thromboplastin and Chemical-and-Drug-Induced-Liver-Injury

A randomised clinical trial was undertaken to compare the value of a factor II, IX, and X concentrate (Prothromplex) with intravenous vitamin K1 (2-5 mg) in reversing an overdose of oral anticoagulants. Rapid partial correction of the prothrombin time, partial thromboplastin time, and the clotting factor assays were observed with the concentrate, but these changes were not always sustained. In contrast vitamin K1 did not show any great effect at two hours but at 24 hours there was always over-correction despite the conservative dosage, prothrombin times being shorter than the therapeutic range. The prothrombin complex concentrate provides a quicker, more controlled but less sustained method of reversing the coumarin defect than vitamin K1. But there remains a significant risk of hepatitis even with a preparation for which strenuous efforts have been made to minimise this risk by screening for hepatitis B virus. The risk should be carefully considered before such concentrates are infused in non-urgent conditions.

Topics: Anticoagulants; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Combinations; Factor IX; Factor X; Humans; Poisoning; Prothrombin; Prothrombin Time; Thromboplastin; Time Factors; Vitamin K

Retinoid receptors (RRs), RAR-α and RXR-α, work as transcription factors that regulate cell growth, differentiation, survival, and death. Hepatic stellate cells (HSCs) store retinoid and release its RRs as lipid droplets upon their activation.. We test the hypothesis that loss of retinoid receptors RAR-α and RXR-α from HSCs is dependent on tissue factor (TF) during thioacetamide (TAA)-induced liver injury.. Liver toxicity markers, TF, fibrin, cleaved caspase-3, and cyclin D1 as well as histopathology were investigated.. Increased TF, fibrin, cleaved caspase-3, and cyclin D1 protein expression is seen in zone of central vein after TAA injection compared with vehicle-treated mice. A strong downregulation of RAR-α and RXR-α is seen in TAA-induced liver injury. In addition, histopathological obliteration and pericentral expression of cleaved caspase 3 and cyclin D1 are observed after TAA injection compared with the normal vehicle-treated mice. No changes have been seen in TAA/TF-sense (SC) in whole parameters compared with TAA-treated animals. TAA/TF-antisense (AS)-treated mice show normal expression of all parameters and normal histopathological features when compared with the control mice. In conclusion, this study declares that the strong downregulation of RAR-α and RXR-α may cause liver injury and particularly activation of HSCs in TAA-induced toxicity. TF-AS treatment not only downregulates TF protein expression but also alleviates loss of liver RAR-α and RXR-α and suppresses the activated apoptosis signals in TAA-induced liver toxicity. Finally, TF and RAR-α/RXR-α are important regulatory molecules in TAA induced acute liver injury.

Topics: Animals; Chemical and Drug Induced Liver Injury; Male; Mice; Nuclear Receptor Subfamily 1, Group F, Member 1; Oligonucleotides, Antisense; Retinoid X Receptor alpha; Thioacetamide; Thromboplastin

Topics: Animals; Cell Line; Chemical and Drug Induced Liver Injury; Cytokines; Dose-Response Relationship, Drug; Fibrin; Gene Expression Regulation; Humans; Inflammation; Macrolides; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Specific Pathogen-Free Organisms; Stilbenes; Thromboplastin

Tissue factor (TF) is a membranous glycoprotein that activates the coagulation system when blood vessels or tissues are damaged. TF was up-regulated in monocrotaline (MCT)/lipopolysaccharide (LPS) hepatotoxicity model. The present study aimed to test the hypothesis that TF-dependent fibrin deposition occurs in liver toxicity induced by CCl4 in mice. Pericentral deposition of TF and fibrin is induced after CCl4-induced liver toxicity. The toxicity was evaluated by determination of serum activities of ALT, AST and ALP as well as GSH content and histopathological changes. The results showed that injection of mice with TF-antisense deoxyoligonucleotide (TF-AS) prevented the accumulation of TF and fibrin in the hepatic tissues. Furthermore, it significantly restored blood biochemical parameters, GSH content and distorted histopathological features caused by CCl4. The current study demonstrates that TF activation is associated with CCl4-induced liver injury. Furthermore, administration of TF-AS successfully prevented this type of liver injury.

Topics: Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Disease Models, Animal; DNA, Antisense; Fibrin; Gene Expression Regulation, Enzymologic; Glutathione; Male; Mice; Thromboplastin; Transaminases

Tissue factor (TF) is a membranous glycoprotein that functions as a receptor for coagulation factor VII/VIIa and activates the coagulation system when blood vessels or tissues are damaged. TF was upregulated in our monocrotaline (MCT)/lipopolysaccharide (LPS) hepatotoxicity model. We tested the hypothesis that TF-dependent fibrin deposition and lipid peroxidation in the form of oxidized low-density-lipoprotein (ox-LDL) accumulation contribute to liver inflammation induced by MCT/LPS in mice. In the present study, we blocked TF using antisense oligodeoxynucleotides against mouse TF (TF-ASO). TF-ASO (5.6 mg kg(-1) ) was given i.v. to ND4 male mice 30 min after administration of MCT (200 mg kg(-1) ) p.o. followed after 3.5 h by LPS i.p. (6 mg kg(-1) ). Blood alanine aminotransferase (ALT), TF, ox-LDL, platelets, hematocrit and keratinocyte-derived chemokine (KC) levels were evaluated in different treatment groups. Fibrin deposition and ox-LDL accumulation were also analyzed in the liver sections using immunofluorescent staining. The results showed that TF-ASO significantly restored blood ALT, hematocrit and KC levels, distorted after MCT/LPS co-treatment, as well as preventing the accumulation of ox-LDL and the deposition of fibrin in the liver tissues, and thereby inhibited liver injury caused by MCT/LPS. In a separate experiment, TF-ASO administration significantly prolonged animal survival. The current study demonstrates that TF is associated with MCT/LPS-induced liver injury. Administration of TF-ASO successfully prevented this type of liver injury.

Topics: Alanine Transaminase; Animals; Blood Coagulation; Chemical and Drug Induced Liver Injury; Chemokines; Cytokines; Hematocrit; Lipid Metabolism; Lipopolysaccharides; Lipoproteins, LDL; Liver; Male; Mice; Monocrotaline; Oligonucleotides, Antisense; Thromboplastin

In this study, we characterized tissue factor (TF) expression in mouse hepatocytes (HPCs) and evaluated its role in mouse models of HPC transplantation and acetaminophen (APAP) overdose. TF expression was significantly reduced in isolated HPCs and liver homogenates from TF(flox/flox)/albumin-Cre mice (HPC(ΔTF) mice) compared with TF(flox/flox) mice (control mice). Isolated mouse HPCs expressed low levels of TF that clotted factor VII-deficient human plasma. In addition, HPC TF initiated factor Xa generation without exogenous factor VIIa, and TF activity was increased dramatically after cell lysis. Treatment of HPCs with an inhibitory TF antibody or a cell-impermeable lysine-conjugating reagent prior to lysis substantially reduced TF activity, suggesting that TF was mainly present on the cell surface. Thrombin generation was dramatically reduced in APAP-treated HPC(ΔTF) mice compared with APAP-treated control mice. In addition, thrombin generation was dependent on donor HPC TF expression in a model of HPC transplantation. These results suggest that mouse HPCs constitutively express cell surface TF that mediates activation of coagulation during hepatocellular injury.

Topics: Acetaminophen; Albumins; Analgesics, Non-Narcotic; Animals; Blood Coagulation; Blotting, Western; Chemical and Drug Induced Liver Injury; Factor VIIa; Female; Flow Cytometry; Hepatocytes; Humans; Immunoenzyme Techniques; Integrases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thrombin; Thromboplastin

Cholestatic liver injury induced by alpha-naphthylisothiocyanate (ANIT) is provoked by injury to intrahepatic bile ducts and the progression of hepatic necrosis requires the procoagulant protein tissue factor (TF) and extrahepatic cells including neutrophils. Recent studies have shown that myeloid cell TF contributes to neutrophil activation. We tested the hypothesis that myeloid cell TF contributes to neutrophil activation in ANIT-treated mice. TF activity in liver homogenates increased significantly in TF(flox/flox) mice treated with ANIT, but not in TF(flox/flox)/LysMCre mice (TF(ΔMyeloid) mice), which have reduced TF expression in monocytes/macrophages and neutrophils. Myeloid cell-specific TF deficiency did not alter expression of the chemokines KC or MIP-2 but reduced hepatic neutrophil accumulation in ANIT-treated mice at 48 h as indicated by tissue myeloperoxidase (MPO) activity. Myeloid cell TF deficiency significantly reduced CD11b expression by blood neutrophils in ANIT-treated mice, and this was associated with reduced plasma MPO protein levels, an index of neutrophil degranulation. However, myeloid cell-specific TF deficiency had no effect on ANIT-induced coagulation cascade activation. The increase in serum ALT and ALP activities in ANIT-treated mice was reduced by myeloid cell TF deficiency (p<0.05), but the myeloid cell TF deficiency did not reduce hepatic necrosis at 48 h, as determined by histopathology and morphometry. The results suggest that myeloid cell TF contributes to neutrophil CD11b expression during cholestasis by a coagulation-independent pathway. However, the resultant reduction in neutrophil accumulation/activation is insufficient to substantially reduce ANIT hepatotoxicity, suggesting that myeloid cell TF is only one of many factors modulating hepatic necrosis during cholestasis.

Topics: 1-Naphthylisothiocyanate; Animals; Blood Coagulation; CD11b Antigen; Chemical and Drug Induced Liver Injury; Chemokines; Cholestasis; Intercellular Adhesion Molecule-1; Liver; Male; Mice; Myeloid Cells; Neutrophil Activation; Neutrophils; Peroxidase; Thromboplastin; Xenobiotics

These studies were aimed at characterizing an animal model of inflammation-induced hepatotoxicity that would mimic features of idiosyncratic liver toxicity observed in humans. An attempt was made to identify oxidative damage and the involvement of coagulation system in liver after monocrotaline (MCT) administration under the modest inflammatory condition induced by lipopolysaccharide (LPS) exposure. Mice were given MCT (200 mg/kg) or an equivalent volume of sterile saline (Veh.) po followed 4 h later by ip injection of LPS (6 mg/kg) or vehicle. Mice co-treated with MCT and LPS showed increased plasma alanine aminotransferase (ALT), decrease in platelet number, and a reduction in hematocrit. Accumulation of oxidized low-density lipoprotein (ox-LDL) was remarkably higher in the liver sections of mice co-treated with MCT and LPS compared to those given MCT or LPS alone. A similar trend was observed in the expression of CXCL16 receptor in the same liver sections. Elevated expression of tissue factor (TF) and fibrinogen was also observed in the liver sections of MCT/LPS co-treated mice. The in vitro results showed that incubation of HepG2 cells with CXCL16 antibody strongly diminished uptake of ox-LDL. Expression of ox-LDL, CXCL16, and TF represents an early event in the onset of hepatotoxicity induced by MCT/LPS; thus, it may contribute to our understanding of idiosyncratic liver injury and points to potential targets for protection or intervention.

Topics: Alanine Transaminase; Animals; Cell Culture Techniques; Chemical and Drug Induced Liver Injury; Chemokine CXCL16; Chemokine CXCL6; Chemokines, CXC; Collagen; Data Interpretation, Statistical; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Hep G2 Cells; Humans; Lipopolysaccharides; Lipoproteins, LDL; Liver; Male; Mice; Mice, Inbred Strains; Monocrotaline; Oxidation-Reduction; Receptors, Scavenger; Thromboplastin

Separation of concentrated bile acids from hepatic parenchymal cells is a key function of the bile duct epithelial cells (BDECs) that form intrahepatic bile ducts. Using coimmunostaining, we found that tissue factor (TF), the principal activator of coagulation, colocalized with cytokeratin 19, a marker of BDECs in the adult mouse liver. BDEC injury induced by xenobiotics such as alpha-naphthylisothiocyanate (ANIT) causes cholestasis, inflammation, and hepatocellular injury. We tested the hypothesis that acute ANIT-induced cholestatic hepatitis is associated with TF-dependent activation of coagulation and determined the role of TF in ANIT hepatotoxicity. Treatment of mice with ANIT (60 mg/kg) caused multifocal hepatic necrosis and significantly increased serum biomarkers of cholestasis and hepatic parenchymal cell injury. ANIT treatment also significantly increased liver TF expression and activity. ANIT-induced activation of the coagulation cascade was shown by increased plasma thrombin-antithrombin levels and significant deposition of fibrin within the necrotic foci. ANIT-induced coagulation and liver injury were reduced in low-TF mice, which express 1% of normal TF levels. The results indicate that ANIT-induced liver injury is accompanied by TF-dependent activation of the coagulation cascade and that TF contributes to the progression of injury during acute cholestatic hepatitis.

Topics: 1-Naphthylisothiocyanate; Animals; Blood Coagulation; Chemical and Drug Induced Liver Injury; Cholestasis; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Thromboplastin

This study examined dose-response relationships between activated recombinant factor VII (rFVIIa) and (1) in vivo haemostasis and (2) in vitro measures of coagulation and platelet function. Anesthetized swine were used. Ear bleeding time (BT) was measured and blood was sampled following increasing doses of rFVIIa (0, 90, 180, 360 and 720 microg/kg; n=6) or saline (n=6). BT was not altered by rFVIIa. Prothrombin time (PT) using standard or pig-specific methods was decreased by rFVIIa. Activated clotting time (ACT) was decreased by rFVIIa. Thromboelastography using collagen (COLL) or pig thromboplastin (p-ThP) as agonist demonstrated shorter reaction times, shortened time to reach maximum velocity of clot formation, and increased alpha-angle in the presence of rFVIIa. rFVIIa dosing increased maximum velocity of clot formation when p-ThP was used to initiate the reaction but not when COLL was used. rFVIIa at the highest concentration increased maximum amplitude when COLL was used to initiate the reaction. Platelet aggregation was not altered by rFVIIa. Following completion of the dose escalation phase, a severe liver injury was produced. rFVIIa altered neither blood loss nor survival time following injury but improved mean arterial pressure. A small increase in systemic thrombin-antithrombin III complex occurred after administration of rFVIIa at doses of 180 microg/kg and above. However, there was no histological evidence of intravascular coagulation after rFVIIa administration. In summary, rFVIIa activity was detectable in vitro but did not change haemostasis in normal swine.

Topics: Animals; Antithrombin III; Blood Coagulation; Blood Coagulation Tests; Blood Pressure; Chemical and Drug Induced Liver Injury; Collagen; Dose-Response Relationship, Drug; Factor VII; Factor VIIa; Hemostasis; Kinetics; Peptide Hydrolases; Platelet Activation; Platelet Function Tests; Recombinant Proteins; Swine; Thromboplastin

Topics: Adult; Aerosols; Alanine Transaminase; Alkaline Phosphatase; Blood Proteins; Chemical and Drug Induced Liver Injury; Creatine Kinase; Female; Heart Diseases; Humans; Isoenzymes; L-Lactate Dehydrogenase; Male; Metaproterenol; Middle Aged; Phenols; Thromboplastin

Topics: Adult; Biopsy; Chemical and Drug Induced Liver Injury; Chromium Isotopes; Environmental Exposure; Erythrocyte Aging; Erythrocytes; Female; Hematopoiesis; Humans; Jaundice; Male; Methods; Middle Aged; Occupational Diseases; Poisoning; Prothrombin Time; Reticulocytes; Thromboplastin; Trinitrotoluene

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Liver; Rabbits; 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