Effects on coagulation factor production following primaryhepatomitogen-induced direct hyperplasia

Abstract

AIM:To investigate the molecular mechanisms involved in coagulation factor expression and/or function during direct hyperplasia (DH)-mediated liver regeneration. METHODS:Direct hyperplasia-mediated liver regeneration was induced in female C57BL/6 mice by administering 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), a representative hepatomitogen. Mice were weighed and sacrificed at various time points [Day 0 (D0: prior to injection), 3 h, D1, D2, D3, and D10] after TCPOBOP administration to obtain liver and blood samples. Using the RNA samples extracted from the liver, a comprehensive analysis was performed on the hepatic gene expression profiling of coagulation-related factors by real-time RT-PCR (fibrinogen, prothrombin, factors Ⅴ, Ⅶ, Ⅷ, Ⅸ, Ⅹ, Ⅺ, Ⅻ, XⅢβ, plasminogen, antithrombin, protein C, protein S, ADAMTS13, and VWF). The corresponding plasma levels of coagulation factors (fibrinogen, prothrombin, factors Ⅴ, Ⅶ, Ⅷ, Ⅸ, Ⅹ, Ⅺ, Ⅻ, XⅢ, and VWF) were also analyzed and compared with their mRNA levels. RESULTS:Gavage administration of TCPOBOP (3 mg/kg body weight) resulted in a marked and gradual increase in the weight of the mouse livers relative to the total body weight to 220% by D10 relative to the D0 (control) ratios. At the peak of liver regeneration (D1 and D2), the gene expression levels for most of the coagulationrelated factors (fibrinogen, prothrombin, factors Ⅴ, Ⅶ, Ⅷ, Ⅸ, Ⅺ, Ⅻ, XⅢβ, plasminogen, antithrombin, protein C, ADAMTS13, VWF) were found to be downregulated in a time-dependent manner, and gradually recovered by D10 to the basal levels. Only mRNA levels of factor Ⅹ and protein S failed to show any decrease during the regenerative phase. As for the plasma levels, 5 clotting factors (prothrombin, factors Ⅷ, Ⅸ, Ⅺ, and Ⅻ) demonstrated a significant decrease (P < 0.05) during the regeneration phase compared with D0. Among these 5 factors, factor Ⅸ and factor Ⅺ showed the most dramatic decline in their activities by about 50% at D2 compared to the basal levels, and these reductions in plasma activity for both factors were consistent with our RT-PCR findings. In contrast, the plasma activities of the other coagulation factors (fibrinogen, factors Ⅴ, Ⅶ, XⅢ, and VWF) were not significantly reduced, despite the reduction in the liver mRNA levels. Unlike the other factors, FX showed a temporal increase in its plasma activity, with significant increases (P < 0.05) detected at D1. CONCLUSION:Investigating the coagulation cascade protein profiles during liver regeneration by DH may help to better understand the basic biology of the liver under normal and pathological conditions.

Liver gene regulation of hemostasis-related factors is altered by experimental snake envenomation in mice

“…Differently from the early pattern of F3 gene expression during envenomation, gene expression of Adamts13, Serpinc1 and Proc decreased, whilst that of F10 increased at a later period of envenomation (24 h). Similar results were reported in an experimental model of direct liver hyperplasia and were associated to liver regeneration [77]. This may suggest that the impairment of anticoagulants during envenomation may be aggravated by the decrease in their hepatic synthesis.…”

Human Hepatocyte Propagation System in the Mouse Livers: Functional Maintenance of the Production of Coagulation and Anticoagulation Factors

“…An alternative possibility is that nonparenchymal cells, but hepatocytes, are the main responsive cells for human factor VIII productions. Although the liver has been shown to be the major site of factor VIII production as evidenced by previous liver transplantation clinical experiences (10,13,33), the precise type of liver cells contributing to factor VIII production has not been fully identified (4,6,8,16). In either the case, the present in-mouse hepatocyte propagation system using uPA/SCID mouse might be a valuable tool for the elucidation of cellular mechanism of factor VIII synthesis and production.…”

“…Production of coagulation and anticoagulation factors is one of the important functions of the liver, and most of these coagulation-related factors are produced by hepatocytes (4,6,30,31,33). There are various types of congenital bleeding disorders that lack a production of coagulation factor in the liver, showing a symptomatic bleeding tendency.…”

Adverse Outcome Pathways for Regulatory Applications: Examination of Four Case Studies With Different Degrees of Completeness and Scientific Confidence

“…Tissue factor, a transmembrane glycoprotein, is involved in activating the coagulation cascade and is expressed by tumor cells promoting growth and metastasis (Kasthuri et al, 2009). Tatsumi et al (2009) found decreases in prothrombin and coagulation factors during direct hyperplasia in mice induced by 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene and coagulation disorders associated with cancer are well documented (Falanga et al, 2103;Kvolik et al, 2010).…”