Combined anticoagulation protocol using TFPI, antithrombin and thrombomodulin during cardiopulmonary bypass

• Project/Area Number: 23390332
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular surgery
• Research Institution: University of Tsukuba
• Principal Investigator: HIRAMATSU Yuji 筑波大学, 医学医療系, 教授 (30302417)
• Co-Investigator(Kenkyū-buntansha): AGEYAMA Naohide 独立行政法人医薬基盤研究所, 霊長類医科学センター, 研究員 (50399458) ; SAKAKIBARA Yuzuru 筑波大学, 医学医療系, 教授 (60192085) ; HASEGAWA Yuichi 筑波大学, 医学医療系, 准教授 (00251059) ; GOTO Yukinobu 筑波大学, 医学医療系, 講師 (20451700)
• Project Period (FY): 2011-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2011: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 体外循環 / トロンビン / 組織因子 / 外因系凝固 / 内因系凝固 / TFPI / アンチトロンビン / トロンボモジュリン / 抗凝固 / ヘパリン / カニクイザル / 心臓外科 / 霊長類

Outline of Final Research Achievements

We aimed to establish a new anticoagulation protocol during cardiopulmonary bypass (CPB). Our hypothesis was that administration of high-dose heparin causes massive release of tissue factor pathway inhibitor (TFPI) from endothelial cells, and antithrombin or thrombomodulin provides additional thrombin inhibition. We performed experiments using primate (Macaca fascicularis, 5kg) CPB model. Plasma TFPI was enhanced by pre-heparinization, and levels of thrombin generation were reduced through inhibition of extrinsic pathway when compared with control group. Inhibition of thrombin generation was further enhanced by the addition of antithrombin and thrombomodulin. Anti-inflammatory effects of either drug were not revealed in our anticoagulation protocol. Combined anticoagulation protocol with TFPI, antithrombin and thrombomodulin may be a promising alternative to heparin toward inhibition of both intrinsic and extrinsic pathways during CPB.

Research Products

• [Journal Article] Cardiopulmonary bypass induces recruitment of bone marrow-derived leukocytes to the lungs in monkeys (2014)
  • Author(s): Goto Y, Hiramatsu Y, Ageyama N, Sato S, Kanemoto S, Sato Y, Sakakibara Y.
  • Journal Title: The Annals of Thoracic Surgery Volume: ９７ Pages: 617-623
  • Peer Reviewed
• [Journal Article] Early heparin administration attenuates tissue factor mediated thrombin generation during simulated cardiopulmonary bypass (2014)
  • Author(s): Morizumi S, Hiramatsu Y, Matsuzaki K, Goto Y, Sato S, Abe M, Kato H, Matsubara M, Sakakibara Y.
  • Journal Title: Journal of Cardiac Surgery Volume: ２９ Pages: 35-40
  • Peer Reviewed
• [Presentation] カニクイザルを用いたin vivo体外循環モデルの確立 (2014)
  • Author(s): 森谷忠生, 平松祐司, 古垣達也, 茂木芳賢, 縮 恭一, 山本純偉, 金本真也, 後藤行延, 揚山直英, 松下昌之助, 榊原 謙.
  • Organizer: 第52回日本人工臓器学会大会
  • Place of Presentation: 京王プラザホテル札幌（札幌市）
  • Year and Date: 2014-10-19
• [Presentation] Early heparin administration increases plasma tissue factor pathway inhibitor and attenuates tissue factor mediated thrombin generation during simulated cardiopulmonary bypass (2011)
  • Author(s): Sei Morizumi, Yuji Hiramatsu, Yuzuru Sakakibara
  • Organizer: Federation of American Societies for Experimental Biology (FASEB)
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2011-04-09
• [Presentation] Cardiopulmonary bypass accelerates bone-marrow leukocyte release and recruitment into the lung in primate model
  • Author(s): Yukinobu Goto, Yuji Hiramatsu
  • Organizer: American Thoracic Society International Conference 2012
  • Place of Presentation: San Francisco Convention Center, CA, USA