The mechanism of adenosine diphosphate receptor mediated thrombus formation in antiphospholipid syndrome.

• Project/Area Number: 25670455
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Collagenous pathology/Allergology
• Research Institution: Hokkaido University
• Principal Investigator: ATSUMI Tatsuya 北海道大学, 医学(系)研究科(研究院), 教授 (20301905)
• Co-Investigator(Kenkyū-buntansha): OKU Kenji 北海道大学, 北海道大学病院, 助教 (70544295)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 抗リン脂質抗体 / 血小板 / アデノシン2リン酸（ADP） / アデノシン2リン酸

Outline of Final Research Achievements

With any of the subtypes of 231D, a mouse monoclonal antiphospholipid antibody, dysfunction of adenosine diphosphate (ADP) induced platelet aggregation was not detected in a reproducible manner. By contrast, EY2C9, a human monoclonal antiphospholipid antibody or purified IgG from sera of antiphospholipid syndrome(APS) patients induced suppression of ADP triggered platelet aggregation. The mechanism of the phenomena is under analysis.
In flow-analysis with the micro-tip mimicked sclerotic-artery, monoclonal antiphospholipid antibody did not show the decisive tendency of creating white blood clot. Inhibitor of P2Y12, the major ADP receptor on the platelet membrane, is widely used for the prophylaxis of thrombosis in patients with the history of arterial thrombosis including APS patients. However, our data suggest that there may be certain amount of patients in APS that the ADP inhibitor is not effective enough for preventing the recurrent thrombosis.

Research Products

• [Journal Article] Clinical features and pregnancy outcome in antiphospholipid syndrome patients with history of severe pregnancy complications. (2015)
  • Author(s): Matsuki Y, Atsumi T, Yamaguchi K, Hisano M, Arata N, Oku K, Watanabe N, Sago H, Takasaki Y, Murashima A
  • Journal Title: Modern Rheumatology Volume: 25(2) Issue: 2 Pages: 215-218
  • DOI: 10.3109/14397595.2014.942503
  • Peer Reviewed / Open Access
• [Journal Article] An independent validation of the Global Anti-Phospholipid Syndrome Score in a Japanese cohort of patients with autoimmune diseases. (2015)
  • Author(s): Oku K, Amengual O, Bohgaki T, Horita T, Yasuda S, Atsumi T.
  • Journal Title: Lupus Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comparative analysis of different enzyme immunoassays for assessment of phosphatidylserine-dependent antiprothrombin antibodies. (2014)
  • Author(s): Amengual O, Horita T, Binder W, Norman GL, Shums Z, Kato M, Otomo K, Fujieda Y, Oku K, Bohgaki T, Yasuda S, Atsumi T
  • Journal Title: Rheumatol Int. Volume: 34 Issue: 9 Pages: 1225-1230
  • DOI: 10.1007/s00296-014-2951-0
  • NAID: 120005656328
  • Peer Reviewed / Open Access
• [Journal Article] Long-term outcome in Japanese patients with lupus nephritis. (2014)
  • Author(s): Kono M, Yasuda S, Kato M, Kanetsuka Y, Kurita T, Fujieda Y, Otomo K, Horita T, Oba K, Kondo M, Mukai M, Yanai M, Fukasawa Y, Atsumi T
  • Journal Title: Lupus Volume: 23 Issue: 11 Pages: 1124-1132
  • DOI: 10.1177/0961203314536246
  • Peer Reviewed / Open Access
• [Journal Article] Testing for antiphospholipid antibodies with solid phase assays: guidance from the SSC of the ISTH. (2014)
  • Author(s): Devreese KM, Pierangeli SS, de Laat B, Tripodi A, Atsumi T, Ortel TL
  • Journal Title: J Thromb Haemost Volume: 12(5) Issue: 5 Pages: 792-795
  • DOI: 10.1111/jth.12537
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Antiphospholipid Scoring: significance in diagnosis and prognosis. (2014)
  • Author(s): Oku K, Amengual O, Atsumi T
  • Journal Title: Lupus Volume: 23 Issue: 12 Pages: 1269-1272
  • DOI: 10.1177/0961203314537361
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Autoantibodies to IgG/HLA class II complexes are associated with rheumatoid arthritis susceptibility (2014)
  • Author(s): Jin H, Arase N, Hirayasu K, Kohyama M, Suenaga T, Saito F, Tanimura K, Matsuoka S, Ebina K, Shi K, Toyama-Sorimachi N, Yasuda S, Horita T, Hiwa R, Takasugi K, Ohmura K, Yoshikawa H, Saito T, Atsumi T, Sasazuki T, Katayama I, Lanier LL, Arase H
  • Journal Title: Proceedings of National Academy of Science USA Volume: 111 Issue: 10 Pages: 3787-3792
  • DOI: 10.1073/pnas.1401105111
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced formation and disordered regulation of NETs in MPO-ANCA-associated microscopic polyangiitis. (2014)
  • Author(s): Nakazawa D, Shida H, Tomaru U, Yoshida M, Nishio S, Atsumi T, Ishizu A.
  • Journal Title: J Am Soc Nephrol Volume: -
  • Peer Reviewed
• [Journal Article] Psychological stress in a Japanese population with systemic lupus erythematosus: Finding from KYSS study. (2014)
  • Author(s): Takahashi H, Washio M, Kiyohara C, Tada Y, Asami T, Ide S, Atsumi T, Kobashi G, Yamamoto M, Horiuchi T.
  • Journal Title: Mod Rheumatol Volume: -
  • Peer Reviewed
• [Journal Article] Modifying effect of N-acetyltransferase 2 genotype on the association between systemic lupus erythematosus and consumption of alcohol and caffeine-rich beverages. (2014)
  • Author(s): Kiyohara C1, Washio M, Horiuchi T, Asami T, Ide S, Atsumi T, Kobashi G, Takahashi H, Tada Y; Kyushu Sapporo SLE (KYSS) Study Group.
  • Journal Title: Arthritis Care Res (Hoboken) Volume: 66 Issue: 7 Pages: 1048-1056
  • DOI: 10.1002/acr.22282
  • Peer Reviewed / Open Access
• [Journal Article] Amerged presentation of clinical and radiographic data using probability plots in a clinical trial, the JESMR study (2013)
  • Author(s): Kameda H, Kanbe K, Sato E, Ueki Y, Saito K, Nagaoka S, Hidaka T, Atsumi T, Tsukano M, Kasama T, Shiozawa S, Tanaka Y, Yamanaka H, Takeuchi T
  • Journal Title: Ann Rheum Dis Volume: 72 Issue: 2 Pages: 310-2
  • DOI: 10.1136/annrheumdis-2012-201804
  • Peer Reviewed
• [Journal Article] Elevation of KL-6 serum levels in clinical trials of tumor necrosis factor inhibitors in patients withrheumatoid arthritis: a report from the Japan College of Rheumatology Ad Hoc Committee for Safety of Biological DMARDs (2013)
  • Author(s): Harigai M, Takamura A, Atsumi T, Dohi M, Hirata S, Kameda H, Nagasawa H, Seto Y, Koike T, Miyasaka N
  • Journal Title: Mod Rheumatol Volume: 23(2) Issue: 2 Pages: 284-96
  • DOI: 10.1007/s10165-012-0657-2
  • NAID: 10031167700
  • Peer Reviewed
• [Journal Article] A retrospective study of serum KL-6 levels during treatment with biological disease-modifyingantirheumatic drugs in rheumatoid arthritis patients: a report from the Ad Hoc Committee for Safety of Biological DMARDs of the Japan College of Rheumatology (2013)
  • Author(s): Takamura A, Hirata S, Nagasawa H, Kameda H, Seto Y, Atsumi T, Dohi M, Koike T, Miyasaka N, Harugau M
  • Journal Title: Mod Rheumatol Volume: 23(2) Issue: 2 Pages: 297-303
  • DOI: 10.1007/s10165-012-0658-1
  • Peer Reviewed
• [Journal Article] Overexpression of TNF-α-converting enzyme in fibroblasts augments dermal fibrosis after inflammation. (2013)
  • Author(s): Fukaya S
  • Journal Title: Lab Invest. Volume: 93 Issue: 1 Pages: 72-80
  • DOI: 10.1038/labinvest.2012.153
  • Peer Reviewed
• [Journal Article] Essential role of the p38 mitogen-activated protein kinase pathway in tissue factor gene expression mediated by the phosphatidylserine-dependent antiprothrombin antibody. (2013)
  • Author(s): Oku K, Amengual O, Zigon P, Horita T, Yasuda S, Atsumi T.
  • Journal Title: Rheumatology (Oxford). Volume: 52 Issue: 10 Pages: 1775-1784
  • DOI: 10.1093/rheumatology/ket234
  • Peer Reviewed
• [Journal Article] The involvement of CD36 in monocyte activation by antiphospholipid antibodies. (2013)
  • Author(s): Kato M, Atsumi T, Oku K, Amengual O, Nakagawa H, Fujieda Y, Otomo K, Horita T, Yasuda S, Koike T.
  • Journal Title: Lupus Volume: 22 Issue: 8 Pages: 761-771
  • DOI: 10.1177/0961203313490242
  • Peer Reviewed
• [Journal Article] AMPK is involved in the regulation of incretin receptors expression in pancreatic islets under a low glucose concentration. (2013)
  • Author(s): Tajima K, Shirakawa J, Togashi Y, Inoue H, Sato K, Orime K, Ito Y, Kaji M, Sakamoto E, Nakamura A, Aoki K, Goshima Y, Atsumi T, Terauchi Y.
  • Journal Title: PLoS One. Volume: 8 Issue: 5 Pages: e64633-e64633
  • DOI: 10.1371/journal.pone.0064633
  • Peer Reviewed
• [Journal Article] Prediction of response to treatment by gene expression profiling of peripheral blood in patients with microscopic polyangiitis. (2013)
  • Author(s): Ishizu A, Tomaru U, Murai T, Yamamoto T, Atsumi T, Yoshiki T, Yumura W, Yamagata K, Yamada H, Kumagai S, Kurokawa MS, Suka M, Makino H, Ozaki S.
  • Journal Title: PLOS ONE Volume: 8 Issue: 5 Pages: e63182-e63182
  • DOI: 10.1371/journal.pone.0063182
  • Peer Reviewed
• [Journal Article] Epalrestat improves diabetic wound healing via increased expression of nerve growth factor. (2013)
  • Author(s): Osamu Nakagaki
  • Journal Title: Exp Clin Endocrinol Diabetes Volume: 121(2) Issue: 02 Pages: 84-89
  • DOI: 10.1055/s-0032-1333279
  • Peer Reviewed
• [Journal Article] Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl/6 Mice. (2013)
  • Author(s): Tajima K, Nakamura A, Shirakawa J, Togashi Y, Orime K, Sato K, Inoue H, Kaji M, Sakamoto E, Ito Y, Aoki K, Nagashima Y, Atsumi T, Terauchi Y.
  • Journal Title: Am. J. Physiol. Endocrinol. Metab. Volume: 305 Issue: 8 Pages: 987-998
  • DOI: 10.1152/ajpendo.00133.2013
  • Peer Reviewed
• [Journal Article] Phospholipid scramblase 1 expression is enhanced in patients with antiphospholipid syndrome (2012)
  • Author(s): Amengual O, Atsumi T, Oku K, Suzuki E, Horita T, Yasuda S, Koike T
  • Journal Title: Mod Rheumatol Volume: 23(1) Issue: 1 Pages: 81-8
  • DOI: 10.1007/s10165-012-0642-9
  • NAID: 10031167669
  • Peer Reviewed
• [Journal Article] Positive synovial vascularity in patients with low disease activity indicates smouldering inflammation leading to joint damage in rheumatoid arthritis: time-integrated joint inflammation estimated by synovialvascularity in each finger joint (2012)
  • Author(s): Fukae J, Isobe M, Kitano A, Henmi M, Sakamoto F, Narita A, Ito T, Mitsuzaki A, Shimizu M, Tanimura K, Matsuhashi M, Kamishima T, Atsumi T, Koike T
  • Journal Title: Rheumatology Volume: 52(3) Issue: 3 Pages: 523-8
  • DOI: 10.1093/rheumatology/kes310
  • Peer Reviewed
• [Presentation] Markers of thrombotic events in autoimmune diseases:comparison of Antiphospholipid Score (aPL-S) and Global Anti-phospholipid Syndrome Score (GAPSS) (2014)
  • Author(s): 1.Oku K, Amengual O, Hisada R, Oomura K, Nakagawa I, Watanabe T, Bohgaki T, Horita T, Yasuda S, Atsumi T.
  • Organizer: The 78th American College of Rheumatology Annual Meeting
  • Place of Presentation: Boston convention Exhibision center(Boston,USA)
  • Year and Date: 2014-11-14 – 2014-11-19
• [Presentation] The protective effects of statins for thrombosis in patients with systemic lupus erythematosus positive for antiphospholipid antibodies. (2014)
  • Author(s): Watanabe T, Oku K, Amengual O, Sugawara E, Hisada R, Ohmura K, Shimamura S, Nakagawa I, Noguchi A, Fukui T, Shida H, Kono M, Shimizu Y, Kurita T, Bohgaki T, Horita T, Yasuda S, Atsumi T
  • Organizer: The 78th Annual Meeting of American College of Rheumatology
  • Place of Presentation: Boston convention Exhibision center(Boston,USA)
  • Year and Date: 2014-11-14 – 2014-11-19
• [Presentation] International multi-centre study in Phosphatidylserine-dependent-antiprothrombin antibodies (aPS/PT) for the diagnosis of antiphospholipid syndrome. (2014)
  • Author(s): Atsumi T
  • Organizer: 60th Annual Meeting of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH).
  • Place of Presentation: The Wisconsin Center (Milwaukee,USA)
  • Year and Date: 2014-06-23 – 2014-06-26
  • Invited
• [Presentation] Antiphospholipid syndrome. (2014)
  • Author(s): Atsumi T.
  • Organizer: 9th International Congress on Autoimmunity.
  • Place of Presentation: Nice - Acropolis 1 (Nice, France)
  • Invited
• [Presentation] Antiphospholipid Scoring: significance in diagnosis and prognosis. (2013)
  • Author(s): Atsumi T.
  • Organizer: 14th International Congress on Antiphospholipid Antibodies
  • Place of Presentation: Hotel Sofitel Rio de Janeiro Copacabana(Rio de Janeiro, Brazil)
  • Invited
• [Presentation] Antibodies to Prothrombin. (2013)
  • Author(s): Atsumi T, Amengual O.
  • Organizer: 14th International Congress on Antiphospholipid Antibodies
  • Place of Presentation: Hotel Sofitel Rio de Janeiro Copacabana(Rio de Janeiro, Brazil)
  • Invited
• [Presentation] Rheumatology and Autoimmune diseases: from Manyo-shu to future. (2013)
  • Author(s): Atsumi T.
  • Organizer: Seoul, South Korea, 1st HUH-SNUH Joint Symposium
  • Place of Presentation: Seou University Hospital (Seoul, South Korea)
  • Invited
• [Book] 木崎昌弘 編：血液病学 (2014)
  • Author(s): 渡邊俊之、渥美達也
  • Total Pages: 688
  • Publisher: 中外医学社
• [Book] 矢崎義雄総編：内科学 第10版 (2014)
  • Author(s): 渥美達也
  • Total Pages: 2548
  • Publisher: 朝倉書店
• [Book] 永井良三、大田健編集：今日の治療と看護 改訂第３版 (2013)
  • Author(s): 渥美達也
  • Total Pages: 1493
  • Publisher: 南江堂
• [Book] 田中良哉 編：免疫・アレルギー疾患の分子標的と治療薬事典 (2013)
  • Author(s): 坊垣暁之、渥美達也
  • Total Pages: 375
  • Publisher: 羊土社