Involvement of ADAMTS 13 in liver failure after hepatectomy and establishment of novel liver failure treatment strategy

• Project/Area Number: 16K10580
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Nara Medical University
• Principal Investigator: Nomi Takeo 奈良県立医科大学, 医学部, 学内講師 (50570991)
• Co-Investigator(Kenkyū-buntansha): 松本 雅則 奈良県立医科大学, 医学部, 教授 (60316081)
• Research Collaborator: Obara Shinsaku
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ADAMTS13 / vWFマルチマー / 肝不全 / 虚血再灌流障害 / 肝切除 / Pringle法 / VWF抗原量 / UL-VWFマルチマー / UL-VWFマルチマー発現 / von Willebrand factor

Outline of Final Research Achievements

This study aimed to clarify the effect of hepatectomy on UL-VWFMs. Thirty-five patients who underwent hepatectomy were eligible for the study. Multimer analysis of plasma VWF was performed. For analyses, patients were categorized according to UL-VWFM positivity after hepatectomy. The UL-VWFMs indices were significantly increased from 0.2% (0.0%-7.8%) before the operation to 4.2% (0.1%-16.3%)on postoperative day seven after the operation (p < 0.001).Seven patients remained UL-VWFMs-negative and 22 patients became UL-VWFMs-positive after operation. By multivariable analysis, Pringle’s maneuver duration was significantly associated with increased UL-VWFMs level after hepatectomy(p = 0.043). UL-VWFMs index was significantly correlated with Pringle’s maneuver duration (r = 0.444, p = 0.017). In conclusion, Plasma UL-VWFMs levels increased after hepatectomy due to ischemia-reperfusion injury with Pringle’s maneuver.

Academic Significance and Societal Importance of the Research Achievements

これまでADAMTS13, vWF, VWFマルチマーと肝切除及びPringe法との関連に着目した検討は，国内外において報告がない.本研究により，UL-VWFマルチマーと術中Pringle法による虚血再灌流障害の関連が明らかにされたことで，今後，肝切除後肝不全に対する新たな治療戦略となり得る可能性が示唆される．さらに研究がすすめば，効率的な肝切除後肝不全治療戦略となる可能性がある．ADAMTS13関連因子は病的血栓との関連から心筋梗塞や脳梗塞の治療薬としての可能性も示されており，肝臓のみならず他臓器疾患への波及効果が期待される．

Research Products

• [Journal Article] Involvement of the ADAMTS13-VWF axis in acute Kawasaki disease and effects of intravenous immunoglobulin (2019)
  • Author(s): Tsujii Nobuyuki、Nogami Keiji、Matsumoto Masanori、Yoshizawa Hiroyuki、Takase Toshio、Tanaka Ichiro、Sakai Toshiyuki、Fukuda Kazuyoshi、Hayakawa Masaki、Sakai Kazuya、Isonishi Ayami、Matsuura Kayoko、Fujimura Yoshihiro、Shima Midori
  • Journal Title: Thrombosis Research Volume: 179 Pages: 1-10
  • DOI: 10.1016/j.thromres.2019.04.026
  • Peer Reviewed
• [Journal Article] Upshaw-Schulman syndrome diagnosed during pregnancy complicated by reversible cerebral vasoconstriction syndrome (2018)
  • Author(s): Mariko Tsuda, Motoaki Shiratsuchi, Motohiko Ikeda, Masanori Matsumoto, Yoshihiro Fujimura, Koichi Kokame, Takamitsu Matsushima, Yasuhiro Nakashima, Yoshihiro Ogawa
  • Journal Title: Transfusion and Apheresis Science Volume: 57 Issue: 6 Pages: 790-792
  • DOI: 10.1016/j.transci.2018.10.023
  • Peer Reviewed
• [Journal Article] von Willebrand factor is a useful biomarker for liver fibrosis and prediction of hepatocellular carcinoma development in patients with hepatitis B and C. (2018)
  • Author(s): Takaya H, Kawaratani H, Tsuji Y, Nakanishi K, Saikawa S, Sato S, Sawada Y, Kaji K, Okura Y, Shimozato N, Kitade M, Akahane T, Moriya K, Namisaki T, Mitoro A, Matsumoto M, Fukui H, Yoshiji H
  • Journal Title: United European Gastroenterol J. Volume: 6 Issue: 9 Pages: 1401-1409
  • DOI: 10.1177/2050640618779660
  • Peer Reviewed
• [Journal Article] Complement activation associated with ADAMTS13 deficiency may contribute to the characteristic glomerular manifestations in Upshaw-Schulman syndrome (2018)
  • Author(s): Itami Hiroe、Hara Shigeo、Matsumoto Masanori、Imamura Shin、Kanai Rie、Nishiyama Kei、Ishimura Masataka、Ohga Shouichi、Yoshida Makiko、Tanaka Ryojiro、Ogawa Yoshiyuki、Asada Yujiro、Sekita-Hatakeyama Yoko、Hatakeyama Kinta、Ohbayashi Chiho
  • Journal Title: Thrombosis Research Volume: 170 Pages: 148-155
  • DOI: 10.1016/j.thromres.2018.08.020
  • Peer Reviewed
• [Journal Article] Intravitreal injection of aflibercept, an anti-VEGF antagonist, down-regulates plasma von Willebrand factor in patients with age-related macular degeneration (2018)
  • Author(s): Yamashita Mariko、Matsumoto Masanori、Hayakawa Masaki、Sakai Kazuya、Fujimura Yoshihiro、Ogata Nahoko
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1491-1491
  • DOI: 10.1038/s41598-018-19473-0
  • Peer Reviewed
• [Journal Article] Differences and similarities between disseminated intravascular coagulation and thrombotic microangiopathy (2018)
  • Author(s): Wada H, Matsumoto T, Suzuki K, Imai H, Katayama N, Iba T, Matsumoto M
  • Journal Title: Thromb J Volume: 16 Issue: 1 Pages: 14-14
  • DOI: 10.1186/s12959-018-0168-2
  • Peer Reviewed / Open Access
• [Presentation] Pringle法に伴う虚血再灌流障害はUnusually Large Von Willebrand Factor Multimersを誘導する (2018)
  • Author(s): 吉川高宏，野見武男
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] 移植後TMAの病態と治療 (2018)
  • Author(s): 松本雅則
  • Organizer: 第75回日本血液学会学術集会
• [Presentation] 科学的根拠に基づいた血液製剤の適正使用 (2018)
  • Author(s): 松本雅則
  • Organizer: 日本臨床麻酔学会第38回大会
• [Presentation] Pringle法に伴う虚血再灌流傷害はunusually large Von Willebrand Factor multimersを誘導する (2018)
  • Author(s): 吉川高宏，野見武男，庄雅之
  • Organizer: 第118回日本外科学会
• [Presentation] Ischemia-reperfusion injury with Pringle’s maneuver induces increasing of unusually large von Willebrand factor multimers after hepatectomy (2017)
  • Author(s): Takahiro Yoshikawa, Takeo Nomi, Masayuki Sho, Masanori Matsumoto
  • Organizer: 第59回米国血液学会
  • Int'l Joint Research