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

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

Natural inhibitors of coagulation, in other words, antithrombin (AT), the protein C system, and tissue factor pathway inhibitor (TFPI), play an important role in controlling the activation of coagulation during disseminated intravascular coagulation (DIC). Furthermore, they may not only influence coagulation but also attenuate inflammatory responses during sepsis. Low circulating levels of AT and protein C have been associated with poor outcome. Replacement therapy with AT, activated protein C (APC), and TFPI has been shown to attenuate thrombin generation and to reduce mortality in experimental sepsis models. Experience with AT and APC in patients is promising. Data from large phase III trials of AT and APC as treatment of patients with severe sepsis will soon be available. Recombinant TFPI is currently in phase II clinical trials for severe sepsis.
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PMID:Anticoagulant factor concentrates in disseminated intravascular coagulation: rationale for use and clinical experience. 1174 Jun 90

Derangements in coagulation and fibrinolysis are frequent complications of systemic infection, and septic shock is the most common recognized cause of disseminated intravascular coagulation. Anticoagulant therapy has been used as a treatment strategy for severe sepsis for several decades without compelling evidence of efficacy until the 2001 publication of the phase III trial with recombinant human activated protein C. Major phase III international trials with antithrombin and tissue factor pathway inhibitor also have been completed recently. The molecular mechanisms by which the clotting system interacts with the innate immune response have greatly facilitated the understanding of coagulation and the pathophysiology of septic shock. Anticoagulants such as recombinant human activated protein C and related agents may become the mainstay of adjuvant therapies for severe sepsis in the near future.
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PMID:Clinical impact of novel anticoagulation strategies in sepsis. 1180 32

The incidence of sepsis and complications stemming from septicemia has remained constant in recent years despite improved levels of monitoring and care. Disseminated intravascular coagulation (DIC), a syndrome that occurs frequently in septic patients, is associated with increased mortality. Organ dysfunction is also a common sequela that is strongly correlated with DIC. Cytokines released early in the course of sepsis stimulate a procoagulant state that causes development of intravascular fibrin deposition. In a later stage of DIC, bleeding may occur in parallel because of consumption of clotting factors and inhibitors. Therapeutic strategies to attenuate or reverse these conditions have focused on multiple stages of the molecular cascade of events, including preventing cytokine induction, inhibiting coagulation processes, and promoting fibrinolysis. Recent clinical trials have supported the use of antithrombin and activated protein C supplementation in DIC associated with severe sepsis. Studies of other novel therapeutic avenues are still ongoing. Future efforts may be directed at combining 2 or more agents to achieve prompt and successful reversal of DIC.
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PMID:Pathogenesis and treatment of disseminated intravascular coagulation in the septic patient. 1181 2

Beriplex, a prothrombin complex concentrate (PCC), was administered to 42 patients requiring immediate reversal of their oral anticoagulant therapy. The dose administered was determined using the pretreatment International Normalized Ratio (INR). Blood samples were obtained before treatment and at 20, 60 and 120 min after treatment. The following investigations were performed on all samples - INR, clotting factors II, VII, IX and X, coagulation inhibitors protein C (PC) and antithrombin (AT), and other markers of disseminated intravascular coagulation, plasma fibrinogen, D-dimer and platelet count. Immediate reversal of the INR, the vitamin K-dependent clotting factors and PC was achieved in virtually all patients. Reduced AT levels were present in 18 patients before treatment. Further slight AT reductions occurred in four patients, but other associated abnormalities of haemostasis were observed in only one of the four patients. One patient with severe peripheral vascular disease, sepsis and renal and cardiac failure died of a thrombotic stroke following leg amputation, 48 h after receiving Beriplex. No other arterial and no venous thromboembolic events occurred within 7 d of treatment. Beriplex is effective in rapidly reversing the anticoagulant effects of warfarin, including PC deficiency, without inducing coagulation activation. Caution should continue to be exercised in the use of these products in patients with disseminated intravascular coagulation, sepsis or liver disease.
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PMID:Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. 1184 21

The roles of inflammation and coagulation in the pathophysiology of sepsis are described. Sepsis results when an infectious insult triggers a localized inflammatory reaction that then spills over to cause systemic symptoms of fever or hypothermia, tachycardia, tachypnea, and either leukocytosis or leukopenia. These clinical symptoms are called the systemic inflammatory response syndrome. Severe sepsis is defined by dysfunction of one of the major organ systems or unexplained metabolic acidosis. The inflammatory reaction is mediated by the release of cytokines, including tumor necrosis factor-alpha, interleukins, and prostaglandins, from neutrophils and macrophages. The cytokines activate the extrinsic coagulation cascade and inhibit fibrinolysis. These overlapping processes result in microvascular thrombosis; thrombosis is one potential factor producing organ dysfunction. Activation of the coagulation system leads to consumption of endogenous anticoagulants (e.g., protein C and antithrombin); this may be an important factor in the development of microvascular coagulation. Antiinflammatory mediators as well as inflammatory mediators have a role in sepsis, and an excess of either can result in poor patient outcomes. Sepsis is a complex syndrome involving activation of a variety of systems.
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PMID:Pathophysiology of sepsis. 1188 12

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

Antithrombin has been used for over two decades as adjuvant therapy in severe sepsis, especially when associated with coagulopathy. A positive effect has been demonstrated in several experimental sepsis models and a number of small clinical trials have suggested a beneficial effect. A large confirmatory randomized clinical trial with 2,314 evaluable patients with severe sepsis was recently completed [1]. No treatment effect of antithrombin was demonstrated (28 day overall mortality was 38.9% and 38.7% in the treatment and placebo groups, respectively). Among various secondary effect and subgroup analyses, it is noteworthy that no trend indicating a beneficial effect of antithrombin substitution was found even in the subgroup of patients with plasma levels of antithrombin < 60% on randomization (n = 1,117). In summary, there is presently no support for the general use of antithrombin as adjuvant therapy in severe sepsis/septic shock.
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PMID:[Antithrombin therapy of no value in sepsis according to a large clinical trial]. 1198 56

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

Following on the heels of multiple failed clinical trials of adjunctive therapeutic agents in sepsis, the positive outcome of a recent phase III study using activated protein C (APC) has led to a renewed optimism in targeted biotherapies for this syndrome. A growing body of data (both preclinical and clinical) suggests that the protection against death afforded by APC cannot be solely explained by its antithrombotic activity but rather is likely explained by its associated anti-inflammatory and profibrinolytic effects. Although a recent phase III study failed to demonstrate any protective effect of another important antithrombotic molecule, antithrombin, it is premature to conclude that the benefit observed with APC is unique among inhibitors of the coagulation system. The result of a third phase III study examining the effect of tissue factor pathway inhibitor (TFPI) in sepsis is currently awaited, and the possibility that other antithrombotic agents--and combinations thereof--have a place in the therapeutic armamentarium will undoubtedly be the topic of future studies.
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PMID:Coagulation inhibition for sepsis. 1217 60


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