thromboplastin and Hepatitis

AMP activated protein kinase (AMPK) is a pivotal metabolic regulatory enzyme and novel target of controlling inflammation. Our previous studies had demonstrated that 5-amino-4-imidazolecarboxamide riboside (AICAR), an AMPK activator, attenuated lipopolysaccharide (LPS)/D-galactosamine (D-gal)-induced fulminant hepatitis via suppressing inflammatory response. Since inflammation usually activates the coagulation response and aggravates inflammation-induced tissue injury, the present study was to explore the effects of AICAR on inflammation-induced activation of coagulation. Male BALB/c mice received LPS/D-gal intraperitoneal injection were used as fulminant hepatitis model. Western blot was used to detect tissue factor (TF) and hypoxia-inducible factor 1α (HIF-1α) protein expressions in hepatic tissue, as well as nuclear factor kappa B (NF-κB) p65 translocation into the nucleus. Real-time quantitative PCR was used to analyze erythropoietin (EPO) mRNA expression level. Lactic acid (LA) level in hepatic tissue was detected by kit. The results showed that LPS/D-gal induced the enhanced expression of TF, elevation of NF-κB p65 nuclear translocation, up-regulation of HIF-1α and EPO expressions, and increased LA level. These above alterations could be suppressed by AICAR. These results suggest that AICAR may down-regulate LPS/D-gal-induced TF expression (coagulation activity), and relieve hepatic hypoxia and metabolic disorder via suppressing the activity of NF-κB, which may be a novel mechanism of the beneficial effect of AICAR on LPS/D-gal-induced fulminant hepatitis.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Down-Regulation; Erythropoietin; Hepatitis; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Lipopolysaccharides; Male; Mice; NF-kappa B; Thromboplastin; Up-Regulation

Failure to inhibit hepatic gluconeogenesis is a major mechanism contributing to fasting hyperglycemia in type 2 diabetes and, along with steatosis, is the hallmark of hepatic insulin resistance. Obesity is associated with chronic inflammation in multiple tissues, and hepatic inflammation is mechanistically linked to both steatosis and hepatic insulin resistance. Here, we delineate a role for coagulation signaling via tissue factor (TF) and proteinase-activated receptor 2 (PAR2) in obesity-mediated hepatic inflammation, steatosis, and gluconeogenesis. In diet-induced obese mice, TF tail signaling independent of PAR2 drives CD11b(+)CD11c(+) hepatic macrophage recruitment, and TF-PAR2 signaling contributes to the accumulation of hepatic CD8(+) T cells. Transcripts of key pathways of gluconeogenesis, lipogenesis, and inflammatory cytokines were reduced in high-fat diet-fed mice that lack the cytoplasmic domain of TF (F3) (TF(ΔCT)) or that are deficient in PAR2 (F2rl1), as well as by pharmacological inhibition of TF-PAR2 signaling in diet-induced obese mice. These gluconeogenic, lipogenic, and inflammatory pathway transcripts were similarly reduced in response to genetic ablation or pharmacological inhibition of TF-PAR2 signaling in hematopoietic cells and were mechanistically associated with activation of AMP-activated protein kinase (AMPK). These findings indicate that hematopoietic TF-PAR2 signaling plays a pivotal role in the hepatic inflammatory responses, steatosis, and hepatic insulin resistance that lead to systemic insulin resistance and type 2 diabetes in obesity.

Topics: AMP-Activated Protein Kinases; Animals; Diabetes Mellitus, Type 2; Fatty Liver; Gluconeogenesis; Hematopoietic Stem Cells; Hepatitis; Insulin Resistance; Mice; Mice, Knockout; Mice, Obese; Obesity; Receptor, PAR-2; Signal Transduction; Thromboplastin

Metformin is a widely‑used antidiabetic drug with hypoglycemic activity and previously described anti‑inflammatory properties. Previous studies have demonstrated that metformin attenuates endotoxic hepatitis, however the mechanisms remain unclear. Inflammation and coagulation are closely associated pathological processes, therefore the potential effects of metformin on key steps in activation of the coagulation system were further investigated in endotoxic hepatitis induced by lipopolysaccharide/D‑galactosamine (LPS/D‑Gal). The current study demonstrated that treatment with metformin significantly suppressed the upregulation of tissue factor and plasminogen activator inhibitor‑1 in LPS/D‑Gal‑exposed mice. In addition, a reduction in the expression of interleukin 6 and inhibition of nuclear translocation of nuclear factor‑κB were observed. These data indicate that the LPS/D‑Gal‑induced elevation of the stable protein level of hypoxia inducible factor 1α, the mRNA level of erythropoietin, vascular endothelial growth factor and matrix metalloproteinase‑3, and the hepatic level of lactic acid were also suppressed by metformin. The current study indicates that the suppressive effects of metformin on inflammation‑induced coagulation may be an additional mechanism underlying the hepatoprotective effects of metformin in mice with LPS/D‑Gal‑induced fulminant hepatitis.

Topics: Animals; Anti-Inflammatory Agents; Blood Coagulation; Disease Models, Animal; Erythropoietin; Galactosamine; Hepatitis; Hypoglycemic Agents; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interleukin-6; Lactic Acid; Lipopolysaccharides; Liver; Matrix Metalloproteinase 3; Metformin; Mice; NF-kappa B; Plasminogen Activator Inhibitor 1; RNA, Messenger; Thromboplastin; Up-Regulation; Vascular Endothelial Growth Factor A

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome and contributes to increased risk of cardiovascular disease and liver-related morbidity and mortality. Indeed, obese patients with metabolic syndrome generate greater amounts of thrombin, an indication of coagulation cascade activation. However, the role of the coagulation cascade in Western diet-induced NAFLD has not been investigated. Using an established mouse model of Western diet-induced NAFLD, we tested whether the thrombin receptor protease-activated receptor 1 (PAR-1) and hematopoietic cell-derived tissue factor (TF) contribute to hepatic steatosis. In association with hepatic steatosis, plasma thrombin-antithrombin levels and hepatic fibrin deposition increased significantly in C57Bl/6J mice fed a Western diet for 3 months. PAR-1 deficiency reduced hepatic inflammation, particularly monocyte chemoattractant protein-1 expression and macrophage accumulation. In addition, PAR-1 deficiency was associated with reduced steatosis in mice fed a Western diet, including reduced liver triglyceride accumulation and CD36 expression. Similar to PAR-1 deficiency, hematopoietic cell TF deficiency was associated with reduced inflammation and reduced steatosis in livers of low-density lipoprotein receptor-deficient mice fed a Western diet. Moreover, hematopoietic cell TF deficiency reduced hepatic fibrin deposition. These studies indicate that PAR-1 and hematopoietic cell TF are required for liver inflammation and steatosis in mice fed a Western diet.

Topics: Animals; Blood Coagulation; Bone Marrow Transplantation; Diet; Fatty Liver; Hematopoietic Stem Cells; Hepatitis; Lipogenesis; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Receptor, PAR-1; RNA, Messenger; Signal Transduction; Thromboplastin; Tumor Necrosis Factor-alpha; Weight Gain

During a period when screening for hepatitis B surface antigen (HBsAg) was performed by immunodiffusion using dextran-containing agarose gel, a diffuse precipitation (DP) zone was observed when citrate plasma samples were reacted with certain serum specimens. The DP reaction was noted with a significantly larger number of sera from patients with renal disorders, hepatitis, or certain other virus infections than with sera from apparently healthy blood donors, indicating that it was associated with some type of pathological condition. Highly purified fibrinogen used as detector reagent instead of plasma was sufficient to elicit a precipitation zone similar to that of the DP reaction. In the presence of coagulation inhibitors such as heparin, hirudin and antithrombin III the DP reaction was inhibited, suggesting that the precipitation zone represents coagulation. Cross-linked fibrin was demonstrated in the precipitates of DP-positive sera but not in the corresponding zone of a DP-negative serum.

Topics: Blood Coagulation; Factor X; Fibrin; Hepatitis; Humans; Immunodiffusion; Kidney Diseases; Thrombin; Thromboplastin

20 coagulation parameters were investigated in 144 patients with different liver diseases. The groups of acute hepatitis, chronic active hepatitis and liver cirrhosis were compared and the prognostic value of the coagulation analyses investigated. It is clear that the determination of the factor V activity is a good and easy test for detection of actual liver function. Repeated controls over several weeks revealed with a statistical significance (p less than 0.0005) that all patients with a factor XIII below 35% and a plasminogen below 19% will die in liver coma, if they have not died beforehand from acute gastrointestinal haemorrhage, acute infection or cardiac arrest. Plasminogen is also lower in the group of non-survivors but the values of the two groups are overlapping and of no prognostic help in a single case. The possible causes of the diminution of factor XIII activity are discussed.

Topics: Adolescent; Adult; Aged; Blood Coagulation Tests; Factor V; Factor XIII; Female; Fibrin Fibrinogen Degradation Products; Hepatitis; Humans; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Plasminogen; Prognosis; Prothrombin; Thromboplastin; Time Factors

Topics: Antithrombins; Blood Coagulation Tests; Caseins; Factor V; Factor VIII; Fibrinogen; Fibrinolysis; Hepatitis; Humans; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Mushroom Poisoning; Plasminogen; Prothrombin Time; Thromboplastin

Topics: Biopsy, Needle; Blood Coagulation Disorders; Hemorrhagic Disorders; Hepatitis; Humans; Hypoprothrombinemias; Infant; Infusions, Parenteral; Iron; Liver Function Tests; Malabsorption Syndromes; Male; Prothrombin Time; Thromboplastin; Vitamin K; Vitamin K Deficiency

Topics: Adenocarcinoma; Adult; Aged; Alkaline Phosphatase; Alpha-Globulins; Biopsy; Fatty Liver; Female; Follow-Up Studies; Hepatitis; Humans; Kidney Neoplasms; Male; Middle Aged; Postoperative Care; Preoperative Care; Prothrombin Time; Serum Albumin; Sulfobromophthalein; Thromboplastin

Liver biopsy was performed in 38 patients with fulminant hepatitis and coma and repeated in 22. Stereological estimation of hepatocyte volume was correlated with levels of clotting factors. Early liver biopsy allowed prognosis in 55% of the cases. All patients with a hepatocyte volume of <35% and thromboplastin time /=35% and thromboplastin time >10% recovered consciousness (n = 9) or at least showed evidence of marked liver regeneration (n = 2). On serial liver biopsy a significant increase in hepatocyte volume and clotting factors was only observed in patients who recovered consciousness. The estimated liver cell mass after regeneration in patients who recovered consciousness was >/=45% and <45% in the patients who did not.

Topics: Acute Disease; Biopsy; Factor V; Hepatic Encephalopathy; Hepatitis; Hepatitis A; Humans; Liver; Liver Diseases; Prognosis; Thromboplastin; Time Factors

Topics: Adult; Aged; Arthritis; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Carcinoma; Factor VIII; Female; Fibrinolysin; Hepatitis; Humans; Liver Diseases; Male; Middle Aged; Necrosis; Rectal Neoplasms; Thrombin; Thromboplastin; Vaginal Neoplasms

Topics: ABO Blood-Group System; Adolescent; Adult; Aged; Anemia, Aplastic; Blood Coagulation; Blood Coagulation Tests; Blood Transfusion; Capillary Fragility; Centrifugation; Female; Fibrinolysin; Fibrinolysis; Gastrointestinal Hemorrhage; Hematuria; Hemostasis; Hepatitis; Humans; Leukemia, Myeloid; Male; Middle Aged; Prothrombin Time; Stomach Neoplasms; Stomach Ulcer; Thrombin; Thromboangiitis Obliterans; Thromboplastin

Topics: Barium Sulfate; Blood Coagulation; Blood Coagulation Tests; Blood Proteins; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Hepatitis; Lipoproteins; Massive Hepatic Necrosis; Portal Vein; Prothrombin Time; Rats; Research; Thromboplastin; Thrombosis; Toxicology

Topics: Blood Coagulation Tests; Hepatitis; Hepatitis A; Humans; Liver Function Tests; Prothrombin Time; Research; Thromboplastin

Topics: Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Coagulants; Fibrinogen; Fibrinolysis; Hepatitis; Hepatitis A; Humans; Prothrombin Time; Thromboplastin

Topics: Adrenal Cortex Hormones; Blood Chemical Analysis; Child; Factor IX; Hemophilia A; Hemophilia B; Hepatitis; Hepatitis A; Humans; Infant; Infant, Newborn; Infant, Premature; Jaundice; Jaundice, Obstructive; Leukemia; Pharmacology; Physiology; Purpura; Thromboplastin