Mechanisms of thrombus formation and propagation leading to the onset of atherothrombosis

• Project/Area Number: 19H03445
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: University of Miyazaki
• Principal Investigator: Asada Yujiro 宮崎大学, 医学部, 教授 (70202588)
• Co-Investigator(Kenkyū-buntansha): 前川 和也 宮崎大学, 医学部, 助教 (30754171) ; 佐藤 勇一郎 宮崎大学, 医学部, 准教授 (90347055) ; 山下 篤 宮崎大学, 医学部, 准教授 (90372797)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2020: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2019: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: アテローム血栓症 / アテローム血栓

Outline of Research at the Start

心筋梗塞や脳梗塞に代表されるアテローム血栓症は、動脈硬化性プラークの破綻に伴う血栓形成により発症する。このため、これまでの研究の多くはプラーク破綻の機序をターゲット としたものであったが、近年、無症候性プラーク破綻が多く存在することが明らかとなり、本疾患の発症には、プラーク破綻部の血栓が増大・成長するプロセスが重要であることが推察される。
本研究は、プラーク破綻後の血栓の増大・成長機序に焦点を当て、人体病理標本を中心に、病理形態学・代謝解析・血流レオロジーの観点から包括的に検討を進め、アテローム血栓症の発症病態の解明と新たな治療法への展開に繋げる。

Outline of Final Research Achievements

The mechanism of thrombus formation leading to the onset of atherothrombosis was investigated using human pathological specimens and animal models. We also examined the target factors for antithrombotic drugs without bleeding risk.
As a result, the coagulation system is significantly enhanced at the disruption sites of atherosclerotic lesions, and platelets are aggregated on the von Willebrand factor and fibrin as a scaffold, in addition, neutrophil extracellular trap contributes to the early stage of thrombus organization. From a comprehensive analysis of thrombi and atheromatous plaques, we found several molecules that are targets for new diagnostic imaging of coronary high-risk plaques. Inhibition of coagulation factor XI confirmed a significant antithrombotic effect with a slight risk of bleeding, suggesting the anti-factor XI compound would be possible candidate for a novel and safer antithrombotic drug.

Academic Significance and Societal Importance of the Research Achievements

心筋梗塞や脳卒中に代表されるアテローム血栓症は、動脈硬化巣の破綻による血栓形成で発症する。このため血栓形成の機序解明と血栓の画像診断の質的向上は本疾患の診断に重要である。また現在使用されている抗血栓薬は出血リスクを伴うものが多く、安全な抗血栓薬の開発は喫緊の課題とされている。
本研究では、人体病理と実験病理の立場から研究を進め、プラーク破綻部での血栓形成の新たな機序と血栓の画像診断のターゲットとなる分子を複数同定した。加えて、凝固XI因子の阻害は出血リスクを伴わずに抗血栓作用を有することを明らかにした。
これらの結果は、我が国のアテローム血栓症の診断・予防・治療の発展に寄与する内容である。

Research Products

• [Int'l Joint Research] Cornell University(米国)
• [Journal Article] Intracellular glutamine level determines vascular smooth muscle cell-derived thrombogenicity. (2021)
  • Author(s): Koyama S, Yamashita A, Matsuura Y, Saito Y, Maekawa K, Gi T, Kitamura K, Asada Y
  • Journal Title: Atherosclerosis Volume: 328 Pages: 62-73
  • DOI: 10.1016/j.atherosclerosis.2021.05.012
  • Peer Reviewed / Open Access
• [Journal Article] Brazilian propolis (AF-08) inhibits collagen-induced platelet aggregation without affecting blood coagulation (2021)
  • Author(s): Chihiro Sugita, Atsushi Yamashita, Shigetoshi Tsutsumi, Hisahiro Kai, Tohru Sonoda, Hiroki Yoshida, Ryuichi Yamamoto, Yujiro Asada, Masahiko Kurokawa．
  • Journal Title: J Nat Med Volume: 75 Pages: 975-984
  • DOI: 10.1007/s11418-021-01518-w
  • NAID: 40022681000
  • Peer Reviewed / Open Access
• [Journal Article] In situ strategy for biomedical target localization via nanogold nucleation and secondary growth. (2021)
  • Author(s): Sawaguchi A, Kamimura T, Takahashi N, Yamashita A, Asada Y, Imazato H, Aoyama F, Wakui A, Sato T, Choijookhuu N, Hishikawa Y.
  • Journal Title: Communications Biology Volume: 4 Pages: 710-710
  • DOI: 10.1038/s42003-021-02246-3
  • Peer Reviewed / Open Access
• [Journal Article] Translocator protein imaging with 18F-FEDAC-positron emission tomography in rabbit atherosclerosis and its presence in human coronary vulnerable plaques. (2021)
  • Author(s): Maekawa K, Tsuji AB, Yamashita A, Sugyo A, Katoh C, Tang M, Nishihira K, Shibata Y, Koshimoto C, Zhang MR, Nishii R, Yoshinaga K, Asada Y
  • Journal Title: Atherosclerosis Volume: 337 Pages: 7-17
  • DOI: 10.1016/j.atherosclerosis.2021.10.003
  • Peer Reviewed / Open Access
• [Journal Article] Pathological features of ruptured coronary plaque and thrombus interfaces: fibrin and von Willebrand factor as platelet scaffolds on rupture sites (2021)
  • Author(s): Yamashita A, Nishihira K, Gi T, Maekawa K, Hatakeyama K, Horiuchi S, Wada K, Shibata Y, Asada Y.
  • Journal Title: Thrombosis and Haemostasis Volume: 121 Pages: 234-241
  • DOI: 10.1055/s-0040-1716539
  • Peer Reviewed / Open Access
• [Journal Article] Improving Thermodynamic Stability and Anticoagulant Activity of a Thrombin Binding Aptamer by Incorporation of 8-trifluoromethyl-2′-deoxyguanosine (2021)
  • Author(s): Bao Hong-Liang、Ishizuka Takumi、Yamashita Atsushi、Furukoji Eiji、Asada Yujiro、Xu Yan
  • Journal Title: J Med Chem Volume: 64 Pages: 711-718
  • DOI: 10.1021/acs.jmedchem.0c01711
  • Peer Reviewed
• [Journal Article] Upregulated Kynurenine Pathway Enzymes in Aortic Atherosclerotic Aneurysm: Macrophage Kynureninase Downregulates Inflammation (2021)
  • Author(s): Nishimura Masanori、Yamashita Atsushi、Matsuura Yunosuke、Okutsu Junichi、Fukahori Aiko、Hirata Tsuyoshi、Nishizawa Tomohiro、Ishii Hirohito、Maekawa Kazunari、Nakamura Eriko、Kitamura Kazuo、Nakamura Kunihide、Asada Yujiro
  • Journal Title: J Atheroscler Thromb Volume: - Issue: 11 Pages: 000-000
  • DOI: 10.5551/jat.58248
  • NAID: 130008110108
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access
• [Journal Article] Pathophysiology of atherothrombosis: Mechanisms of thrombus formation on disrupted atherosclerotic plaques. (2020)
  • Author(s): Asada Y, Yamashita A, Sato Y, Hatakeyama K.
  • Journal Title: Pathol Int Volume: 70 Pages: 309-322
  • DOI: 10.1111/pin.12921
  • Peer Reviewed / Open Access
• [Journal Article] High signal intensity on diffusion-weighted images reflects acute phase of deep vein thrombus. (2020)
  • Author(s): Gi T, Kuroiwa Y, Yamashita A, Mizutani Y, Asanuma T, Miyati T, Maekawa K, Aman M, Imamura T, Asada Y. Gi T, Kuroiwa Y, Yamashita A, Mizutani Y, Asanuma T, Miyati T, Maekawa K, Aman M, Imamura T, Asada Y.
  • Journal Title: Thrombosis and Haemostasis Volume: 120 Pages: 1463-1473
  • DOI: 10.1055/s-0040-1714280
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of Carotid Plaque Components by Quantitative Susceptibility Mapping. (2020)
  • Author(s): Azuma M, Maekawa K, Yamashita A, Yokogami K, Enzaki M, Khant ZA, Takeshima H, Asada Y, Wang Y, Hirai T.
  • Journal Title: AJNR Am J Neuroradiol Volume: 41 Pages: 310-317
  • DOI: 10.3174/ajnr.a6374
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Coronary high-signal-intensity plaques on T(1)-weighted magnetic resonance imaging reflect intraplaque hemorrhage (2019)
  • Author(s): Kuroiwa Y, Uchida A, Yamashita A, Miyati T, Maekawa K, Gi T, Noguchi T, Yasuda S, Imamura T, Asada Y
  • Journal Title: Cardiovascular Pathology Volume: 40 Pages: 24-31
  • DOI: 10.1016/j.carpath.2019.01.002
  • Peer Reviewed / Open Access
• [Journal Article] Higher lactate and purine metabolite levels in erythrocyte-rich fresh venous thrombus: Potential markers for early deep vein thrombosis (2019)
  • Author(s): Maekawa Kazunari、Sugita Chihiro、Yamashita Atsushi、Moriguchi-Goto Sayaka、Furukoji Eiji、Sakae Tatefumi、Gi Toshihiro、Hirai Toshinori、Asada Yujiro
  • Journal Title: Thromb Res Volume: 177 Pages: 136-144
  • DOI: 10.1016/j.thromres.2019.03.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 動脈硬化性大動脈瘤におけるキヌレニン代謝酵素の発現と局在 (2021)
  • Author(s): 西村正憲、山下 篤、松浦祐之介、奥津潤一、深堀愛子、平田 剛之、西澤友宏、石井廣人、前川和也、中村都英、中村恵理子、浅田祐士郎
  • Organizer: 第43回日本血栓止血学会学術集会
• [Presentation] 細胞内グルタミン濃度は血管平滑筋細胞の血栓性を規定する (2021)
  • Author(s): 小山彰平、山下 篤、松浦祐之介、斎藤祐介、前川和也、魏 峻洸、北村和雄
  • Organizer: 第43回日本血栓止血学会学術集会
• [Presentation] 家兎静脈血栓モデルによる経口活性化凝固XI因子阻害薬(ONO-1600586)の抗血栓作用と止血への影響 (2021)
  • Author(s): 大栗伸行、山下 篤、神山 祥、大川星美、浅田祐士郎
  • Organizer: 第43回日本血栓止血学会学術集会
• [Presentation] マクロファージに富む動脈硬化巣における代謝指標の同定 (2021)
  • Author(s): 中村恵理子、山下 篤、前川和也、西東洋一、菰原義弘、浅田祐士郎
  • Organizer: 第43回日本血栓止血学会学術集会
• [Presentation] Increased vascular glutamine level is a possible mediator of antithrombotic effect after everolimus-eluting stent implantation. (2021)
  • Author(s): Koyama S, Yamashita A, Matsuura Y, Saito Y, Maekawa K, Gi T, Kitamura K, Kaikita K, Asada Y
  • Organizer: The 19th International Symposium on Atherosclerosis
  • Int'l Joint Research
• [Presentation] Identifying metabolic biomarker of unstable plaque toward coronary artery imaging. (2020)
  • Author(s): Nakamura E, Yamashita A, Maekawa K, Saito Y, Komohara Y, Asada Y
  • Organizer: 第109回日本病理学会総会
• [Presentation] Contribution of fibrin and von Willebrand factor to platelet adhesion on ruptured atherosclerotic plaque in acute myocardial infarction. (2020)
  • Author(s): Yamashita A, Nishihira K, Maekawa K, Gi T, Saki Horiuchi, Hatakeyama K, Shibata Y, Asada Y.
  • Organizer: 28th Congress of International Society on Thrombosis and Haemostasis
  • Int'l Joint Research
• [Presentation] ONO-1600586, an oral direct factor XIa inhibitor, suppresses thrombus formation in rabbit jugular vein without bleeding tendency. (2020)
  • Author(s): Oguri N, Yamashita A, Okawa H, Kouyama S, Asada Y.
  • Organizer: 28th Congress of International Society on Thrombosis and Haemostasis
  • Int'l Joint Research
• [Presentation] 動脈硬化性血栓の形成機序 (2020)
  • Author(s): 山下 篤、浅田祐士郎
  • Organizer: 第109回日本病理学会総会
  • Invited
• [Presentation] 血管病理と心血管イメージング：プラーク代謝とイメージング (2019)
  • Author(s): 山下 篤、浅田祐士郎
  • Organizer: 第51回日本動脈硬化学会総会
  • Invited
• [Presentation] 冠動脈の血栓形成能評価に繋がる血管代謝イメージング (2019)
  • Author(s): 山下 篤、浅田祐士郎
  • Organizer: 第29回日本心血管画像動態学会
  • Invited
• [Remarks]
  • URL: http://www.med.miyazaki-u.ac.jp/home/pathophysiology/