Role of intrinsic coagulation factors on atherothrombosis

• Project/Area Number: 16K08670
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: University of Miyazaki
• Principal Investigator: Yamashita Atsushi 宮崎大学, 医学部, 助教 (90372797)
• Co-Investigator(Kenkyū-buntansha): 盛口 清香 宮崎大学, 医学部, 助教 (90468041)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 動脈硬化性血栓 / 血液凝固FXI因子 / 組織因子 / キヌレニン代謝酵素 / 血液凝固XI因子 / 動脈硬化症 / 血栓症 / 内因系凝固因子 / 動脈血栓症 / 動脈硬化性血栓症

Outline of Final Research Achievements

We investigated the role of intrinsic coagulation factors and extrinsic coagulation factor (TF: tissue factor) on atherothrombus formation. We found small amounts of collagenous matrix and neutrophil extracellular trap, activator of intrinsic factors, on ruptured coronary plaques. TF but not coagulation factor XI contributed mural thrombus formation in a rabbit model of plaque erosion. We found over expression of a tryptophan metabolic enzyme in thrombotic coronary plaques and its contribution of TF expression on activated macrophages. It is necessary to examine the role of intrinsic coagulation factors on thrombus growth on disrupted plaques.

Academic Significance and Societal Importance of the Research Achievements

本研究では、動脈硬化性プラークにおける内因系凝固因子（FXI)、外因系因子(組織因子)の機能を検討し、動脈硬化性血栓の形成メカニズムの解明を目的としました。冠動脈の血栓性プラークには内因系因子の活性化因子が少なく、組織因子が過剰に発現していました。その組織因子発現にトリプトファンのキヌレニン代謝酵素が作用していることを明らかにしました。動物モデルの検討で、組織因子は血栓形成の早期に作用していましたが、血液凝固FXI因子はその作用は明確ではありませんでした。今後、血栓の成長過程におけるFXIの作用を検討する必要があります。

Research Products

• [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: Cardiovasc Pathol 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: Thrombosis Research Volume: 177 Pages: 136-144
  • DOI: 10.1016/j.thromres.2019.03.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Thrombus Formation and Propagation in the Onset of Cardiovascular Events (2018)
  • Author(s): Asada Y, Yamashita A, Sato Y, Hatakeyama K
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 25 Issue: 8 Pages: 653-664
  • DOI: 10.5551/jat.RV17022
  • NAID: 130007429519
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2018-08-01
  • Peer Reviewed / Open Access
• [Journal Article] Indoleamine 2,3-dioxygenase 1 in coronary atherosclerotic plaque enhances tissue factor expression in activated macrophages (2018)
  • Author(s): Watanabe Yuki、Koyama Shohei、Yamashita Atsushi、Matsuura Yunosuke、Nishihira Kensaku、Kitamura Kazuo、Asada Yujiro
  • Journal Title: Research and Practice in Thrombosis and Haemostasis Volume: 2 Issue: 4 Pages: 726-735
  • DOI: 10.1002/rth2.12128
  • Peer Reviewed / Open Access
• [Journal Article] Informative three-dimensional survey of cell/tissue architectures in thick paraffin sections by simple low-vacuum scanning electron microscopy (2018)
  • Author(s): Sawaguchi A, Kamimura T, Yamashita A, Takahashi N, Ichikawa K, Aoyama F, Asada Y
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 7479-7479
  • DOI: 10.1038/s41598-018-25840-8
  • Peer Reviewed / Open Access
• [Journal Article] In vitro uptake and metabolism of [14C]acetate in rabbit atherosclerotic arteries: biological basis for atherosclerosis imaging with [11C]acetate. (2018)
  • Author(s): Yamasaki K, Yamashita A, Zhao Y, Shimizu Y, Nishii R, Kawai K, Tamaki N, Zhao S, Asada Y, Kuge Y.
  • Journal Title: Nucl Med Biol. Volume: 56 Pages: 21-25
  • DOI: 10.1016/j.nucmedbio.2017.08.003
  • NAID: 120006546743
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between thrombus age in aspirated coronary material and mid-term major adverse cardiac and cerebrovascular events in patients with acute myocardial infarction. (2018)
  • Author(s): Nishihira K, Shibata Y, Yamashita A, Kuriyama N, Asada Y.
  • Journal Title: Atherosclerosis. Volume: 268 Pages: 138-144
  • DOI: 10.1016/j.atherosclerosis.2017.12.001
  • Peer Reviewed / Open Access
• [Journal Article] Altered glucose metabolism and hypoxic response in alloxan-induced diabetic atherosclerosis in rabbits. (2017)
  • Author(s): Matsuura Y, Yamashita A, Zhao Y, Iwakiri T, Yamasaki K, Sugita C, Koshimoto C, Kitamura K, Kawai K, Tamaki N, Zhao S, Kuge Y, Asada Y.
  • Journal Title: PLoS One. Volume: 12 Issue: 4 Pages: e0175976-e0175976
  • DOI: 10.1371/journal.pone.0175976
  • Peer Reviewed / Open Access
• [Journal Article] Pathology of Coronary Atherosclerotic Plaques and Mechanisms of Plaque Disruption (2017)
  • Author(s): Yamashita A, Asada Y.
  • Journal Title: Annals of Nuclear Cardiology Volume: 3 Issue: 1 Pages: 66-72
  • DOI: 10.17996/anc.17-00011
  • NAID: 130006191110
  • ISSN: 2189-3926, 2424-1741
  • Peer Reviewed / Open Access
• [Journal Article] Asymptomatic Plaques of Lower Peripheral Arteries and Their Association with Cardiovascular Disease: An Autopsy Study (2017)
  • Author(s): Nakamura E, Sato Y, Iwakiri T, Yamashita A, Moriguchi-Goto S, Maekawa K, Gi T, Asada Y.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 24 Issue: 9 Pages: 921-927
  • DOI: 10.5551/jat.39669
  • NAID: 130006038435
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access
• [Journal Article] Morphological features of coronary plaques in WHHLMI rabbits (<i>Oryctolagus cuniculus</i>), an animal model for familial hypercholesterolemia (2017)
  • Author(s): Yamada S, Koike T, Nakagawa T, Kuniyoshi, N Ying Y, Itabe H, Yamashita A, Asada Y, Shiomi M.
  • Journal Title: Experimental Animals Volume: 66 Issue: 2 Pages: 145-157
  • DOI: 10.1538/expanim.16-0078
  • NAID: 130005635564
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed / Open Access
• [Journal Article] CD163 macrophage and erythrocyte contents in aspirated deep vein thrombus are associated with the time after onset: a pilot study. (2016)
  • Author(s): YFurukoji E, Gi T, Yamashita A, Moriguchi-Goto S, Kojima M, Sugita C, Sakae T, Sato Y, Hirai T, Asada Y.
  • Journal Title: Thromb J. 2016 Volume: 14 Issue: 1 Pages: 46-46
  • DOI: 10.1186/s12959-016-0122-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] プラークびらんと血流・血栓形成 (2018)
  • Author(s): 山下 篤
  • Organizer: 第50回日本動脈硬化学会総会
  • Invited
• [Presentation] 血栓形成における内因系凝固因子の関与：第XI因子の役割. (2018)
  • Author(s): 山下 篤
  • Organizer: 第59回日本脈感学会総会、第10回JCACシンポジウム
  • Invited
• [Remarks] 宮崎大学医学部病理学講座構造機能病態学分野
  • URL: http://www.med.miyazaki-u.ac.jp/home/pathophysiology/
• [Remarks] 宮崎大学医学部病理学講座構造機能病態学分野
  • URL: http://www.miyazaki-med.ac.jp/patho1/index.html