{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T08:01:52Z","timestamp":1778659312366,"version":"3.51.4"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,7,18]],"date-time":"2016-07-18T00:00:00Z","timestamp":1468800000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2016,7,18]],"date-time":"2016-07-18T00:00:00Z","timestamp":1468800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Bone Marrow Transplant"],"published-print":{"date-parts":[[2017,1]]},"DOI":"10.1038\/bmt.2016.195","type":"journal-article","created":{"date-parts":[[2016,7,18]],"date-time":"2016-07-18T13:44:41Z","timestamp":1468849481000},"page":"73-79","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The fifth epidermal growth factor-like region of thrombomodulin exerts cytoprotective function and prevents SOS in a murine model"],"prefix":"10.1038","volume":"52","author":[{"given":"T","family":"Ikezoe","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Nishioka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Furihata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H","family":"Yurimoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G","family":"Honda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Yokoyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,7,18]]},"reference":[{"key":"BFbmt2016195_CR1","doi-asserted-by":"publisher","first-page":"1891","DOI":"10.1002\/j.1460-2075.1987.tb02448.x","volume":"6","author":"K Suzuki","year":"1987","unstructured":"Suzuki K, Kusumoto H, Deyashiki Y, Nishioka J, Maruyama I, Zushi M et al. Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation. EMBO J 1987; 6: 1891\u20131897.","journal-title":"EMBO J"},{"key":"BFbmt2016195_CR2","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1182\/blood.V75.2.329.329","volume":"75","author":"WA Dittman","year":"1990","unstructured":"Dittman WA, Majerus PW . Structure and function of thrombomodulin: a natural anticoagulant. Blood 1990; 75: 329\u2013336.","journal-title":"Blood"},{"key":"BFbmt2016195_CR3","doi-asserted-by":"publisher","first-page":"3310","DOI":"10.1016\/j.febslet.2005.03.001","volume":"579","author":"B Dahlback","year":"2005","unstructured":"Dahlback B, Villoutreix BO . The anticoagulation protein C pathway. FEBS Lett 2005; 579: 3310\u20133316.","journal-title":"FEBS Lett"},{"key":"BFbmt2016195_CR4","doi-asserted-by":"crossref","first-page":"3352","DOI":"10.1016\/S0021-9258(18)94073-1","volume":"264","author":"DJ Stearns","year":"1989","unstructured":"Stearns DJ, Kurosawa S, Esmon CT . Microthrombomodulin. Residues 310\u2013486 from the epidermal growth factor precursor homology domain of thrombomodulin will accelerate protein C activation. J Biol Chem 1989; 264: 3352\u20133356.","journal-title":"J Biol Chem"},{"key":"BFbmt2016195_CR5","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1172\/JCI22782","volume":"115","author":"K Abeyama","year":"2005","unstructured":"Abeyama K, Stern DM, Ito Y, Kawahara K, Yoshimoto Y, Tanaka M et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel anti-inflammatory mechanism. J Clin Invest 2005; 115: 1267\u20131274.","journal-title":"J Clin Invest"},{"key":"BFbmt2016195_CR6","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1084\/jem.20020077","volume":"196","author":"EM Conway","year":"2002","unstructured":"Conway EM, Van de Wouwer M, Pollefeyt S, Jurk K, Van Aken H, De Vriese et al. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways. J Exp Med 2002; 196: 565\u2013577.","journal-title":"J Exp Med"},{"key":"BFbmt2016195_CR7","doi-asserted-by":"publisher","first-page":"2259","DOI":"10.1161\/ATVBAHA.112.251157","volume":"32","author":"T Ikezoe","year":"2012","unstructured":"Ikezoe T, Yang J, Nishioka C, Honda G, Furihata M, Yokoyama A . Thrombomodulin protects endothelial cells from a calcineurin inhibitor-induced cytotoxicity by upregulation of extracellular signal-regulated kinase\/myeloid leukemia cell-1 signaling. Arterioscler Thromb Vasc Biol 2012; 32: 2259\u20132270.","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"BFbmt2016195_CR8","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1038\/bmt.2009.242","volume":"45","author":"M Sakai","year":"2010","unstructured":"Sakai M, Ikezoe T, Bandobashi K, Togitani K, Yokoyama A . Successful treatment of transplantation-associated thrombotic microangiopathy with recombinant human soluble thrombomodulin. Bone Marrow Transplant 2010; 45: 803\u2013805.","journal-title":"Bone Marrow Transplant"},{"key":"BFbmt2016195_CR9","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1038\/bmt.2009.217","volume":"45","author":"T Ikezoe","year":"2010","unstructured":"Ikezoe T, Togitani K, Komatsu N, Isaka M, Yokoyama A . Successful treatment of sinusoidal obstructive syndrome after hematopoietic stem cell transplantation with recombinant human soluble thrombomodulin. Bone Marrow Transplant 2010; 45: 783\u2013785.","journal-title":"Bone Marrow Transplant"},{"key":"BFbmt2016195_CR10","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/bmt.2010.158","volume":"46","author":"T Ikezoe","year":"2011","unstructured":"Ikezoe T, Takeuchi A, Taniguchi A, Togitani K, Yokoyama A . Recombinant human soluble thrombomodulin counteracts capillary leakage associated with engraftment syndrome. Bone Marrow Transplant 2011; 46: 616\u2013618.","journal-title":"Bone Marrow Transplant"},{"key":"BFbmt2016195_CR11","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.1038\/bmt.2011.65","volume":"46","author":"E Carreras","year":"2011","unstructured":"Carreras E, Diaz-Ricart M . The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transplant 2011; 46: 1495\u20131502.","journal-title":"Bone Marrow Transplant"},{"key":"BFbmt2016195_CR12","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1111\/ejh.12188","volume":"91","author":"T Ikezoe","year":"2013","unstructured":"Ikezoe T, Takeuchi A, Chi S, Takaoka M, Anabuki K, Kim T et al. Effect of recombinant human soluble thrombomodulin on clinical outcomes of patients with coagulopathy after hematopoietic stem cell transplantation. Eur J Haematol 2013; 91: 442\u2013447.","journal-title":"Eur J Haematol"},{"key":"BFbmt2016195_CR13","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1111\/j.1538-7836.2006.02267.x","volume":"5","author":"H Saito","year":"2007","unstructured":"Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 2007; 5: 31\u201341.","journal-title":"J Thromb Haemost"},{"key":"BFbmt2016195_CR14","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1038\/bmt.2010.229","volume":"46","author":"M Tsubokura","year":"2011","unstructured":"Tsubokura M, Yamashita T, Inagaki L, Kobayashi T, Kakihana K, Wakabayashi S et al. Fatal intracranial hemorrhage following administration of recombinant thrombomodulin in a patient after cord blood transplantation. Bone Marrow Transplant 2011; 46: 1030\u20131031.","journal-title":"Bone Marrow Transplant"},{"key":"BFbmt2016195_CR15","volume-title":"Methods in Molecular Biology","author":"CM James","year":"2007","unstructured":"James CM. Pichia protocols 2nd edn. Methods in Molecular Biology Vol. 389. Springer: New York, NY, 2007."},{"key":"BFbmt2016195_CR16","doi-asserted-by":"publisher","first-page":"2058","DOI":"10.1271\/bbb.68.2058","volume":"68","author":"H Yurimoto","year":"2004","unstructured":"Yurimoto H, Yamane M, Kikuchi Y, Matsui H, Kato N, Sakai Y . The pro-peptide of Streptomyces mobaraensis transglutaminase functions in cis and in trans to mediate efficient secretion of active enzyme from methylotrophic yeasts. Biosci Biotechnol Biochem 2004; 68: 2058\u20132069.","journal-title":"Biosci Biotechnol Biochem"},{"key":"BFbmt2016195_CR17","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1124\/mol.64.6.1521","volume":"64","author":"T Ikezoe","year":"2003","unstructured":"Ikezoe T, Yang Y, Heber D, Taguchi H, Koeffler HP . PC-SPES: a potent inhibitor of nuclear factor-kappa B rescues mice from lipopolysaccharide-induced septic shock. Mol Pharmacol 2003; 64: 1521\u20131529.","journal-title":"Mol Pharmacol"},{"key":"BFbmt2016195_CR18","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1182\/blood-2003-07-2203","volume":"104","author":"T Ikezoe","year":"2004","unstructured":"Ikezoe T, Tanosaki S, Krug U, Liu B, Cohen P, Taguchi H et al. Insulin-like growth factor binding protein-3 antagonizes the effects of retinoids in myeloid leukemia cells. Blood 2004; 104: 237\u2013242.","journal-title":"Blood"},{"key":"BFbmt2016195_CR19","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1006\/biol.2001.0318","volume":"30","author":"S Niimi","year":"2002","unstructured":"Niimi S, Oshizawa T, Naotsuka M, Ohba S, Yokozawa A, Murata T et al. Establishment of a standard assay method for human thrombomodulin and determination of the activity of the Japanese reference standard. Biologicals 2002; 30: 69\u201376.","journal-title":"Biologicals"},{"key":"BFbmt2016195_CR20","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1111\/liv.12420","volume":"34","author":"K Nakamura","year":"2014","unstructured":"Nakamura K, Hatano E, Miyagawa-Hayashino A, Okuno M, Koyama Y, Narita M et al. Soluble thrombomodulin attenuates sinusoidal obstruction syndrome in rat through suppression of high mobility group box 1. Liver Int 2014; 34: 1473\u20131487.","journal-title":"Liver Int"},{"key":"BFbmt2016195_CR21","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.1161\/01.CIR.0000160364.05405.B5","volume":"111","author":"CS Shi","year":"2005","unstructured":"Shi CS, Shi GY, Chang YS, Han HS, Kuo CH, Liu C et al. Evidence of human thrombomodulin domain as a novel angiogenic factor. Circulation 2005; 111: 1627\u20131636.","journal-title":"Circulation"},{"key":"BFbmt2016195_CR22","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1016\/j.bbmt.2010.02.016","volume":"16","author":"C Cutler","year":"2010","unstructured":"Cutler C, Kim HT, Ayanian S, Bradwin G, Revta C, Aldridge J et al. Prediction of veno-occlusive disease using biomarkers of endothelial injury. Biol Blood Marrow Transplant 2010; 16: 1180\u20131185.","journal-title":"Biol Blood Marrow Transplant"},{"key":"BFbmt2016195_CR23","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.yexmp.2014.12.008","volume":"98","author":"J Qiao","year":"2015","unstructured":"Qiao J, Fu J, Fang T, Huang Y, Mi H, Yang N et al. Evaluation of the effects of preconditioning regimens on hepatic veno-occlusive disease in mice after hematopoietic stem cell transplantation. Exp Mol Pathol 2015; 98: 73\u201378.","journal-title":"Exp Mol Pathol"},{"key":"BFbmt2016195_CR24","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1182\/blood.V67.6.1773.1773","volume":"67","author":"B Rio","year":"1986","unstructured":"Rio B, Andreu G, Nicod A, Arrago JP, Dutrillaux F, Samama M et al. Thrombocytopenia in venocclusive disease after bone marrow transplantation or chemotherapy. Blood 1986; 67: 1773\u20131776.","journal-title":"Blood"},{"key":"BFbmt2016195_CR25","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1084\/jem.192.4.565","volume":"192","author":"U Andersson","year":"2000","unstructured":"Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 2000; 192: 565\u2013570.","journal-title":"J Exp Med"},{"key":"BFbmt2016195_CR26","doi-asserted-by":"publisher","first-page":"19919","DOI":"10.1074\/jbc.274.28.19919","volume":"274","author":"HJ Huttunen","year":"1999","unstructured":"Huttunen HJ, Fages C, Rauvala H . Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem 1999; 274: 19919\u201319924.","journal-title":"J Biol Chem"},{"key":"BFbmt2016195_CR27","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1038\/nm.2813","volume":"18","author":"H Geiger","year":"2012","unstructured":"Geiger H, Pawar SA, Kerschen EJ, Nattamai KJ, Hernandez I, Liang HP et al. Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity. Nat Med 2012; 18: 1123\u20131129.","journal-title":"Nat Med"},{"key":"BFbmt2016195_CR28","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1093\/cvr\/cvu239","volume":"105","author":"CH Kuo","year":"2015","unstructured":"Kuo CH, Sung MC, Chen PK, Chang BI, Lee FT, Cho CF et al. FGFR1 mediates recombinant thrombomodulin domain-induced angiogenesis. Cardiovasc Res 2015; 105: 107\u2013117.","journal-title":"Cardiovasc Res"},{"key":"BFbmt2016195_CR29","doi-asserted-by":"publisher","first-page":"1745","DOI":"10.1111\/j.1538-7836.2004.00927.x","volume":"2","author":"S Moll","year":"2004","unstructured":"Moll S, Lindley C, Pescatore S, Morrison D, Tsuruta K, Mohri M et al. Phase I study of a novel recombinant human soluble thrombomodulin, ART-123. J Thromb Haemost 2004; 2: 1745\u20131751.","journal-title":"J Thromb Haemost"},{"key":"BFbmt2016195_CR30","doi-asserted-by":"publisher","first-page":"247","DOI":"10.4172\/2157-7633.1000247","volume":"4","author":"S Nomura","year":"2014","unstructured":"Nomura S, Ishii K, Maeda Y, Katayama Y, Yagi H, Fujishima N et al. The preventative effects of recombinant thrombomodulin on transplantation-associated coagulopathy after allogeneic hematopoietic stem cell transplantation. J Stem Cell Res Therapy 2014; 4: 247.","journal-title":"J Stem Cell Res Therapy"},{"key":"BFbmt2016195_CR31","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/bmt.2014.208","volume":"50","author":"T Ikezoe","year":"2015","unstructured":"Ikezoe T, Yang J, Nishioka C, Yokoyama A . Thrombomodulin alleviates murine GVHD in association with an increase in the proportion of regulatory T cells in the spleen. Bone Marrow Transplant 2015; 50: 113\u2013120.","journal-title":"Bone Marrow Transplant"},{"key":"BFbmt2016195_CR32","doi-asserted-by":"publisher","first-page":"1550","DOI":"10.1016\/S0140-6736(09)60237-3","volume":"373","author":"JL Ferrara","year":"2009","unstructured":"Ferrara JL, Levine JE, Reddy P, Holler E . Graft-versus-host disease. Lancet 2009; 373: 1550\u20131561.","journal-title":"Lancet"}],"container-title":["Bone Marrow Transplantation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/bmt2016195.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/bmt2016195","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/bmt2016195.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T19:05:50Z","timestamp":1648062350000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/bmt2016195"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7,18]]},"references-count":32,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2017,1]]}},"alternative-id":["BFbmt2016195"],"URL":"https:\/\/doi.org\/10.1038\/bmt.2016.195","relation":{},"ISSN":["0268-3369","1476-5365"],"issn-type":[{"value":"0268-3369","type":"print"},{"value":"1476-5365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7,18]]},"assertion":[{"value":"13 April 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 June 2016","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 June 2016","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 July 2016","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"GH is an employee of Asahi Kasei Pharma. The remaining authors declare no competing financial interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}