Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial protein C receptor (EPCR) is primarily localized on the endothelial cells of large blood vessels and is very low or absent in the microvascular endothelium of most tissues. EPCR augments the thrombin/thrombomodulin-dependent activation of protein C by 5- to 20-fold. EPCR appears to be physiologically significant in the control of blood coagulation and inflammation and in the host response to gram-negative sepsis. Here, the authors report an 8-month-old boy, who had chronic liver disease due to undetermined cause. He had Staphylococcus aureus and Candida albicans sepsis and died due to gastrointestinal, lung, and peritoneal bleeding during follow-up. Serum soluble EPCR level of the patient was high (225 ng/mL) during sepsis. A homozygous 23-bp insertion of EPCR gene was demonstrated. This case indicates the importance the EPCR gene plaus in pediatric sepsis. Homozygous 23-bp insertion of the EPCR gene may be associated with a tendency to sepsis and poor outcome.
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PMID:Homozygous 23-bp insertion of endothelial protein c receptor gene in a child with fatal sepsis. 1745 90

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high mortality rates despite therapeutic advances. The pathogenesis of ALI and ARDS is similar to that of sepsis, as these disease states involve uncontrolled host defense responses that lead to inflammation, endothelial damage, enhanced coagulation, diminished fibrinolysis, and fibroproliferation. Recent studies of anticoagulants have shown positive outcomes in patients with severe sepsis. In addition, emerging evidence suggests that the use of anticoagulants, such as tissue factor pathway inhibitor, antithrombin, thrombomodulin, heparin, activated protein C, and fibrinolytics (plasminogen activators and particularly tissue plasminogen activator), may be useful in the treatment of ALI and ARDS. Data from experimental models of sepsis, ALI, and ARDS indicate that some of these agents improve lung function and oxygenation. Although clinical data are less convincing than these findings, results from clinical trials may influence the design of future studies.
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PMID:Emerging role of anticoagulants and fibrinolytics in the treatment of acute respiratory distress syndrome. 1754 69

The systemic inflammation associated to the simultaneous activation of blood coagulation and the alterated blood fibrinolysis, leads to microvascular endothelial injury, acute organ dysfunction and possibly death. Activated Protein C, a natural, multifunctional protein, has demonstrated antithrombotic, anti-inflammatory, and profibrinolitic properties and may be an important modulator of the vicious cycle whereby inflammation initiates coagulation and coagulation amplifies inflammation. Protein C couples with its receptor, EPCR (endothelial-cell protein-C receptor), and the ligand-receptor complex then interact with thrombin-thrombomodulin on endothelial surface to produce activated protein C (APC). Once activated, protein C then interact with its cofactor, protein S, to catalyze the inactivation of factors Va and VIIILa, two important accelerators of the clotting cascade, reducing thrombin generation and microvascular thrombosis. In addiction to its anticoagulant activity APC promotes profibrinolytic activity through the inhibition of plasminogen activator inhibitor-1, which is upregulated during inflammation. Inhibition of thrombin generation by APC decreases inflammation by inhibiting platelet activation, neutrophil recruitment, and mast-cell degranulation. APC also shows direct antiinflammatory properties, including blocking of cytokines production by monocytes and blocking cell adhesion. Moreover, APC has antiapoptotic properties that may contribute to its efficacy. In conclusion, APC, besides its physiologic role in the coagulation cascade, plays a key role in the pathophysiology of systemic inflammation justifying its potential therapeutic role in sepsis and systemic inflammatory responses.
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PMID:[The numerous properties of the anticoagulant protein C]. 1756 22

Thrombin activatable fibrinolysis inhibitor (TAFI), when activated, forms a basic carboxypeptidase that can inhibit fibrinolysis. Potential physiologic activators include both thrombin and plasmin. In vitro, thrombomodulin and glycosaminoglycans increase the catalytic efficiency of TAFI activation by thrombin and plasmin, respectively. The most relevant (patho-) physiologic activator of TAFI has not been disclosed. Our purpose was to identify the physiologic activator of TAFI in vivo. Activation of protein C (a thrombin-thrombomodulin-dependent reaction), prothrombin, and plasminogen occurs during sepsis. Thus, a baboon model of Escherichia coli-induced sepsis, where multiple potential activators of TAFI are elaborated, was used to study TAFI activation. A monoclonal antibody (mAbTAFI/TM#16) specifically inhibiting thrombin-thrombomodulin-dependent activation of TAFI was used to assess the contribution of thrombin-thrombomodulin in TAFI activation in vivo. Coinfusion of mAbTAFI/TM#16 with a lethal dose of E coli prevented the complete consumption of TAFI observed without mAbTAFI/TM#16. The rate of fibrin degradation products formation is enhanced in septic baboons treated with the mAbTAFI/TM#16; therefore, TAFI activation appears to play a key role in the extent of fibrin(ogen) consumption during E coli challenge, and thrombin-thrombomodulin, in a baboon model of E coli-induced sepsis, appears to be the predominant activator of TAFI.
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PMID:Thrombin-thrombomodulin connects coagulation and fibrinolysis: more than an in vitro phenomenon. 1764 33

Activated protein C (APC) is a glycoprotein derived from its precursor, protein C and formed by the cleavage of an activation peptide by thrombin bound to thrombomodulin. Originally thought to be synthesized exclusively by the liver, recent reports have shown that protein C is synthesized by endothelial cells, keratinocytes and some hematopoietic cells. APC functions as a physiological anticoagulant with cytoprotective, anti-inflammatory and anti-apoptotic properties. In vitro and preclinical data have revealed that APC exerts its protective effects via an intriguing mechanism requiring endothelial protein C receptor and the thrombin receptor, protease-activated receptor-1. Remarkably, even though APC cleaves this receptor in an identical fashion to thrombin, it exerts opposing effects. Recently approved as a therapeutic agent for severe sepsis, APC is now emerging as a potential treatment for a number of autoimmune and inflammatory diseases including lung disorders, spinal cord injury and chronic wounds. The future pharmacologic use of APC holds remarkable promise.
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PMID:Activated protein C--an anticoagulant that does more than stop clots. 1824 79

Despite recent advances in supportive care, acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are clinical entities with high morbidity and high mortality. In systemic inflammation, like sepsis, uncontrolled host defense can lead to systemic activation of coagulation on the one hand, and attenuation of fibrinolysis on the other. In ALI/ARDS similar but local disturbances in fibrin turnover occur, leading to excessive alveolar fibrin deposition compromising pulmonary integrity and function. Therapies in patients with sepsis have specifically focused on coagulation disturbances. Evidence from preclinical and clinical investigations suggests pharmacologically targeting pulmonary "coagulopathy" could be of benefit to patients with ALI/ARDS as well. Recent animal studies have demonstrated that administration of heparins, activated protein C (APC), Antithrombin (AT), Tissue factor-Factor VIIa (TF-FVIIa) pathway inhibitors, plasminogen activators (PA) and thrombomodulin (TM) can attenuate pulmonary coagulopathy and reduce lung injury and/or improve oxygenation. Some of these studies have also shown anti-inflammatory effects of treatment targeting at coagulation. To date there are no published studies that have specifically studied the effects of anticoagulants on ALI/ARDS however there are on-going clinical trials. A solid base has to be provided by preclinical studies to justify clinical studies on new pharmacologic therapies for ALI/ARDS. In this systematic literature review we give an overview of the models for ALI/ARDS that have been used so far on the topic of pulmonary coagulopathy and focus on the pharmacological interventions that have been evaluated with these models. Finally, the applicability of the different approaches for future research on this subject will be discussed.
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PMID:Pulmonary coagulopathy as a new target in lung injury--a review of available pre-clinical models. 1833 73

Critically ill children in pediatric intensive care units are commonly indicated for blood transfusion due to many reasons. Children are quite different from adults during growth and development, and that should be taken into consideration. It is very difficult to establish a universal transfusion guideline for critically ill children, especially preterm neonates. Treating underlying disease and targeted replacement therapy are the most effective approaches. Red blood cells are the first choice for replacement therapy in decompensated anemic patients. The critical hemoglobin concentration may be higher in critically ill children for many reasons. Whole blood is used only in the following conditions or diseases: (1) exchange transfusion; (2) after cardiopulmonary bypass; (3) extracorporeal membrane oxygenation; (4) massive transfusion, especially in multiple component deficiency. The characteristics of hemorrhagic diseases are so varied that their therapy should depend on the specific needs associated with the underlying disease. In general, platelet transfusion is not needed when a patient has platelet count greater than 10,000/mm3 and is without active bleeding, platelet functional deficiency or other risk factors such as sepsis. Patients with risk factors or age less than 4 months should be taken into special consideration, and the critical thrombocyte level will be raised. Platelet transfusion is not recommended in patients with immune-mediated thrombocytopenia or thrombocytopenia due to acceleration of platelet destruction without active bleeding or life-threatening hemorrhage. There are many kinds of plasma-derived products, and recombinant factors are commonly used for hemorrhagic patients due to coagulation factor deficiency depending on the characteristics of the diseases. The most effective way to correct disseminated intravascular coagulation (DIC) is to treat the underlying disease. Anticoagulant therapy is very important; heparin is the most common agent used for DIC but the results are usually not satisfactory. Antithrombin III, protein C, or recombinant thrombomodulin has been used successfully to treat this condition. For reducing the risk of organism transmission and adverse reactions resulting from blood transfusion, the following measures have been suggested: (1) replacement therapy using products other than blood (e.g., erythropoietin, iron preparation, granulocyte colony-stimulating factor); (2) special component replacement therapy for specific diseases; (3) autotransfusion; (4) subdividing whole packed blood products into smaller volumes to reduce donor exposure; (5) advances in virus-inactivating procedures. To avoid viral transmission, vapor-heated or pasteurized products and genetic recombinant products are recommended. Cytomegalovirus (CMV)-seronegative blood, leukoreduced and/or irradiated blood are recommended for prevention of CMV infection, graft-versus-host-disease and alloimmunization in neonate and immunocompromised patient transfusion. There is no reason to prescribe a plasma product for nutritional supplementation because of the risk of complications. The principle: complications of transfusion must be avoided, the rate of blood exposure should be reduced and the safety of the transfused agents or components should be maintained must always be kept in mind.
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PMID:Transfusion therapy in critically ill children. 1894 9

Inflammation shifts the hemostatic mechanisms in favor of thrombosis. Multiple mechanisms are at play including up regulation of tissue factor leading to the initiation of clotting, amplification of the clotting process by augmenting exposure of cellular coagulant phospholipids, inhibition of fibrinolysis by elevating plasminogen activator inhibitor 1 (PAI-1) and decreases in natural anticoagulant pathways, particularly targeted toward down regulation of the protein C anticoagulant pathway through multiple mechanisms. The decreased function of the natural anticoagulant pathways may be particularly problematic because these appear to play a role in dampening inflammatory responses. The protein C anticoagulant pathway provides a useful model for the impact of inflammation on coagulation. This pathway plays a major role in preventing microvascular thrombosis. The pathway is initiated when thrombin binds to thrombomodulin (TM) on the surface of the endothelium. An endothelial cell protein C receptor (EPCR) augments protein C activation by the thrombin-TM complex more than 10-fold in vivo. EPCR is shed from the endothelium 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 extravisation. EPCR can undergo translocation from the plasma membrane to the nucleus where it redirects gene expression. During translocation it 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 and IL-6 can depress levels of protein S in experimental animals. Inhibition of protein C pathway function increases cytokine elaboration, endothelial cell injury and leukocyte extravisation in response to endotoxin, processes that are decreased by infusion of APC. In vitro, APC inhibits 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:Crosstalk between inflammation and thrombosis. 1506 84

Sepsis remains a major health threat in intensive care medicine. The physiological functions of the coagulation cascade extend beyond blood coagulation and play a pivotal role in inflammation. We investigated whether the use of recombinant thrombomodulin (rTM), which has activity comparable with antithrombin, tissue factor pathway inhibitor, and activated protein C, could inhibit secretion of cytokines and high-mobility group box 1 (HMGB1) protein, thus reducing lung damage in a rat model of LPS-induced systemic inflammation. Rats treated with an intravenous injection of either rTM or saline were injected concurrently with intravenous LPS. In addition, mouse macrophage RAW264.7 cells were stimulated with LPS, with or without simultaneous rTM treatment. Histological examination revealed marked reductions of interstitial congestion, edema, inflammation, and hemorrhage in lung tissue harvested 12 h after treatment with both agents compared with LPS administration alone. LPS-induced secretion of proinflammatory cytokines and HMGB1 protein was inhibited by treatment with rTM. The presence of HMGB1 protein in the lung was examined by immunohistochemistry; the number of HMGB1-positive cells was significantly lower in LPS-treated animals that also received rTM. In the in vitro studies, rTM administration inhibited the activation of nuclear factor-kappa B by inhibiting I kappa B phosphorylation. The anticoagulant rTM blocked the LPS-induced inflammatory response and protected against acute lung injury normally associated with endotoxemia in this rat sepsis model. Given these results, rTM is a strong candidate as a therapeutic agent for various systemic inflammatory diseases.
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PMID:In vivo and in vitro effects of the anticoagulant, thrombomodulin, on the inflammatory response in rodent models. 1953 47

Sepsis remains the leading cause of death in intensive care units. Uncontrolled systemic inflammation and an impaired protein C pathway are two important contributors to sepsis pathophysiology. Based on the beneficial effects of the saponin fraction from Astragalus membranaceus roots (SAM) against inflammation, liver dysfunction, and endothelium injury, we investigated the potential protective roles and underlying mechanisms of SAM on polymicrobial sepsis induced by cecal ligation and puncture (CLP) in mice. SAM, orally administered 1 h before and after CLP, significantly elevated the survival rate of mice. At 96 h after CLP operation, all mice in the model group died, whereas 33.3% of mice in the SAM (400 mg/kg)-treated group survived. SAM attenuated both inflammatory factors and their abilities to induce tissue dysfunction, which was mainly evidenced by decreased infiltration of polymorphonuclear leukocytes, tissue edema, and lung wet-to-dry weight ratio, lowered levels of myeloperoxidase (MPO), nitric oxide (NO), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in serum, as well as downregulated expressions of iNOS and IL-1beta mRNA in livers. Furthermore, we addressed the effects of SAM on the protein C (PC) pathway, closely linked with sepsis. In CLP-induced septic mice, SAM elevated the impaired expression of PC mRNA in livers. In vitro, SAM reversed the decreased expressions of thrombomodulin (TM) and endothelial PC receptor (EPCR) mRNA induced by lipopolysaccharide (LPS) in endothelial cells. These findings suggest that SAM is able to restore the impaired protein C pathway. Taken together, the current study demonstrates that SAM has protective effects on polymicrobial sepsis in mice. The mechanisms of action involve anti-inflammation and upregulation of the PC pathway.
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PMID:Saponin fraction from Astragalus membranaceus roots protects mice against polymicrobial sepsis induced by cecal ligation and puncture by inhibiting inflammation and upregulating protein C pathway. 1954 65


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