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)

The effect of supernatant from phorbol myristate acetate (PMA) stimulated human polymorphonuclear granulocytes (PMN) on human factor VII was studied in vitro. The supernatant caused a rapid loss in factor VII coagulant activity by the action of human leukocyte elastase (HLE) and cathepsin G in the supernatant, as demonstrated by the use of specific inhibitors of the two serine proteases, respectively. Preincubation of the supernatant with the elastase inhibitor and the cathepsin G inhibitor preserved 80% and 25% of the clotting activity, respectively. Calcium protected factor VII completely from the supernatant mediated inactivation. Cathepsin G and HLE purified from PMN each destroyed the coagulant activity of factor VII when added to a non-plasma system. There were, however, no effect on factor VII activity when cathepsin G was added to plasma. Polyacrylamide gel electrophoresis in the presence of SDS indicated that HLE and cathepsin G cleaved the zymogen in the same manner, producing (a) peptide(s) of low molecular mass and a single large product of 48 kDa. Preincubation of factor VII with calcium ions inhibited the proteolytic action of HLE and cathepsin G. It is suggested that HLE and cathepsin G from activated granulocytes may be partly responsible for the loss in factor VII activity that is observed during sepsis.
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PMID:Human leukocyte elastase and cathepsin G inactivate factor VII by limited proteolysis. 805 78

The risk of acquiring diseases from transfusion of blood and blood products is well recognized and the issue of parvovirus in haemophiliacs is not a new one. We report two patients with haemophilia acquiring iatrogenic parvovirus B19 infection, resulting in life-threatening sepsis in one, and immunocompetent adult. Over the last 10 years there has been great progress in manufacturing safer products with regard to enveloped viruses such as HIV, hepatitis B and C. A recent outbreak across Europe of hepatitis A in haemophiliacs treated with plasma-derived factor VII concentrates has made haemophilic treaters concerned about the known (parvovirus B19 and hepatitis A) and the unknown non-lipid enveloped viruses that may be contained in the clotting factor concentrates, because these are resistant to the existing viral inactivating techniques. The possibility of HIV itself mutating into a non-lipid enveloped virus emphasizes the need to seek and use safer products.
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PMID:Transmission of symptomatic parvovirus B19 infection by clotting factor concentrate. 863 48

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

Tissue factor, a member of the cytokine-receptor superfamily and high-affinity receptor and cofactor for plasma factor VII/VIIa (ref. 1), is the primary cellular initiator of blood coagulation. It is involved in thrombosis and inflammation associated with sepsis, atherosclerosis and cancer, and can participate in other cellular processes including intracellular signalling, metastasis, tumor-associated angiogenesis, and embryogenesis. Here we report that inactivation of the tissue factor gene (TF) results in abnormal circulation from yolk sac to embryo beyond embryonic day 8.5, leading to embryo wasting and death. Vitelline vessels from null mice were deficient in smooth-muscle alpha-actin-expressing mesenchymal cells, which participate in organization of the vessel wall. This implies that tissue factor has a role in blood vessel development.
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PMID:Role of tissue factor in embryonic blood vessel development. 877 17

Tissue factor (TF), a small membrane bound high affinity receptor for factor VII, has an important procoagulant role in the haemostatic dysfunction associated with severe sepsis. Using an in vitro model of human endothelial TF expression, defined strains of Neisseria meningitidis were found to upregulate endothelial cell procoagulant activity (PCA) in a dose dependent manner. This TF response was detected with as little as 10(4) cfu/ml and reached similar levels to those seen with high concentrations of purified endotoxin (> 1 ng/ml). Treatment of N. meningitidis with either adult donor immune serum, penicillin or gentamicin failed to enhance this PCA. Limulus amoebocyte lysate assay of lipopolysaccharide in bacterial culture filtrates together with polymyxin B inhibition experiments suggest that endotoxin is largely responsible for endothelial TF induction by N. meningitidis. Incubation of endothelial cells with N. meningitidis B1940 and B1940 siaD- (an eight-fold more adherent unencapsulated isogenic strain), revealed a significantly greater TF response to B1940 siaD- (P < 0.01). In conclusion, bacterial adhesion to the vessel wall and therefore local levels of endotoxin may be important determinants of the endothelial procoagulant response to N. meningitidis and the consequent coagulopathy commonly associated with the disease.
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PMID:Induction of human endothelial tissue factor expression by Neisseria meningitidis: the influence of bacterial killing and adherence to the endothelium. 916 Feb 96

Isolated acquired factor VII deficiency is uncommon. We report 11 cases of acquired factor VII deficiency associated with severe systemic sepsis. All patients initially displayed a heterozygous-like factor VII deficiency confirmed by both clotting and amidolytic assays, associated with low factor VII antigen levels, and increased haemostasis markers (D-dimers, prothrombin fragments 1.2, thrombin-antithrombin complexes). After sepsis recovery, normal factor VII levels were evidenced. Isolated factor VII consumption or proteolytic degradation by leucocyte proteases can be evoked, but the mechanism of acquired factor VII deficiency during sepsis remains to be elucidated. The knowledge of this syndrome should avoid false diagnosis of congenital factor VII deficiency.
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PMID:Acquired isolated factor VII deficiency during sepsis. 921 52

The expression of tissue factor (TF) by monocytes/macrophages leads to thrombin generation and contributes to their physiological and pathophysiological roles in wound repair, disseminated intravascular coagulation linked to sepsis, postoperative thrombosis, unstable angina, atherosclerosis, chronic inflammation and cancer. Regulation of TF expression in monocytes is controlled by the transcription factors NF-kappaB and AP-1. In whole blood, the activation of the transcription factors is mediated through the phospholipase A2 pathway. Platelets play a crucial role in the expression of TF activity in monocytes, and granulocytes are mandatory in provoking the platelet effect in a P-selectin-dependent reaction. Although all induced or constitutive TF is expressed on the surface of monocytes, its catalytic activity is only about 10% compared to the activity of lysed cells. This phenomenon has been attributed to the increased availability of anionic phospholipid (phosphatidylserine) after cell lysis. At the surface of viable cells, the transmembrane phospholipid distribution and its regulation may be important for the expression of the catalytic activity of the complex of TF and activated factor VII. Phosphatidylserine pathophysiologically exposed at the outer surface of monocytes may, similar to that for platelet membranes, provide a strong stimulus for thrombin generation.
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PMID:Tissue factor expression by monocytes: regulation and pathophysiological roles. 981 23

Thirty normal subjects were given a single loading dose of warfarin sodium, 1.5 mg/kg of body weight. The drug was metabolized slowly (mean biological half-life, 47 hr) and showed a prolonged biological effect (over 6 days). In two separate experiments no loading dose was given; instead, daily doses of 15 mg and 10 mg were administered to 15 of the subjects. The prothrombin complex responses were compared with those obtained in the same subjects after the large loading dose. The mean time in days to reach the therapeutic range (prothrombin complex activity < 35% of normal) was 1.1 days with the dose of 1.5 mg/kg of body weight, 2.7 days with the dose of 15 mg/day, and 5.2 days with 10 mg/day. With all three methods the therapeutic range was reached soon after a level of warfarin of 2 mg/L plasma was attained. The rates of fall of the four vitamin K-dependent clotting factors (II, VII, IX, and X) with the large loading dose and with the daily dosage of 15 mg were compared in six of the subjects. With the loading dose, factor VII activity was less during the first 48 hr, but there was no other significant difference between the two methods of drug administration in the amount of reduction of any of the four factors. Since the role of factor VII in thrombogenesis is questioned, these results provide a rational basis for the induction of prophylactic anticoagulant therapy without large loading doses of warfarin. Avoidance of the customary loading dose should reduce the danger of hemorrhage, particularly in patients who are sensitive to the drug because of advanced age, sepsis, liver disease, congestive heart failure, or recent surgery or trauma.
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PMID:Studies on coumarin anticoagulant drugs. Initiation of warfarin therapy without a loading dose. 1171 86

Tissue factor (TF) is a cell surface receptor for factor VII(a), and the binding of factor VII(a) to TF initiates the coagulation cascade. Inappropriate in vivo expression of TF in vascular cells has been shown to be responsible for thrombotic disorders associated with a variety of pathological conditions, including gram-negative sepsis, cancer and atherosclerosis. A number of epidemiological studies suggest that moderate consumption of red wine provides protective effects against coronary heart disease mortality. Recently, we have shown that resveratrol, a polyphenolic compound found in wine, inhibited the induction of TF expression in endothelial cells and mononuclear cells (Pendurthi UR, Williams JT, Rao LVM. Arterioscler Thromb Vasc Biol 1999: 19: 419-426). In the present study, we examined the mechanism by which resveratrol inhibits the expression of TF in monocytes by using a monocytic cell line, THP-1, as a model cell. Northern blot analysis, gel mobility shift assays and transfection studies with various TF promoter constructs, as well as other transcription regulatory constructs, were used to elucidate the inhibitory mechanism of resveratrol. The data show that resveratrol inhibited lipopolysaccharide (LPS)-induced expression of TF in human monocytes and monocytic cell line, THP-1 in a dose dependent manner. Resveratrol did not significantly alter the binding of various transcription factors involved in TF gene expression to DNA. However, resveratrol suppressed the transcription of cloned human TF promoter. Further experiments revealed that resveratrol reduced kappaB- but not AP-1-driven transcriptional activity. Additional experiments showed that resveratrol suppressed the phosphorylation of p65 and its transactivation. In summary, our results indicate that resveratrol does not inhibit the activation or translocation of NF-kappaB/Rel proteins but inhibits NF-kappaB/Rel-dependent transcription by impairing the transactivation potential of p65.
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PMID:Mechanism of resveratrol-mediated suppression of tissue factor gene expression. 1185 83

The enhanced extrinsic coagulation in response to inflammation could contribute to disseminated intravascular coagulation, often manifesting cardiovascular complications. The complex mechanism remains unclear. Nor is the effective anticoagulation well established. The search for arresting hypercoagulation is of antithrombotic relevance. The ability of polybrene (PB) to inhibit tissue factor (TF)-initiated extrinsic blood coagulation was demonstrated at the protein and cellular levels as well as in human plasma samples. In a single-stage clotting assay, PB dose-dependently offset bacterial endotoxin (lipopolysaccharide)-induced monocytic TF (mTF) hypercoagulation and inhibited rabbit brain thromboplastin (rbTF) procoagulation. Consistent with these findings, the significantly prolonged prothrombin time indicated the depressed extrinsic coagulation by PB. However, PB showed no effect on thrombin time. We dissected the extrinsic pathway to further determine the inhibitory site(s) of PB. A two-stage chromogenic assay monitoring S-2288 hydrolysis showed that PB readily blocked mTF-dependent or rbTF-dependent FVII activation, which was verified by the diminished activated factor VII (FVIIa) formation derived from the proteolytic cleavage of its zymogen factor VII on Western blotting analyses. PB had no effect on FVIIa and activated factor X amidolytic activity. Nor was the dissected TF/FVIIa-catalyzed factor X activation affected. In conclusion, the preferential downregulation of factor VII activation was responsible for the depressed extrinsic coagulation. PB could present a novel anticoagulant antagonizing the extrinsic hypercoagulation for the prevention of thrombotic complication following sepsis and inflammations.
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PMID:Novel anticoagulant activity of polybrene: inhibition of monocytic tissue factor hypercoagulation following bacterial endotoxin induction. 1191 54


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