Arterial thrombosis and platelet integrin activation.

• Project/Area Number: 25461448
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Osaka University
• Principal Investigator: Kashiwagi Hirokazu 大阪大学, 医学(系)研究科(研究院), 講師 (10432535)
• Co-Investigator(Kenkyū-buntansha): TOMIYAMA Yoshiaki 大阪大学, 医学部附属病院, 准教授 (80252667)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); 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: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 血小板 / GPIIb/IIIa / inside-outシグナル / 血栓症 / インテグリン / 活性化

Outline of Final Research Achievements

The regulation of platelet activation is quite important for prevention of arterial thrombosis. To explore the mechanism of platelet activation, the intraplatelet signaling was analyzed in platelets of patients with macrothrombocytopenia. Increased FAK phosphorylation in all of the platelets with integrin αIIb cytoplasmic tail mutations suggests the importance ofαIIb cytoplasmic tail in platelet signaling. The effect of mutation in αIIb cytoplasmic tail was also studied using αIIb-(R995W) knock-in mice. The number of platelets, platelet production, and the surface expression of αIIbβ3 were decreased in knock-in mice. Furthermore, in vitro thrombus formation under flow condition was significantly impaired in knock-in mice. The analysis of a patient with bleeding problems due to CalDAG-GEFI deficiency clearly showed the role of CalDAG-GEFI in αIIbβ3 inside-out signaling. These results will contribute for better anti-platelet therapy in patients with arterial thrombosis.

Research Products

• [Journal Article] Efficacy and safety of rituximab in Japanese patients with relapsed chronic immune thrombocytopenia refractory to conventional therapy (2015)
  • Author(s): Miyakawa Y, Katsutani S, Yano T, Nomura S, Nishiwaki K, Tomiyama Y, Higashihara M, Shirasugi Y, Nishikawa M, Ozaki K, Abe T, Kikuchi K, Kanakura Y, Fujimura K, Ikeda Y, Okamoto S
  • Journal Title: Int J Hematol Volume: 102 Pages: 654-661
  • Peer Reviewed
• [Journal Article] Efficacy and safety of the thrombopoietin receptor agonist romiplostim in patients aged ≥65 years with immune thrombocytopenia. (2015)
  • Author(s): Michel M, Wasser J, Godeau B, Aledort L, Cooper N, Tomiyama Y, Khellaf M, Wang X.
  • Journal Title: Ann Hematol. Volume: 94 Issue: 12 Pages: 1973-1980
  • DOI: 10.1007/s00277-015-2485-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Clinical significance of IPF% or RP% measurement in distinguishing primary immune thrombocytopenia from aplastic thrombocytopenic disorders. (2015)
  • Author(s): Sakuragi M, Hayashi S, Maruyama M, Kabutomori O, Kiyokawa T, Nagamine K, Kato H, Kashiwagi H, Kanakura Y, Tomiyama Y.
  • Journal Title: Int J Hematol. Volume: 101 Issue: 4 Pages: 369-375
  • DOI: 10.1007/s12185-015-1741-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ITPの病態と治療の進歩 (2015)
  • Author(s): 柏木 浩和、冨山 佳昭
  • Journal Title: 臨床血液 Volume: 56 Pages: 177-184
  • NAID: 130004920706
• [Journal Article] Trans-fatty acid promotes thrombus formation in mice by aggravating antithrombogenic endothelial functions via Toll-like receptors. (2014)
  • Author(s): Kondo K, Ishida T, Yasuda T, Nakajima H, Mori K, Tanaka N, Mori T, Monguchi T, Shinohara M, Irino Y, Toh R, Rikitake Y, Kiyomizu K, Tomiyama Y, Yamamoto J, Hirata K.
  • Journal Title: Molecular Nutrition & Food Research Volume: 59 Issue: 4 Pages: 729-740
  • DOI: 10.1002/mnfr.201400537
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A case of neonatal alloimmune thrombocytopenia in the presence of both anti-HPA-4b and anti-HPA-5b antibody: clinical and serological analysis of the subsequent pregnancy (2014)
  • Author(s): Kiyokawa, T. Koh, Y. Mimura, K. Nakayama, K. Hosokawa, M. Sakuragi, M. Morikawa, T. Nakao, M. Aochi, H. Fukumori, Y. Kanagawa, T. Nagamine, K. Kimura, T. Tomiyama, Y.
  • Journal Title: Int J Hematol Volume: 100 Issue: 4 Pages: 398-401
  • DOI: 10.1007/s12185-014-1620-0
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Eliminate dark side from antiplatelet therapy. (2014)
  • Author(s): Tomiyama Y
  • Journal Title: Blood Volume: 123 Issue: 17 Pages: 2599-2601
  • DOI: 10.1182/blood-2014-03-560417
  • Peer Reviewed / Open Access
• [Journal Article] 特発性血小板減少性紫斑病(ITP)の治療 (2014)
  • Author(s): 柏木浩和、冨山佳昭
  • Journal Title: 臨床血液 Volume: 55 Pages: 2087-2094
  • NAID: 130004696103
• [Journal Article] Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype. (2013)
  • Author(s): Kashiwagi H, Kunishima S, Kiyomizu K, Amano Y, Shimada H, Morishita M, Kanakura Y, Tomiyama Y.
  • Journal Title: Mol Genet Genomic Med Volume: 1 Issue: 2 Pages: 77-86
  • DOI: 10.1002/mgg3.9
  • Peer Reviewed
• [Journal Article] Pathophysiology and management of primary immune thrombocytopenia. (2013)
  • Author(s): Kashiwagi H, Tomiyama Y.
  • Journal Title: Int J Hematol Volume: 98 Issue: 1 Pages: 24-33
  • DOI: 10.1007/s12185-013-1370-4
  • NAID: 10031189594
  • Peer Reviewed
• [Presentation] Severe bleeding tendency and impaired platelet function in a patient with CalDAG-GEFI deficiency (2015)
  • Author(s): 加藤恒、中沢洋三、盛田大介、黒川由美、柏木浩和、森川陽一郎、金倉譲、冨山佳昭
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: ホテル日航金沢（石川県、金沢市）
  • Year and Date: 2015-10-16
• [Presentation] Severe bleeding tendency and impaired platelet function in a patient with CalDAG-GEFI deficiency (2015)
  • Author(s): Kato H, Nakazawa Y, Kashiwagi H, Tadokoro S, Morikawa Y, Morita D, Kurokawa Y, Kanakura Y, Tomiyama Y
  • Organizer: Th 25th Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: The Metro Tronto Convention Centre, Tronto, Canada
  • Year and Date: 2015-06-24
  • Int'l Joint Research
• [Presentation] Clinical significance of IPF% or RP% measuremetn in distinguishing primary immune thrombocytopenia from aplastic thrombocytopenic disorders (2015)
  • Author(s): Sakuragi M, Hayashi S, Maruyama M, Kabutomori O, Kiyokawa T, Nagamine K, Kato H, Kashiwagi H, Kanakura Y, Tomiyama Y
  • Organizer: Th 25th Congress of the International Society on Thrombosis and Haemostasi
  • Place of Presentation: The Metro Tronto Convention Centre, Tronto, Canada
  • Year and Date: 2015-06-24
  • Int'l Joint Research
• [Presentation] Immature platelet franction (IPF) measurement for the diagnosis of ITP (2015)
  • Author(s): Tomiyama Y
  • Organizer: Th 25th Congress of the International Society on Thrombosis and Haemostasi
  • Place of Presentation: The Metro Tronto Convention Centre, Tronto, Canada
  • Year and Date: 2015-06-20
  • Int'l Joint Research
• [Presentation] ABO血液型メジャー不適合成人生体肝移植におけるリツキシマブ投与例、非投与例の抗A、抗B抗体価の推移とFFPの使用状況 (2015)
  • Author(s): 細川美香、中山小太郎純友、櫻木美基子、中尾まゆみ、森川珠世、清川知子、青地寛、永峰啓丞、和田浩志、丸橋繁、江口英利、永野浩昭、冨山佳昭
  • Organizer: 第63回日本輸血・細胞移植学会総会
  • Place of Presentation: 京王プラザホテル（東京都、新宿区）
  • Year and Date: 2015-05-30
• [Presentation] ITP診断における網状血小板測定の臨床的意義：FCM法、自動血球分析装置XE-2100, およびXN-1000との比較検討 (2015)
  • Author(s): 櫻木美基子、林悟、丸山美保、兜森修、清川知子、永峰敬丞、加藤恒、柏木浩和、金倉譲、冨山佳昭
  • Organizer: 第63回日本輸血・細胞移植学会総会
  • Place of Presentation: 京王プラザホテル（東京都、新宿区）
  • Year and Date: 2015-05-29
• [Presentation] 抗HPA4bと抗HPA5b抗体を有するNAIT（第一子）：第二子の経過からの考察 (2015)
  • Author(s): 冨山佳昭、清川知子、中山小太郎純友、細川美香、櫻木美基子、森川珠世、中尾まゆみ、青地寛、永峰啓丞、味村和哉、木村正、高陽淑、石井博之
  • Organizer: 第63回日本輸血・細胞移植学会総会
  • Place of Presentation: 京王プラザホテル（東京都、新宿区）
  • Year and Date: 2015-05-28
• [Presentation] ITP診断における網状血小板測定の臨床的意義～FCM法、IPF法（XN1000とXE2100)の比較 (2015)
  • Author(s): 林悟、櫻木美基子、丸山美保、兜森修、清川知子、永峰敬丞、加藤恒、柏木浩和、金倉譲、冨山佳昭
  • Organizer: 第37回日本血栓止血学会学術集会
  • Place of Presentation: 甲府総合市民会館（山梨県、甲府市）
  • Year and Date: 2015-05-23
• [Presentation] αIIbβ3活性化変異、αIIb（R990W)KIマウスは巨大血小板減少症とともに血小板機能障害をきたす (2015)
  • Author(s): 柏木浩和、清水一亘、國島伸治、坂野史明、加藤恒、森川陽一郎、田所誠司、小亀浩市、本田繁則、宮田敏行、金倉譲、冨山佳昭
  • Organizer: 第37回日本血栓止血学会学術集会
  • Place of Presentation: 甲府総合市民会館（山梨県、甲府市）
  • Year and Date: 2015-05-22
• [Presentation] αIIb(R990W), a consitutive activating mutation of integrin αIIbβ3, knock-in mice show macrothrombocytopenia with impairment of platelet function (2014)
  • Author(s): Kiyomizu K, Kashiwagi H, Kunishima S, Banno F, Kato H, Morikawa Y, Tadokoro S, Kokame K, Honda S, Miyata T, Kanakura Y, Tomiyama Y
  • Organizer: The American Society of Hematology 56th Annual Meeting
  • Place of Presentation: Moscone Center, San Francisco, CA, USA
  • Year and Date: 2014-12-08
• [Presentation] αIIbβ3活性化変異、αIIb(R990W)ノックインマウスは巨大血小板減少症を伴う血小板無力症様の表現型を呈す (2014)
  • Author(s): 清水一亘、柏木浩和、國島伸治、坂野史明、森川陽一郎、加藤恒、田所誠司、小亀浩市、本田繁則、宮田敏行、金倉譲、冨山佳昭
  • Organizer: 第７６回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪市）
  • Year and Date: 2014-11-02
• [Presentation] Diagnostic value of IPF% measured by XN-1000 analyzer for primary ITP is comparable with FCM method (2014)
  • Author(s): 櫻木美基子、林悟、丸山美保、兜森修、清川知子、永峰啓丞、加藤恒、柏木浩和、金倉譲、冨山佳昭
  • Organizer: 第７６回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪市）
  • Year and Date: 2014-11-02
• [Presentation] ITP患者における血小板機能評価：フローサイトメトリーを用いた検討 (2014)
  • Author(s): 柏木浩和、清水一亘、加藤恒、田所誠司、森川陽一郎、金倉譲、冨山佳昭
  • Organizer: 第７６回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪市）
  • Year and Date: 2014-11-01
• [Presentation] 特発性血小板減少症（ITP)の治療 (2014)
  • Author(s): 柏木浩和
  • Organizer: 第７６回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪市）
  • Year and Date: 2014-10-31
  • Invited
• [Presentation] インテグリンαIIbβ3活性化変異、αIIb(R990W)ノックインマウスの検討 (2014)
  • Author(s): 清水一亘、柏木浩和、國島伸治、坂野史明、森川陽一郎、加藤恒、田所誠司、小亀浩市、本田繁則、宮田敏行、金倉譲、冨山佳昭
  • Organizer: 第３６回日本血栓止血学会学術集会
  • Place of Presentation: 大阪国際交流センター（大阪市）
  • Year and Date: 2014-05-31
• [Presentation] Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype (2013)
  • Author(s): Kashiwagi H, Kunishima S, Kiyomizu K, Amano Y, Shimada H, Morishita M, Kanakura Y, Tomiyama Y
  • Organizer: The 24th Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Amsterdam RAI (Amsterdam), Netherland
• [Presentation] αIIbβ3細胞内活性化変異と 血小板顆粒放出異常 (2013)
  • Author(s): 柏木浩和，清水一亘，田所誠司，冨山佳昭，金倉 譲
  • Organizer: 第35回日本血栓止血学会学術集会
  • Place of Presentation: 山形国際ホテル（山形）
• [Presentation] Pathophysiology of thrombocytopenia associated with chronic hepatitis C (2013)
  • Author(s): 林 悟，柏木浩和，清水一亘，西口修平，金倉 譲，冨山佳昭
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: ロイトン札幌他（札幌）