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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endogenous plasma anticoagulant proteins tissue factor pathway inhibitor (TFPI) and antithrombin (AT) have both been extensively studied in large, multinational phase III clinical trials in patients with severe sepsis. The TFPI and AT trials failed to result in significant reductions in the 28-day, all-cause mortality rates in their respective study populations. However, there appear to be definable patient populations within each study that may have benefited from TFPI or AT. Drug-drug interactions and dosing issues were observed in both trials. The similarities and differences of each anticoagulant and the lessons learned from the recent phase III clinical trials are examined in this review.
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PMID:Tissue factor pathway inhibitor and antithrombin trial results. 1599 66

Disseminated intravascular coagulation is a frequent complication of sepsis. Coagulation activation, inhibition of fibrinolysis, and consumption of coagulation inhibitors lead to a procoagulant state resulting in inadequate fibrin removal and fibrin deposition in the microvasculature. As a consequence, microvascular thrombosis contributes to promotion of organ dysfunction. Recently, three randomized, double-blind, placebo-controlled trials investigated the efficacy of antithrombin, activated protein C (APC), and tissue factor pathway inhibitor, respectively, in sepsis patients. A significant reduction in mortality was demonstrated in the APC trial. In this article, we first discuss the physiology of coagulation and fibrinolysis activation. Then, the pathophysiology of coagulation activation, consumption of coagulation inhibitors, and the inhibition of fibrinolysis leading to a procoagulant state are described in more detail. Moreover, therapeutic concepts as well as the three randomized, double-blind, placebo-controlled studies are discussed.
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PMID:Disseminated intravascular coagulation in sepsis. 1623 64

Tissue factor plays an essential role in the initiation of coagulation in vivo. In severe conditions, including sepsis and acute lung injury, increased expression of tissue factor may induce disseminated intravascular coagulation and fibrin deposition in organs, which are believed to have a determining impact on patient outcome. Tissue factor also acts as a signaling receptor and is involved in the systemic inflammatory response, as in cancer progression and atherosclerosis. Interventions aiming at limiting tissue factor activities have been evaluated in multiple experimental studies and the observed results have supported the potential benefits for coagulation disorders, inflammation, and survival. The effects of the main physiological inhibitor of tissue factor, tissue factor pathway inhibitor, have been evaluated in two large clinical trials in sepsis. Even though they are not associated with an improved outcome, the observed data support further clinical studies.
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PMID:Pharmacological inhibition of tissue factor. 1647 64

The haemostatic system is greatly modified during severe infections. The early activation of coagulation is triggered by tissue factor expression and secondary fibrinolysis impaired by the upregulation of fibrinolysis inhibitors. This imbalance is a major cause of subsequent organ dysfunction. Natural anticoagulants (Tissue factor pathway inhibitor (TFPI), Antithrombin (AT), and Protein C (PC) are consumed or inhibited in this pathological process justifying a therapeutic supplementation with these inhibitors to improve sepsis-induced organ failure and mortality. No effect on the mortality rate could be documented in controlled studies using recombinant TFPI or AT concentrates but a biological interaction with heparin therapy could have biased the results. Treatment with recombinant activated PC was associated with a significant reduction in the mortality rate of severely ill patients. An increase in the rate of hemorrhagic adverse effects was observed with these compounds, justifying a strict observance of contraindications and of patient selection.
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PMID:[Hemostasis disorders in severe infections: state of the art]. 1719 28

Sepsis is a common and life-threatening condition with a high mortality rate. Severe sepsis includes multiorgan dysfunction syndrome. The organ most often affected is the lung, with development of acute lung injury (ALI), which, in its most severe form, is referred to as acute respiratory distress syndrome (ARDS). Our understanding of inflammation in the pathogenesis of sepsis and ALI is continually growing. However, therapies aimed at the inflammatory cascade in sepsis have been unsuccessful. These failures have led investigators to consider other pathways that may be important in the development of sepsis and ALI, including the coagulation and fibrinolytic cascades. In fact, the first therapy to reduce mortality in sepsis modulates the coagulation cascade. With this clinical success, administration of drotecogin alfa (recombinant activated protein C), the importance of coagulation in the pathogenesis of human sepsis is becoming clearer. This review summarizes the current understanding of the role of coagulation and fibrinolytic abnormalities in sepsis and the development of ALI and ARDS. Both in vitro and in vivo studies of the role of the coagulation cascade in sepsis and lung injury will be discussed, including initiation of coagulation through modulation of tissue factor and tissue factor pathway inhibitor, propagation of coagulation via protein C and thrombomodulin, inhibition of thrombin generation and resolution through thrombolysis by plasminogen activator, and plasminogen activator inhibitor-1.
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PMID:The role of the coagulation cascade in the continuum of sepsis and acute lung injury and acute respiratory distress syndrome. 1690 70

The liver can be injured and its functions altered by activation of the coagulation and inflammatory processes in sepsis. The objective of the present study was to investigate the pattern of protease- activated receptors (PARs) over time in a model of acute liver injury induced by lipopolysaccharide (LPS); and whether PARs play a role in this process and exert their effects through inflammation and coagulation. Levels of tumor necrosis factor-a (TNF-a) were significantly expressed 1 h after LPS administration followed by: i) an increase in levels of tissue factor, factor VIIa, thrombin and plasminogen activator inhibitor-1; ii) unchanged or steady levels of tissue factor pathway inhibitor; and iii) subsequent deposition of fibrin in the liver tissue, that led to the elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are associated with liver injury. The expression of all PAR isoforms (1-4) was elevated, and each isoform had a distinct cellular localization (hepatocytes, Kupffer cells, the portal triad area, and central veins) and a time-dependent pattern of expression. The immuno-reactivity of PAR2 and 4 in Kupffer cells was intense. Interestingly, PAR2 blocking peptide improved the healing of liver injuries, an effect that was associated with suppression of TNF-a elevation, and normalization of coagulation and fibrinolysis. This ultimately led to decreased fibrin formation in the injured liver. The present study reveals a distinct chronological expression and cellular localization of PARs in LPS-mediated liver injury and shows that blockade of PAR2 may play a crucial role in treating liver injury, via normalization of inflammation, coagulation and fibrinolytic pathways.
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PMID:Chronological expression of PAR isoforms in acute liver injury and its amelioration by PAR2 blockade in a rat model of sepsis. 1713 80

The haemostatic system is greatly modified during severe infections. The early activation of coagulation is triggered by tissue factor expression and secondary fibrinolysis impaired by the upregulation of fibrinolysis inhibitors. This imbalance is a major cause of subsequent organ dysfunction. Natural anticoagulants (Tissue factor pathway inhibitor (TFPI), Antithrombin (AT), and Protein C (PC) are consumed or inhibited in this pathological process justifying a therapeutic supplementation with these inhibitors to improve sepsis-induced organ failure and mortality. No effect on the mortality rate could be documented in controlled studies using recombinant TFPI or AT concentrates but a biological interaction with heparin therapy could have biased the results. Treatment with recombinant activated PC was associated with a significant reduction in the mortality rate of severely ill patients. An increase in the rate of hemorrhagic adverse effects was observed with these compounds, justifying a strict observance of contraindications and of patient selection.
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PMID:[Hemostasis disorders in severe infections: State of the art]. 1671 62

Systemic inflammation can induce blood hypercoagulability, even disseminated intravascular coagulation (DIC), and "cross talk" exists between inflammatory and coagulation system. So anticoagulation should be helpful in the treatment of systemic inflammatory response syndrome (SIRS) or sepsis. The success in the use of recombinant human activated protein C (rhAPC) is a strong evidence to support anticoagulation strategy in the treatment of sepsis. Unexpectedly, other two anticoagulation studies, KyberSept and OPTIMIST, respectively with antithrombin and tissue factor pathway inhibitor (TFPI) failed to show improvement in 28-day survival rate. Blame had been laid on the combined use of heparin or low molecular weight heparin (LMWH), as it might interfere with efficacy of antithrombin and TFPI. However, no compelling evidence was found to support this hypothesis, as there was no significant difference in result between the patients with and without heparin or LMWH in the treatment groups in these two studies. Contrarily, significant differences in outcome were found between patients with and without heparin or LMWH in control groups, and the survival rate of patients with heparin or LMWH in control groups was higher than that of the treatment groups. These results strongly suggested heparin or LMWH could be effective in the treatment of sepsis. It is our understanding that any anticoagulant should have some potential effect in treatment of sepsis. Therefore, it seems to be necessary to explore the efficacy of traditional anticoagulant, and compare the effects between the new and old drugs.
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PMID:[Highlighting the potential of heparin in the treatment of sepsis in view of failure of KyberSept and OPTIMIST projects]. 1737 63

Adrenomedullin (ADM) is a vasodilator peptide that has a variety of effects, including antithrombotic activities and resistant roles to lipopolysaccharide (LPS)-induced septic shock. During sepsis, LPS triggers the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation. It is unknown whether the antithrombotic activities of ADM contribute to its resistance to sepsis. In the present study, we investigated the effects of ADM on tissue factor pathway inhibitor (TFPI) (primary anticoagulant factor) expression in human umbilical vein endothelial cells (HUVECs) exposed to LPS, and the possible underlying mechanism for these effects. Exposure of HUVECs to LPS for 12 hours caused significant decrease of TFPI protein activities and mRNA expression. These effects were abolished by treatment with ADM (10(-10) to 10(-6) M), cAMP analogue and calcium antagonist. Accordingly, cAMP antagonist inhibited the counteraction effect of ADM on LPS in TFPI expression. Electrophoresis mobility shift assay (EMSA) and Western blot analysis showed that the protein level of GATA-2 and SP1 transcriptional factors and their binding to the corresponding regulatory sequences decreased by LPS treatment. And these effects of LPS were antagonized by ADM. Promoter-reporter assays and mutational analysis also confirmed the roles of GATA-2 and SP1 motifs from -1247 to -381 bp promoter sequence in TFPI inducible expression. Taken together, these results indicate that ADM antagonizes the effect of LPS on TFPI expression, which is mediated by affecting transcriptional factor GATA-2 and SP1 through cAMP and calcium signaling pathway.
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PMID:Crucial roles of GATA-2 and SP1 in adrenomedullin-affected expression of tissue factor pathway inhibitor in human umbilical vein endothelial cells exposed to lipopolysaccharide. 1747 96

Pulmonary coagulopathy and hyperinflammation may contribute to an adverse outcome in sepsis. The present study determines the effects of natural inhibitors of coagulation on bronchoalveolar haemostasis and inflammation in a rat model of endotoxaemia. Male Sprague-Dawley rats were randomised to treatment with normal saline, recombinant human activated protein C (APC), plasma-derived antithrombin (AT), recombinant human tissue factor pathway inhibitor (TFPI), heparin or recombinant tissue plasminogen activator (tPA). Rats were intravenously injected with lipopolysaccharide (LPS), which induced a systemic inflammatory response and pulmonary inflammation. Blood and bronchoalveolar lavage were obtained at 4 and 16 h after LPS injection, and markers of coagulation and inflammation were measured. LPS injection caused an increase in the levels of thrombin-AT complexes, whereas plasminogen activator activity was attenuated, both systemically and within the bronchoalveolar compartment. Administration of APC, AT and TFPI significantly limited LPS-induced generation of thrombin-AT complexes in the lungs, and tPA stimulated pulmonary fibrinolytic activity. However, none of the agents had significant effects on the production of pulmonary cytokines, chemokines, neutrophil influx and myeloperoxidase activity. Natural inhibitors of coagulation prevent bronchoalveolar activation of coagulation, but do not induce major alterations of the pulmonary inflammatory response in rat endotoxaemia.
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PMID:Natural anticoagulants limit lipopolysaccharide-induced pulmonary coagulation but not inflammation. 1753 62


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