{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:01:35Z","timestamp":1787022095815,"version":"build-2736575974"},"reference-count":33,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T00:00:00Z","timestamp":1638144000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Several direct oral anticoagulants have been developed to prevent cardiogenic thrombosis in patients with atrial fibrillation, on the other hand, have the complication of bleeding. Since clinical course after bleeding with direct oral anticoagulant remains unclear, the present retrospective cohort study was to clarify the course after hemorrhage among patients receiving direct oral anticoagulants. Among all 2005 patients prescribed dabigatran, rivaroxaban, apixaban, or edoxaban between April 2011 and June 2017, subjects comprised 96 patients with non-valvular atrial fibrillation who experienced relevant bleeding during direct oral anticoagulant therapy (Bleeding Academic Research Consortium type 2 or above). The clinical course after hemorrhage was reviewed to examine whether rebleeding or thrombotic events occurred up to the end of December 2019. Gastrointestinal bleeding was the most frequent cause of initial bleeding (57 patients, 59%). Rebleeding occurred in 11 patients (4.5%\/year), with gastrointestinal bleeding in 10 and subarachnoid hemorrhage in 1. All rebleeding occurred in patients who resumed anticoagulation therapy. Another significant factor related with rebleeding included past history of gastrointestinal bleeding. On the other hand, major adverse cardiac and cerebrovascular events occurred in 6 patients older than 75 years old or more (2.5%\/year), with systemic thrombosis in 4 and cardiac death in 2. All 4 patients with systemic thrombosis withheld anticoagulants after index bleeding, although only 10 patients withheld anticoagulation therapy. Rebleeding should be taken care of when anticoagulants are resumed after bleeding, particularly among patients who initially experienced gastrointestinal bleeding. Systemic thrombosis occurred at a high rate when anticoagulant therapy was withheld after bleeding.<\/jats:p>","DOI":"10.1371\/journal.pone.0260585","type":"journal-article","created":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T13:41:53Z","timestamp":1638193313000},"page":"e0260585","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Thrombotic events and rebleeding after hemorrhage in patients taking direct oral anticoagulants for non-valvular atrial fibrillation"],"prefix":"10.1371","volume":"16","author":[{"given":"Daisuke","family":"Yanagisawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2577-2977","authenticated-orcid":true,"given":"Koichiro","family":"Abe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirohito","family":"Amano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shogo","family":"Komatsuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Honda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Manabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirosada","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Kozuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Kodashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinari","family":"Asaoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takatsugu","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,11,29]]},"reference":[{"key":"pone.0260585.ref001","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1016\/j.amjcard.2013.05.063","article-title":"Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population","volume":"112","author":"S Colilla","year":"2013","journal-title":"Am J Cardiol"},{"key":"pone.0260585.ref002","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.ijcard.2008.06.029","article-title":"Prevalence of atrial fibrillation in the general population of Japan: an analysis based on periodic health examination","volume":"137","author":"H Inoue","year":"2009","journal-title":"Int J Cardiol"},{"key":"pone.0260585.ref003","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1056\/NEJMoa0905561","article-title":"RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation","volume":"361","author":"SJ Connolly","year":"2009","journal-title":"N Engl J Med"},{"key":"pone.0260585.ref004","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1056\/NEJMoa1009638","article-title":"ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation","volume":"365","author":"MR Patel","year":"2011","journal-title":"N Engl J Med"},{"key":"pone.0260585.ref005","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1056\/NEJMoa1107039","article-title":"ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation","volume":"365","author":"CB Granger","year":"2011","journal-title":"N Engl J Med"},{"key":"pone.0260585.ref006","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1056\/NEJMoa1310907","article-title":"ENGAGE AF-TIMI 48 Investigators. Once-daily edoxaban versus warfarin in patients with atrial fibrillation","volume":"369","author":"RP Giugliano","year":"2013","journal-title":"N Engl J Med"},{"key":"pone.0260585.ref007","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1016\/j.cgh.2017.04.031","article-title":"Risk of gastrointestinal bleeding in patients taking non-vitamin K antagonist oral anticoagulants: a systematic review and meta-analysis","volume":"15","author":"CS Miller","year":"2017","journal-title":"Clin Gastroenterol Hepatol"},{"key":"pone.0260585.ref008","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.thromres.2014.10.002","article-title":"A meta-analysis of phase III randomized controlled trials with novel oral anticoagulants in atrial fibrillation: comparisons between direct thrombin inhibitors vs. factor Xa inhibitors and different dosing regimens","volume":"134","author":"R Providencia","year":"2014","journal-title":"Thromb Res"},{"key":"pone.0260585.ref009","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.gie.2013.04.179","article-title":"Novel oral anticoagulants in gastroenterology practice","volume":"78","author":"J Desai","year":"2013","journal-title":"Gastrointest Endosc"},{"key":"pone.0260585.ref010","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/j.jacc.2013.11.013","article-title":"Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation","volume":"63","author":"SG Goodman","year":"2014","journal-title":"J Am Coll Cardiol"},{"key":"pone.0260585.ref011","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1053\/j.gastro.2013.02.041","article-title":"New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis","volume":"145","author":"IL Holster","year":"2013","journal-title":"Gastroenterology"},{"key":"pone.0260585.ref012","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1001\/jamainternmed.2014.5398","article-title":"Risk of bleeding with dabigatran in atrial fibrillation","volume":"175","author":"I Hernandez","year":"2015","journal-title":"JAMA Intern Med"},{"key":"pone.0260585.ref013","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/ajg.2014.398","article-title":"The risks of thromboembolism vs. recurrent gastrointestinal bleeding after interruption of systemic anticoagulation in hospitalized inpatients with gastrointestinal bleeding: a prospective study","volume":"110","author":"N Sengupta","year":"2015","journal-title":"Am J Gastroenterol"},{"key":"pone.0260585.ref014","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.amjcard.2013.10.044","article-title":"Restarting anticoagulation and outcomes after major gastrointestinal bleeding in atrial fibrillation","volume":"113","author":"W Qureshi","year":"2014","journal-title":"Am J Cardiol"},{"key":"pone.0260585.ref015","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1001\/archinternmed.2012.4261","article-title":"Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding","volume":"172","author":"DM Witt","year":"2012","journal-title":"Arch Intern Med"},{"key":"pone.0260585.ref016","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.ijcard.2018.03.053","article-title":"Restarting oral anticoagulant therapy after major bleeding in atrial fibrillation: a systematic review and meta-analysis","volume":"261","author":"M Proietti","year":"2018","journal-title":"Int J Cardiol"},{"key":"pone.0260585.ref017","doi-asserted-by":"crossref","first-page":"399","DOI":"10.2147\/VHRM.S187656","article-title":"When to withhold oral anticoagulation in atrial fibrillation\u2014an overview of frequent clinical discussion topics","volume":"15","author":"J Seelig","year":"2019","journal-title":"Vasc Health Risk Manag"},{"key":"pone.0260585.ref018","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1016\/j.cgh.2018.05.005","article-title":"Rebleeding vs thromboembolism after hospitalization for gastrointestinal bleeding in patients on direct oral anticoagulants","volume":"16","author":"N Sengupta","year":"2018","journal-title":"Clin Gastroenterol Hepatol"},{"key":"pone.0260585.ref019","doi-asserted-by":"crossref","first-page":"2736","DOI":"10.1161\/CIRCULATIONAHA.110.009449","article-title":"Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the bleeding academic research consortium","volume":"123","author":"R Mehran","year":"2011","journal-title":"Circulation"},{"key":"pone.0260585.ref020","article-title":"The HAS-BLED, ATRIA, and ORBIT bleeding scores in atrial fibrillation patients using non-vitamin K antagonist oral anticoagulants","volume":"131","author":"GYH Lip","year":"2018","journal-title":"Am J Med"},{"key":"pone.0260585.ref021","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1007\/s00380-019-01425-x","article-title":"Clinical risk factors of stroke and major bleeding in patients with non-valvular atrial fibrillation under rivaroxaban: the EXPAND Study sub\u2011analysis","volume":"34","author":"I Sakuma","year":"2019","journal-title":"Heart Vessels"},{"key":"pone.0260585.ref022","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1378\/chest.10-0134","article-title":"A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey","volume":"138","author":"R Pisters","year":"2010","journal-title":"Chest"},{"key":"pone.0260585.ref023","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1253\/circj.CJ-14-0144","article-title":"Validation of CHA2DS2-VASc and HAS-BLED scores in Japanese patients with nonvalvular atrial fibrillation: an analysis of the J-RHYTHM Registry","volume":"78","author":"K Okumura","year":"2014","journal-title":"Circ J"},{"key":"pone.0260585.ref024","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1093\/eurheartj\/ehw210","article-title":"2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS","volume":"37","author":"P Kirchhof","year":"2016","journal-title":"Eur Heart J"},{"key":"pone.0260585.ref025","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-020-77174-z","article-title":"Clinical factors associated with safety and efficacy in patients receiving direct oral anticoagulants for non-valvular atrial fibrillation","volume":"10","author":"H Yamato","year":"2020","journal-title":"Sci Rep"},{"key":"pone.0260585.ref026","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1053\/j.gastro.2015.05.002","article-title":"Prevention of dabigatran-related gastrointestinal bleeding with gastroprotective agents: a population-based study","volume":"149","author":"EW Chan","year":"2015","journal-title":"Gastroenterology"},{"key":"pone.0260585.ref027","doi-asserted-by":"crossref","first-page":"7123607","DOI":"10.1155\/2018\/7123607","article-title":"Difference between the upper and the lower gastrointestinal bleeding in patients taking nonvitamin K oral anticoagulants","volume":"2018","author":"K Maruyama","year":"2018","journal-title":"Biomed Res Int"},{"key":"pone.0260585.ref028","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1053\/j.gastro.2016.08.054","article-title":"Association of proton pump inhibitors with reduced risk of warfarin-related serious upper gastrointestinal bleeding","volume":"151","author":"WA Ray","year":"2016","journal-title":"Gastroenterology"},{"key":"pone.0260585.ref029","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1001\/jama.2018.17242","article-title":"Association of oral anticoagulants and proton pump inhibitor cotherapy with hospitalization for upper gastrointestinal tract bleeding","volume":"320","author":"WA Ray","year":"2018","journal-title":"JAMA"},{"key":"pone.0260585.ref030","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1016\/j.cgh.2014.11.007","article-title":"Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants","volume":"13","author":"A Lanas","year":"2015","journal-title":"Clin Gastroenterol Hepatol"},{"key":"pone.0260585.ref031","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.amjmed.2018.10.008","article-title":"Concomitant use of direct oral anticoagulants with antiplatelet agents and the risk of major bleeding in patients with nonvalvular atrial fibrillation","volume":"132","author":"A Douros","year":"2019","journal-title":"Am J Med"},{"key":"pone.0260585.ref032","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ahj.2018.03.003","article-title":"Predictors of oral anticoagulant non-prescription in patients with atrial fibrillation and elevated stroke risk","volume":"200","author":"SA Lubitz","year":"2018","journal-title":"Am Heart J"},{"key":"pone.0260585.ref033","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1160\/TH11-11-0768","article-title":"Oral anticoagulation use by patients with atrial fibrillation in Germany. Adherence to guidelines, causes of anticoagulation under-use and its clinical outcomes, based on claims-data of 183,448 patients","volume":"107","author":"T Wilke","year":"2012","journal-title":"Thromb Haemost"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0260585","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T13:42:22Z","timestamp":1638193342000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0260585"}},"subtitle":[],"editor":[{"given":"Tomohiko","family":"Ai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,11,29]]},"references-count":33,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11,29]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0260585","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,29]]}}}