{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T00:17:07Z","timestamp":1771028227165,"version":"3.50.1"},"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T00:00:00Z","timestamp":1733356800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20K18988"],"award-info":[{"award-number":["JP20K18988"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP22H03368"],"award-info":[{"award-number":["JP22H03368"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP23K24626"],"award-info":[{"award-number":["JP23K24626"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>Traumatic brain injury (TBI) is exacerbated in patients on antithrombotic medications, with warfarin leading to increased bleeding in some cases. However, the extent to which this bleeding increases lethality and its long-term effects remain unclear. This study aimed to investigate the exacerbation of TBI by warfarin treatment and comprehensively evaluate the impact of TBI on the anticoagulant effects of warfarin.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>We induced TBI in mice after pre-treatment with warfarin and analyzed TBI exacerbation based on the prothrombin time-international normalized ratio (PT-INR) value, brain hemorrhage volume, blood warfarin and 7-hydroxywarfarin levels, and cytochrome P450 2C9 (CYP2C9) protein expression. C57BL\/6J mice fed with a vitamin K-deficient diet received oral warfarin (low dose, 0.35 mg\/kg\/24 h; high dose, 0.70 mg\/kg\/24 h), and focal brain damage was induced in the cerebral cortices using a brain contusion device. Warfarin-treated injured mice were compared with sham-treated mice (scalp incision alone or scalp incision + bone window formation).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>When warfarin was administered, the PT-INR value and brain hemorrhage volume associated with cerebral contusion increased on the first day post-injury. High blood warfarin and 7-hydroxywarfarin levels were observed. However, no significant differences in CYP2C9 expression were observed between the groups.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Discussion<\/jats:title>\n<jats:p>Elevated warfarin levels post-injury can increase cerebral hemorrhage risk, possibly worsening TBI. TBI might also elevate warfarin levels, heightening its anticoagulant effects. Therefore, assessing injury severity levels and PT-INR values in patients with TBI on warfarin is crucial to anticipate delayed bleeding risks.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0314765","type":"journal-article","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T19:02:00Z","timestamp":1733425320000},"page":"e0314765","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mechanism of exacerbation of traumatic brain injury under warfarin anticoagulation in male mice"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0700-5700","authenticated-orcid":true,"given":"Yuki","family":"Tatara","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken-ichiro","family":"Nakao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Shimada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6510-5215","authenticated-orcid":true,"given":"Kazuhiko","family":"Kibayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,12,5]]},"reference":[{"key":"pone.0314765.ref001","doi-asserted-by":"crossref","first-page":"112","DOI":"10.3389\/fneur.2020.00112","article-title":"The increasing age of TBI patients at a single level 1 trauma center and the discordance between GCS and CT Rotterdam scores in the elderly","volume":"11","author":"N Garza","year":"2020","journal-title":"Front Neurol"},{"key":"pone.0314765.ref002","author":"World Health Organization","year":"2022","journal-title":"Journal of Aging and Health"},{"key":"pone.0314765.ref003","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.iatssr.2019.06.004","article-title":"Prevention of head trauma and death in patients with head injuries: a forensic autopsy study","volume":"43","author":"K. Kibayashi","year":"2019","journal-title":"IATSS Res"},{"key":"pone.0314765.ref004","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s40266-013-0113-9","article-title":"The effects of fall-risk-increasing drugs on postural control: a literature review","volume":"30","author":"MH de Groot","year":"2013","journal-title":"Drugs Aging"},{"key":"pone.0314765.ref005","author":"World Health Organization","year":"2020","journal-title":"The top 10 causes of death"},{"key":"pone.0314765.ref006","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.2146\/ajhp160756","article-title":"Trends in utilization of warfarin and direct oral anticoagulants in older adult patients with atrial fibrillation","volume":"74","author":"AA Alalwan","year":"2017","journal-title":"Am J Health Syst Pharm"},{"key":"pone.0314765.ref007","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1016\/j.jacc.2022.02.047","article-title":"Antithrombotic therapy after left atrial appendage occlusion in patients with atrial fibrillation","volume":"79","author":"JV Freeman","year":"2022","journal-title":"J Am Coll Cardiol"},{"key":"pone.0314765.ref008","doi-asserted-by":"crossref","first-page":"4051","DOI":"10.1111\/bcp.14833","article-title":"Drug-drug interactions with warfarin: a systematic review and meta-analysis","volume":"87","author":"M Wang","year":"2021","journal-title":"Br J Clin Pharmacol"},{"key":"pone.0314765.ref009","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1097\/TA.0000000000000542","article-title":"Preinjury warfarin, but not antiplatelet medications, increases mortality in elderly traumatic brain injury patients","volume":"78","author":"R Grandhi","year":"2015","journal-title":"J Trauma Acute Care Surg"},{"key":"pone.0314765.ref010","doi-asserted-by":"crossref","first-page":"e209","DOI":"10.1016\/j.wneu.2018.02.167","article-title":"Patients with moderate and severe traumatic brain injury: impact of preinjury platelet inhibitor or warfarin treatment","volume":"114","author":"MH Tollefsen","year":"2018","journal-title":"World Neurosurg"},{"key":"pone.0314765.ref011","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1097\/01.ta.0000224220.89528.fc","article-title":"Advanced age and preinjury warfarin anticoagulation increase the risk of mortality after head trauma","volume":"61","author":"J Franko","year":"2006","journal-title":"J Trauma"},{"key":"pone.0314765.ref012","doi-asserted-by":"crossref","first-page":"7S","DOI":"10.1378\/chest.1412S3","article-title":"Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines","volume":"141","author":"GH Guyatt","year":"2012","journal-title":"Chest"},{"key":"pone.0314765.ref013","doi-asserted-by":"crossref","first-page":"73","DOI":"10.4103\/0022-3859.175004","article-title":"Inappropriate preinjury warfarin use in trauma patients: a call for a safety initiative","volume":"62","author":"HH Hon","year":"2016","journal-title":"J Postgrad Med"},{"key":"pone.0314765.ref014","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00068-018-0924-9","article-title":"Evaluation of a protocol for early detection of delayed brain hemorrhage in head injured patients on warfarin","volume":"45","author":"JL Huang","year":"2019","journal-title":"Eur J Trauma Emerg Surg"},{"key":"pone.0314765.ref015","first-page":"525","article-title":"Degree of anticoagulation, but not warfarin use itself, predicts adverse outcomes after traumatic brain injury in elderly trauma patients","volume":"63","author":"FM Pieracci","year":"2007","journal-title":"J Trauma"},{"key":"pone.0314765.ref016","doi-asserted-by":"crossref","first-page":"3397","DOI":"10.1161\/STROKEAHA.108.517482","article-title":"Experimental model of warfarin-associated intracerebral hemorrhage","volume":"39","author":"C Foerch","year":"2008","journal-title":"Stroke"},{"key":"pone.0314765.ref017","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1089\/neu.2011.2104","article-title":"Traumatic brain injury during warfarin anticoagulation: an experimental study in mice","volume":"29","author":"C Foerch","year":"2012","journal-title":"J Neurotrauma"},{"key":"pone.0314765.ref018","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/nbt1195","article-title":"In silico pharmacogenetics of warfarin metabolism","volume":"24","author":"Y Guo","year":"2006","journal-title":"Nat Biotechnol"},{"key":"pone.0314765.ref019","doi-asserted-by":"crossref","first-page":"e26087","DOI":"10.1371\/journal.pone.0026087","article-title":"Warfarin anticoagulation exacerbates the risk of hemorrhagic transformation after rt-PA treatment in experimental stroke: therapeutic potential of PCC","volume":"6","author":"W Pfeilschifter","year":"2011","journal-title":"PLoS One"},{"key":"pone.0314765.ref020","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/sj.tpj.6500182","article-title":"Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin","volume":"3","author":"H Takahashi","year":"2003","journal-title":"Pharmacogenomics J"},{"key":"pone.0314765.ref021","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1538\/expanim.60.481","article-title":"Effect of three types of mixed anesthetic agents alternate to ketamine in mice","volume":"60","author":"S Kawai","year":"2011","journal-title":"Exp Anim"},{"key":"pone.0314765.ref022","doi-asserted-by":"crossref","first-page":"e64078","DOI":"10.1371\/journal.pone.0064078","article-title":"Rapamycin attenuates the development of posttraumatic epilepsy in a mouse model of traumatic brain injury","volume":"8","author":"D Guo","year":"2013","journal-title":"PloS One"},{"key":"pone.0314765.ref023","doi-asserted-by":"crossref","first-page":"3417","DOI":"10.1038\/s41467-022-31072-2","article-title":"Brain-wide reconstruction of inhibitory circuits after traumatic brain injury","volume":"13","author":"JC Frankowski","year":"2022","journal-title":"Nat Commun"},{"key":"pone.0314765.ref024","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/jcbfm.2013.226","article-title":"Rivaroxaban does not increase hemorrhage after thrombolysis in experimental ischemic stroke","volume":"34","author":"R Ploen","year":"2014","journal-title":"J Cereb Blood Flow Metab"},{"key":"pone.0314765.ref025","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1111\/1556-4029.15263","article-title":"Detection of methamphetamine in mouse femurs exposed to high temperature","volume":"68","author":"KI Nakao","year":"2023","journal-title":"J Forensic Sci"},{"key":"pone.0314765.ref026","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1124\/dmd.30.9.1022","article-title":"Sexual dimorphism and tissue specificity in the expression of CYP4F forms in Sprague Dawley rats","volume":"30","author":"A Kalsotra","year":"2002","journal-title":"Drug Metab Dispos"},{"key":"pone.0314765.ref027","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1089\/089771503322686139","article-title":"Differential effects of traumatic brain injury on the cytochrome P450 system: a perspective into hepatic and renal drug metabolism","volume":"20","author":"A Kalsotra","year":"2003","journal-title":"J Neurotrauma"},{"key":"pone.0314765.ref028","doi-asserted-by":"crossref","first-page":"e40740","DOI":"10.1371\/journal.pone.0040740","article-title":"Serological evidence of Ebola virus infection in Indonesian orangutans","volume":"7","author":"CA Nidom","year":"2012","journal-title":"PLoS One"},{"key":"pone.0314765.ref029","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1214\/aoms\/1177729885","article-title":"Sample criteria for testing outlying observations","volume":"21","author":"FE Grubbs","year":"1950","journal-title":"Ann Math Statistist"},{"key":"pone.0314765.ref030","doi-asserted-by":"crossref","first-page":"106892","DOI":"10.1016\/j.ijscr.2022.106892","article-title":"Perioperative management for patient with congenital factor VII deficiency who underwent laparoscopic cholecystectomy: case report","volume":"92","author":"T Yoshimura","year":"2022","journal-title":"Int J Surg Case Rep"},{"key":"pone.0314765.ref031","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neubiorev.2014.01.001","article-title":"Female mice liberated for inclusion in neuroscience and biomedical research","volume":"40","author":"BJ Prendergast","year":"2014","journal-title":"Neurosci Biobehav Rev"},{"key":"pone.0314765.ref032","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.cobeha.2018.06.016","article-title":"Inclusion of females does not increase variability in rodent research studies","volume":"23","author":"AK Beery","year":"2018","journal-title":"Curr Opin Behav Sci"},{"key":"pone.0314765.ref033","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1126\/science.aaw7570","article-title":"Are hormones a \"female problem\" for animal research?","volume":"364","author":"RM Shansky","year":"2019","journal-title":"Science"},{"issue":"6","key":"pone.0314765.ref034","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1002\/jnr.23841","article-title":"Sex Differences in Pain","volume":"95","author":"RE Sorge","year":"2017","journal-title":"J Neurosci Res"},{"key":"pone.0314765.ref035","volume-title":"The Principles of Humane Experimental Technique","author":"WMS Russell","year":"1959"},{"key":"pone.0314765.ref036","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.1242\/jeb.147058","article-title":"Considering aspects of the 3Rs principles within experimental animal biology","volume":"220","author":"L Sneddon","year":"2017","journal-title":"J Exp Biol"},{"key":"pone.0314765.ref037","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/s13104-018-3291-z","article-title":"Head injury on warfarin: likelihood of delayed intracranial bleeding in patients with negative initial head CT","volume":"11","author":"A Afaneh","year":"2018","journal-title":"BMC Res Notes"},{"key":"pone.0314765.ref038","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.jemermed.2020.01.003","article-title":"Utility of INR for prediction of delayed intracranial hemorrhage among warfarin users with head injury","volume":"58","author":"H Valiuddin","year":"2020","journal-title":"J Emerg Med"},{"key":"pone.0314765.ref039","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s10571-016-0351-6","article-title":"Impacts of blast-induced traumatic brain injury on expressions of hepatic cytochrome P450 1A2, 2B1, 2D1, and 3A2 in rats","volume":"37","author":"J Ma","year":"2017","journal-title":"Cell Mol Neurobiol"},{"key":"pone.0314765.ref040","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/j.1552-4604.1997.tb04771.x","article-title":"Effect of acute phase response on phenytoin metabolism in neurotrauma patients","volume":"37","author":"DS McKindley","year":"1997","journal-title":"J Clin Pharmacol"},{"key":"pone.0314765.ref041","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1006\/bbrc.2000.3219","article-title":"Interleukin-6 negatively regulates the expression of pregnane X receptor and constitutively activated receptor in primary human hepatocytes","volume":"274","author":"JM Pascussi","year":"2000","journal-title":"Biochem Biophys Res Commun"},{"key":"pone.0314765.ref042","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.jns.2015.06.062","article-title":"Temporal profile of M1 and M2 responses in the hippocampus following early 24h of neurotrauma","volume":"357","author":"MA Ansari","year":"2015","journal-title":"J Neurol Sci"},{"key":"pone.0314765.ref043","first-page":"08","article-title":"Introductory chapter: linkages between pharmacokinetics and adverse effects of drugs","author":"N. Malangu","year":"2018","journal-title":"Internet. Pharmacokinetics and adverse effects of drugs\u2014mechanisms and risks factors"},{"key":"pone.0314765.ref044","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S0049-3848(98)00213-8","article-title":"Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat","volume":"94","author":"M Elg","year":"1999","journal-title":"Thromb Res"},{"key":"pone.0314765.ref045","first-page":"500","article-title":"Real world usage of PCC to \"rapidly\" correct warfarin induced coagulopathy","volume":"11","author":"P Toth","year":"2013","journal-title":"Blood Transfus"},{"key":"pone.0314765.ref046","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1111\/j.1538-7836.2006.01815.x","article-title":"Urgent reversal of warfarin with prothrombin complex concentrate","volume":"4","author":"MW Lankiewicz","year":"2006","journal-title":"J Thromb Haemost"},{"key":"pone.0314765.ref047","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1016\/j.jocn.2014.05.001","article-title":"Reversal of warfarin associated coagulopathy with 4-factor prothrombin complex concentrate in traumatic brain injury and intracranial hemorrhage","volume":"21","author":"V Yanamadala","year":"2014","journal-title":"J Clin Neurosci"},{"key":"pone.0314765.ref048","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.jss.2017.11.008","article-title":"Activated prothrombin complex concentrate for warfarin reversal in traumatic intracranial hemorrhage","volume":"223","author":"C Carothers","year":"2018","journal-title":"J Surg Res"},{"key":"pone.0314765.ref049","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1001\/jama.2023.4080","article-title":"Efficacy and safety of early administration of 4-factor prothrombin complex concentrate in patients with trauma at risk of massive transfusion: the PROCOAG randomized clinical trial","volume":"329","author":"P Bouzat","year":"2023","journal-title":"JAMA"},{"key":"pone.0314765.ref050","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1089\/neu.2020.7118","article-title":"Effects of preexisting diabetes mellitus on the severity of traumatic brain injury","volume":"38","author":"Y Tatara","year":"2021","journal-title":"J Neurotrauma"},{"key":"pone.0314765.ref051","doi-asserted-by":"crossref","first-page":"112352","DOI":"10.1016\/j.bbr.2019.112352","article-title":"Automated radial 8-arm maze: a voluntary and stress-free behavior test to assess spatial learning and memory in mice","volume":"381","author":"J Mei","year":"2020","journal-title":"Behav Brain Res"},{"key":"pone.0314765.ref052","doi-asserted-by":"crossref","first-page":"1230082","DOI":"10.3389\/fnbeh.2023.1230082","article-title":"Challenges and advanced concepts for the assessment of learning and memory function in mice","volume":"17","author":"B Lang","year":"2023","journal-title":"Front Behav Neurosci"},{"key":"pone.0314765.ref053","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1038\/jcbfm.2014.31","article-title":"Translational insights into traumatic brain injury occurring during dabigatran or warfarin anticoagulation","volume":"34","author":"JH Schaefer","year":"2014","journal-title":"J Cereb Blood Flow Metab"},{"key":"pone.0314765.ref054","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/sj.jcbfm.9600258","article-title":"Traumatic brain injury in mice deficient in Bid: effects on histopathology and functional outcome","volume":"26","author":"D Bermpohl","year":"2006","journal-title":"J Cereb Blood Flow Metab"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0314765","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T19:02:21Z","timestamp":1733425341000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0314765"}},"subtitle":[],"editor":[{"given":"Anna-Leena","family":"Sir\u00e9n","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2024,12,5]]},"references-count":54,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0314765","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,5]]}}}