe sepsis is a major public health concern and a burden on the healthcare system. Despite improvements in efforts to control the source of infection and increased recognition by healthcare providers of patients with the disease, the mortality rate remains unacceptably high, from 30% to 50%. The systemic inflammatory response syndrome criteria are used as diagnostic indicators of sepsis when they occur in patients with known or suspected infection. The outcome of a patient with severe sepsis is often related to the occurrence of sepsis-induced multiple organ dysfunction syndrome. Multiple organ dysfunction syndrome appears to result from a cascade of organism-related factors, inflammatory mediators, endothelial injury, disturbed hemostasis, and microcirculatory abnormalities. In patients with severe sepsis, derangements of inflammation and coagulation are tightly linked. Although numerous clinical trials focused on interventions in one or the other of the inflammatory and coagulation systems failed to show reduced mortality due to sepsis, a member of a new class of drugs called "cogins" was effective. In its active form, protein C has anti-inflammatory, antithrombotic, and profibrinolytic properties that can reduce organ injury associated with severe sepsis. A recombinant form of activated protein C, drotrecogin alfa (activated), significantly reduces 28-day mortality due to all causes in patients with severe sepsis and has an acceptable safety profile. This review provides an overview of severe sepsis, highlighting recent advances in treatment of the disease and the role of critical care nurses.
 ...
PMID:Advances in the understanding of clinical manifestations and therapy of severe sepsis: an update for critical care nurses. 1262 70

Human activated protein C (APC) is an antithrombotic, antiinflammatory serine protease that plays a central role in vascular homeostasis, and activated recombinant protein C, drotrecogin alfa (activated), has been shown to reduce mortality in patients with severe sepsis. Similar to other serine proteases, functional APC levels are regulated by the serine protease inhibitor family of proteins including alpha(1)-antitrypsin and protein C inhibitor. Using APC-substrate modeling, we designed and produced a number of derivatives with the goal of altering the proteolytic specificity of APC such that the variants exhibited resistance to inactivation by protein C inhibitor and alpha(1)-antitrypsin yet maintained their primary anticoagulant activity. Substitutions at Leu-194 were of particular interest, because they exhibited 4- to 6-fold reductions in the rate of inactivation in human plasma and substantially increased pharmacokinetic profiles compared with wild-type APC. This was achieved with minimal impairment of the anticoagulant/antithrombotic activity of APC. These data demonstrate the ability to selectively modulate substrate specificity and subsequently affect in vivo performance and suggest therapeutic opportunities for the use of protein C derivatives in disease states with elevated serine protease inhibitor levels.
 ...
PMID:Engineering the proteolytic specificity of activated protein C improves its pharmacological properties. 1267 Oct 72

Disseminated intravascular coagulation (DIC) is characterized by systemic activation of the haemostasis. In many instances the release of inflammatory cytokines and tissue factor trigger the system in septic or traumatic conditions. Initially, the increased activation of haemostasis can be compensated by natural inhibitor systems. As release of the triggers persists, inhibitors (e.g. antithrombin and protein C) will be consumed leading to intravascular clotting. In this process many coagulation factors, most notably fibrinogen and platelets are consumed too, resulting in a failure of haemostasis system and in a diffuse bleeding (decompensated DIC). Fresh frozen plasma, blood transfusion, and fibrinogen concentrate correct the bleeding, if needed, in the case of traumatic (obstetric) DIC. Arrest of the activated haemostasis by heparin and natural anticoagulants (antithrombin or/and protein C) is recommended, mainly in septic conditions with systemic inflammatory reactions. A case of stercoral sepsis usefully treated by recombinant human activated protein C is reported.
 ...
PMID:[Disseminated intravascular coagulation syndrome and protein C]. 1268 50

In neonates and infants numerous clinical and environmental conditions such as the use of central lines, cardiac diseases and polycythemia, renal diseases such as congenital nephrotic syndrome and neonatal hemolytic uremic syndrome, peripartal asphyxia, infants of diabetic mothers, dehydration, septicemia, necrotizing enterocolitis, acute respiratory distress syndrome, and extracorporeal membrane oxygenation lead to elevated thrombin generation and subsequent thrombus formation. Genetic prothrombotic defects [protein C, protein S and antithrombin deficiency, mutations of coagulation factor V and factor II, elevated lipoprotein (a)] have been established as risk factors for thromboembolic events. The interpretation of laboratory results relies on age-dependent normal reference values. Because appropriate clinical trials are missing in these age groups, treatment recommendations are adapted from small-scale studies in neonates and infants and from guidelines relating to adult patient protocols. Secondary long-term anticoagulation should be administered on an individual basis.
 ...
PMID:Neonatal thromboembolism. 1270 27

Activation of protein C by thrombin bound to thrombomodulin is enhanced by endothelial protein C receptor. This pathway may inhibit inflammation. We investigated effects of protein C and activated protein C on neutrophils as well as whether an endothelial protein C receptor is involved in mediating protein C effects. Neutrophils were from venous blood of healthy donors. Cell migration, respiratory burst, phagocytic activity, and apoptosis were studied by micropore filter assays and fluorometry. Receptor expression was investigated by reverse transcriptase-polymerase chain reaction (PCR) for mRNA, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and autoradiography of immunoprecipitated receptor protein, and fluorescence-activated cell-sorter scanner (FACS) analysis using the anti-endothelial protein C receptor antibody RCR-252. Neither protein C nor activated protein C induced migration, yet both of them inhibited neutrophil chemotaxis triggered by interleukin-8, formyl-Met-Leu-Phe, antithrombin, or C5a. A protein C activation-blocking antibody against endothelial protein C receptor diminished inhibitory effects of protein C or activated protein C on migration. No effect of either protein C preparation was seen in neutrophil's respiratory burst, bacterial phagocytosis, or apoptosis assays. Endothelial protein C receptor immunoreactivity was confirmed on neutrophils by FACS. De novo synthesis is suggested by endothelial protein C receptor mRNA expression as demonstrated by reverse transcriptase PCR and immunoprecipitation SDS-PAGE analyses. Data suggest that an endothelial protein C receptor is expressed by human neutrophils whose active site ligation with either protein C or activated protein C arrests directed cell migration. Inhibitory effects of these components of the protein C pathway on neutrophil function may play a role in the protein C-based treatment of severe sepsis.
 ...
PMID:Expression and function of the endothelial protein C receptor in human neutrophils. 1271 92

Cellular signaling by proteases of the blood coagulation cascade through members of the protease-activated receptor (PAR) family can profoundly impact on the inflammatory balance in sepsis. The coagulation initiation reaction on tissue factor expressing cells signals through PAR1 and PAR2, leading to enhanced inflammation. The anticoagulant protein C pathway has potent anti-inflammatory effects, and activated protein C signals through PAR1 upon binding to the endothelial protein C receptor. Activation of the coagulation cascade and the downstream endothelial cell localized anticoagulant pathway thus have opposing effects on systemic inflammation. This dichotomy is of relevance for the interpretation of preclinical and clinical data that document nonuniform responses to anticoagulant strategies in sepsis therapy.
 ...
PMID:Science review: role of coagulation protease cascades in sepsis. 1272 May 55

Inflammatory and procoagulant host responses are closely related in sepsis. The protein C pathway serves as a regulatory pathway with anti-inflammatory and anticoagulant properties. Recently, recombinant human activated protein C (rhAPC) was shown to reduce mortality in severe sepsis. Nevertheless, the effects of rhAPC in humans are still ill defined. The infusion of low endotoxin doses into humans provides a standardized model to study inflammatory and hemostatic mechanisms. Thus, we investigated whether rhAPC acts as an anticoagulant or anti-inflammatory drug in human endotoxemia. There were 24 volunteers randomized to receive either 24 microg/kg per hour rhAPC or placebo intravenously for 8 hours. Lipopolysaccharide (LPS, 2 ng/kg) was administered 2 hours after starting the infusions. rhAPC decreased basal tissue factor (TF)-mRNA expression, and thrombin formation and action. In contrast, rhAPC did not significantly blunt LPS-induced thrombin generation. Consistently, rhAPC did not reduce LPS-induced levels of TF-mRNA or D-dimer and had no effect on fibrinolytic activity or inflammation. Finally, endogenous APC formation was enhanced during endotoxemia and appeared to be associated with inflammation rather than thrombin formation. In conclusion, even low-grade endotoxemia induces significant protein C activation. Infusion of rhAPC decreases "spontaneous" activation of coagulation but does not blunt LPS-induced, TF-mediated coagulation in healthy volunteers, which is in contrast to a number of anticoagulants.
 ...
PMID:Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia. 1275 Jan 66

Decreased circulating protein C and increased circulating thrombomodulin are markers of the prothrombotic, antifibrinolytic state associated with poor outcomes in sepsis but have not been measured in patients with ALI (acute lung injury)/ARDS (acute respiratory distress syndrome). We measured circulating and intra-alveolar protein C and thrombomodulin in 45 patients with ALI/ARDS from septic and nonseptic causes and correlated the levels with clinical outcomes. Plasma protein C levels were lower in ALI/ARDS compared with normal. Lower levels of protein C were associated with worse clinical outcomes, including death, fewer ventilator-free days, and more nonpulmonary organ failures, even when only patients without sepsis were analyzed. Levels of thrombomodulin in pulmonary edema fluid from ALI/ARDS patients were >10-fold higher than normal plasma and 2-fold higher than ALI/ARDS plasma. Higher edema fluid thrombomodulin levels were associated with worse clinical outcomes. The higher levels in edema fluid compared with plasma suggest local release of soluble thrombomodulin in the lung, possibly from a lung epithelial source. To determine whether lung epithelial cells can release thrombomodulin, A549 cells and primary isolates of human alveolar type II cells were exposed to H2O2 or inflammatory cytokines. Both epithelial cell types released thrombomodulin into the media. In summary, the protein C system is markedly disrupted in patients with ALI/ARDS from both septic and nonseptic causes. The protein C system may be a potential therapeutic target in patients with ALI/ARDS.
 ...
PMID:Protein C and thrombomodulin in human acute lung injury. 1275 94

OBJECTIVE: To report successful treatment of three patients admitted with purpura fulminans. DESIGN: Three cases with purpura fulminans: clinical presentation, laboratory findings, treatment, and outcome. SETTING: A seven-bed medical and general surgical Intensive therapy unit in a district general hospital. PATIENTS: Three young patients with clinical and laboratory findings of severe meningococcal sepsis and purpura. INTERVENTIONS: Early replacement therapy with antithrombin concentrate after a single initial plasma exchange, together with conventional antibiotic and supportive treatment. MEASUREMENTS AND MAIN RESULTS: All three cases had abnormal coagulation profile consistent with disseminated intravascular coagulation, adult respiratory distress syndrome, impaired renal function, and severe hemodynamic instability requiring inotropic support. Plasma antithrombin levels were measured in all cases. All patients survived and made a good recovery. CONCLUSIONS: We consider that correction of antithrombin to supranormal levels may have a beneficial effect on survival and outcome in purpura fulminans despite sustained low levels of protein C.
 ...
PMID:Antithrombin concentrate with plasma exchange in purpura fulminans. 1281 93


<< Previous 1 2 3 4 5 6 7 8 9 10