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

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.
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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.
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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.
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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.
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PMID:Antithrombin concentrate with plasma exchange in purpura fulminans. 1281 93

The protein C anticoagulant pathway is critical for controlling microvascular thrombosis and is initiated when thrombin binds to thrombomodulin (TM) on the surface of the endothelium. Protein C activation is augmented by an endothelial cell protein C receptor (EPCR). EPCR is shed from the vasculature by inflammatory mediators and thrombin. EPCR binds to activated neutrophils in a process that involves proteinase 3 and Mac-1 and appears to inhibit leukocyte extravasation. EPCR can undergo translocation from the plasma membrane to the nucleus where it re-directs gene expression. During translocation, EPCR can carry activated protein C (APC) to the nucleus, possibly accounting for the ability of APC to modulate inflammatory mediator responses in the endothelium. TNF-alpha and other inflammatory mediators can down-regulate EPCR and TM. Inhibition of protein C pathway function increases cytokine elaboration, endothelial cell injury and leukocyte extravasation in response to endotoxin and infusion of APC reverses these processes. In vitro, APC has been reported to inhibit TNF-alpha elaboration from monocytes and to block leukocyte adhesion to selectins. Since thrombin can elicit many inflammatory responses in microvascular endothelium, loss of control of microvascular thrombin generation due to impaired protein C pathway function probably contributes to microvascular dysfunction in sepsis.
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PMID:Coagulation and inflammation. 1283 62

In patients diagnosed with sepsis, severe sepsis or septic shock, cytokine-mediated endothelial injury, and TF activation initiate a cascade of events that culminate in the development of coagulation dysfunction characterized as procoagulant and antifibrinolytic. This abnormal state predisposes the patient to develop microvascular thrombosis, tissue ischemia, and organ hypoperfusion. Multiple organ dysfunction syndrome may be a product of this pertubation in coagulation regulation. Treatments aimed at correcting this coagulation dysfunction have met with mixed success. Current data suggest that AT III replacement therapy has limited efficacy in adults with severe sepsis. In contrast, adult patients diagnosed with severe sepsis and organ failure and treated with aPC (drotrecogin alfa activate) have a significantly reduced risk of death when compared with placebo-treated patients. A phase III trial examining the efficacy of protein C replacement therapy in pediatric patients with severe sepsis and organ failure is underway.
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PMID:Coagulation dysfunction in sepsis and multiple organ system failure. 1284 14

Sepsis is associated with systemic inflammation, coagulopathy, and disrupted protein C (PC) pathway function. The effect of prothrombotic polymorphism, factor V Leiden (Arg506Gln; FV Leiden), was examined in a large clinical trial (PROWESS) of severe sepsis and a mouse endotoxemia model. In PROWESS, 4.1% (n = 65) of patients were heterozygous FV Leiden (VL+/-) carriers. The 28-day mortality was lower in VL+/- (13.9%) than in non-FV Leiden (VL-/-; 27.9%) patients (P =.013). The mortality benefit of recombinant human activated PC (rhAPC) treatment was similar in VL+/- (placebo, 15.6%; rhAPC,12.1%) and VL-/- patients (placebo, 31.0%; rhAPC, 24.7%; interaction P =.981). VL+/- status did not appear to influence baseline biomarkers of coagulopathy and inflammation or disease severity, with the exception that vasopressor usage was less in VL+/- patients (46.2% versus 63.0%; P =.009). In a median lethal dose (40 mg/kg) endotoxin mouse model, VL+/- mice had lower mortality than wild-type mice (19% versus 57%; P =.008), whereas the mortality of homozygous (VL+/+) mice was almost identical to that of wild-type mice (65% versus 57%; P =.76). The findings suggest that FV Leiden constitutes a rare example of a balanced gene polymorphism that maintains the FV Leiden mutation in the general gene pool due to a survival advantage of VL+/- in severe sepsis.
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PMID:Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. 1286 95

Activated protein C (APC) serves as an 'on demand' anticoagulant. Defects in the APC anticoagulant pathway are underlying risk factors for the development of venous and arterial thrombosis. APC has recently been shown to significantly reduce mortality in patients with severe sepsis, presumably by virtue of its ability to down-regulate coagulation as well as inflammation. Our objective was to develop an assay that, for the first time, permits rapid detection of plasma APC. This assay will expedite studies of APC in a variety of vascular disease states including sepsis, severe atherosclerosis, diabetes, and vasculitis. By generating a highly APC-specific monoclonal antibody (HAPC 1555), we have developed an assay that, for the first time, allows rapid detection of plasma APC. The Kd measured for the interaction between APC and HAPC 1555 based on BIAcore studies and binding to immobilized HAPC on microtiter plates is 6.2 +/- 0.9 and 8.8 +/- 1.0 nmol L(-1), respectively. The interaction between HAPC 1555 and APC is Ca2+-dependent, with a Ca2+ concentration of 313 +/- 48 micro mol L(-1) required for half maximal binding. HAPC 1555 interferes with APC-mediated inactivation of factor (F)Va in the presence and absence of phospholipids, suggesting that HAPC 1555 binds to the FVa binding domain of APC. When HAPC 1555 was used in an APC enzyme capture assay, therapeutic APC levels could be measured in 1.5 h, and physiologic levels of APC could be detected between 3 and 19 h. APC levels were also shown to vary markedly in patients with severe sepsis. The rapidity of our APC assay makes APC detection in patients practical clinically. This assay will expedite studies of APC in a variety of vascular disease states including sepsis, severe atherosclerosis, diabetes, and vasculitis.
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PMID:A monoclonal antibody against activated protein C allows rapid detection of activated protein C in plasma and reveals a calcium ion dependent epitope involved in factor Va inactivation. 1499 20

This review describes disseminated intravascular coagulation (DIC) as a syndrome in which hemostatic factors are activated. The syndrome ranges in severity from a decompensated coagulopathy (overt-DIC) to the subclinical compensated activation of hemostatic factors (nonovert DIC). The first part of this review emphasizes two points. First, activation of the hemostatic system is controlled by a vast network of capillaries and venules through anticoagulant and anti-inflammatory regulatory factors that operate from the endothelium (e.g., protein C and thrombomodulin, tissue factor pathway inhibitor). These hemostatic regulators can be overridden by procoagulant disorders such as amniotic fluid embolism or degraded by proinflammatory disorders such as sepsis. Second, because this link between the microvascular endothelium and circulating hemostatic factors is so close, even a relatively mild disturbance of the microvasculature targeted by the inflammatory process may be reflected systemically by changes in molecular biomarkers of hemostatic activity. Therefore, application of criteria for the diagnosis of nonovert DIC should be of value in detecting a compensated response to inflammatory stress of the microvasculature in patients who are at risk before they develop an uncompensated over DIC response and organ failure. The second part of this review covers the recent experience investigators have had in diagnosing and following the response of patients to treatment with biomarkers.
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PMID:The diagnosis and management of disseminated intravascular coagulation. 1290 Nov 23

Sepsis is an infection-induced inflammatory syndrome that results in a complex network of adaptive and maladaptive alterations in homeostatic mechanisms. Severe sepsis, defined as sepsis associated with acute organ failure, is a serious disease with a mortality rate of 30-50%. The coagulation system, through complex interactions, has an important role in the final outcome of the sepsis-induced inflammatory cascade. A fine and delicate balance that normally exists between anticoagulant mechanisms and the procoagulant response is altered in sepsis. Activated protein C, an endogenous vitamin K-dependent anticoagulant, plays a major role in the down-regulation of the procoagulant arm. It also possesses anti-inflammatory properties. Endothelial damage during sepsis impairs the endothelium-dependent activation of protein C, thus shifting the balance towards thrombosis. This shift may contribute to the development of sepsis-related multi-organ failure. Evidence suggesting that activation of the coagulation system may contribute to sepsis-related morbidity and mortality has led to extensive research attempting to correct the hemostatic defects seen in septic patients. Indeed, a recent randomized controlled trial demonstrated a reduction in overall mortality in patients with severe sepsis treated with APC. In this review we discuss the pathogenesis of the coagulopathy of sepsis, as well as the new therapeutic approaches aimed at correcting the defects in the coagulation system.
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PMID:The coagulopathy of sepsis: pathophysiology and management. 1290 Dec 50


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