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)

Antithrombin III (AT III) supplementation has proven to be effective in the treatment of disseminated intravascular coagulation. Administration of AT III is also useful for prevention of organ failure in animals challenged with endotoxin or bacteria and it increases the survival rate of such animals. Since inhibition of coagulation abnormalities failed to prevent organ failure in animals given bacteria, AT III may exert a therapeutic effect independent of its anticoagulant effect. This therapeutic mechanism of AT III has been explored using an animal model of septicemia. AT III prevented pulmonary vascular injury by inhibiting leukocyte activation in rats given endotoxin. This effect is mediated by the promotion of endothelial release of prostacyclin which inhibits leukocyte activation. Interaction of AT III with heparin-like glycosaminoglycans (GAGs) on the endothelial cell surface appears to be important for this effect. Heparin inhibits these therapeutic effects of AT III by preventing AT III from interacting with the cell surface heparin-like GAGs. This activity of AT III may explain why AT III prevents organ failure as well as coagulation abnormalities in patients with sepsis. This antiinflammatory activity of AT III may be useful for the treatment of organ failure such as in ischemia/reperfusion-induced organ dysfunction, in which activated leukocytes play a critical role.
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PMID:The anti-inflammatory properties of antithrombin III: new therapeutic implications. 951 77

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.
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PMID:Antithrombin prevents endotoxin-induced pulmonary vascular injury by inhibiting leukocyte activation. 966 67

Heparin Cofactor II (HCII) is a glycoprotein in human plasma which inactivates thrombin rapidly in the presence of dermatan sulfate. Inhibition occurs by formation of a stable equimolar complex between HCII and thrombin. HCII association with thrombotic events has not always been observed, thus decreased HCII does not appear to be a strong risk factor for thromboembolic events. Reduced HCII levels have been detected in different clinical conditions, such as hepatic failure, disseminated intravascular coagulation, thalasemina, sickle cell anemia. Increased physiological levels have been found in pregnant women and oral contraception. In our laboratory, we measured HCII plasmatic levels in the normal Buenos Aires city population and in patients under different clinical conditions, such as sepsis, diabetis, burns, oral anticoagulation and in patients treated with heparin, hyperhomcysteinemia in whom septic and diabetic patients showed decreased values. HCII thrombin inhibition possibly takes place in extravascular sites where dermatan sulfate is present. HCII activity would be important in the regulation of wound healing, inflammation, or neuronal development.
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PMID:[Heparin cofactor II, a thrombin inhibitor with a still not clarified physiologic role]. 1034 31

We evaluated the effectiveness of antithrombin III (AT III) infusions designed to achieve supraphysiologic plasma levels of this serine protease inhibitor in preventing vascular permeability and disseminated intravascular coagulation in a pig model of sepsis. In addition, we determined whether high AT III doses were associated with increased bleeding risk. Sepsis was induced in 18 pigs by injection of lipopolysaccharide (LPS) (0.25 microg/kg per h for 3 h). At 90 min after the start of LPS infusion, pigs were randomized (n = 6 per group) to receive either human serum albumin as a placebo, AT III 120/5 (120 U/kg, 30-min bolus + 5 U/kg per h for 240 min), or AT III 250/10 (250 U/kg + 10 U/kg per h). Three additional animals served as negative controls (no LPS, no AT III). Treatment with AT III significantly reduced the amount of effluents in body cavities and fibrin monomers. AT III did not significantly increase bleeding risk as determined by organ hemorrhage. An additional assessment of AT III's bleeding risk [skin bleeding time (SBT)] was carried out in 35 nonseptic pigs treated with either AT III alone (120/5 or 250/10) or in the combination with heparin. Heparin administration alone produced a dose-dependent increase in SBT, but AT III alone did not. Addition of AT III 120/5 to heparin did not induce a further increase in bleeding time over heparin alone. These results indicate that administration of AT III in doses designed to achieve very high plasma concentrations significantly ameliorates symptoms of sepsis-induced vascular leakage and disseminated intravascular coagulation without increasing bleeding risk.
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PMID:Treatment of porcine sepsis with high-dose antithrombin III reduces tissue edema and effusion but does not increase risk for bleeding. 1155 99

A recent clinical sepsis trial reported a significant reduction in 90-day mortality by antithrombin (AT) exclusively in the subgroup of patients without simultaneous heparin prophylaxis. Patients additionally receiving heparin did not benefit from AT treatment. Herein, we studied the microhemodynamic and cellular mechanisms of this adverse effect of heparin on AT actions by the use of intravital microscopy and granulocyte culturing. In Syrian golden hamsters normotensive endotoxemia was induced by 2 mg/kg endotoxin (LPS, E. coli) i.v. In a first group of animals, AT (AT, 250 IU/kg i.v., n = 6) was given 5 min before LPS administration. A second group of animals (Heparin + AT, n = 5) received AT (250 IU/kg i.v.) combined with unfractionated heparin (sodium heparin, 100 IU/kg/24 h, i.v.). Additional animals (LMWH + AT, n = 5) received AT (250 IU/kg i.v.) combined with LMWH (nadroparin 47.5 IU anti-Xa/kg, s.c., 2 h before LPS). LPS-treated animals, which received only saline, served as controls (control, n = 6). Using dorsal skinfold fold preparations, LPS-induced microvascular leukocyte-endothelial cell interaction (LE) and alteration of functional capillary density (FCD) were studied by intravital video fluorescence microscopy. In controls, LPS induced a massive increase in LE with a maximum at 8 h and an impressive decrease in FCD over a 24-hour period. Both LPS effects were effectively prevented by AT treatment (p < 0.01), whereas Heparin + AT and LMWH + AT animals showed microcirculatory alterations comparable to that in controls. In additional in vitro chemotaxis assays. AT blocked neutrophil chemotaxis, an effect reversed by both unfractionated heparin and LMWH. Thus, our study elucidates a relevant in vivo and in vitro unfractionated heparin and LMWH adverse effect in the microcirculatory actions of AT during endotoxemia. These results indicate that heparin should be avoided to permit AT to modulate LPS-induced inflammatory responses.
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PMID:Adverse effect of heparin on antithrombin action during endotoxemia: microhemodynamic and cellular mechanisms. 1219 96

Silicone oxygenators are the standard devices used for Extracorporeal Life Support (ECLS), but they have some limitations. Microporous polypropylene hollow fiber oxygenators overcome many of these problems but, unfortunately, develop plasma leak. Polymethyl-pentene (PMP) is a novel oxygenator material. We report our initial experience with the Medos Hilite 7000LT, a PMP hollow fiber oxygenator, in six adult respiratory ECLS patients with these characteristics: age, mean 32.2 (+/-13) years; weight, mean 81.2 (+/-17) kg; PaO2/FIO2, mean 62.8 [+/-33] mm Hg; Murray Score, mean 3.4 [+/-0.3]; and sepsis related organ failure assessment score, mean 9.6 [+/-2.3]. One patient was cannulated within 10 hours of multiple trauma and 1 hour after thoracolaparotomy; another patient was cannulated 12 hours after a thoracotomy. All six patients survived. Heparin was infused (7.8-32.5 u/kg/hr) to maintain activated clotting time at 162 to 238 seconds; international normalized ratio was 0.9 to 3.4. Two of the six patients required transfusions of fresh frozen plasma, receiving one and five units, respectively. Fibrinogen was 1.4 to 6 g/dl; no cryoprecipitate was needed. Platelet counts were between 65 and 306, and very little platelet transfusion (mean 2.33; +/-3.03 units per patient) was required to maintain these levels. Two patients did not require any platelet transfusion. Maximum blood flow was 5.3 L/min, sweep was 3 to 10 L/min, and resistance was 11 to 43 Paul Wood Units. There were no oxygenator failures. Mean duration of ECLS was 151.7 hours (+/-75.6). Our initial experience with PMP oxygenators in adults was satisfactory, and platelet consumption and resistance to blood flow seem to be greatly reduced with PMP.
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PMID:Early experience with a polymethyl pentene oxygenator for adult extracorporeal life support. 1229 66

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by systemic formation of microthrombi and fibrin deposition in the vasculature. Cancer is one of the leading cause of DIC, which often complicates bleeding tendency and organ dysfunction. Even though DIC therapy is expectant, it is still important, since the bleeding tendency limits the quality of patients' life remarkably. Heparin, low molecular weight heparin, danaparoid, protease inhibitors for coagulation factors and antithrombin III are the choices for DIC. However, since the selection of the drugs is different depending on the basal disease, it is important to understand the pathophysiology of the individual situation. In general, protease inhibitors is recommended for 'fibrinolysis dominant DIC' like DIC associated with leukemia and terminal stage solid cancer, in contrast, danaparoid and antithrombin III are the first choice for 'coagulation dominant DIC' like sepsis. Supplement of concentrated platelets and fresh frozen should be limited for the patients whose primary disease can be controlled.
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PMID:[Disseminated intravascular coagulation]. 1280 52

Heparin is frequently used in preterm infants to prolong the patency of intravascular catheters. The aim of this study was to evaluate the prevalence of heparin-dependent platelet-activating antibodies in newborns. A cross-section of all preterm newborn infants expected to require heparin to maintain patency of a central venous access line were enrolled. A blood sample was obtained soon after birth before heparin exposure to exclude the possibility of placental transfer of maternal heparin-dependent platelet-activating antibodies. A second sample was obtained at termination of heparin use (mean duration of heparin exposure was 23 +/- 13 days; range, 6-67). Paired samples, at birth and after heparin use, were available for 42 infants with a mean gestational age of 27.8 +/- 2.2 weeks and birth weight of 1036 +/- 267 g. Thrombocytopenia developed in 57% (24/42) of the infants. None of these infants had clinical suspicion of thrombosis during the study period. The etiology of thrombocytopenia was confirmed sepsis in six, presumed sepsis in three, necrotizing enterocolitis in one, and unclear in 14 infants. Anti-heparin/platelet factor 4 antibodies measured using the standard assays for heparin-induced thrombocytopenia (two commercially available enzyme-linked immunosorbent assay tests and the functional platelet serotonin release assay) were negative on all infants. Although it could be related to the poor ability of these infants to mount an immunologic response, further research is necessary to fully understand this lack of response to heparin and to elucidate further the reasons for thrombocytopenia in very-low-birth-weight infants.
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PMID:Prevalance of heparin-dependent platelet-activating antibodies in preterm newborns after exposure to unfractionated heparin. 1549 19

An 84-year-old man was referred to the emergency department with severe dyspnea. Based on his physical findings, electrocardiogram, X-ray and echocardiographic findings, congestive heart failure was suspected and drip infusion of prophylactic heparin against intracardiac thrombosis was commenced together with dopamine, nitroglycerin and furosemide. Diuresis occurred and the pulmonary congestion ameliorated remarkably. Starting on the 20th hospital day, the platelet count was gradually reduced (from 256,000 to 55,000 /microl) and the fibrin degradation product concentration rose (27.6 microg/ml). However, prothrombin time was not prolonged (89%), the concentration of antithrombin III was low -normal (69%) and the fibrinogen concentration was high (650 mg/dl). Thus, heparin-induced thrombocytopenia (HIT), rather than disseminated intravascular coagulation (DIC), was suspected. Heparin was withdrawn on the 24th hospital day and replaced by nafamostat mesilate after which the platelet count was restored to 100,000 /microl. Enzyme-linked immunosorbent assay for HIT antibodies was positive. Unfortunately, the patient died from uncontrolled sepsis on the 29th hospital day. At autopsy, platelet-rich thrombi were found in the small pulmonary arteries and intestinal arteries. No evidence of DIC, such as fibrin-rich thrombosis, was observed. This is the first autopsy report of HIT in Japan.
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PMID:A case of heparin-induced thrombocytopenia with sepsis and congestive heart failure--first autopsy report on Japan--. 1556 10

The Kunitz-type proteinase inhibitor, tissue factor pathway inhibitor (TFPI), is the only endogenous inhibitor of the tissue factor (TF)-mediated coagulation pathway that plays a dominant role in normal haemostasis. TFPI exerts its action by binding to factor Xa (FXa) forming a TFPI-FXa complex that then, in a second step, binds and effectively inhibits the TF-factor VIIa (FVIIa) complex. Both full-length TFPI and chemically modified forms (e.g., truncated, glycosylated or phosphorylated TFPI variants) exert various pharmacological effects. The anticoagulant and antiplatelet actions of TFPI, its potency in inhibiting thrombin and FXa generation, as well as its favourable antithrombotic effectiveness seen in different animal models of venous and arterial thrombosis make this inhibitor a promising agent that could be potentially useful in several clinical indications. The inhibitory action of TFPI is accelerated by heparin. Heparin, as well as low molecular weight heparin (LMWH) derivatives, release TFPI from the vascular endothelium, an effect which seems to contribute mainly to the antithrombotic effectiveness of these drugs. The clinical relevance of TFPI is still undefined. Based on the beneficial actions in animal studies, as well as on the results obtained in first clinical investigations, TFPI is expected to be effective in the treatment of various diseases, such as disseminated intravascular coagulation, sepsis, coronary syndromes, stroke and acute respiratory distress syndrome (ARD). Further clinical trials should clarify the role of TFPI and more importantly define its potential usefulness as a prophylactic and/or therapeutic agent.
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PMID:Recombinant TFPI and variants: potential implications in the treatment of cardiovascular disorders. 1599 20


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