Elucidation of mechanisms under prothrombotic state with aging

• Project/Area Number: 24591421
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Saitama Medical University (2015); Nagoya University (2012-2014)
• Principal Investigator: Yamamoto Koji 埼玉医科大学, 医学部, 教授 (90362251)
• Co-Investigator(Kenkyū-buntansha): KOJIMA Tetsuhito 名古屋大学, 医学部, 教授 (40161913)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 血栓症 / 老化 / ストレス / 炎症 / サイトカイン / 線溶 / 脂肪細胞 / PAI-1 / 突然死 / 血管内皮細胞 / 心筋細胞 / 血栓 / 菌体毒素 / 腎糸球体 / 交感神経 / 神経細胞 / 敗血症

Outline of Final Research Achievements

Elevated expression of plasminogen activator inhibitor-1 (PAI-1), a key molecule in developing thrombosis, was demonstrated in plasma and several tissues of a murine model of aging, e.g., 12-month-old or 24-month-old mice and klotho mutant (kl/kl) mice, in comparison with young mice. Renal glomerular fibrin deposition was also detected in aged mice and klotho mice, suggesting that aged mice are hypercoagulable due to the high expression of PAI-1. Endotoxin challenge and restraint stress induced PAI-1 gene expression together with renal fibrin deposition in a murine model of aging. High expression of PAI-1 mRNA corresponded to vascular endothelium and smooth muscle cells, hepatocytes, renal tubular epithelial cells, adrenomedullar cells, cardiomyocytes, and adipose cells in aged mice in respons to those stimuli. Thus, aged animals may be hyperresponsive to prothrombotic stimuli through the higher induction of PAI-1 gene compared to young counterparts.

Research Products

• [Journal Article] Long acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: Results of a phase 3 trial. (2016)
  • Author(s): Santagostino E, Martinowitz U, Lissitchkov T, Pan-Petesch B, Hanabusa H, Oldenburg J, Boggio L, Negrier C, Pabinger I, von Depka-Prondzinski M, Altisent C, Castaman G, Yamamoto K, Álvarez-Román M-T, Voigt C, Blackman N, Jacobs I, for the PROLONG-9FP Investigators Study Group.
  • Journal Title: Blood Volume: in press Issue: 14 Pages: 1761-1769
  • DOI: 10.1182/blood-2015-09-669234
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Functional Difference between Membrane-Bound and Soluble Human Thrombomodulin. (2015)
  • Author(s): Miwa Y, Yazaki S, Iwamoto M, Suzuki S, Iwasaki K, Haneda M, Yamamoto K, Maruyama S, Onishi A, Kobayashi T.
  • Journal Title: Transplantation Volume: 99 Issue: 4 Pages: 702-709
  • DOI: 10.1097/tp.0000000000000571
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Accelerated activation of the coagulation pathway during cardiopulmonary bypass in aortic replacement surgery: a prospective observational study. (2015)
  • Author(s): Sato H, Yamamoto K, Kakinuma A, Nakata Y, Sawamura S.
  • Journal Title: Journal of Cardiothoracic Surgery Volume: 10 Issue: 1 Pages: 84-84
  • DOI: 10.1186/s13019-015-0295-9
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 加齢と血栓傾向． (2015)
  • Author(s): 山本晃士
  • Journal Title: 日本血栓止血学会誌 Volume: 26 Pages: 265-271
  • NAID: 130005078051
  • Peer Reviewed
• [Journal Article] 日本輸血・細胞治療学会による学会認定・アフェレーシスナース制度の導入． (2015)
  • Author(s): 池田和眞、井関徹、奥山美樹、山本晃士、金森平和、松﨑浩史、室井一男、大戸斉
  • Journal Title: 日本輸血細胞治療学会誌 Volume: 61 Pages: 567-570
  • NAID: 130005125959
  • Peer Reviewed
• [Journal Article] SVA retrotransposition in exon 6 of the coagulation factor IX gene causing severe hemophilia B. (2015)
  • Author(s): Nakamura Y, Murata M, Takagi Y, Kozuka T, Nakata Y, Hasebe R, Takagi A, Kitazawa JI, Shima M, Kojima T.
  • Journal Title: Int J Hematol Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Increased SPHK2 transcription of human colon cancer cells in serum-depleted culture: the involvement of CREB transcription factor. (2015)
  • Author(s): Mizutani N, Omori Y, Tanaka K, Ito H, Takagi A, Kojima T, Nakatochi M, Ogiso H, Kawamoto Y, Nakamura M, Suzuki M, Kyogashima M, Koizumi K, Nozawa Y, Murate T.
  • Journal Title: J Cell Biochem Volume: 116 Issue: 10 Pages: 2227-2238
  • DOI: 10.1002/jcb.25173
  • Peer Reviewed
• [Journal Article] A complex genomic abnormality found in a patient with antithrombin deficiency and autoimmune disease-like symptoms. (2014)
  • Author(s): Kato I, Takagi Y, Ando Y, Nakamura Y, Murata M, Takagi A, Murate T, Matsushita T, Nakashima T, Kojima T.
  • Journal Title: Int J Hematol Volume: 100 Issue: 2 Pages: 200-205
  • DOI: 10.1007/s12185-014-1596-9
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Antithrombin- resistant prothrombin Yukuhashi mutation also causes thrombomodulin resistance in fibrinogen clotting but not in protein C activation. (2014)
  • Author(s): Takagi Y, Kato I, Ando Y, NakamuraY, Murata M, Takagi A, Murate T, Kojima T
  • Journal Title: Thromb Res. Volume: 134 Issue: 4 Pages: 914-917
  • DOI: 10.1016/j.thromres.2014.07.040
  • Peer Reviewed
• [Journal Article] Fibrinogen concentrate administration attributes to significant reductions of blood loss and transfusion requirements in thoracic aneurysm repair. (2014)
  • Author(s): Yamamoto K, Usui A, Takamatsu J.
  • Journal Title: J Cardiovasc Surg Volume: 9 Issue: 1 Pages: 90-90
  • DOI: 10.1186/1749-8090-9-90
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Angiotensin II receptor blocker ameliorates stress-induced adipose tissue inflammation and insulin resistance. (2014)
  • Author(s): Hayashi M, Takeshita K, Uchida Y, Yamamoto K, Kikuchi R, Nakayama T, Nomura E, Cheng XW, Matsushita T, Nakamura S, Murohara T.
  • Journal Title: PLoS One Volume: 9 Issue: 12 Pages: e116163-e116163
  • DOI: 10.1371/journal.pone.0116163
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Rhof promotes murine marginal zone B cell development. (2014)
  • Author(s): Kishimoto M, Matsuda T, Yanase S, Katsumi A, Suzuki N, Ikejiri M, Takagi A, Ikawa M, Kojima T, Kunishima S, Kiyoi H, Naoe T, Matsushita T, Maruyama M.
  • Journal Title: Nagoya J Med Sci Volume: 76 Pages: 293-305
  • NAID: 120005468127
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] High prophylactic LMWH dose successfully suppressed hemostatic activation in pregnant woman with a new prpthrombin c.1787G>A mutation. (2014)
  • Author(s): Kovac M, Elezovic I, Mikovic V, Djordjevic V, Radojkovic D, Lalic-Cosic S, Murata M, Takagi A, Kojima T
  • Journal Title: Thromb Res. Volume: 135 Issue: 2 Pages: 420-422
  • DOI: 10.1016/j.thromres.2014.12.008
  • Peer Reviewed
• [Journal Article] Development of a new laboratory test to evaluate antithrombin resistance in plasma. (2014)
  • Author(s): Murata M, Takagi A, Suzuki A, Okuyama E, Takagi Y, Ando Y, Kato I, Nakamura Y, Murate T, Matsushita T, Saito H, Kojima T.
  • Journal Title: Thromb Res Volume: 133 Issue: 2 Pages: 293-298
  • DOI: 10.1016/j.thromres.2013.11.021
  • Peer Reviewed
• [Journal Article] Recovery of flow-mediated vasodilatation after repetitive measurements is involved in early vascular impairment: comparison with indices of vascular tone. (2014)
  • Author(s): Inaba H, Takeshita K, Uchida Y, Hayashi M, Okumura T, Hirashiki A, Yoshikawa D, Ishii H, Yamamoto K, Nakayama T, Hirayama M, Matsumoto H, Matsushita T, Murohara T
  • Journal Title: PLOS one Volume: 9(1) Issue: 1 Pages: 1-9
  • DOI: 10.1371/journal.pone.0083977
  • Peer Reviewed / Open Access
• [Journal Article] Sphingosine kinase 1 expression is downregulated during differentiation of Friend cells due to decreased c-MYB. (2013)
  • Author(s): Mizutani N, Kobayashi M, Sobue S, Ichihara M, Ito H, Tanaka K, Iwaki S,Fujii S,Ito Y, Tamiya-Koizumi K, Takagi A, Kojima T, Naoe T, Suzuki M, Nakamura M, Banno Y, Nozawa Y, Murate T.
  • Journal Title: Biochimica et Biophysica Acta -Molecular Cell Research Volume: 1833 Issue: 5 Pages: 1006-16
  • DOI: 10.1016/j.bbamcr.2013.01.001
  • Peer Reviewed
• [Journal Article] Molecular mechanisms of syndecan-4 upregulation by TNF-α in the endothelium-like EAhy926 cells. (2013)
  • Author(s): Okuyama E, Suzuki A, Murata M, Ando Y, Kato I, Takagi Y, Takagi A, Murate T, Saito H, Kojima T.
  • Journal Title: J Biochem Volume: 154 Issue: 1 Pages: 41-50
  • DOI: 10.1093/jb/mvt024
  • Peer Reviewed
• [Journal Article] A novel prothrombin mutation in two families with prominent thrombophilia--the first cases of antithrombin resistance in a Caucasian population. (2013)
  • Author(s): Djordjevic V, Kovac M, Miljic P, Murata M, Takagi A, Pruner I, Francuski D, Kojima T, Radojkovic D.
  • Journal Title: J Thromb Haemost Volume: 11 Issue: 10 Pages: 1936-1939
  • DOI: 10.1111/jth.12367
  • Peer Reviewed
• [Journal Article] Establishment of mouse model of MYH9 disorders: heterozygous R702C mutation provokes macrothrombocytopenia with leukocyte inclusion bodies, renal glomerulosclerosis and hearing disability. (2013)
  • Author(s): Suzuki N, Kunishima S, Ikejiri M, Maruyama S, Sone M, Takagi A, Ikawa M, Okabe M, Kojima T, Saito H, Naoe T, Matsushita T.
  • Journal Title: PLoS One Volume: 8 Issue: 8 Pages: 41-50
  • DOI: 10.1371/journal.pone.0071187
  • NAID: 120006957397
  • Peer Reviewed
• [Journal Article] フィブリノゲン製剤等の適正使用に対する提言についての意見． (2013)
  • Author(s): 山本晃士
  • Journal Title: 日本輸血・細胞治療学会誌 Volume: 59 Pages: 752-753
  • Peer Reviewed
• [Journal Article] Comparison of the efficacy of ribavirin plus peginterferon alfa-2b for chronic hepatitis C infection in patients with and without coagulation disorders. (2013)
  • Author(s): Honda T, Katano Y, Kuzuya T, Hayashi K, Ishigami M, Itoh A, Hirooka Y, Nakano I, Ishikawa T, Toyoda H, Kumada T, Yamamoto K, Matsushita T, Kojima T, Takamatsu J, Goto H
  • Journal Title: J Med Virol. Volume: 85(2) Issue: 2 Pages: 228-234
  • DOI: 10.1002/jmv.23444
  • Peer Reviewed
• [Journal Article] Production of cloned pigs expressing human thrombomodulin in endothelial cells (2012)
  • Author(s): Yazaki S, Iwamoto M, Onishi A, Miwa Y, Hashimoto M, Oishi T, Suzuki S, Fuchimoto D, Sembon S, Furusawa T, Liu D, Nagasaka T, Kuzuya T, Ogawa H, Yamamoto K, Iwasaki K, Haneda M, Maruyama S, Kobayashi T.
  • Journal Title: Xenotransplantation Volume: 19 Issue: 2 Pages: 82-91
  • DOI: 10.1111/j.1399-3089.2012.00696.x
  • Peer Reviewed
• [Journal Article] Stress Augments Insulin Resistance and Prothrombotic State : Role of Visceral Adipose-Derived Monocyte Chemoattractant Protein-1 (2012)
  • Author(s): Uchida Y
  • Journal Title: Diabetes Volume: (In press) Issue: 6 Pages: 1552-61
  • DOI: 10.2337/db11-0828
  • Peer Reviewed
• [Journal Article] 生体肝移植レシピエント術中の凝固系管理～輸血量を減らす工夫～． (2012)
  • Author(s): 山本晃士
  • Journal Title: Thrombosis Medicine Volume: 2 Pages: 13-19
• [Journal Article] 産科大量出血の病態と輸血治療． (2012)
  • Author(s): 山本晃士
  • Journal Title: 日本輸血・細胞治療学会誌 Volume: 58 Pages: 745-752
  • NAID: 10031147621
  • Peer Reviewed
• [Presentation] 貯血式自己血における前置・低位胎盤症例の最適な自己血貯血量． (2016)
  • Author(s): 酒井あゆみ、松永茂剛、舘 明子、阿南昌弘、江良澄子、小野義久、髙井 泰、斉藤正博、山本晃士、関 博之、前田平生
  • Organizer: 第29回日本自己血輸血学会学術総会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2016-03-11
• [Presentation] 産科DICによる大量出血の病態と止血治療． (2015)
  • Author(s): 山本晃士
  • Organizer: 第119回日本産科麻酔学会学術集会
  • Place of Presentation: 都市センターホテル（東京都千代田区）
  • Year and Date: 2015-11-28
  • Invited
• [Presentation] Accelerated activation of the coagulation pathway during cardiopulmonary bypass in aortic replacement surgery: a suggested hemostatic therapy for critical intraoperative coagulopathy. (2015)
  • Author(s): Yamamoto K
  • Organizer: Pioneer Century Science World Congress of Cardiothoracic-Renal Disease-2015
  • Place of Presentation: ワルシャワ（ポーランド）
  • Year and Date: 2015-10-30
  • Int'l Joint Research
• [Presentation] Qualified apheresis nurse certification by the Japan Society of Transfusion Medicine and Cell Therapy to promote safety and efficiency in apheresis through encouraging learning. (2015)
  • Author(s): Ikeda K, Iseki T, Yamamoto K, Okuyama Y, Kanamori H, Matsuzaki K, Muroi K, Ohto H.
  • Organizer: The 25th Regional Congress of the International Society of Blood Transfusion
  • Place of Presentation: ロンドン（イギリス）
  • Year and Date: 2015-06-27
  • Int'l Joint Research
• [Presentation] Efficacy and safety results of a phase III pivotal clinical study of recombinant fusion protein linking coagulation factor IX with albumin (RIX-FP) in previously treated patients with hemophilia B. (2015)
  • Author(s): Santagostino E, Martinowitz U, Lissitchkov T, Pan-Petesch B, Hanabusa H, Oldenburg J, Boggio L, Negrier C, Pabinger-Fasching I, von Depka-Prondzinski M, Altisent C, Castaman G, Yamamoto K, Román MA, Voigt C, Jacobs I, PROLONG-9FP Investigators.
  • Organizer: XXV Congress, International Society of Thrombosis and Haemostasis
  • Place of Presentation: トロント（カナダ）
  • Year and Date: 2015-06-20
  • Int'l Joint Research
• [Presentation] 外科領域の止血不全における線溶亢進と第XIII因子の重要性． (2015)
  • Author(s): 山本晃士
  • Organizer: 第9回日本血栓止血学会SSCシンポジウム
  • Place of Presentation: 野村コンファレンスプラザ日本橋（東京都中央区）
  • Year and Date: 2015-02-28
• [Presentation] 大量出血時の止血検査と輸血療法． (2014)
  • Author(s): 山本晃士
  • Organizer: 第21回日本輸血・細胞治療学会秋季シンポジウム
  • Place of Presentation: ひめぎんホール（愛媛県松山市）
  • Year and Date: 2014-10-18
  • Invited
• [Presentation] Irbesartan ameliorates stress-induced prothrombotic state. (2014)
  • Author(s): Takeshita K, Yamamoto K, Hayashi M, Matsushita T, Murohara T.
  • Organizer: 22th International Congress of Fibrinolysis and Proteolysis
  • Place of Presentation: マルセイユ（フランス）
  • Year and Date: 2014-07-06 – 2014-07-09
• [Presentation] 術中大量出血におけるフィブリノゲンの重要性． (2014)
  • Author(s): 山本晃士
  • Organizer: 第37回日本血栓止血学会総会シンポジウム
  • Place of Presentation: 大阪国際交流センター（大阪府大阪市）
  • Year and Date: 2014-05-29 – 2014-05-31
  • Invited
• [Presentation] 心臓血管外科手術中に起こるDICの病因と病態－実症例における解析－． (2014)
  • Author(s): 山本晃士、佐藤秀雄、澤村成史
  • Organizer: 第37回日本血栓止血学会総会
  • Place of Presentation: 大阪国際交流センター（大阪府大阪市）
  • Year and Date: 2014-05-29 – 2014-05-31
• [Presentation] 胸部大動脈瘤手術中におけるトロンビン／フィブリン生成とフィブリノゲン値への影響－弁置換術症例との比較－． (2014)
  • Author(s): 山本晃士、佐藤秀雄、澤村成史
  • Organizer: 第62回日本輸血・細胞治療学会総会
  • Place of Presentation: 奈良県新公会堂（奈良県奈良市）
  • Year and Date: 2014-05-15 – 2014-05-17
• [Presentation] 新鮮凍結血漿の使用指針を見直す． (2014)
  • Author(s): 山本晃士
  • Organizer: 第62回日本輸血・細胞治療学会総会シンポジウム
  • Place of Presentation: 奈良県新公会堂（奈良県奈良市）
  • Year and Date: 2014-05-05 – 2014-05-17
  • Invited
• [Presentation] 大量出血におけるクリオプレシピテートおよびフィブリノゲン製剤の投与効果． (2013)
  • Author(s): 山本晃士
  • Organizer: 第61回日本輸血・細胞治療学会総会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Invited
• [Presentation] 重症患者に対するアルブミン製剤投与の医学的意義． (2012)
  • Author(s): 山本晃士
  • Organizer: 第38回日本熱傷学会総会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Invited
• [Presentation] 産科大量出血の病態と輸血治療． (2012)
  • Author(s): 山本晃士
  • Organizer: 第48回日本周産期・新生児医学会
  • Place of Presentation: 大宮ソニックシティ（埼玉県さいたま市）
  • Invited
• [Presentation] 大量出血時におけるフィブリノゲン製剤の適応と効果．
  • Author(s): 山本晃士
  • Organizer: 第20回日本輸血・細胞治療学会秋季シンポジウム
  • Place of Presentation: 札幌コンベンションセンター（札幌市）
  • Invited
• [Book] 新・血栓止血血管学 (2015)
  • Author(s): 山本晃士
  • Total Pages: 251
  • Publisher: 金芳堂
• [Book] 血液専門医テキスト改訂第２版 (2015)
  • Author(s): 山本晃士
  • Total Pages: 584
  • Publisher: 南江堂
• [Book] 別冊日本臨床 血液症候群（第２版）III－その他の血液疾患を含めて－「先天性プロテインＣ欠乏症・異常症」 (2013)
  • Author(s): 山本晃士、辻肇、鈴木宏冶、高木夕希、岡本貴行、高橋幸博、一瀬白帝、尾崎司、大山陽子、平瀬主税、田中宏和、井山諭、平山泰生、亀田拓郎、久冨木庸子、北中明、高松泰、小松則夫、田中淳司、佐藤勉、他
  • Total Pages: 767
  • Publisher: 日本臨床社
• [Book] 基本薬の選び方と使い方のコツ「貧血治療薬（鉄剤）」 (2013)
  • Author(s): 山本晃士、大花正也、水野成人、羽白高、田中清、加藤徹、野出孝一、辻井悟、石井均、平塚いづみ、山田祐一郎、鳥居洋太、入谷修司、尾崎紀夫、小林孝文、中村道三、阪口正和、青山武、増山理、横田良司、他
  • Total Pages: 342
  • Publisher: 文光堂