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

Severe sepsis, defined as sepsis associated with acute organ dysfunction, results from a generalized inflammatory and procoagulant host response to infection. Coagulopathy in severe sepsis is commonly associated with multiple organ dysfunction, and often results in death. The molecule that is central to these effects is thrombin, although it may also have anticoagulant and antithrombotic effects through the activation of Protein C and induction of prostacyclin. In recent years, it has been recognized that chemicals produced by endothelial cells play a key role in the pathogenesis of sepsis. Thrombomodulin on endothelial cells coverts Protein C to Activated Protein C, which has important antithrombotic, profibrinolytic and anti-inflammatory properties. A number of studies have shown that Protein C levels are reduced in patients with severe infection, or even in inflammatory states without infection. Because coagulopathy is associated with high mortality rates, and animal studies have indicated that therapeutic intervention may result in improved outcomes, it was rational to initiate clinical studies.
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PMID:Microvascular endothelial dysfunction: a renewed appreciation of sepsis pathophysiology. 1137 85

It is becoming increasingly clear that coagulation augments inflammation and that anticoagulants, particularly natural anticoagulants, can limit the coagulation induced increases in the inflammatory response. The latter control mechanisms appear to involve not only the inhibition of the coagulation proteases, but interactions with the cells that either generate anti-inflammatory substances, such as prostacyclin, or limit cell activation. Recent studies have demonstrated a variety of mechanisms by which coagulation, particularly the generation of thrombin, factor Xa and the tissue factor-factor VIIa complex, can augment acute inflammatory responses. Many of these responses are due to the activation of one or more of the protease activated receptors. Activation of these receptors on endothelium can lead to the expression of adhesion molecules and platelet activating factor, thereby facilitating leukocyte activation. Therefore, anticoagulants that inhibit any of these factors would be expected to dampen the inflammatory response. The three major natural anticoagulant mechanisms seem to exert a further inhibition of these processes by impacting cellular responses. Antithrombin has been shown in vitro to increase prostacyclin responses and activated protein C has been shown to inhibit a variety of cellular responses including endotoxin induced calcium fluxes in monocytes and the nuclear translocation of NFKB, a key step in the generation of the inflammatory response. In some, but not all, in vivo models, these natural anticoagulants have been able to inhibit endotoxin/E. coli-mediated leukocyte activation and to diminish cytokine elaboration (TNF, IL-6 and IL-8). Phase III clinical studies for treatment of patients with severe sepsis have been completed for APC, which was successful (1), and for antithrombin, which was not (2). A phase III trial with tissue factor pathway inhibitor is in progress. In this review, the mechanisms by which the different natural anticoagulants are thought to function will be reviewed.
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PMID:Role of coagulation inhibitors in inflammation. 1148 41

Antithrombin (AT) prevents Escherichia coli-induced hypotension in animal models of sepsis, and it further reduces the mortality of patients with septic shock. In the present study, we examined whether AT may prevent the endotoxin (ET)-induced hypotension by promoting the endothelial release of prostacyclin (PGI(2)) in rats. Intravenous administration of AT (250 U/kg) prevented both hypotension and the increases in plasma levels of NO(2)(-)/NO(3)(-) in rats given ET. Lung expression of messenger RNA (mRNA) for tumor necrosis factor-alpha (TNF-alpha) was transiently increased after ET administration, followed by the increases in lung tissue levels of TNF-alpha. Both the lung activity of the inducible form of nitric oxide synthase (iNOS) and the lung expression of iNOS mRNA in animals administered ET were gradually increased after the TNF-alpha mRNA expression had peaked. Administration of AT significantly inhibited these increases. Neither DEGR-F.Xa, a selective inhibitor of thrombin generation, nor Trp(49)-modified AT, which is not capable of promoting the endothelial release of PGI(2), showed any effects on these changes induced by ET. Administration of antirat TNF-alpha antibody produced effects similar to those induced by AT. Indomethacin pretreatment abrogated the effects induced by AT. Iloprost, a stable derivative of PGI(2), produced effects similar to those of AT. These findings suggested that AT prevents the ET-induced hypotension by inhibiting the induction of iNOS through inhibiting TNF-alpha production. These effects of AT could be mediated by the promotion of endothelial release of PGI(2) and might at least partly explain the therapeutic effects for septic shock.
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PMID:Antithrombin prevents endotoxin-induced hypotension by inhibiting the induction of nitric oxide synthase in rats. 1186 Dec 78

Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous prostacyclin has proven to be effective. However, this treatment requires a permanent central venous catheter with the associated risk of serious complications such as sepsis, thromboembolism, or syncope. Treprostinil, a stable prostacyclin analogue, can be administered by a continuous subcutaneous infusion, avoiding these risks. We conducted a 12-week, double-blind, placebo-controlled multicenter trial in 470 patients with pulmonary arterial hypertension, either primary or associated with connective tissue disease or congenital systemic-to-pulmonary shunts. Exercise capacity improved with treprostinil and was unchanged with placebo; the between treatment group difference in median six-minute walking distance was 16 m (p = 0.006). Improvement in exercise capacity was greater in the sicker patients and was dose-related, but independent of disease etiology. Concomitantly, treprostinil significantly improved indices of dyspnea, signs and symptoms of pulmonary hypertension, and hemodynamics. The most common side effect attributed to treprostinil was infusion site pain (85%) leading to premature discontinuation from the study in 8% of patients. Three patients in the treprostinil treatment group presented with an episode of gastrointestinal hemorrhage. We conclude that chronic subcutaneous infusion of treprostinil is an effective treatment with an acceptable safety profile in patients with pulmonary arterial hypertension.
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PMID:Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. 1189 47

Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) are critically involved in activation of the coagulation system in sepsis, leading to disseminated intravascular coagulation (DIC). Natural anticoagulants such as antithrombin (AT) and activated protein C (APC) regulate the coagulation system by inhibiting thrombin generation. In addition to these anticoagulant effects, both AT and APC have been shown to attenuate inflammatory responses induced by various noxious stimuli in rats such as lipopolysaccharide (LPS) challenge. AT promotes the endothelial release of prostacyclin, a potent anti-inflammatory prostaglandin that inhibits the monocytic production of TNF-alpha, by interacting with cell-surface heparin-like substances. APC directly inhibits the production of TNF-alpha by inhibiting the activation of both nudear factor kappaB (NFkappaB) and activator protein-1 in monocytes stimulated with LPS. Thrombomodulin, an endothelial membranous integral protein that binds thrombin, exerts anti-inflammatory effects by generating APC. Furthermore, tissue factor pathway inhibitor, a natural anticoagulant for the extrinsic pathway of the coagulation system, also attenuates LPS-induced inflammatory responses in rats by inhibiting TNF-alpha production by monocytes. These findings strongly suggest that natural anticoagulants could regulate inflammatory responses as well as the coagulation system in rats by inhibiting the monocytic production of TNF-alpha. Such anti-inflammatory properties of natural anticoagulants are potentially important for their replacement in patients with sepsis who frequently develop DIC and organ failure as inflammatory responses.
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PMID:Regulation of inflammatory responses by natural anticoagulants. 1191 84

Leukocyte-endothelial cell interaction and microvascular perfusion failure are characteristic deteriorations of the microcirculation in endotoxaemia and are known to play a crucial role in the development of septic multiple organ dysfunction. Recent studies have indicated that antithrombin III treatment is capable of significantly ameliorating these microcirculatory disorders. Endothelial cells have important anticoagulant systems, including the heparan sulfate-antithrombin system. Antithrombin III stimulates prostacyclin generation in endothelial cells by interacting with heparan sulfate of endothelial cells and inhibits cytokine and tissue factor production in endothelial cells and monocytes. Similar mechanisms may be involved in cellular actions of antithrombin III causing desensitization of chemoattractant receptors of leukocytes by activating the heparan sulfate proteoglycan, syndecan-4. Thus, antithrombin III might be among the useful agents for treating coagulation abnormalities associated with sepsis or other inflammation because it inhibits not only coagulation but also downregulation of anticoagulant activities of endothelial cells and affects leukocyte activation.
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PMID:The anti-inflammatory actions of antithrombin--a review. 1216 69

Antithrombin (AT) is a plasma-derived, single-chain glycoprotein with a molecular weight of 58 kDa. It is a serine protease inhibitor (serpin), sharing about 30% homology in amino acid sequence with other serpins. AT is a complex molecule with multiple biologically important properties. It is a potent anticoagulant that has been demonstrated to provide benefit in animal models and small cohorts of patients with coagulation disorders. AT also has remarkable anti-inflammatory properties, several of which result from its actions in the coagulation cascade. Activated coagulation proteases like activated factor X and thrombin contribute to inflammation; for instance, by the release of pro-inflammatory mediators. Inhibition of these proteases by AT prevents their specific interaction with cells and subsequent reactions. Anti-inflammatory properties of AT independent of coagulation involve direct interactions with cells leading to the release of, for instance, prostacyclin. Binding of AT to a recently identified cellular receptor, syndecan-4, leads to the interference with the intracellular signal induced by mediators like lipopolysaccharides and, thereby, to a down-modulation of the inflammatory response. AT has been shown to be effective in prospective and well-controlled small-scale studies of patients with inflammatory conditions, including sepsis. Although AT did not decrease overall patient mortality in a double-blind, placebo-controlled, phase III trial of patients with sepsis, it is important to note that AT improved the survival of individuals in this study not receiving heparin as a prophylactic regimen, which can be explained by the impaired interaction of AT with its cellular receptor in the presence of heparin, resulting in the reduction of the anti-inflammatory properties. Accordingly, the supplementation of AT without concomitant heparin may be beneficial in disorders with inflammatory characteristics, which has to be demonstrated in further clinical studies. Finally, recent results suggest that latent AT can induce apoptosis of endothelial cells by disrupting cell-matrix interactions. Further investigations will have to demonstrate whether latent and/or cleaved AT are physiological means to control angiogenesis. A potential prophylactic or therapeutic use as an anti-angiogenic and antitumor agent merits further exploration, including whether the growth of vessels in tumor tissues or close to tumors can be controlled by latent AT without affecting the formation of blood vessels during wound healing processes.
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PMID:Antithrombin: a new look at the actions of a serine protease inhibitor. 1244 4

Antithrombin (AT) supplementation in patients with severe sepsis has been shown to improve organ failures in which activated leukocytes are critically involved. However, the precise mechanism(s) for the therapeutic effects of AT is not well understood. We examined in rats whether AT reduces ischemia/reperfusion (I/R)-induced renal injury by inhibiting leukocyte activation. AT markedly reduced the I/R-induced renal dysfunction and histologic changes, whereas neither dansyl glutamylglycylarginyl chloromethyl ketone-treated factor Xa (DEGR-F.Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Renal tissue levels of 6-keto-PGF(1 alpha), a stable metabolite of prostacyclin (PGI(2)), increased after renal I/R. AT enhanced the I/R-induced increases in renal tissue levels of 6-keto-PGF(1 alpha), whereas neither DEGR-F.Xa nor Trp49-modified AT had any effect. AT significantly inhibited I/R-induced decrease in renal tissue blood flow and the increase in the vascular permeability. Ischemia/reperfusion-induced increases in renal tissue levels of tumor necrosis factor-alpha, cytokine-induced neutrophil chemoattractant, and myeloperoxidase were significantly inhibited in animals given AT. Pretreatment of animals with indomethacin reversed the effects induced by AT. Iloprost, an analog of PGI(2), produced effects similar to those induced by AT. These observations strongly suggest that AT reduces the I/R-induced renal injury by inhibiting leukocyte activation. The therapeutic effects of AT might be mainly mediated by PGI(2) released from endothelial cells through interaction of AT with cell surface glycosaminoglycans.
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PMID:Antithrombin reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation through promotion of prostacyclin production. 2354 58

Sepsis and septic shock represent a frequent cause of mortality in Intensive Care Units, despite of the progress in antibiotic therapy and in the hemodynamic and respiratory support. The most frequent cause of death is the Multi Organ Dysfunction Syndrome (MODS), which is the clinical manifestation of the irreversibile damage of the microvascular bed. During sepsis and septic shock both activation of coagulation /fibrinolysis and release of mediators of inflammation contribute to the pathogenesis of disseminated intravascular coagulation (DIC); in particular the formation of fibrin in the microvascular bed is the pathological substrate of the clinical development of MODS. The rationale for employing antithrombin (AT) concentrates in the treatment of DIC associated to sepsis is based on the consideration that AT plasma levels are always decreased in patients with sepsis or septic shock; furthermore, the degree of the decrease is directly proportional to the severity of the disease and the prognosis and low AT plasma activities correlate with high mortality. AT has a double function: anticoagulant and anti-inflammatory. The most important mechanism responsible of the anti-inflammatory properties of AT is the binding to the glycosaminoglycans of the endothelial cells and the consequent release of prostacyclin. During sepsis and septic shock, treatment with AT was able, especially in animal models but also in clinical studies, to decrease plasma levels of mediators of inflammation and in some case to preserve organ failure and to reduce mortality.
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PMID:[Antithrombin: prospects in clinical practice. Sespsi: anticoagulant or anti-inflammatory agents?]. 1276 69

The effects of selective ((5,5-dimethyl-3-(3-florophenyl)-4-(4-methylsulphonyl-2(5H)-furanon); DFU) and (N-(2-cyclohexyloxy-4-nitrophenyl)-methansulphonamide; NS 398)) or non-selective (diclophenac and proquazon) inducible cyclooxygenase (COX-2) inhibitors on the survival, nitrite (stable product of nitric oxide (NO) as an index for inducible NO synthase (iNOS) activity) and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha), stable product of prostacyclin as an index for COX-2 activity) production in serum, lungs, brain and/or kidney were investigated in endotoxin-induced sepsis model in mice. Endotoxin (10 mg x kg(-1), i.p.)-induced mortality was prevented by DFU, NS 398 and proquazon (0.1, 10 and 1 mg x kg(-1), respectively) and enhanced 2.6-fold with 0.1mg x kg(-1) diclophenac. Endotoxin-induced increase in the serum levels of nitrite was only inhibited by 10 mg x kg(-1) diclophenac. Endotoxin caused a significant decrease only in the brain levels of nitrite without affecting 6-keto-PGF(1alpha) levels in all tissues. The decreased levels of nitrite induced by endotoxin is further reduced by 0.1mg x kg(-1) DFU and 1 and 10mg x kg(-1) diclophenac while 10 mg x kg(-1) DFU and 1mg x kg(-1) proquazon increased it. On the other hand, 1mg x kg(-1) diclophenac and proquazon, and 10 mg x kg(-1) NS 398 increased the endotoxin-induced lung levels of 6-keto-PGF(1alpha). The results suggest that the COX inhibitors may have different effects on the survival and NO production depending on tissue and dose.
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PMID:Effects of cyclooxygenase inhibitors on nitric oxide production and survival in a mice model of sepsis. 1277 May 13


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