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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endotoxemia is often associated with extreme inflammatory responses and disseminated intravascular coagulation. Protease-activated receptors (PARs) mediate cellular responses to coagulation proteases, including platelet activation and endothelial cell reactions predicted to promote inflammation. These observations suggested that PAR activation by coagulation proteases generated in the setting of endotoxemia might promote platelet activation, leukocyte-mediated endothelial injury, tissue damage, and death. Toward testing these hypotheses, we examined the effect of PAR deficiencies that ablate platelet and endothelial activation by coagulation proteases in a mouse endotoxemia model. Although coagulation was activated as measured by thrombin-antithrombin (TAT) production and antithrombin III (ATIII) depletion, Par1(-/-), Par2(-/-), Par4(-/-), Par2(-/-):Par4(-/-), and Par1(-/-):Par2(-/-) mice all failed to show improved survival or decreased cytokine responses after endotoxin challenge compared with wild type. Thus, our results fail to support a necessary role for PARs in linking coagulation to inflammation or death in this model. Interestingly, endotoxin-induced thrombocytopenia was not diminished in Par4(-/-) mice. Thus, a mechanism independent of platelet activation by thrombin was sufficient to cause thrombocytopenia in our model. These results raise the possibility that decreases in platelet count in the setting of sepsis may not be caused by disseminated intravascular coagulation but instead report on a sometimes parallel but independent process.
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PMID:Roles of protease-activated receptors in a mouse model of endotoxemia. 1643 93

In disseminated intravascular coagulation (DIC) there is extensive crosstalk between activation of inflammation and coagulation. Endogenous anticoagulatory pathways are downregulated by inflammation, thus decreasing the natural anti-inflammatory mechanisms that these pathways possess. Supportive strategies aimed at inhibiting activation of coagulation and inflammation may theoretically be justified and have been found to be beneficial in experimental and initial clinical studies. This review assembles the available experimental and clinical data on biological mechanisms of antithrombin in inflammatory coagulation activation. Preclinical research has demonstrated partial interference of heparin--administered even at low doses--with the therapeutic effects of antithrombin, and has confirmed--at the level of cellular mechanisms--a regulatory role for antithrombin in DIC. Against this biological background, re-analyses of data from randomized controlled trials of antithrombin in sepsis suggest that antithrombin has the potential to be developed further as a therapeutic agent in the treatment of DIC. Even though there is a lack of studies employing satisfactory methodology, the results of investigations conducted thus far into the mechanisms of action of antithrombin allow one to infer that there is biological plausibility in the value of this agent. Final assessment of the drug's effectiveness, however, must await the availability of positive, prospective, randomized and placebo-controlled studies.
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PMID:Clinical review: molecular mechanisms underlying the role of antithrombin in sepsis. 1654 81

A randomised, prospective, placebo-controlled phase III multicentre clinical trial (KyberSept) has been performed to test the efficacy of high-dose antithrombin therapy in patients with severe sepsis. Concomitant low-dose heparin has been routinely given in two thirds of patients for deep vein thrombosis prophylaxis. This study analyses heparin - antithrombin interactions in terms of long-term mortality, adverse events, and thromboembolic events. From a total of 2,314 patients with severe sepsis (placebo: n = 1,157; antithrombin: n = 1,157) 1,616 patients (placebo: 811, antithrombin: 805) received heparin concomitantly with study drug (antithrombin 30,000 IU) over four days, whereas 698 patients (346 and 352, respectively) did not. In patients with no concomitant heparin, 28-day mortality was lower with antithrombin than with placebo (37.8% vs. 43.6%; absolute reduction: 5.8%; risk ratio: 0.860 [0.725-1.019]), which increased until day-90 (44.9% vs. 52.5%; absolute reduction: 7.6%; risk ratio: 0.851 [0.735-0.987]). In patients with concomitant heparin, no effect of antithrombin on mortality was seen (28-day mortality: 39.4% vs. 36.6%; absolute increase: 2.8%; risk ratio: 1.08 [0.96-1.22]). Frequency of use of concomitant heparin increased during conduct of the study. Increased bleeding incidences were reported with antithrombin plus concomitant heparin as compared to antithrombin alone. Rates of thromboembolic events were similar when antithrombin was given with or without concomitant heparin. In the treatment of severe sepsis, high-dose antithrombin may sufficiently protect against development of venous thromboembolism when no concomitant heparin is given. Combined administration of the two increases bleeding risk and probably abolishes efficacy of antithrombin.
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PMID:Benefit/risk profile of high-dose antithrombin in patients with severe sepsis treated with and without concomitant heparin. 1667 61

The meaning, the utility, and the prognostic significance of the International Society of Thrombosis and Hemostasis overt disseminated intravascular coagulation (DIC) score and other parameters of coagulation activation including soluble fibrin monomer complexes (SFMC), antithrombin and protein C consumption, and formation of lipoprotein-C-reactive protein (LP-CRP) complexes (MDA slope 1 and flag A2) were evaluated in 165 inpatients from a general hospital for whom DIC testing was required by the attending physicians. Of these 165 patients, 148 had an underlying disease that clearly justified the laboratory request from our systematic post hoc review of the clinical charts. Of these 148 patients, 28 had a positive overt DIC score, 19 had an A2 flag, and 4 had both. The DIC score was strongly related to several major markers of coagulation activation such as D-dimers, thrombin-antithrombin complexes, and soluble fibrin and was inversely related to antithrombin and protein C levels, which began to fall from DIC score 4 or higher. The formation of LP-CRP complexes was only related to Gram-negative sepsis and these patients had a strong inflammatory reaction. Independent risk factors for death were high creatininemia, positive overt DIC score, and/or presence of SFMC. In patients with positive DIC score, SFMC positivity and low levels of antithrombin and/or protein C were additional risk factors. The ISTH overt DIC score proves useful and adequate as a marker for clinically significant DIC. Illness severity is further defined by SFMC, antithrombin, and protein C levels. LP-CRP complexes are related to sepsis but not to actual overt DIC and lethal prognosis.
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PMID:Diagnosis and prognosis of overt disseminated intravascular coagulation in a general hospital -- meaning of the ISTH score system, fibrin monomers, and lipoprotein-C-reactive protein complex formation. 1668 Jul 42

A 17-year-old girl presented with Neisseria meningitidis sepsis, with evidence of disseminated intravascular coagulation. Substitution therapy with both antithrombin and protein C concentrates was initiated, leading to clinical and biological improvement. Sequential dosages were performed for biological markers including thrombin-activatable fibrinolysis inhibitor (TAFI). Substitution therapy with both antithrombin and protein C concentrates led to a clinical and biological improvement. Biological markers showed a decrease in thrombin generation and in plasminogen activator inhibitor 1 (PAI-1) and a return of TAFI to a normal value. Discontinuation of substitutive treatment was marked by a clinical relapse at 24 h, with thrombin generation and increase in PAI-1, while TAFI remained unchanged. This report shows the evolution of hemostasis markers during septic shock and provides new data concerning the effects of a substitutive therapy.
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PMID:Evolution of thrombin formation and fibrinolysis markers, including thrombin-activatable fibrinolysis inhibitor, during severe meningococcemia. 1677 41

We evaluated the score for disseminated intravascular coagulation (DIC) recently published by the International Society for Thrombosis and Haemostasis (ISTH) in a well-defined series of sepsis patients. Thirty-two patients suffering from severe sepsis and eight patients with septic shock were evaluated following the ISTH DIC score. Fibrin monomer and D-dimer were chosen as fibrin-related markers (FRM), respectively. DIC scores for nonsurvivors (n = 13) as well as for septic shock patients were higher (P < 0.04) compared with survivors and patients with severe sepsis, respectively. Using fibrin monomer and D-dimer, 30 and 25% of patients suffered from overt DIC. Overt DIC was associated with significantly elevated thrombin-antithrombin complexes and plasminogen activator inhibitor type-1 levels as well as with significantly lower factor VII clotting activity. Patients with overt DIC had a significantly higher risk of death and of developing septic shock. Since more than 95% of the sepsis patients had elevated FRM, the DIC score was strongly dependent on prolongation of the prothrombin time and platelet counts. The ISTH DIC score is useful to identify patients with coagulation activation, predicting fatality and disease severity. It mainly depends on the prolongation of the prothrombin time and platelet counts.
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PMID:International Society on Thrombosis and Haemostasis score for overt disseminated intravascular coagulation predicts organ dysfunction and fatality in sepsis patients. 1690 47

The objective was to estimate the effect of antithrombin therapy on mortality in disseminated intravascular coagulation (DIC) of severe sepsis and septic shock. Randomized clinical trials (RCT) on patients with DIC and severe sepsis or septic shock assigned to intravenous antithrombin or placebo were searched. Eligible studies reported death as the outcome measure. Of 35 RCT, 32 trials were excluded because patients were not randomized to antithrombin versus placebo, or no separate data on patients with DIC were given. In three RCT, 364 patients with severe sepsis or septic shock and DIC were randomized. The disease severity, definition of DIC, dose and duration of treatment varied among the trials. In two of the three RCT, data were from subgroup analyses (patients not stratified by DIC). The combined odds ratio for short-term all-cause mortality in those who received antithrombin was 0.649 (95% confidence interval, 0.422-0.998). Data on bleeding complications in patients treated with antithrombin were reported only in one of the RCT and were not considered suitable for systematic safety estimation. In sepsis patients with DIC, administration of antithrombin concentrate may increase overall survival. Current available evidence, however, is not suited to sufficiently inform clinical practice.
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PMID:A systematic review of antithrombin concentrate use in patients with disseminated intravascular coagulation of severe sepsis. 1698 45

There are many complex pathophysiologic changes of the coagulation system in sepsis. The fibrinolytic system was evaluated in septic children using the global fibrinolytic capacity (GFC), a new technique reflecting the overall fibrinolytic activity. The study consisted of 24 children with sepsis, 36 children with sepsis plus disseminated intravascular coagulation (DIC), and 20 healthy age-matched control individuals. Compared with controls, 86% of sepsis patients and 87% of sepsis plus DIC patients had decreased GFC levels. Between the sepsis plus DIC and sepsis groups there was no significant difference in terms of GFC levels. While 19 patients (52.7%) died in the sepsis plus DIC group, only three patients (12.5%) died in the sepsis group. When survivors and nonsurvivors were compared in terms of coagulation tests, there were significant differences for protein C, antithrombin, platelet, fibrinogen, aspartate aminotransferase, alanine aminotransferase, prothrombin time, and white blood cell values. In conclusion, the level of GFC reduced in most of the pediatric sepsis patients but no difference was observed between patients with sepsis and patients with sepsis plus DIC. While inhibition of fibrinolysis is an important finding in sepsis, the mortality is mainly associated with the presence of end-organ damage and the status of coagulation parameters.
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PMID:Global fibrinolytic capacity in pediatric patients with sepsis and disseminated intravascular coagulation. 1698 53

Haemostatic changes in septic patients are complex, with both procoagulant and anticoagulant changes. Thirty-eight patients with severe sepsis and 32 controls were investigated by coagulation screens, individual factor assays, calibrated automated thrombography (CAT), whole blood low-dose-tissue factor activated (LD-TFA) Rotem and LD-TFA waveform analysis. Thirty-six of 38 patients had an abnormal coagulation screen. The mean levels of factors II, V (P < 0.05), VII, X, XI and XII, antithrombin and protein C (P < 0.01) was decreased in sepsis compared with controls. The mean factor VIII and fibrinogen level (P < 0.001) was increased. CAT in platelet rich and poor plasma showed a prolonged lag time (P < 0.02), decreased peak thrombin (P < 0.02) and delayed time to peak thrombin (P < 0.001) in sepsis patients, however, the endogenous thrombin potential was equivalent in sepsis and controls. In LD-TFA Rotem, septic patients had delayed clot times (P = 0.04) but an increased maximum velocity of clot formation (P < 0.01) and area under the clot elasticity curve (P < 0.01). LD-TFA waveform analysis showed a delayed onset time but an increased rate of clot formation (P < 0.005). In conclusion, global tests of haemostasis suggest that in this patient group, activation of haemostasis is delayed but once initiated thrombin generation and clot formation are normal or enhanced.
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PMID:Global tests of haemostasis in critically ill patients with severe sepsis syndrome compared to controls. 1701 48

New molecular markers of coagulation and fibrinolysis activation have been developed and used to identify patient subgroups that frequently develop increased procoagulant turnover and, hence, disseminated intravascular coagulation and organ dysfunction. The idea of inhibiting the coagulation hyperactivation by the administration of antithrombin has led to experimental findings that pinpoint an anti-inflammatory action of antithrombin. Preliminary clinical trials of high-dose antithrombin administration in sepsis are promising. Point-of-care coagulation testing remains controversial since a variety of perioperative therapeutic regimens such as aprotinin administration obviously do not require 'on-line' coagulation monitoring.
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PMID:Consequences of haemostasis disorders on anaesthestic management. 1701 37


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