血栓症発症を予測するために、前血栓症状態/過凝固症の検討

2017 Fiscal Year Research-status Report

• Project/Area Number: 15K08645
• Research Institution: Mie University
• Principal Investigator: 和田 英夫 三重大学, 医学系研究科, 准教授 (40158704)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: APTT波形 / D-dimer / 抗Xa活性 / 遺伝子解析

Outline of Annual Research Achievements

・妊婦、外科手術患者、担癌患者などの血栓症発症リスクのある患者を、プロスペクティブかつ経日的に、活性化部分トロンボプラスチン時間(APTT)波形、可溶性フィブリン（SF）、D-dimer、抗Xa活性ならびにthrombin-antithrombin complex (TAT)などの止血系マーカーを測定し、血栓症診断ならびに予測するためのカットオフ値を決定した。妊婦における血栓症発症リスクを示すD-dimerのカットオフ値は、約3.0μg/mlであった。整形外科全関節置換術患者での血栓症発症リスクを示すD-dimerのカットオフ値は約1.2μg/mlであった。APTT波形では、血栓症発症前に加速度高や速度高が著しく高値であった。
・妊婦の血栓症ではantithrombin（AT）異常症が高頻度に認められた。また、妊婦ではAT、Protein C (PC)ならびにProtein S(PS)などの血液凝固阻害因子は、不育症のリスク因子にはならなかった。妊娠週数が増加するに従い、APTT波形の加速度高や速度高が著しく高値となった。フィブリノゲα鎖p.Thr331Ala遺伝子多型は不育症のリスクとなり、血栓性素因はそのリスクを軽減した。非定型性溶血性尿毒症症候群（aHUS）の遺伝子異常は、三重県ではp.Ile1157Thr変異が圧倒的に多かった。また、aHUSの診断に血漿C5b-9の測定は有用であった。
・複数の播種性血管内凝固（DIC）診断スコアリングシステムの評価をおこなったところ、AT、SF/TAT、血小板減少を一般的止血検査に加えたスコアリングの組み合わせが、DIC診断における感度・特異度とも最も高かった。また、この新しいDIC診断スコアリングシステムはDICの早期診断も可能であったが、生命予後の予測に関しては画期的に改善するものはなかった。APTT波形はDICの病型分類にも有用であった。

Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

新たに、過凝固状態の指標として、APTT波形をを検討した。
このため、機器の更新を行い、多数例の測定ならびに解析を行った。
このため、期間の延長を必要とした。

Strategy for Future Research Activity

・D-dimerの標準化あるいは換算式の検討を行う。さらに症例数を増加させ、Odds比を向上させる必要がある。D-dimer以外で、SF、FDP、CLEC2、ヒストン、HMGB-1などのdataを集積したい。
・上腸管静脈血栓症や門脈血栓で、凝固阻害因子の蛋白ならびに遺伝子の検討を行う。フィブリノゲα鎖p.Thr331Ala遺伝子多型と血栓症との関係も調べる。
・DICと生命予後、治療効果と生命予後との関係は充分解析されていない。治療を選択できるようなバイオマーカーを検討する。
・aHUSで補体系の活性化が確認されたが、C5b-9のカットオフ値の決定など多数例での測定を行う。その他の、C5aやC3aなどの測定を行う。

Causes of Carryover

予定した止血系分子マーカーの検討において、測定する過凝固症検体数の必要量が、当初の計画よりも少なく済んだため、平成30年度に行うAPTT波形や新しい分子マーカーの測定に使用する予定である。

Research Products

• [Journal Article] The Evaluation of Fibrin-Related Markers for Diagnosing or Predicting Acute or Subclinical Venous Thromboembolism in Patients Undergoing Major Orthopedic Surgery. (2018)
  • Author(s): Hasegawa M, Wada H, Miyazaki S, Yamaguchi T, Wakabayashi H, Fujimoto N, Matsumoto T, Ohishi K, Sakaguchi A, Yamada N, Ito M, Yamashita Y, Katayama N, Nakatani K, Sudo A
  • Journal Title: Clin Appl Thromb Hemost Volume: 24 Pages: 107-114
  • DOI: 10.1177/1076029616674824
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Evaluation of D-Dimer Levels for the Comparison of Fibrinogen and Fibrin Units Using Different D-Dimer Kits to Diagnose VTE. (2018)
  • Author(s): Hasegawa M, Wada H, Yamaguchi T, Wakabayashi H, Fujimoto N, Matsumoto T, Hasegawa K, Yamada N, Ito M, Yamashita Y, Katayama N, Nakatani K, Sudo A
  • Journal Title: Clin Appl Thromb Hemost Volume: 24 Pages: 655-662
  • DOI: 10.1177/1076029617706755
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Monitoring of hemostatic abnormalities in major orthopedic surgery patients treated with edoxaban by APTT waveform (2018)
  • Author(s): Hasegawa M, Wada H, Tone S, Yamaguchi T, Wakabayashi H, Ikejiri M, Watanabe M, Fujimoto N, Matsumoto T, Ohishi K, Yamashita Y, Katayama N, Sudo A
  • Journal Title: Int J Lab Hematol Volume: 40 Pages: 49-55
  • DOI: 10.1111/ijlh.12727
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A Proposal of the Modification of Japanese Society on Thrombosis and Hemostasis (JSTH) Disseminated Intravascular Coagulation (DIC) Diagnostic Criteria for Sepsis-Associated DIC. (2018)
  • Author(s): Iba T, Di Nisio M, Thachil J, Wada H, Asakura H, Sato K, Saitoh D
  • Journal Title: Clin Appl Thromb Hemost Volume: 24 Pages: 439-445
  • DOI: doi: 10.1177/1076029617720069
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Platelet Activation Assessed by Glycoprotein VI/Platelet Ratio Is Associated With Portal Vein Thrombosis After Hepatectomy and Splenectomy in Patients With Liver Cirrhosis. (2018)
  • Author(s): Matsui T, Usui M, Wada H, Iizawa Y, Kato H, Tanemura A, Murata Y, Kuriyama N, Kishiwada M, Mizuno S, Sakurai H, Isaji S
  • Journal Title: Clin Appl Thromb Hemost. Volume: 24 Pages: 254-262
  • DOI: 10.1177/1076029617725600
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] An Evaluation of Hemostatic Abnormalities in Patients With Hemophilia According to the Activated Partial Thromboplastin Time Waveform. (2018)
  • Author(s): Katayama H, Matsumoto T, Wada H, Fujimoto N, Toyoda J, Abe Y, Ohishi K, Yamashita Y, Ikejiri M, Habe K, Katayama N:
  • Journal Title: Clin Appl Thromb Hemost Volume: open ac Pages: open ac
  • DOI: 10.1177/1076029618757344
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Elevated Soluble Platelet Glycoprotein VI Levels in Patients After Living Donor Liver Transplantation. (2017)
  • Author(s): Takahashi N, Usui M, Naitoh K, Wada H, Mastsui T, Kobayashi T, Matsumoto T, Uemoto S, Isaji S
  • Journal Title: Clin Appl Thromb Hemost. Volume: 23 Pages: 274-281
  • DOI: 10.1177/1076029615604047
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] High prevalence of congenital thrombophilia in patients with pregnancy-related or idiopathic venous thromboembolism/pulmonary embolism. (2017)
  • Author(s): Ikejiri M, Wada H, Yamada N, Nakamura M, Fujimoto N, Nakatani K, Matsuda A, Ogihara Y, Matsumoto T, Kamimoto Y, Ikeda T, Katayama N, Ito M
  • Journal Title: Int J Hematol Volume: 105 Pages: 272-279
  • DOI: 10.1007/s12185-016-2111-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Attempt to Harvest a Sufficient Number of Mononuclear Cells in an Appropriate Blood Product Volume By Modification of the Default Apheresis Setting. (2017)
  • Author(s): Tanaka Y, Ohishi K, Sawai T, Iwasaki H, Kageyama S, Masuya M, Matsumoto T, Tanigawa T, Wada H, Shiku H, Ito M, Katayama N
  • Journal Title: Ther Apher Dial. Volume: 21 Pages: 507-511
  • DOI: 10.1111/1744-9987.12562
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] An Evaluation of the Activated Partial Thromboplastin Time Waveform (2017)
  • Author(s): Matsumoto T, Wada H, Fujimoto N, Toyoda J, Abe Y, Ohishi K, Yamashita Y, Ikejiri M, Hasegawa K, Suzuki K, Imai H, Nakatani K, Katayama N
  • Journal Title: Clin Appl Thromb Hemost Volume: Epub Pages: Epub
  • DOI: 10.1177/1076029617724230
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comparison of three different anti-Xa assays in major orthopedic surgery patients treated with direct oral anticoagulant. (2017)
  • Author(s): Ikejiri M, Wada H, Tone S, Wakabayashi H, Hasegawa M, Matsumoto T, Fujimoto N, Yamada N, Ito M, Nakatani K, Sudo A .
  • Journal Title: Thromb J Volume: open ac Pages: Oct 12;15:27
  • DOI: 10.1186/s12959-017-0150-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Plasma Levels of ADAMTS-13, von Willebrand Factor, VWFpp, and Fibrin-Related Markers in Patients With Systemic Sclerosis Having Thrombosis (2017)
  • Author(s): Habe K, Wada H, Higashiyama A, Akeda T, Tsuda K, Mori R, Kakeda M, Matsumoto T, Ohishi K, Yamanaka K, Katayama N, Mizutani H.
  • Journal Title: Clin Appl Thromb Hemost Volume: 23 Pages: 622-630
  • DOI: 10.1177/1076029617736382
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] : Protection From Pregnancy Loss in Women With Hereditary Thrombophilia When Associated With Fibrinogen Polymorphism Thr331Ala. (2017)
  • Author(s): IKejiri M, Wada H, Kamimoto Y, Nakatani K, Ikeda T
  • Journal Title: Clin Appl Thromb Hemost Volume: 23 Pages: 494-495
  • DOI: 10.1177/1076029616645400
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] For TTP group of Blood Coagulation Abnormalities Research Team, Research on Rare and Intractable Disease supported by Health, Labour, and Welfare Sciences Research Grants.: Diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (TTP) 2017 in Japan. (2017)
  • Author(s): Matsumoto M, Fujimura Y, Wada H, Kokame K, Miyakawa Y, Ueda Y, Higasa S, Moriki T, Yagi H, Miyata T, Murata M;
  • Journal Title: Int J Hematol Volume: 106 Pages: 3-15
  • DOI: 10.1007/s12185-017-2264-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] DIC subcommittee of the Japanese Society on Thrombosis and Hemostasis.: The approval of revised diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. (2017)
  • Author(s): Wada H, Takahashi H, Uchiyama T, Eguchi Y, Okamoto K, Kawasugi K, Madoiwa S, Asakura H
  • Journal Title: Thromb J Volume: open ac Pages: July 3: 15: 17
  • DOI: 10.1186/s12959-017-0142-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Emicizumab Prophylaxis in Hemophilia A with Inhibitors. (2017)
  • Author(s): Wada H, Matsumoto T, Katayama N
  • Journal Title: N Engl J Med Volume: 377 Pages: 2193-2194
  • DOI: 10.1056/NEJMc1712683
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hypofibrinogenemia and the α-Fibrinogen Thr312Ala Polymorphism may be Risk Factors for Early Pregnancy Loss. (2017)
  • Author(s): Kamimoto Y, Wada H, Ikejiri M, Nakatani K, Sugiyama T, Osato K, Murabayashi N, Habe K, Mizutani H, Matsumoto T, Ohishi K, Ikeda T
  • Journal Title: Clin Appl Thromb Hemost Volume: 23 Pages: 52-57
  • DOI: 10.1177/1076029615594003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] An Evaluation of the Modified Diagnostic Criteria for DIC Established by the Japanese Society of Thrombosis and Hemostasis. (2017)
  • Author(s): Aota T, Wada H, Yamashita Y, Matsumoto T, Ohishi K, Suzuki K, Imai H, Usui M, Isaji S, Asakura H, Okamoto K, Katayama N.
  • Journal Title: Clin Appl Thromb Hemost Volume: 23 Pages: 579-584
  • DOI: 10.1177/1076029616672582
  • Peer Reviewed / Int'l Joint Research
• [Presentation] フォンダパリヌクスならびにエドキサバン投与患者の抗Xa活性によるモニター (2018)
  • Author(s): 和田英夫、池尻 誠、松本剛史
  • Organizer: 第12回日本血栓止血学会学術標準化委員会シンポジウム
• [Presentation] 抗Xa活性ならびにAPTT波形によるDOACのモニター (2018)
  • Author(s): 和田英夫、池尻 誠、松本剛史
  • Organizer: 第12回日本血栓止血学会学術標準化委員会シンポジウム
• [Presentation] Comparison of three different anti-Xa assays in major orthopedic surgery patients treated with direct oral anticoagulant (2017)
  • Author(s): Wada H, Matsumoto T, Ikejiri M, Sudo A
  • Organizer: XXVIth ISTH Congress
  • Int'l Joint Research
• [Presentation] An evaluation of the activated partial thromboplastin time waveform. (2017)
  • Author(s): Matsumoto T, Wada H, Ohishi K, Katayama N
  • Organizer: XXVIth ISTH Congress
  • Int'l Joint Research
• [Presentation] 血栓症/出血マーカーー、シンポジウム「臨床検査の最新知見」 (2017)
  • Author(s): 和田英夫
  • Organizer: 第56回 日本臨床検査医学会東海・北陸支部総会第334回 日本臨床化学会東海・北陸支部例会
  • Invited
• [Presentation] Natural history of disseminated intravascular coagulation. JSLH/ISLH Joint symposium 1: Disseminated intravascular coagulation (DIC) (2017)
  • Author(s): Wada H
  • Organizer: 第18回日本検査血液学会学術集会
  • Invited
• [Book] 病気がみえる改訂2版。血液 (2017)
  • Author(s): 伊豆津宏二、神田善伸、後藤明彦、和田英夫、増田亜希子、松村譲じ、鈴木隆浩、岡田 賢、朝倉英策、室井一男監修
  • Total Pages: 290
  • Publisher: メディックメディア
  • ISBN: 978-4-89632-652-9