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We highlight areas of management that have evolved within the past 5 years, including the use of dual-pathway inhibition in atherosclerotic disease, antithrombotic therapy selection in embolic stroke of undetermined source and left ventricular thrombus, the role of closure of patent foramen ovale for secondary stroke prevention, and the thrombotic potential of coronavirus disease 2019 infection and vaccination. We conclude with a representative case to illustrate the application of the diagnostic framework and discuss the importance of consideration of bleeding risk and patient preference in determining the appropriate management plan.<\/jats:p>","DOI":"10.1182\/hematology.2021000235","type":"journal-article","created":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T12:22:40Z","timestamp":1639138960000},"page":"76-84","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":28,"title":["Unexplained arterial thrombosis: approach to diagnosis and treatment"],"prefix":"10.1182","volume":"2021","author":[{"given":"Jori E.","family":"May","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Hematology\/Oncology, University of Alabama at Birmingham, Birmingham, AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Moll","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology, University of North Carolina School of Medicine, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2021,12,10]]},"reference":[{"issue":"9","key":"2021121012093657700_hem2021000235C1","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1161\/CIRCRESAHA.115.306841","article-title":"Global burden of thrombosis: epidemiologic aspects","volume":"118","author":"Wendelboe","year":"2016","journal-title":"Circ Res"},{"issue":"3","key":"2021121012093657700_hem2021000235C2","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.jacl.2019.04.010","article-title":"Use of lipoprotein(a) in clinical practice: a biomarker whose time has come. 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