Animal models and hemostatic pathophysiology of acquired von Willebrand syndrome (AvWS)

• Project/Area Number: 25461445
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Nagoya University
• Principal Investigator: Matsushita Tadashi 名古屋大学, 医学部附属病院, 教授 (30314008)
• Co-Investigator(Kenkyū-buntansha): TAKESHITA KYOUSUKE 名古屋大学, 医学部附属病院, 講師 (70444403) ; SUZUKI NOBUAKI 名古屋大学, 医学部附属病院, 助教 (70637686)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: von Willebrand因子 / von Willebrand病 / AvWS / 血友病 / ADAMTS13 / マウスモデル / AvwS

Outline of Final Research Achievements

Acquired von Willebrand Syndrome (AvWS) has a unique bleeding symptom, that has not been observed in other hemostatic disorders. This study had a strategic approach to establish AvWS animal models and aimed to unveil the specific mechanisms underlining the development of AvWS bleeding diathesis. Our recent clinical observation indicated that activation of extrinsic pathways had some potential in controlling bleeding in patients with AvWS. We therefore observed the unique pattern of thrombin generation assay and ROTEM (Rotation thromboelastgram) assays to enable the novel therapeutic approach to this disorder.

Research Products

• [Journal Article] A case of MYH9 disorders caused by a novel mutation (p.K74E). (2016)
  • Author(s): Kanematsu T, Suzuki N, Yoshida T, Kishimoto M, Aoki T, Ogawa M, Kagami Y, Kiyoi H, Matsushita T, Kunishima S.
  • Journal Title: Ann Hematol. Volume: 95(1) Issue: 1 Pages: 161-3
  • DOI: 10.1007/s00277-015-2506-9
  • Peer Reviewed / Open Access
• [Journal Article] The first case of antithrombin-resistant prothrombin Belgrade mutation in Japanese. (2015)
  • 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: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Acquired von Willebrand syndrome in a patient with immune thrombocytopenic purpura (2015)
  • Author(s): Ihara A, Suzuki N, Matsushita T, Ichinose A.
  • Journal Title: Rinsho Ketsueki Volume: 56 Issue: 7 Pages: 901-904
  • DOI: 10.11406/rinketsu.56.901
  • NAID: 130005093126
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed / Open Access
• [Journal Article] Endoscopic treatment of esophageal varices in hemophiliac patients with liver cirrhosis (2015)
  • Author(s): Ishizu Y, Ishigami M, Suzuki N, Kuzuya T, Honda T, Hayashi K, Katano Y, Hirooka Y, Ishikawa T, Matsushita T, Goto H.
  • Journal Title: Gastrointest Endosc Volume: 81 Issue: 4 Pages: 1059-1060
  • DOI: 10.1016/j.gie.2014.11.043
  • Peer Reviewed / Open Access
• [Journal Article] The International Immune Tolerance Induction Study and its follow-up study on Japanese hemophilia A patients with inhibitors. (2015)
  • Author(s): Yoshioka A, Ishii E, Ueno T, Usami I, Kobayashi M, Kobayashi R, Sotomatsu M, Shirahata A, Suzuki T, Taki M, Ishida Y, Matsushita T, Shima M, Nogami K, Sakai M, Kigasawa H, Fukutake K
  • Journal Title: Int J Hematol. Volume: 101(4) Issue: 4 Pages: 362-8
  • DOI: 10.1007/s12185-015-1734-z
  • Peer Reviewed / Open Access
• [Journal Article] Current progress and future direction of hemophilia treatment (2015)
  • Author(s): 松下正
  • Journal Title: Rinsho Ketsueki Volume: 56 Issue: 10 Pages: 2100-2109
  • DOI: 10.11406/rinketsu.56.2100
  • NAID: 130005103289
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed / Open Access
• [Journal Article] Asymptomatic left atrial thrombus in a dialysis-dependent patient free of thrombogenic abnormalities. (2015)
  • Author(s): Takeshita K, Matsushita T, Murohara T
  • Journal Title: Ther Apher Dial. Volume: 19(1) Issue: 1 Pages: 93-4
  • DOI: 10.1111/1744-9987.12201
  • Peer Reviewed
• [Journal Article] Angiotensin II receptor blocker ameliorates stress-induced adipose tissue inflammation and insulin resistance. (2014)
  • Author(s): Hayashi M, Takeshita K, Uchida Y, Yamamoto K, Kikuchi R, Nakayama T, Nomura E, Cheng XW, Matsushita T, Nakamura S, Murohara T.
  • Journal Title: PLoS One Volume: 9 Issue: 12 Pages: e116163-e116163
  • DOI: 10.1371/journal.pone.0116163
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease. (2014)
  • Author(s): Kikuchi R, Nakamura K, MacLauchlan S, Ngo DT, Shimizu I, Fuster JJ, Katanasaka Y, Yoshida S, Qiu Y, Yamaguchi TP, Matsushita T, Murohara T, Gokce N, Bates DO, Hamburg NM, Walsh K
  • Journal Title: Nat Med Volume: 20(12) Issue: 12 Pages: 1464-71
  • DOI: 10.1038/nm.3703
  • Peer Reviewed
• [Journal Article] Hepatectomy for hepatocellular carcinoma in patients with hemophilia. (2014)
  • Author(s): Inokawa Y, Sugimoto H, Kanda M, Yamada S, Fujii T, Nomoto S, Takeda S, Suzuki N, Matsushita T, Kodera Y
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: 21(11) Issue: 11 Pages: 824-8
  • DOI: 10.1002/jhbp.142
  • 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] Thrombomodulin alfa treatment in patients with acute promyelocytic leukemia and disseminated intravascular coagulation: a retrospective analysis of an open-label, multicenter, post-marketing surveillance study cohort. (2014)
  • Author(s): Matsushita T, Watanabe J, Honda G, Mimuro J, Takahashi H, Tsuji H, Eguchi Y, Kitajima I, Sakata Y
  • Journal Title: Thromb Res. Volume: 133(5) Issue: 5 Pages: 772-81
  • DOI: 10.1016/j.thromres.2014.02.025
  • Peer Reviewed
• [Journal Article] Development of a 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 Issue: 2 Pages: 293-298
  • DOI: 10.1016/j.thromres.2013.11.021
  • Peer Reviewed
• [Journal Article] Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A. (2013)
  • Author(s): Tiede A, Brand B, Fischer R, Kavakli K, Lentz SR, Matsushita T, Rea C, Knobe K, Viuff D
  • Journal Title: J Thromb Haemost. Volume: 2013 Apr;11 Issue: 4 Pages: 670-8
  • DOI: 10.1111/jth.12161
  • Peer Reviewed
• [Journal Article] Impact of recombinant soluble thrombomodulin (thrombomodulin alfa) on disseminated intravascular coagulation. (2013)
  • Author(s): Mimuro J, Takahashi H, Kitajima I, Tsuji H, Eguchi Y, Matsushita T, Kuroda T, Sakata Y.
  • Journal Title: Thromb Res. Volume: in press Issue: 5 Pages: 436-443
  • DOI: 10.1016/j.thromres.2013.03.008
  • Peer Reviewed
• [Journal Article] Establishment of mouse model of MYH9 disorders: heterozygous R702C mutation provokes macrothrombocytopenia with leukocyte inclusion bodies, renal glomerulosclerosis and hearing disability. (2013)
  • Author(s): Suzuki N, Kunishima S, Ikejiri M, Maruyama S, Sone M, Takagi A, Ikawa M, Okabe M, Kojima T, Saito H, Naoe T, Matsushita T.
  • Journal Title: PLoS One Volume: 20
  • NAID: 120006957397
  • Peer Reviewed
• [Journal Article] 【検査値を読む2013】 血栓・止血検査 von Willebrand因子(抗原,活性,マルチマー解析を含む) (2013)
  • Author(s): 岸本磨由子、松下正
  • Journal Title: 内科(0022-1961) Volume: 111 Pages: 1129-1130
• [Presentation] 全血凝固分析装置ROTEMの基礎的検討 (2015)
  • Author(s): 亀山 なつみ, 鈴木 伸明, 高津 真由美, 山本 ゆか子, 前田 奈弥, 杉浦 由姫乃, 鈴木 敦夫, 梶浦 容子, 松本 祐之, 松下 正
  • Organizer: 第16回日本検査血液学会学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-07-11
• [Presentation] エクソーム解析によるvon Willebrand病遺伝子解析の一例 (2015)
  • Author(s): 三田 直美, 鈴木 伸明, 梶浦 容子, 中村 栄男, 松下 正
  • Organizer: 第16回日本検査血液学会学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-07-11
• [Presentation] von Willebrand病の検査と日常診療 (2015)
  • Author(s): 松下正
  • Organizer: 第16回日本検査血液学会学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-07-11
• [Presentation] 新規変異を有するMYH9異常症の1例 (2015)
  • Author(s): 兼松 毅, 鈴木 伸明, 小川 実加, 岸本 磨由子, 國島 伸治, 松下 正
  • Organizer: 第37回日本血栓止血学会学術集会
  • Place of Presentation: 甲府市総合市民会館(山梨県甲府市）
  • Year and Date: 2015-05-21
• [Presentation] 血小板無力症に同定されたGPIIb遺伝子のミスセンス変異とスプライス変異の複合ヘテロ変異解析 (2015)
  • Author(s): 橋本 恵梨華, 村田 萌, 槇山 愛弓, 河村 奈美, 小塚 敏弘, 中田 悠紀子, 長谷部 暸, 高木 夕希, 水谷 直貴, 高木 明, 國島 伸治, 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: 甲府市総合市民会館(山梨県甲府市）
  • 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: 甲府市総合市民会館(山梨県甲府市）
  • Year and Date: 2015-05-21
• [Presentation] プ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: 甲府市総合市民会館(山梨県甲府市）
  • Year and Date: 2015-05-21
• [Presentation] 凝固第VIII因子インヒビターとその対策 (2015)
  • Author(s): 松下正
  • Organizer: 第37回日本血栓止血学会学術集会
  • Place of Presentation: 甲府市総合市民会館(山梨県甲府市）
  • Year and Date: 2015-05-21
• [Presentation] 抗VWFインヒビターを発症したVWD type3の遺伝子解析 (2014)
  • Author(s): 松下 正, 三田 直美, 鈴木 伸明, 岸本 磨由子, 梶浦 容子, 松本 祐之, 中村 栄男
  • Organizer: 第61回日本臨床検査医学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2014-11-22 – 2014-11-25
• [Presentation] クロスミキシングテストにおける37℃インキュベーション付加がAPTT測定に与える影響 (2014)
  • Author(s): 梶浦 容子, 山本 ゆか子, 松本 祐之, 鈴木 伸明, 松下 正
  • Organizer: 日本臨床検査自動化学会第46回大会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2014-10-09 – 2014-10-11
• [Presentation] 大量出血時のフィブリノゲン製剤について考える 凝固因子補充療法とフィブリノゲン濃縮製剤 (2014)
  • Author(s): 松下正
  • Organizer: 日本心臓血管麻酔学会第19回学術大会
  • Place of Presentation: ホテル阪急エキスポバーク（大阪府吹田市）
  • Year and Date: 2014-09-20 – 2014-09-22
  • Invited
• [Presentation] 血友病B・40家系における血液凝固第IX因子遺伝子解析 (2014)
  • Author(s): 中村 友紀, 村田 萌, 安藤 裕実, 加藤 衣央, 高木 夕希, 高木 明, 兼松 毅, 岸本 磨由子, 鈴木 伸明, 松下 正, 齋藤 英彦, 小嶋 哲人
  • 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（大阪府大阪市）
  • Year and Date: 2014-05-29 – 2014-05-31
• [Presentation] 抗VWFインヒビターを発症したVWD type3の遺伝子解析 (2014)
  • Author(s): 三田 直美, 鈴木 伸明, 岸本 磨由子, 梶浦 容子, 松本 祐之, 中村 栄男, 松下 正
  • 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（大阪府大阪市）
  • Year and Date: 2014-05-29 – 2014-05-31