Studies on the mechanisms of activation and inactivation of factor VIII: Applications of novel (anti-)coagulant therapy

• Project/Area Number: 15K09663
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Nara Medical University
• Principal Investigator: Nogami Keiji 奈良県立医科大学, 医学部, 准教授 (50326328)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 第VIII因子 / トロンビン / 活性型第VII因子 / 組織因子 / 凝固機序 / 活性化 / 第X因子 / FVIII / FVIIa / 内因系 / 外因系 / 結合領域 / 血液凝固 / 活性化第VII因子 / 活性化/不活化

Outline of Final Research Achievements

Regards the coagulant factor (F)VIII protein that is essential to both sides of hemorrhage and hemostasis in the blood coagulation, we for the first time identified the thrombin-binding sites responsible for the cleavages at Arg372 and Arg1689 in the FVIII activation. In addition, in terms of activated FVII/tissue factor (FVIIa/TF), we found not only the extrinsic-related coagulation mechanism, the intrinsic-related coagulation mechanism by the FVIII-FVIa/TF-related regulation exerts, consequently both mechanisms function in the initial phase of coagulation process.

Research Products

• [Journal Article] Factor (F)VIII/VIIa enhances global haemostatic function in the co-presence of bypassing agents and FVIII among patients with haemophilia A with inhibitor (2018)
  • Author(s): Nogami K, Matsumoto T, Yada K, Ogiwara K, Furukawa S, Shida Y, Takeyama M, Shima M
  • Journal Title: Br J Haematol Volume: ahead of printing Issue: 4 Pages: 528-536
  • DOI: 10.1111/bjh.15209
  • Peer Reviewed / Open Access
• [Journal Article] Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors. (2017)
  • Author(s): Shima M, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K, Kasai R, Yoneyama K, Yoshida H, Nogami K.
  • Journal Title: Blood Adv. Volume: 1(22) Issue: 22 Pages: 1891-1899
  • DOI: 10.1182/bloodadvances.2017006684
  • Peer Reviewed / Open Access
• [Journal Article] Successful prophylaxis using activated prothrombin complex concentrates (aPCC) in a severe haemophilia A patient with inhibitor previously unresponsive to on-demand daily infusions of aPCC. (2017)
  • Author(s): Furukawa S, Nogami K, Ogiwara K, Yada K, Shima M.
  • Journal Title: Haemophilia. Volume: 23 Issue: 5
  • DOI: 10.1111/hae.13310
  • Peer Reviewed
• [Journal Article] The utility of thromboelastography in inherited and acquired bleeding disorders. (2016)
  • Author(s): Keiji Nogami
  • Journal Title: British Journal of Haematology Volume: 174(4) Pages: 503-514
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Assessing the clinical severity of type 1 von Willebrand disease patients with a microchip flow-chamber system. (2016)
  • Author(s): Nogami K, Ogiwara K, Yada K, Shida Y, Takeyama M, Yaoi H, Minami H, Furukawa S, Hosokawa K, Shima M.
  • Journal Title: Journal of Thrombosis and Haemostasis Volume: 14(4) Pages: 667-674
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A new parameter in the thrombin generation assay, mean velocity to peak thrombin, reflects factor VIII activity in patients with haemophilia A (2016)
  • Author(s): Takeyama M, Nogami K, Shima M.
  • Journal Title: Haemophilia Volume: 22(5) Pages: 474-477
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Phenotypic heterogeneity of hemostasis in severe hemophilia (2015)
  • Author(s): Nogami K, Shima M.
  • Journal Title: Seminars in Thrombosis and Hemostasis Volume: 41 Pages: 826-831
  • Peer Reviewed
• [Journal Article] Systematic monitoring of hemostatic management in hemophilia A patients with inhibitor in the perioperative period using rotational thromboelastometry. (2015)
  • Author(s): Furukawa S, Nogami K, Ogiwara K, Yada K, Minami H, Shima M.
  • Journal Title: Journal of Thrombosis and Haemostasis Volume: 13 Pages: 1279-1284
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mild hemophilia A patient with novel Pro1809Leu mutation develops an anti-C2 antibody inhibiting allogeneic but not autologous factor VIII activity. (2015)
  • Author(s): Yada K, Nogami K, Takeyama M, Ogiwara K, Wakabayashi H, Shima M.
  • Journal Title: Journal of Thrombosis and Haemostasis Volume: 13 Pages: 1843-1853
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 第VIII因子A1残基346-349はArg372の開裂を制御する新たなトロンビン結合部位である (2017)
  • Author(s): 南博明, 野上恵嗣, 笹井香那, 古川晶子, 武山雅博, 嶋緑倫
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] 凝固初期相におけるFVIII活性化を介したTF依存性内因系tenase促進機序 (2017)
  • Author(s): 古川晶子, 野上恵嗣, 荻原建一, 嶋緑倫
  • Organizer: 第39回日本血栓止血学会学術集会
• [Presentation] Tenase(Xase) 反応軸に基づく中等症・軽症血友病Aにおける異常FVIIIの多元的機能解析 (2017)
  • Author(s): 矢田弘史, 野上恵嗣, 竹中亜利沙, 河村武志, 嶋緑倫
  • Organizer: 第39回日本血栓止血学会学術集会
• [Presentation] 血液凝固第VII因子の軌跡と今後の展望 (2017)
  • Author(s): 野上恵嗣
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] 包括的ダイナミック解析による血友病の凝固線溶動態の特性 (2017)
  • Author(s): 松本智子, 野上恵嗣, 笹井香那, 荻原建一, 竹中亜利沙, 嶋緑倫
  • Organizer: 第39回日本血栓止血学会学術集会
• [Presentation] A novel mechanism on thrombin-catalyzed activation of factor VIII molecule during the clot formation (2016)
  • Author(s): Keiji Nogami
  • Organizer: 第38回日本血栓止血学会学術集会 SPCシンポジウム
  • Place of Presentation: 奈良
  • Year and Date: 2016-06-16
• [Book] 第VIII因子と第V因子の基礎と臨床 新・血栓止血血管学 凝固と炎症 (2015)
  • Author(s): 野上恵嗣
  • Total Pages: 13
  • Publisher: 金芳堂