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

In patients with sepsis and septic shock, both coagulation and fibrinolysis are activated frequently leading to the syndrome of diffuse intravascular coagulation (DIC). The different mechanisms leading to abnormalities in coagulation and fibrinolysis are discussed in detail. The coagulation and fibrinolytic system appear to be influenced by the septic process largely independently, leading to a procoagulant imbalance between these systems. Coagulation is initiated by mediator-induced expression of tissue factor and is associated with consumption of the natural coagulation inhibitors antithrombin III, protein C, and protein S. As a result, high plasma levels of thrombin-antithrombin complex (TAT) can be found. The effects on fibrinolysis are dominated by (highly) increased levels of plasminogen activator inhibitor type 1 (PAI-1), leading to inadequate fibrinolysis. Although levels of plasminogen activator antigen are increased, its activity is almost completely inhibited by PAI-1. The resulting effects predispose to a procoagulant state, with widespread fibrin deposition, which may be an important mechanism contributing to multiple organ failure. A thorough understanding of the pathophysiological mechanisms underlying the DIC-syndrome is a prerequisite for a rational approach and future therapy for this severe complication of sepsis.
 ...
PMID:Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. 951 78

Sepsis and its associated complications of disseminated intravascular coagulation (DIC) and multiple organ dysfunction syndrome (MODS) continue to be a major cause of morbidity and mortality. Improved detection of all forms of DIC is essential to assure earlier diagnosis. Studies already indicate that the therapeutic use of antithrombin (AT) concentrate may produce a more positive outcome for sepsis-associated DIC. If DIC could be identified earlier and AT concentrate could then be given earlier in the sepsis continuum, study results for the use of AT concentrate in humans might reveal a statistically significant difference versus placebo, and the efficacy of AT concentrate for this syndrome is more likely to be proved. Fixed-bolus doses of AT concentrate based on body weight are currently preferred, but improved, user-friendly assays for plasma AT levels would permit more rapid turnaround time for AT results and could help fine-tune the use of AT concentrate to the specific needs of each patient. Clinical trials involving the therapeutic use of AT concentrate in sepsis should continue, and it can be hoped that their design will reflect the concepts and conclusions offered by this panel of investigators.
 ...
PMID:Therapeutic use of antithrombin concentrate in sepsis. 957 41

We previously demonstrated that antithrombin III reduced the injury to endothelial cells caused by activated leukocytes in rats administered endotoxin. This occurred via the increase of the endothelial release of prostaglandin I2, which is a potent inhibitor of leukocyte activation. We evaluated the dose of antithrombin III required to prevent such endothelial cell injury in rats administered endotoxin, by comparing the effects of various antithrombin II doses on the pulmonary vascular injury. The intravenous administration of endotoxin, 5 mg/kg, produced a transient accumulation of leukocytes in the lung, followed by pulmonary vascular injury, as indicated by an increase in the pulmonary vascular permeability, and coagulation abnormalities. The dose of 250 U/kg significantly inhibited all such effects of endotoxin. While lower doses of antithrombin III (50 and 100 U/kg) significantly inhibited such coagulation abnormalities, they failed to prevent either the pulmonary accumulation of leukocytes or the subsequent pulmonary vascular injury. Rats administered endotoxin exhibited an accumulation of neutrophils and edematous changes in the pulmonary interstitial space. Although such changes were reduced after 250 U/kg of antithrombin III, they were unaffected by lower doses of 50 and 100 U/kg. Plasma levels of 6-keto-PGF1alpha were markedly increased in rats 90 min after the administration of endotoxin, and were significantly decreased in the endotoxin-treated rats administered the lower doses of antithrombin III (50 and 100 U/kg), but not altered in those endotoxin-treated rats receiving 250 U/kg of antithrombin III. These findings suggest that a higher antithrombin III dose is necessary to prevent endothelial cell injury than is required to inhibit coagulation abnormalities in an animal model of sepsis. These observations support the notion that antithrombin III may prevent endotoxin-induced endothelial cell injury by promoting endothelial release of prostaglandin I2 and thus inhibiting leukocyte activation.
 ...
PMID:Effects of various doses of antithrombin III on endotoxin-induced endothelial cell injury and coagulation abnormalities in rats. 964 17

To determine the role of plasma tissue factor on disseminated intravascular coagulation (DIC) in trauma and septic patients, and also to investigate the relationships between tissue factor and various thrombin markers, we made a prospective cohort study. Forty trauma patients and 20 patients with sepsis were classified into subgroups according to the complication of DIC. Plasma tissue factor antigen concentration (tissue factor), prothrombin fragment F1+2 (PF1+2), thrombin antithrombin complex (TAT), fibrinopeptide A (FPA), and D-dimer were measured on the day of admission (day 0), and on days 1, 2, 3, and 4 after admission. The levels of plasma tissue factor in the DIC group were more elevated than those of the non-DIC group in both the trauma and the septic patients. In patients with sepsis, tissue factor levels on days 0 through 4 in the non-DIC group showed markedly higher values than those in the control patients (135 +/- 8 pg/ml). Significant correlations between tissue factor and PF1+2, TAT, FPA, and D-dimer were observed in the DIC patients, however, no such correlations were found in the non-DIC patients. These results suggest that elevated plasma tissue factor in patients with trauma and sepsis gives rise to thrombin generation, followed by intravascular coagulation.
 ...
PMID:Significant correlations between tissue factor and thrombin markers in trauma and septic patients with disseminated intravascular coagulation. 965 33

Replacement of antithrombin has proved to be effective for treating disseminated intravascular coagulation. The administration of antithrombin is also useful for preventing organ failure in animals challenged with endotoxin or bacteria, and it increases the survival rate of such animals. Since inhibition of coagulation abnormalities by heparin failed to prevent organ failure in animals challenged with bacteria, antithrombin might exert therapeutic effects independently of its anticoagulant effect. These therapeutic mechanisms of antithrombin have been explored by using animal models of septicemia. Antithrombin prevents pulmonary vascular injury by inhibiting leukocyte activation in rats challenged with endotoxin. A higher dose of antithrombin was required to prevent pulmonary vascular injury than was required to inhibit disseminated intravascular coagulation. This preventive effect of antithrombin is mediated by the promotion of endothelial release of prostacyclin, an inhibitor of leukocyte activation. An interaction between antithrombin and heparin-like glycosaminoglycans on the endothelial cell surface appears to be important for this effect. Heparin inhibits such therapeutic effects of antithrombin by preventing it from interacting with the cell surface heparin-like glycosaminoglycans. Since activated leukocytes are of critical importance in patients with sepsis-associated organ failure, this anti-inflammatory activity of antithrombin may explain why it can prevent organ failure as well as coagulation abnormalities in patients with sepsis.
 ...
PMID:Antithrombin prevents endotoxin-induced pulmonary vascular injury by inhibiting leukocyte activation. 966 67

During severe sepsis, the sustained consumption and/or inhibition of antithrombin leads to a prolonged procoagulant state, which indicates that the administration of antithrombin may be useful in this condition. Animal studies have shown that high doses of antithrombin concentrates can prevent disseminated intravascular coagulation and death. In humans, high doses of antithrombin are required to maintain supranormal antithrombin levels and overcome the magnitude of antithrombin consumption. Three placebo-controlled, double-blind studies of antithrombin concentrates have been performed in France, Germany and northwestern Europe. A meta-analysis of these three studies showed a nonsignificant 22% reduction in 30-day, all-cause mortality. A multicenter phase III trial is needed to demonstrate that antithrombin administration can reduce mortality in septic patients.
 ...
PMID:Therapeutic applications of antithrombin concentrates in systemic inflammatory disorders. 966 68

Sepsis and major trauma are the two most common causes of disseminated intravascular coagulation (DIC) and are characterized by a sudden increase in inflammatory mediators. In general, the outcome of the patient is determined by the degree of the inflammatory response. In severe cases of sepsis and trauma, cascade systems, such as the coagulation, fibrinolytic and complement systems, are activated beyond the capacity of the autoregulatory mechanisms. During DIC, plasma levels of antithrombin (AT)--a serine protease inhibitor that acts mainly on the serine proteases of the coagulation system--decrease due to the formation and subsequent elimination of complexes between AT and activated coagulation factors. The consumption of AT may start a vicious circle by facilitating further intravascular fibrin formation, followed by ischaemic tissue injury and accelerated activation of blood coagulation. Infusion of AT has an anti-inflammatory effect through its ability to counteract microvascular thrombosis. Furthermore, AT induces the release of prostacyclin from the vessel wall by binding to glycosaminoglycans on the surface of endothelial cells. Prostacyclin has a marked anti-inflammatory effect as a result of its inhibitory effect on neutrophils, monocytes and platelets.
 ...
PMID:The effect of antithrombin on the systemic inflammatory response in disseminated intravascular coagulation. 1010 94

Sepsis is a frequent complication of critically ill patients and its incidence is increasing. Currently, septic shock is the most common cause of death in non-coronary intensive care units. Over the last 10 to 15 years, new antibiotics and increasingly sophisticated critical care have had little impact on the mortality rate of septic shock. The Italian SEPSIS Study, carried out in 99 intensive care units in 1994, reported mortality rates of 52% and 82% for severe sepsis and septic shock respectively. New therapeutic approaches aimed at neutralizing microbial toxins and modulating host mediators have shown some efficacy in large clinical trials and/or in animal models, but to date, no therapy of sepsis aimed at reversing the effects of bacterial toxins or of harmful endogenous mediators of inflammation has gained widespread clinical acceptance. Because of the strong association of severe sepsis with a state of activation of blood coagulation and of the potential role of capillary thrombosis in the development of the multiple organ dysfunction syndrome, anticoagulant agents have been tested in the setting of septic shock. However, neither administration of heparin nor of active site-blocked factor Xa or of anti-tissue factor antibodies have proven effective in preventing deaths due to septic shock in animal models. In contrast, infusion of antithrombin, protein C, or tissue factor pathway inhibitor all resulted in a significant survival advantage in animals receiving lethal doses of E. Coli. Antithrombin concentrates have been used in a significant number of critically ill patients. A double-blind, placebo controlled study carried out in 3 italian intensive care units has recently shown that the administration of antithrombin aimed to normalize plasma antithrombin activity had a net beneficial effect on 30-day survival of patients requiring respiratory and/or hemodynamic support because of severe sepsis and/or post-surgery complications.
 ...
PMID:Antithrombin replacement in patients with sepsis and septic shock. 1032 25

Solvent/detergent (S/D)-treated plasma is currently marketed by the American Red Cross as a virally inactivated alternative to fresh-frozen plasma (FFP). The serpin-type serine proteinase inhibitors have a flexible reactive site loop (RSL) that can convert from the active conformation to the inactive latent or polymerized conformations when exposed to heat and/or detergents. We have compared the conformational stability and inhibitory activity of 3 plasma serpins-antithrombin, antitrypsin, and antiplasmin-in S/D plasma and FFP. In S/D plasma, virtually 100% of the antiplasmin and approximately 50% of the antitrypsin are in either the latent or polymerized conformation and lack inhibitory activity, while in FFP only the active conformation is present. Interestingly, antithrombin is not affected by S/D treatment and remains fully active. These data demonstrate that S/D plasma is not simply a virally inactivated equivalent of FFP. The lack of antiplasmin activity and decreased antitrypsin activity in S/D plasma suggest that it may not be as effective as FFP for the treatment of bleeding in patients with systemic activation of proteolytic cascades, such as disseminated intravascular coagulation and sepsis, acquired fibrinolytic states, and large-volume transfusion. Although there has been extensive use of S/D plasma in several European countries with no reports of adverse effects, clinical studies directly comparing the efficacy of these 2 plasma products are needed to directly evaluate the relative therapeutic efficacy of FFP and S/D plasma for the treatment of these diseases.
 ...
PMID:Solvent/detergent-treated plasma has decreased antitrypsin activity and absent antiplasmin activity. 1057 9

Inhibition of the tissue factor pathway has been shown to attenuate the activation of coagulation and to prevent death in a gram-negative bacteremia primate model of sepsis. It has been suggested that tissue factor influences inflammatory cascades other than the coagulation system. The authors sought to determine the effects of 2 different doses of recombinant tissue factor pathway inhibitor (TFPI) on endotoxin-induced coagulant, fibrinolytic, and cytokine responses in healthy humans. Two groups, each consisting of 8 healthy men, were studied in a double-blind, randomized, placebo-controlled crossover study. Subjects were studied on 2 different occasions. They received a bolus intravenous injection of 4 ng/kg endotoxin, which was followed by a 6-hour continuous infusion of TFPI or placebo. Eight subjects received 0.05 mg/kg per hour TFPI after a bolus of 0.0125 mg/kg (low-dose group), and 8 subjects received 0.2 mg/kg per hour after a bolus of 0.05 mg/kg (high-dose group). Endotoxin injection induced the activation of coagulation, the activation and subsequent inhibition of fibrinolysis, and the release of proinflammatory and antiinflammatory cytokines. TFPI infusion induced a dose-dependent attenuation of thrombin generation, as measured by plasma F1 + 2 and thrombin-antithrombin complexes, with a complete blockade of coagulation activation after high-dose TFPI. Endotoxin-induced changes in the fibrinolytic system and cytokine levels were not altered by either low-dose or high-dose TFPI. The authors concluded that TFPI effectively and dose-dependently attenuates the endotoxin-induced coagulation activation in humans without influencing the fibrinolytic and cytokine response. (Blood. 2000;95:1124-1129)
 ...
PMID:Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. 1066 80


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>