Brief Article
Copyright ©2009 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Nov 14, 2009; 15(42): 5307-5315
Published online Nov 14, 2009. doi: 10.3748/wjg.15.5307
Effects on coagulation factor production following primary hepatomitogen-induced direct hyperplasia
Kohei Tatsumi, Kazuo Ohashi, Sanae Taminishi, Soichi Takagi, Rie Utoh, Akira Yoshioka, Midori Shima, Teruo Okano
Kohei Tatsumi, Kazuo Ohashi, Soichi Takagi, Rie Utoh, Teruo Okano, Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
Kohei Tatsumi, Sanae Taminishi, Akira Yoshioka, Midori Shima, Department of Pediatrics, Nara Medical Univrsity, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Author contributions: Tatsumi K and Ohashi K designed the research; Tatsumi K, Ohashi K, Taminishi S, and Takagi S performed the experiments; Tatsumi K, Ohashi K, Takagi S, Utoh R, Yoshioka A, Shima M, and Okano T analyzed the data; Tatsumi K and Ohashi K wrote the paper.
Supported by Grants for AIDS Research from the Ministry of Health, Labor and Welfare of Japan (Shima M), Special Coordination Funds for Promoting Science and Technology (Ohashi K and Okano T) and Grant-in-Aid (Ohashi K, No. 21300180) from the Ministry of Education, Culture, Sports and Science and Technology (MEXT) of Japan (Ohashi K and Okano T), Novartis Foundation Japan (Ohashi K), and Bayer Hemophilia Award Program (Ohashi K)
Correspondence to: Kazuo Ohashi, MD, PhD, Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
Telephone: +81-3-33538111 Fax: +81-3-33596046
Received: June 3, 2009
Revised: August 28, 2009
Accepted: September 5, 2009
Published online: November 14, 2009

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 coagulation-related factors (fibrinogen, prothrombin, factors V, VII, VIII, IX, XI, XII, XIIIβ, plasminogen, antithrombin, protein C, ADAMTS13, VWF) were found to be down-regulated 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.

Keywords: Coagulation factor, 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene, Direct hyperplasia, Liver regeneration