{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T19:26:25Z","timestamp":1774293985900,"version":"3.50.1"},"reference-count":26,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,2]],"date-time":"2022-05-02T00:00:00Z","timestamp":1651449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"apan Grants-in-Aid for Scientific Research (KAKENHI)","award":["18K08890"],"award-info":[{"award-number":["18K08890"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Yamakagashi (Rhabdophis tigrinus) inhabits Japan widely, and incidents involving its bites occur every year. Its bite causes disseminated intravascular coagulation when the amount of infused venom is high, and it can be fatal if treatment with Yamakagashi antivenom is delayed. Although Yamakagashi antivenom is used for treating Yamakagashi bites, it is an unapproved drug and its capacity for storage is limited. Hence, it is difficult to administer to patients promptly. As a therapeutic agent for this bite, we investigated the application of recombinant thrombomodulin alpha, a commercially available disseminated intravascular coagulation therapeutic agent. Its therapeutic effect on Yamakagashi venom was confirmed in a coagulation system of human plasma using in vitro Yamakagashi venom as well as a rat experimental model of disseminated intravascular coagulation using in vivo Yamakagashi venom. The administration of recombinant thrombomodulin alpha induced an effect that prolonged the blood coagulation time of Yamakagashi venom in vitro, and the drug was administered in vivo within 0.5 h after the administration of Yamakagashi venom to save rats. Blood coagulation markers such as platelet count, prothrombin time, fibrinogen concentration, and D-dimer levels recovered to normal values in rats. Therefore, recombinant thrombomodulin alpha may be used as a therapeutic agent for Yamakagashi bites.<\/jats:p>","DOI":"10.3390\/toxins14050322","type":"journal-article","created":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T08:21:25Z","timestamp":1651652485000},"page":"322","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Attempt for a Recombinant Thrombomodulin Alpha Treatment in a Rat Disseminated Intravascular Coagulation Model Using Yamakagashi (Rhabdophis tigrinus) Venom"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9400-1060","authenticated-orcid":false,"given":"Akihiko","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Management Department of Biosafety and Laboratory Animal, and Pathogen Bank, National Institute of Infectious Diseases, Tokyo 208-0011, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Biomedical Laboratory Sciences, Faculty of Life Sciences Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toru","family":"Hifumi","sequence":"additional","affiliation":[{"name":"Emergency and Critical Care Medicine, St. Luke\u2019s International Hospital, Tokyo 104-8560, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1055\/s-0039-1687890","article-title":"Disseminated intravascular coagulation in cancer: An update","volume":"45","author":"Levi","year":"2019","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1055\/s-0038-1673684","article-title":"The clinical significance of fibrin monomers","volume":"118","author":"Refaai","year":"2018","journal-title":"Thromb. Haemost."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"269","DOI":"10.4266\/acc.2019.00591","article-title":"Risk factor, monitoring, and treatment for snakebite induced coagulopathy: A multicenter retrospective study","volume":"34","author":"Jeon","year":"2019","journal-title":"Acute Crit. Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8","DOI":"10.5358\/hsj.33.8","article-title":"Home range and movements of Rhabdophis tigrinus in a mountain habitat of Kyoto, Japan","volume":"33","author":"Kojima","year":"2014","journal-title":"Curr. Herpetol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1080\/15563650.2018.1540045","article-title":"Early pathology in venom-induced consumption coag-ulopathy by Rhabdophis tigrinus (Yamakagashi) envenomation","volume":"57","author":"Ichiki","year":"2019","journal-title":"Clin. Toxicol. (Phila)"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"157","DOI":"10.2131\/jts.31.157","article-title":"Characterization of a novel metalloprotease in duvernoy\u2019s gland of Rhabdophis tigrinus","volume":"31","author":"Komori","year":"2006","journal-title":"J. Toxicol. Sci."},{"key":"ref_7","first-page":"7","article-title":"Study on the pathogenesis of envenomation by the Japanese colubrid snake, Yamakagashi, Rhabdophis Trgrinus Tigrinus 1. Study on the toxicity of the venom","volume":"15","author":"Sakai","year":"1983","journal-title":"Snake"},{"key":"ref_8","first-page":"113","article-title":"Envenomation from the bite of the Japanese colubrid snake Rhabdophis tigrinus (Boie)","volume":"30","author":"Mittleman","year":"1974","journal-title":"Herpetologica"},{"key":"ref_9","first-page":"256","article-title":"A case of severe defibrination syndrome due to snake (Rhabdophis tigrinus) bite","volume":"24","author":"Mori","year":"1983","journal-title":"Rinsho Ketsueki"},{"key":"ref_10","first-page":"11","article-title":"Study on the pathogenesis of envenomation by the Japanese colubrid snake, Yamakagashi, Rhabdophis tigrinus tigrinus","volume":"22","author":"Sakai","year":"1990","journal-title":"Snake"},{"key":"ref_11","first-page":"36","article-title":"A case of defibrinnation syndrome due to Japanese colubrid snake, Yamakagashi (Rhabdophis t. tigrinus), bite treated with antivenom","volume":"23","author":"Akimoto","year":"1991","journal-title":"Snake"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1097\/01.shk.0000239762.90335.68","article-title":"Serum albumin levels anticipate antithrombin III activities before and after antithrombin III agent in critical patients with disseminated intravascular coagulation","volume":"27","author":"Aibiki","year":"2007","journal-title":"Shock"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"604","DOI":"10.3892\/etm.2013.1466","article-title":"Low-dose heparin as treatment for early disseminated intravascular coagulation during sepsis: A prospective clinical study","volume":"7","author":"Liu","year":"2014","journal-title":"Exp. Ther. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e12981","DOI":"10.1097\/MD.0000000000012981","article-title":"Successful treatment of disseminated intravascular coagulation by recombinant human soluble thrombomodulin in patients with acute myeloid leukemia","volume":"97","author":"Ookura","year":"2018","journal-title":"Medicine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s40780-020-00183-7","article-title":"Factors influencing the effectiveness of recombinant human soluble thrombomodulin on disseminated intravascular coagulation: A retrospective study","volume":"6","author":"Asai","year":"2020","journal-title":"J. Pharm. Health Care Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7944","DOI":"10.1016\/S0021-9258(18)34276-5","article-title":"Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation","volume":"257","author":"Esmon","year":"1982","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1002\/j.1460-2075.1987.tb02448.x","article-title":"Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation","volume":"6","author":"Suzuki","year":"1987","journal-title":"EMBO J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/j.1538-7836.2006.02267.x","article-title":"Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: Results of a phase III, randomized, double-blind clinical trial","volume":"5","author":"Saito","year":"2007","journal-title":"J. Thromb. Haemost."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1007\/s00540-021-02971-3","article-title":"Recombinant human thrombomodulin for pneumonia-induced severe ARDS complicated by DIC in children: A preliminary study","volume":"35","author":"Hirata","year":"2021","journal-title":"J. Anesth."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"533","DOI":"10.3748\/wjg.v21.i2.533","article-title":"Thrombomodulin in the management of acute cholangitis-induced disseminated intravascular coagulation","volume":"21","author":"Suetani","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Yamaguchi, T., Kitajima, Y., Miyauchi, Y., Izawa, K., Tanaka, M., Hirata, M., Sadatsuki, Y., and Ogawa, Y. (2018). Assessment of bleeding in patients with disseminated intravascular coagulation after receiving surgery and recombinant human soluble thrombomodulin: A cohort study using a database. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0205146"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/vec.12130","article-title":"Traumatic coagulopathy-Part 1: Pathophysiology and diagnosis","volume":"24","author":"Palmer","year":"2014","journal-title":"J. Vet. Emerg. Crit. Care (San Antonio)"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Yamamoto, A., Ito, T., and Hifumi, T. (2021). Attempt to develop rat disseminated intravascular coagulation model using Yamakagashi (Rhabdophis tigrinus) venom injection. Toxins, 13.","DOI":"10.3390\/toxins13020160"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1016\/j.jacc.2017.09.024","article-title":"A Test in Context: D-Dimer","volume":"70","author":"Jeffrey","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"397","DOI":"10.7883\/yoken.64.397","article-title":"Experimental manufacture of equine antivenom against Yamakagashi (Rhabdophis tigrinus)","volume":"64","author":"Morokuma","year":"2011","journal-title":"Jpn. J. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/0049-3848(92)90188-G","article-title":"Rapid quantitative evaluation of plasma D-dimer levels in thrombotic states using an automated latex photometric immunoassay","volume":"66","author":"Kario","year":"1992","journal-title":"Thromb. Res."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/14\/5\/322\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:05:30Z","timestamp":1760137530000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/14\/5\/322"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,2]]},"references-count":26,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["toxins14050322"],"URL":"https:\/\/doi.org\/10.3390\/toxins14050322","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,2]]}}}