Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Coagulation activation with intravascular fibrin formation is a general finding in patients with sepsis. Low coagulation factors may be caused by disseminated intravascular coagulation, as well as by loss of plasma and impaired hepatic synthesis in the course of sepsis. The leading clinical symptom in consumption coagulopathy is bleeding. Therefore, treatment mainly consists of substitution of coagulation factors and platelets. Meningococcal and pneumococcal, as well as some other infections may lead to sepsis-induced purpura fulminans, a condition associated with microvascular thrombosis, necrosis, and haemorrhage. A typical laboratory sign is a very low plasma protein C level. Treatment with protein C concentrate or recombinant activated protein C (Drotrecogin alfa, activated) has been shown to be beneficial in sepsis-induced purpura fulminans. Unfractionated heparin or low molecular weight heparin has been recommended for prophylaxis of venous thrombosis, but there are no clinical studies specifically on patients with sepsis. Antithrombin concentrate is used in patients with antithrombin deficiency treated with heparin for acute venous thrombosis or embolism, extracorporeal circulation procedures or other invasive procedures. There is no indication for general use of antithrombin concentrate in patients with sepsis even in patients with low plasma antithrombin levels. Drotrecogin alfa, activated, is used for treatment of patients with severe sepsis. Its use is not limited to patients with sepsis-induced disseminated intravascular coagulation, although these patients appear to benefit especially from this therapy.
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PMID:[Sepsis-associated coagulation disorders]. 1592 56

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

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

Antithrombin (AT) has been used for over 25 years to successfully treat disseminated intravascular coagulation (DIC). A four-day AT therapy in patients with DIC in the KyberSept trial has been related to a clear survival benefit in patients not receiving concomitant heparin. Gonano and coworkers performed thrombelastography (TEG) measurements in patients with severe sepsis and clearly showed hypercoagulability, as defined by five TEG parameters, compared to healthy controls. In the AT group they found a trend towards normalization of TEG parameters after treatment, although this did not reach statistical significance. This first clinical evaluation of hypercoagulability during AT treatment could not provide evidence for an attenuation of coagulopathy, an effect that might be due to high inter-individual variability.
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PMID:Antithrombin and hypercoagulability in sepsis: insights from thrombelastography? 1710 15

Antithrombin is a glycoprotein critical to the regulation of coagulation. Its primary action is the inhibition of the activated coagulation factors IIa (thrombin) and Xa. In addition there is growing evidence to suggest that antithrombin also plays a role in the inhibition of inflammation within the environment of the vascular endothelium. Reduced plasma antithrombin may result from congenital deficiency or arise secondarily from a range of disorders such as liver dysfunction, premature infancy and sepsis, or as a result of interventions such as major surgery or cardiopulmonary bypass. Congenital antithrombin deficiency is the most clinically important of the inherited thrombophilias resulting in thrombosis in the majority of those affected. The challenge in managing these patients is preventing potentially life-threatening thrombosis, while minimising the equally significant risk of haemorrhage associated with long-term anticoagulation. This is achieved in the first instance by identifying high-risk episodes such as surgery, immobility and pregnancy for which prophylactic anticoagulation can be used in the short term. Prophylaxis for such periods is best provided by the use of low molecular weight heparin (LMWH) with substitution by or addition of antithrombin concentrate in particularly high-risk circumstances. In the case of pregnancy, antithrombin concentrate is often used around the time of birth when LMWH may increase the risk of post-partum haemorrhage. As patients with congenital antithrombin deficiency get older so their thrombotic risk gradually increases and for many patients long-term anticoagulation becomes unavoidable because of recurrent episodes of venous thromboembolism. There has been much interest in the role of antithrombin deficiency in the setting of sepsis and the critically ill patient where there is a clear correlation between severity of illness and degree of antithrombin reduction. It is not clear yet, however, to what extent the depletion of antithrombin affects the clinical condition of such patients. A number of trials have investigated the use of antithrombin as a treatment in the intensive care setting with the overall conclusion being that there is some benefit to its use but only if large supra-physiological doses are used. It has also become clear that the concurrent use of any form of heparin removes whatever benefit may be derived from antithrombin treatment in this setting. Until recently, antithrombin replacement was only available as a pooled plasma-derived product, which despite effective viral inactivation still carries an uncertain risk of transfusion transmitted infection. A recombinant antithrombin product now under investigation, and recently licensed in Europe, may provide a useful alternative treatment option.
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PMID:Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. 1760 Mar 91

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

Antithrombin (AT) is the principal inhibitor of thrombin and other serine proteases of the coagulation cascade. AT has previously been prepared from human plasma (hpAT), and a transgenic variant from goat milk (tgAT) is now available. Two open-label, parallel pharmacokinetic studies in rats (n=18) and rabbits (n=18) compared plasma concentrations of hpAT and tgAT following intravenous administration; the efficacy of the two preparations in prolonging survival from bacterial-induced sepsis was compared in two open-label, randomised, placebo-controlled studies in rats (n=266). Maximum plasma concentrations were approximately dose-proportional and were similar for both hpAT and tgAT. The elimination of tgAT was faster than hpAT, and the t(1/2) of hpAT was longer than that of tgAT in both rats (0.85-1.92 h versus 0.17-0.73 h) and rabbits (19-38 h versus 1.5-2.2 h). Correspondingly, tgAT showed a lower area under the curve, mean residence time, pharmacokinetic response to dosing and a higher clearance rate. In a meta-analysis of the efficacy studies, the overall hazard ratio for death was 1.36 (tgAT:hpAT; p=0.06; 95% CI 0.99-1.86). HpAT and tgAT have differing pharmacokinetic properties in pre-clinical studies. Further research is necessary to establish whether this translates into efficacy differences in vivo and in the clinical therapy of sepsis.
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PMID:A comparison of the pharmacokinetics of antithrombin derived from human plasma and from transgenic goats and the prevention of sepsis in an animal model. 1855 12

The aim of this study was to clarify the prognostic value of serum pro-Adrenomedullin level (pro-ADM) and Anti thrombin level in neonatal sepsis. 40 term neonates with sepsis were enrolled in this study including 20 cases with mild sepsis and 20 cases with severe sepsis. Twenty healthy matched neonates served as a control group. Serum levels of Pro ADM and Antithrombin were measured in all patients and the control group. Serum Pro ADM level was higher in neonates with sepsis than control group, higher in severe than mild sepsis, and was higher in non survivors. Antithrombin concentrations were lower in sepsis cases than control, lower in severe than mild sepsis, and lower in non-survivors.
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PMID:Prognostic value of plasma pro-adrenomedullin and antithrombin levels in neonatal sepsis. 2155 96

Sepsis is a leading cause of death in critically ill patients and it requires multidisciplinary treatment. The effects of anticoagulant therapy for sepsis-associated disseminated intravascular coagulation have been long discussed and intensively studied. The recent topics in this area are 1) withdrawal of recombinant activated protein C(rAPC) from the market, 2) potential efficacy of the supplement-dose of antithrombin, 3) success of the recombinant thrombomodulin in a Phase 2B trial. rAPC had been the only anticoagulant recommended in the global guideline for the treatment of severe sepsis (Surviving Sepsis Campaign guidelines (SSCG) 2008). However, the recommendation was withdrawn from the latest version of SSCG after rAPC could not demonstrate sufficient efficacy in the most recent randomized controlled trial. Antithrombin concentrate is another anticoagulant which can be effective for sepsis-associated disseminated intravascular coagulation (DIC). However, high-dose antithrombin is recommended not to be used in SSCG 2012 since it did not show any survival benefit and increased the bleeding risks in severe sepsis. Nonetheless, a recent clinical study reported the potential efficacy of supplement-dose antithrombin in septic DIC. Recombinant thrombomodulin has been newly developed and its efficacy for DIC was reported. A recent multinational randomized controlled trial has also demonstrated the potential efficacy of this therapeutic agent for septic DIC and a Phase 3 study is currently underway.
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PMID:The anticoagulant therapy for sepsis-associated disseminated intravascular coagulation. 2356 33

The development of disseminated intravascular coagulation (DIC) is associated with increased sepsis mortality. Antithrombin (AT) is one of several anticoagulants that have been studied in randomized trials of sepsis without benefit. In a recent study, Iba and colleagues reviewed data from patients who were treated for sepsis-related DIC with two lower doses of AT concentrate than studied in prior trials. Patients received 1,500 IU/day (n = 259) or 3,000 IU/day (n = 48) of AT for 3 days. All patients had baseline antithrombin activity <40% and there was no placebo group. The AT 3,000 group had higher 28-day survival as well as a higher rate of DIC resolution than the AT 1,500 group. Though intriguing, the study findings are limited by the non-randomized retrospective nature of the findings, which resulted in baseline differences in multiple confounders that affect mortality, as well as the lack of a placebo group to compare outcomes.
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PMID:Is antithrombin treatment of disseminated intravascular coagulation a quixotic goal? 2522 Aug 51


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