UMLS:C0036690 - FACTA Search

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

The possible involvement of platelet activating factor (PAF) in the pathogenesis of endotoxin-induced disseminated intravascular coagulation (DIC) was investigated in rats using a novel potent PAF antagonist, TCV-309. TCV-309 (> 1 mg/kg, i.v.) showed beneficial effects in rats with experimental DIC induced by a 4-hour sustained infusion of endotoxin (1 mg/kg) in a dose-dependent manner. TCV-309 (1 mg/kg) significantly ameliorated the decrease in platelet count and plasma fibrinogen, the prolongation of prothrombin time (PT) and activated partial thromboplastin time (APTT) and the increase in fibrin and fibrinogen degradation products (FDP) and inhibited glomerular fibrin deposition. Furthermore, plasma tissue factor (TF) activity was greatly increased in the DIC rats, and this was also significantly decreased by TCV-309 (1 mg/kg). TCV-309 (1 mg/kg) did not affect these parameters in normal rats. A 4-hour sustained infusion of PAF (60 micrograms/kg) caused mild but significant changes in some DIC parameters such as PT, fibrinogen and FDP concentration and increased the plasma TF activity. TCV-309 (1 mg/kg) inhibited all these PAF-induced changes. TCV-309 (0.1 mM) itself had no direct in vitro effects on the blood coagulation system including TF activity. These results strongly suggest that PAF plays a role in the pathogenesis of endotoxin-induced DIC via the generation of TF. Prophylactic use of PAF antagonists may therefore be useful for the treatment of DIC with sepsis.
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PMID:Inhibitory effect of TCV-309, a novel platelet activating factor (PAF) antagonist, on endotoxin-induced disseminated intravascular coagulation in rats: possible role of PAF in tissue factor generation. 833 59

The primary hypothesis of this report is that the formation and subsequent removal of fibrin in specific tissues during pathologic processes reflects temporal changes in the local expression of key procoagulant and fibrinolytic genes. To begin to test this hypothesis, we have used quantitative PCR assays and in situ hybridization analysis to examine the effects of endotoxin on the expression of specific genes in murine tissues, and to relate these changes to fibrin deposition/dissolution using immunohistochemical approaches. Endotoxin caused large increases in plasminogen activator inhibitor-1 mRNA and modest increases in tissue factor mRNA in most tissues examined. However, fibrin was only detected in the kidneys and adrenals of endotoxin-treated mice, and it was transient. Unexpectedly, changes in urokinase-type plasminogen activator mRNA but not tissue-type plasminogen activator mRNA correlated with fibrin deposition/dissolution in these tissues. Pretreatment of mice with the fibrinolytic inhibitor epsilon-aminocaproic acid before endotoxin increased both the number of fibrin-positive tissues and the duration of fibrin deposition in the kidneys and adrenals. These results suggest that the absence of fibrin in some tissues reflects ongoing local fibrinolysis, and that increases in plasminogen activator inhibitory and tissue fac- tor gene expression and decreases in urokinase-type plasminogen activator expression are necessary for tissue-specific fibrin deposition. Changes in tissue-type plasminogen activator gene expression do not appear to be essential for fibrin deposition/dissolution in this murine model of sepsis.
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PMID:Fibrin deposition in tissues from endotoxin-treated mice correlates with decreases in the expression of urokinase-type but not tissue-type plasminogen activator. 864 36

Fusion proteins of the human 55-kDa TNF receptor extracellular domain with hinge and C2/C3 constant domains of human IgG1 or IgG3 heavy chains were tested in a primate sepsis model. Twenty-four baboons received 4.6, or 0.2 mg/kg of TNFR5-G1,3, or placebo, before the administration of a lethal dose of live Escherichia coli. Treatment with TNFR5-G1,3 decreased 5-day mortality from 88% in the placebo group to 12% in the TNFR5-G1,3-treated animals (p < 0.01 by Fisher's exact test). Treatments with TNR5-G1 and TNFR5-G3 in doses from 0.2 to 4.6 mg/kg were efficacious. Free plasma TNF was neutralized by all treatments, but inactive TNF/TNFR5-G1,3 complexes remained in circulation for prolonged periods. TNFR5-1,3 treatments attenuated the hemodynamic disturbances, reduced fluid requirements, and decreased the systemic IL-1 beta, IL-6, and IL-8 responses. In addition, TNFR5-G1,3 treatment shortened the granulocytopenia and reduced the loss of cellular TNF receptors from granulocytes. The decrease in fibrinogen concentrations and increase in prothrombin and partial thromboplastin times were significantly attenuated by TNFR5-G1,3 treatment. TNFR5-G1,3 treatment markedly attenuated the rise in plasma lactate concentration. Histologic studies of TNFR5-G1,3 revealed dose-dependent protection against tissue injury by Escherichia coli administration.
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PMID:Protection against lethal Escherichia coli bacteremia in baboons (Papio anubis) by pretreatment with a 55-kDa TNF receptor (CD120a)-Ig fusion protein, Ro 45-2081. 869 Sep 12

Factor VII deficiency is a rare congenital coagulopathy. Prolonged prothrombin time with normal partial thromboplastin time indicates factor VII deficiency. For the definitive diagnosis, the specific factor VII level should be investigated. We report a seven-day-old, male, full-term newborn who was admitted with the diagnosis of sepsis. Hematological tests revealed prolonged prothrombin time and a factor VII level of five percent. After antibiotic therapy and fresh frozen plasma replacement his clinical status improved but the prothrombin time continued to be prolonged. On the 14th day, just before the end of antibiotic therapy, the infant died of sudden intracerebral hemorrhage. In this article, the clinical features and management of factor VII deficiency are discussed.
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PMID:Fatal intracranial hemorrhage in a newborn with factor VII deficiency. 870 95

Local and systemic activation of coagulation is frequently associated with bacterial sepsis. The coagulopathy is due, at least in part, to expression of tissue factor (TF) by monocytes and macrophages. The purpose of this study was to evaluate the expression of procoagulant activity by bovine alveolar macrophages, leukocytes and platelets, and to determine the relative potency of three chemical inhibitors of TF expression (pentoxifylline, retinoic acid, and cyclosporin A). Bovine alveolar macrophages were stimulated with lipopolysaccharide (LPS) derived from Pasteurella haemolytica or recombinant bovine tumour nervous factor (TNF) and dose- and time-dependent effects on TF expression were studied. LPS and TNF induced TF expression in alveolar macrophages and LPS treatment of whole blood induced TF expression in mononuclear cells. Neutrophils and platelets also expressed procoagulant activity, but this activity was not inhibited by anti-bovine TF monoclonal antibody. Pentoxifylline (40 mumol/L), retinoic acid (0.01 mmol/L) and cyclosporin A (0.08 mumol/L) inhibited TF expression when added concurrently with LPS or TNF, but not when added 4 h after stimulation. TF mRNA was not detected in unstimulated alveolar macrophages by Northern blot analysis. In contrast, exposure to LPS or TNF for 6 h induced marked expression of TF mRNA, which was inhibited by treatment with pentoxifylline, retinoic acid and cyclosporin A. Expression of TNF by alveolar macrophages stimulated with LPS was also inhibited by these compounds. Our results indicate that procoagulant activity expressed by alveolar macrophages and monocytes is associated with expression of TF, whereas procoagulant activity expressed by neutrophils and platelets is not. The concentrations of pentoxifylline and retinoic acid necessary for inhibition of TF expression in vitro may not be achievable in vivo owing to their toxic effects. However, the in vitro concentration of cyclosporin A that inhibited TF expression did not exceed the plasma concentration observed in humans, and therefore may be useful for inhibition of TF expression in vivo.
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PMID:In vitro expression and inhibition of procoagulant activity produced by bovine alveolar macrophages and peripheral blood cells. 895 Aug 33

The effect of two arginine-specific cysteine proteinases (gingipain Rs) from Porphyromonas gingivalis, a causative bacterium of adult periodontitis, on human blood coagulation was investigated. Activated partial thromboplastin time and prothrombin time were shortened by these proteinases, with a 95-kDa gingipain R containing adhesin domains being 5-fold more efficient in comparison to a 50-kDa gingipain R containing the catalytic domain alone. The 50-kDa enzyme reduced each coagulation time in several plasmas deficient in various coagulation factors, while it was ineffective in factor X-deficient plasma unless reconstituted with this protein. Each proteinase activated factor X in a dose- and time-dependent manner, with Michaelis constants (Km) being found to be lower than the normal plasma factor X concentration, strongly suggesting that factor X activation by gingipain Rs, especially the 95-kDa form which is strongly activated by phospholipids, could occur in plasma. This is the first report of factor X activation by bacterial proteinases and indicates that the gingipain Rs could be responsible for the production of thrombin and, indirectly, with the generation of prostaglandins, interleukin-1, etc., which have been found to be associated with the development of periodontitis induced by P. gingivalis infections. Furthermore, the data support the hypothesis that induction of blood coagulation by bacterial proteinases may be a causative agent in the pathogenesis of disseminated intravascular coagulation in sepsis.
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PMID:Activation of blood coagulation factor X by arginine-specific cysteine proteinases (gingipain-Rs) from Porphyromonas gingivalis. 918 12

An animal model of gram-positive septicemia was developed to evaluate the effects of antithrombin (AT) concentrates on morbidity, mortality, and laboratory consequences of disseminated intravascular coagulation (DIC). DIC was induced in guinea pigs by infusing Staphylococcus aureus (SA) isolated from blood cultures of patients with DIC (DIC-SA) or without DIC (non-DIC-SA). The non-DIC-SA animals and animals infused with sterile saline served as controls. Varying doses of AT were administered either 30 minutes or 24 hours after infusion of SA. DIC was confirmed within 4 hours by changes in prothrombin time, activated partial thromboplastin time, fibrinogen, fibrinogen-fibrin degradation products, and AT activity. Clinical bleeding was also evident. Mortality of untreated DIC-SA animals was 36% within 24 hours and up to 75% by 72 hours. Intervention with any dose of AT between 125 and 1,000 IU/kg 30 minutes after DIC-SA infusion was associated with 100% survival (P < or = .05 in the 250 IU/kg group) and sustained increases in AT activity and fibrinogen concentrations (P < or = .05). When AT was administered in combination with low molecular weight heparin (LMWH) or if LMWH was adminstered alone, mortality from DIC-SA was slightly, but not significantly reduced compared with untreated DIC-SA. Gross hemorrhage was observed premortem and at autopsy in all of the DIC-SA animals but in substantially fewer animals that received AT (P < or = .001 in the 250, 500, and 1,000 IU/kg groups). In contrast, groups treated with LMWH, alone or with AT, experienced hemorrhage and appeared to develop pathologic DIC. Fibrin formation in end-organs was detected in all guinea pigs in the untreated DIC-SA group and in the groups treated with 125 IU/kg AT and LMWH alone. AT doses between 250 and 1,000 IU/kg administered 30 minutes after DIC-SA infusion prevented fibrin formation in end-organs (P < or = .001 in the 250 and 1,000 IU/kg groups). AT administered 24 hours after DIC-SA could not reverse pre-existing histopathologic evidence of DIC but favorably affected survival, which reached statistical significance in the 1,000 IU/kg AT group (P < or = .025). In summary, suprapharmacologic doses of AT concentrate significantly decreased morbidity and mortality and ameliorated adverse changes in laboratory measures induced by DIC-SA in this guinea pig model and were not associated with untoward hemorrhagic complications. These findings provide justification for studying the use of AT therapy in patients with DIC-SA.
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PMID:The suprapharmacologic dosing of antithrombin concentrate for Staphylococcus aureus-induced disseminated intravascular coagulation in guinea pigs: substantial reduction in mortality and morbidity. 919 63

Hyperimmunoglobulin E syndrome (HIE) is a disorder characterized by extremely elevated serum levels of IgE and recurrent infections. Patients are particularly predisposed to have staphylococcal abscesses, usually involving skin, lungs, and joints; but they are also at risk for infections with other bacteria and fungi. We report the case of a 46-month-old boy with HIE who had Candida endocarditis and sepsis with a large fungal mass extending through the tricuspid valve and into the surrounding heart tissue, requiring surgical excision and replacement with a prosthetic valve. He had an indwelling central line for previous antibiotic therapy and had oral thrush for a month before presentation, which had been treated with oral nystatin. He was first seen with very dark urine, a new murmur, petechial rash, in shock, and disseminated intravascular coagulation. The white blood cell count was 38,700 with 70% segmented neutrophils, 9% banded neutrophils, 15% lymphocytes, 4% monocytes, and 2% eosinophils. Hemoglobin was 7.1, and platelet count was 14,000. Prothrombin time was 15.5, and partial thromboplastin time was 31; fibrinogen level was 110 mg/ml, and fibrin degradation products were greater than 40 mg/ml. Serum IgE was 38,664 and 44,510 on repeat measurement. He has had recurrent staphylococcal pneumonias with pneumatoceles, twice requiring segmental lung resection. Blood and tricuspid valve cultures grew Candida albicans. He was treated with amphotericin and flucytosine, and later switched to fluconazole, with good response to therapy. A literature search revealed no other reported case of Candida endocarditis in patients with HIE. Fungai endocarditis is a rare complication, which may occur in patients with HIE and indwelling central catheters.
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PMID:Candida endocarditis in a child with hyperimmunoglobulinemia E syndrome. 921 44

Changes of endotoxin in plasma, and the response of the coagulation system and blood cells in septicemia of Haemophilus parasuis infection were examined by inoculation with H. parasuis in specific pathogen-free (SPF) pigs. Eight pigs were inoculated intratracheally with 10(5), 10(6) and 10(7) colony formation units (CFU) of the strain Nagasaki (serovar 5). All pigs died 28 to 42 hr after inoculation. Haematologically, severe leukopenia occurred 24 hr post inoculation (hpi) until death. Glucose concentration decreased from 24 hpi to death. In the coagulation system, decrease of platelet counts, prolongation of prothrombin time, activated partial thromboplastin time, and increase of fibrinogen-fibrin degradation products were observed in all inoculated pigs. Endotoxin was detected in the plasma of all the inoculated pigs from 16 hpi to death, and its concentration rose dramatically just before death. H. parasuis was re-isolated from the blood of all inoculated pigs from 16 hpi to death, and also from almost all organs and body fluids of the pigs. The pigs had microthrombi in the kidney, liver and lungs, and many also had pneumonia, meningitis and serositis. H. parasuis antigen was detected in the lesions by the immunoperoxidase technique. The results indicated that disseminated intravascular coagulation (DIC) and endotoxin shock involved aggravation of clinical signs and death on the pigs induced to septicemia of H. parasuis.
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PMID:Effects on endotoxin pathogenicity in pigs with acute septicemia of Haemophilus parasuis infection. 923 19

In preterm infants the activity of antithrombin III (AT-III), the main inhibitor of thrombin, is reduced depending on gestational age and complications such as sepsis or respiratory distress syndrome. Babies with low levels of AT-III have been shown to have a higher mortality and an increased incidence of intracranial hemorrhage. In our study we tried to show the effect of early AT-III substitution on coagulation parameters and the incidence of intraventricular hemorrhage (IVH). One hundred three preterm infants at a gestational age of 25-32 weeks (mean 28.9 weeks; birth weight 600-2,170 g, mean 1,285 g) received AT-III concentrate at a single dosage of 50-200 IU/kg on the day of birth and subsequently only in case of a new decrease below an AT-III activity of 50%. We measured AT-III activity, Quick's prothrombin time (PT), partial thromboplastin time (PTT) and platelet count on the day of birth, and after 1 and 5-9 days in 25 patients. AT-III activity before substitution was lower than described for term infants (20-72%, mean 40%). Within the first week of life Quick's PT and PTT reached almost term values. No significant differences of the platelet count were found within the first week of life. The incidence of IVH was lower than in current epidemiologic studies: in only 13% of the study patients. Six percent of the infants had IVH grade I, 3% grade II, 4% grade III and none grade IV. Therefore, in preterm infants AT-III substitution may reduce the incidence and progression of intracranial hemorrhage.
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PMID:Antithrombin-III substitution in preterm infants--effect on intracranial hemorrhage and coagulation parameters. 926 73

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