Development of new examination methods for thrombotic tendency with TM resistance and FXa AT resistance

• Project/Area Number: 25460683
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Nagoya University
• Principal Investigator: TAKAGI AKIRA 名古屋大学, 医学(系)研究科(研究院), 准教授 (30135371)
• Co-Investigator(Kenkyū-buntansha): KOJIMA Tetsuhito 名古屋大学, 大学院医学系研究科, 教授 (40161913)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 病態検査学 / 静脈血栓塞栓症 / 危険因子 / 病態解析 / プロトロンビン分子異常 / トロンボモジュリン抵抗性 / 血栓傾向

Outline of Final Research Achievements

Venous thromboembolism has attracted attention in recent years as economy class syndrome. In a congenital mutation of the blood coagulation factor control it has been known to increase the risk even in heterozygotes. We found an abnormal prothrombin to resist the control of the coagulation control factor antithrombin by one amino acid mutations, proposed an anti-thrombin resistance as a new disease concept. Thrombin loses the clotting ability to bind to receptor-thrombomodulin of vascular endothelial cell surface, so to exert an anti-clotting ability. We have developed a more of method for measuring changes in coagulation control ability of thrombomodulin by prothrombin mutation. In addition, we are focusing on the blood coagulation factor Xa inhibited by antithrombin.
We found abnormal FXs showing the antithrombin resistance. We have developed a method for analysis of FXa antithrombin resistance.

Research Products

• [Journal Article] The first case of antithrombin-resistant prothrombin Belgrade mutation in Japanese (2016)
  • Author(s): Kishimoto M, Suzuki N, Murata M, Ogawa M, Kanematsu T, Takagi A, Kiyoi H, Kojima T, Matsushita T
  • Journal Title: Ann Hematol. Volume: 95 Pages: 541-542
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 新たな血栓性素因：アンチトロンビンレジスタンス (2016)
  • Author(s): 小嶋哲人、高木明、村田萌、高木夕希
  • Journal Title: 日本産婦人科・新生児血液学会誌 Volume: 25 Pages: 66-72
• [Journal Article] アンチトロンビンレジスタンス ―新しい遺伝性血栓性素因― (2015)
  • Author(s): 小嶋哲人、高木明、村田萌、高木夕希
  • Journal Title: 臨床血液 Volume: 56 Pages: 632-637
  • NAID: 130005093096
  • 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] 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] 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 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 Pages: 293-299
  • 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
• [Presentation] Practical laboratory assay to detect abnormal prothrombin conveying thrombomodulin resistance (2015)
  • Author(s): 高木夕希、水谷直貴、村田萌、小塚敏弘、中田悠紀子、長谷部瞭、河村奈美、槇山愛弓、橋本恵梨華、高木明、小嶋哲人高木夕希、水谷直貴、村田萌、小塚敏弘、中田悠紀子、長谷部瞭、河村奈美、槇山愛弓、橋本恵梨華、高木明、小嶋哲人
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16
• [Presentation] A congenital dysprothrombinemia with both decreased prothrombin activity and antithrombin resistance (2015)
  • Author(s): 高田麻央、森下英里子、谷口文苗、關口暁子、小林英里奈、朝倉英策、高木明、小嶋哲人、大竹茂樹
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16
• [Presentation] 深部静脈血栓症で発症したアンチトロンビンレジスタンス症例の抗凝固療法 (2015)
  • Author(s): 岸本磨由子、鈴木伸明、村田萌、小川実加、兼松毅、高木明、小嶋哲人、松下正
  • Organizer: 第16回日本検査血液検査血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-07-11
• [Presentation] 先天性アンチトロンビン欠乏症８症例SERPINC1遺伝子解析 (2015)
  • Author(s): 中田悠紀子、小塚敏弘、長谷部瞭、高木夕希、村田萌、上牧務、松尾真稔、高木明、松下正、小嶋哲人
  • Organizer: 第16回日本検査血液検査血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-07-11
• [Presentation] アンチトロンビン抵抗性検出検査法の自動凝固検査機器への最適化 Part 2 (2015)
  • Author(s): 村田萌、水谷直貴、高木夕希、長谷部瞭、小塚敏弘、中田悠紀子、高木明、松下正、小嶋哲人
  • Organizer: 第16回日本検査血液検査血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-07-11
• [Presentation] Analysis of prothrombin mutants in NA+ binding domain as a potential candidate conveying antithrombin resistance (2015)
  • Author(s): Moe Murata, Naoki Mizutani, Yuki Takagi, Ryo Hasebe, Toshihiro Kozuka, Yukiko Nakata, Akira Takagi, Tetsuhito Kojima
  • Organizer: XXV Congress of International Society on Thrombosis and Haemostasis
  • Place of Presentation: Toronto, Canada
  • Year and Date: 2015-06-20
• [Presentation] Analysis of prothrombin missense mutants at 596ARG by single nucleotide substitution for anticoagulant system (2015)
  • Author(s): Yuki Takagi, Moe Murata, Yuki Nakamura, Toshihiro Kozuka, Yukiko Nakata, Ryo Hasebe, Akira Takagi, Tetsuhito Kojima
  • Organizer: XXV Congress of International Society on Thrombosis and Haemostasis
  • Place of Presentation: Toronto, Canada
  • Year and Date: 2015-06-20
• [Presentation] ロトロンビン変異による新たなアンチトロンビン抵抗性変異の候補解析 (2015)
  • Author(s): 村田萌、水谷直貴、高木夕希、長谷部瞭、小塚敏弘、中田悠紀子、槇山愛弓、河村奈美、橋本恵梨華、高木明、松下正、小嶋哲人
  • Organizer: 第37回日本血栓止血学会学術集会
  • Place of Presentation: 甲府
  • Year and Date: 2015-05-21
• [Presentation] 深部静脈血栓症で発症しアンチトロンビン抵抗性を示した本邦初 Prothrombin Belgrade 変異の一家系 (2015)
  • Author(s): 岸本磨由子、鈴木伸明、村田萌、小川実加、兼松毅、高木明、小嶋哲人、松下正
  • Organizer: 第37回日本血栓止血学会学術集会
  • Place of Presentation: 甲府
  • Year and Date: 2015-05-21
• [Presentation] プロトロンビンArg596 における一塩基置換ミスセンス変異体のトロンボモジュリン抵抗性評価 (2015)
  • Author(s): 高木夕希、村田萌、中村友紀、小塚敏弘、中田悠紀子、長谷部瞭、橋本恵梨華、高木明、小嶋哲人
  • Organizer: 第37回日本血栓止血学会学術集会
  • Place of Presentation: 甲府
  • Year and Date: 2015-05-21
• [Presentation] Optimization of the antithrombin resistance assay for the automated analyzer (2014)
  • Author(s): Moe Murata, Yuki Takagi, Yuki Nakamura, Ryo Hasebe, Toshihiro Kozuka, Yukiko Nakata, Akira Takagi, Tetsuhito Kojima
  • Organizer: The 8th Congress of Asia Pacific Society of Thrombosis and Hemostasis
  • Place of Presentation: Hanoi
  • Year and Date: 2014-10-09 – 2014-10-11
• [Presentation] Precise genetic abnormalities in four hemophilia B patients with large deletions of X-chromosome including entire F8 (2014)
  • Author(s): Yuki Nakamura, Moe Murata, Yuki Takagi, Toshihiro Kozuka, Yukiko Nakata, Ryo Hasebe, Akira Takagi, Tadashi Matsushita, Tetsuhito Kojima
  • Organizer: The 8th Congress of Asia Pacific Society of Thrombosis and Hemostasis
  • Place of Presentation: Hanoi
  • Year and Date: 2014-10-09 – 2014-10-11
• [Presentation] アンチトロンビン抵抗性の関与が疑われた家族性再発性肺血栓塞栓症の1例 (2014)
  • Author(s): 吉田 律、角田 聖子、長谷川 潤、大木 理次、武本 知之、小山 達也、山崎 弘二、関 晋吾、吉村 道博、高木 明、小嶋 哲人
  • Organizer: 第233回日本循環器学会 関東・甲信越地方会
  • Place of Presentation: 東京
  • Year and Date: 2014-09-06
• [Presentation] 原因不明であった静脈血栓塞栓症にみられたアンチトロンビン抵抗性を示す本邦２家系目のプロトロンビン異常症 (2014)
  • Author(s): 村田 萌、高木 明、岸本磨由子、清井 仁、松下 正、小嶋哲人
  • Organizer: 第33回日本臨床検査医学会東海・北陸支部例会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-08-02
• [Presentation] アンチトロンビン抵抗性検出検査法の自動凝固検査機器への最適化 (2014)
  • Author(s): 村田 萌、高木夕希、中村友紀、長谷部 瞭、小塚敏弘、中田 悠紀子、高木 明、村手 隆、松下 正、小嶋哲人
  • Organizer: 第15回日本検査血液検査血液学会学術集会
  • Place of Presentation: 仙台
  • Year and Date: 2014-07-20 – 2014-07-21
• [Presentation] A clinical laboratory test detecting antithrombin resistance of the new thrombophilia (2013)
  • Author(s): MURATA Moea, TAKAGI Akira, SUZUKI Atsuo,TAKAGI Yuki, KATO Io, ANDO Yumi, MURATE Takashi, MATSUSHITA Tadashi, SAITO Hidehiko, KOJIMA Tetsuhito
  • Organizer: XXIV Congress of International Society on Thrombosis and Haemostasis,
  • Place of Presentation: Amsterdam, The Neterlands
• [Presentation] Effects of prothrombin Yukuhashi mutation on thrombomodulin-protein C system (2013)
  • Author(s): TAKAGI Yuki, KAT O Io, ANDO Yumi, MURATA Moea, SUZUKI Atsuo, TAKAGI Akira, MATSUSHITA Tadashi, SAITO Hidehiko, KOJIMA Tetsuhito
  • Organizer: XXIV Congress of International Society on Thrombosis and Haemostasis,
  • Place of Presentation: Amsterdam, The Neterlands
• [Presentation] アンチトロンビン抵抗性解析法の改良と評価 (2013)
  • Author(s): 村田 萌、高木 明、中村友紀、加藤衣央、安藤裕実、高木夕希、村手 隆、松下 正、小嶋哲人
  • Organizer: 第14回日本検査血液検査血液学会学術集会
  • Place of Presentation: 東京
• [Presentation] プロトロンビンYukuhashi由来変異型トロンビンのトロンボモジュリン・プロテインC系に及ぼす影響 (2013)
  • Author(s): 高木夕希、高木 明、鈴木敦夫、奥山恵理子、村田 萌、加藤衣央、安藤裕実、中村友紀、松下 正、齋藤英彦、小嶋哲人
  • Organizer: 第14回日本検査血液検査血液学会学術集会
  • Place of Presentation: 東京
• [Book] 臨床検査法提要（改訂第34版） (2015)
  • Author(s): 小嶋哲人、高木明
  • Total Pages: 21
  • Publisher: 金原出版株式会社
• [Patent(Industrial Property Rights)] 血栓症のリスク検査法 (2013)
  • Inventor(s): 高木明、小嶋哲人、高木夕希、村田萌
  • Industrial Property Rights Holder: 名古屋大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-07-17