fibrin and Hepatitis--Viral--Human

Fulminant viral hepatitis (FVH) is a life-threatening disease, but its pathogenesis is not fully understood. Neutrophil extracellular traps (NETs) were an unrecognized link between inflammation and coagulation, which are 2 main features of FVH. Here, we investigated the role and mechanism of NETs in the pathogenesis of FVH.. A mouse model of FVH was established by murine hepatitis virus strain-3 infection. Liver leukocytes of infected or uninfected mice were used for single-cell RNA sequencing and whole-transcriptome sequencing. NETs depletion was achieved using DNase 1. Acetaminophen was used to establish a mouse model of non-virus-caused acute liver failure. Clinically, NETs-related markers in liver, plasma, and peripheral neutrophils were assessed in patients with hepatitis B virus (HBV)-related acute liver injury.. Increased hepatic NETs formation was observed in murine hepatitis virus strain-3-infected mice, but not in acetaminophen-treated mice. NETs depletion improved the liver damage and survival rate in FVH by inhibiting hepatic fibrin deposition and inflammation. An adoptive transfer experiment showed that neutrophil-specific fibrinogen-like protein 2 (FGL2) promoted NETs formation. FGL2 was found to directly interact with mucolipin 3, which regulated calcium influx and initiated autophagy, leading to NETs formation. Clinically, increased plasma NETs level was associated with coagulation dysfunction in patients with HBV acute liver injury. Colocalization of FGL2, NETs, and fibrin in liver was observed in these patients.. NETs aggravated liver injury in FVH by promoting fibrin deposition and inflammation. NETs formation was regulated by the FGL2-mucolipin 3-autophagy axis. Targeting NETs may provide a new strategy for the treatment of FVH.

Topics: Acetaminophen; Animals; Autophagy; Calcium; Deoxyribonucleases; Disease Models, Animal; Extracellular Traps; Fibrin; Fibrinogen; Hepatitis, Viral, Animal; Hepatitis, Viral, Human; Inflammation; Mice; Mice, Inbred BALB C; Murine hepatitis virus

Topics: Extracellular Traps; Fibrin; Hepatitis, Viral, Human; Humans; Inflammation

In the present studies, we report the cloning and structural characterization of the HFGL2 gene and its functional role in human fulminant hepatitis. The HFGL2 gene is approximately 7 kb in length with 2 exons. The putative promoter contains cis element consensus sequences that strongly suggest the inducibility of its expression. From the nucleotide sequence of the human gene, a 439-amino acid long protein is predicted. The overall identity between the murine fgl2 and hfgl2 coded proteins is over 70%. About 225 amino acids at the carboxyl end of these molecules are almost 90% identical, and correspond to a well-conserved fibrinogen-related domain. Both HFGL2 and FGL2 encode a type II transmembrane protein with a predicted catalytic domain toward the amino terminus of the protein. Transient transfection of Chinese hamster ovary (CHO) cells with a full-length cDNA of HFGL2 coding region resulted in high levels of prothrombinase activity. Livers from 8 patients transplanted for fulminant viral hepatitis were examined for extent of necrosis, inflammation, fibrin deposition, and HFGL2 induction. In situ hybridization showed positive staining of macrophages in areas of active hepatocellular necrosis. Fibrin stained positively in these areas and was confirmed by electron microscopy. These studies define a unique prothrombinase gene (HFGL2) and implicate its importance in the pathogenesis of fulminant viral hepatitis.

Topics: Adolescent; Adult; Amino Acid Sequence; Animals; Child, Preschool; CHO Cells; Cloning, Molecular; Consensus Sequence; Cricetinae; Female; Fibrin; Fibrinogen; Hepatitis, Viral, Human; Humans; Infant; Liver; Male; Middle Aged; Molecular Sequence Data; Necrosis; Promoter Regions, Genetic; Thromboplastin; Transfection

To evaluate the nature of accelerated fibrinolysis in hepatosplenic schistosomiasis.. The biological activity of plasminogen (Plg), plasminogen activators (PA), alpha 2-antiplasmin (alpha 2-AP) and plasminogen activator inhibitor-1 (PAI-1) was determined by photometric analysis in 15 compensated and 35 decompensated patients with endemic Egyptian hepatosplenomegaly. Quantitative measurement of plasma concentrations of tissue t-PA, t-PA-PAI-1 complex, alpha 2-antiplasmin-plasmin complex (alpha 2-APP), fibrinogen degradation products (FbDP), D-dimers (D-D), thrombin-antithrombin complex (TAT) and prothrombin fragment (F 1 + 2) complexes, using double antibody sandwich enzyme linked immunosorbent assays and grading of the degree of hepatic insufficiency according to the Child-Pugh classification, were also carried out.. The progressive deterioration of liver function in schistosomal patients, which matched the severity of the disease, led to simultaneous defects in profibrinolytic (decreased Plg and increased PA and t-PA) and antifibrinolytic (decreased alpha 2-AP and PAI-1) factors-the latter defects being the most prominent-resulting in significant generation of plasmin (increased APP complexes) and therefore enhanced fibrinolysis (increased FbDP and D-dimer). The raised concentrations of FbDP, D-D, TAT and F 1 + 2 established its secondary nature.. These findings suggest that the amount of PAI-1 available to bind and neutralise circulating t-PA may be a critical factor in the progress of hyperfibrinolysis observed in hepatosplenic schistosomiasis, and that the pronounced reduction in its plasma concentration may be regarded as a potential warning indicator of haemostatic imbalance in decompensated schistosomal patients at high risk of variceal bleeding.

Topics: Adolescent; Adult; Ascites; Female; Fibrin; Fibrinolysin; Fibrinolysis; Hematemesis; Hepatitis, Viral, Human; Humans; Liver Diseases, Parasitic; Male; Middle Aged; Plasminogen; Schistosomiasis mansoni; Severity of Illness Index

Abnormalities of fibrin formation were studied in 42 young adult patients with benign viral hepatitis. It was observed that there was a constant increase in thrombin time and reptilase time, evoking an abnormality of the second stage of fibrin formation, or the aggregation of fibrin monomers. This abnormality is not associated with the presence of inhibitors in the patients' serums, and is maximum at an alkaline pH. The hypothesis of an abnormality of the fibrinogen molecule, a dysfibrinogenemia, is the most likely cause, and this has to be confirmed by biochemical and immunochemical studies.

Topics: Adolescent; Adult; Blood Coagulation Disorders; Blood Coagulation Tests; Fibrin; Hepatitis, Viral, Human; Humans; Thrombin

A case is described in which a patient developed TT prolongation and bleeding during CMV hepatitis following successful renal transplantation. Bence-Jones proteinuria was noted, but there was no other evidence of myeloma. Bence-Jones proteinuria, TT prolongation, and bleeding abated as hepatitis resolved. In vitro, a protein isolated from the patient's urine was capable of prolonging the TT markedly, but it did not impair thrombin esterase activity. The effect of the protein seemed to be inhibition of fibrin polymerization. Sephadex gel filtration revealed a single TT-prolonging peak at 11,000 daltons, containing kappa, lambda, and delta antigens. By radioimmunoassay, virtually all the protein present reacted as beta2-microglobulin. Incubation with anti-beta2-microglobulin antiserum markedly attenuated anticoagulant activity. The paraprotein observed transiently in this patient's urine during hepatitis had potent anticoagulant activity and may well have accounted for his abnormal TT and bleeding diathesis; this paraprotein was not distinguishable from beta2-microglobulin.

Topics: Adult; Bence Jones Protein; beta 2-Microglobulin; Blood Coagulation; Blood Coagulation Tests; Cytomegalovirus; Fibrin; Hepatitis, Viral, Human; Humans; Male; Thrombin

Topics: Adolescent; Adult; Blood Coagulation Disorders; Fibrin; Fibrinogen; Hepatitis, Viral, Human; Humans