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Development of novel therapeutic strategy based on hemostatic characteristics of FVIII in the patients with moderate/mild hemophilia A

Research Project

Project/Area Number 18K07798
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionNara Medical University

Principal Investigator

Yada Koji  奈良県立医科大学, 医学部, 助教 (30635785)

Co-Investigator(Kenkyū-buntansha) 野上 恵嗣  奈良県立医科大学, 医学部, 准教授 (50326328)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords血友病A / インヒビター / 分子異常症 / F8遺伝子変異 / 凝固機能
Outline of Final Research Achievements

Hemophilia(H) A is bleeding disorder caused by quantitative and qualitative factor (F)VIII deficiency, and is classified as severe, moderate and mile type by residual FVIII level in the plasma. The severity and development of inhibitor in the patients with HA are considered to be associated with F8 genotype. In the present study, F8 genotypes were investigated in the patients with moderate/mild HA, and the FVIII mutants with the identified F8 missense variants in the patients with moderate/mild HA were produced by a stable human FVIII expression system utilizing BHK or HEK cells. The functional and structural characteristics of the FVIII mutants were investigated and it was found that mutant FVIII could be catalyzed and activated by FVIIa/TF as well as wild-type FVIII in the early phase of coagulation reaction. The results in the present study will help development of a novel hemostatic therapy for the patients with moderate/mild HA.

Academic Significance and Societal Importance of the Research Achievements

当教室の多彩な手法を駆使した生化学的アプローチによるFVIIIの構造・機能、病態解析やインヒビター研究は、国内では唯一であり、国際的にもトップの一つに挙げられている。本研究の結果、中等症・軽症血友病Aの凝血学的特性とF8遺伝子変異との関連が明らかとなり、F8遺伝子変異によりその特性を分類・評価し得ることが示され、遺伝子解析の重要性を示すものであった。さらに、外因系凝固と内因系凝固のクロストークに関しては、最近、世界的に注目されており、本研究で明らかとなった、中等症・軽症血友病A患者の有するF8変異型FVIIIの外因系凝固因子による活性化反応は、新たな治療開発の上で極めて有意義である。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (9 results)

All 2020 2019 2018

All Journal Article (6 results) (of which Peer Reviewed: 6 results,  Open Access: 3 results) Presentation (3 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Novel Insights and New Developments Regarding Coagulation Revealed by Studies of the Anti-Factor IXa (Activated Factor IX)/Factor X Bispecific Antibody, Emicizumab.2020

    • Author(s)
      Yada K, Nogami K
    • Journal Title

      Arteriosclerosis, Thrombosis, and Vascular Biology.

      Volume: 40(5) Issue: 5 Pages: 1148-1154

    • DOI

      10.1161/atvbaha.120.312919

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Emicizumab improves ex vivo clotting function in patients with mild/moderate hemophilia A2020

    • Author(s)
      Nakajima Yuto、Nogami Keiji、Yada Koji、Furukawa Shoko、Noguchi-Sasaki Mariko、Hirata Michinori、Shima Midori
    • Journal Title

      Thrombosis and Haemostasis

      Volume: オンライン Issue: 06 Pages: 968-976

    • DOI

      10.1055/s-0040-1710315

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Global coagulation function assessed by rotational thromboelastometrypredicts coagulation-steady state in individual hemophilia A patients receiving emicizumab prophylaxis.2019

    • Author(s)
      Yada K , Nogami K, Ogiwara K, Shida Y, Furukawa S, Yaoi H, Takeyama M, Kasai R,Shima M.
    • Journal Title

      International Journal of Haematology

      Volume: 110(4) Issue: 4 Pages: 419-430

    • DOI

      10.1007/s12185-019-02698-8

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Spotlight on emicizumab in the management of hemophilia A:patient selection and special considerations.2019

    • Author(s)
      Yada K , Nogami K
    • Journal Title

      Journal of blood medicine

      Volume: 10 Pages: 171-181

    • DOI

      10.2147/jbm.s175952

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Whole blood ristocetin-induced platelet impedance aggregometry does not reflect clinical severity in patients with type 1 von Willebrand disease. Haemophilia.2019

    • Author(s)
      Nakajima Y, Nogami K, Yada K , Ogiwara K, Furukawa S, Shimonishi N, Shima M.
    • Journal Title

      Haemophilia

      Volume: 25(3) Issue: 3

    • DOI

      10.1111/hae.13725

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [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 inhibitor2018

    • 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

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] インヒビター保有血友病A患者における活性型第VII因子による凝固改善に必要な第X因子に関する定量的検討2019

    • Author(s)
      矢田 弘史、野上 恵嗣、坪田 夏芽、嶋 緑倫
    • Organizer
      第81回 日本血液学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 1.Bドメイン除去(BDD)第VIII 因子(FVIII)においてFVIIa/TF 惹起FVIII 不活化は遷延される2018

    • Author(s)
      中島 由翔,矢田 弘史,野上 恵嗣,嶋 緑倫
    • Organizer
      第40回日本血栓止血学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 4.A Novel Mechanism of Factor VIIa/Tissue Factor (TF)-Catalyzed Activation and Inactivation of B-Domain-Deleted Factor VIII in the Early Initiation Phases of Coagulation2018

    • Author(s)
      Yuto Nakajima, Koji Yada, Keiji Nogami, Midori Shima
    • Organizer
      60th American Society of Hematology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2022-01-27  

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