{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T04:12:56Z","timestamp":1782619976521,"version":"3.54.5"},"reference-count":63,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Arterial thrombosis emerges from the interplay between plaque disruption, platelet activation, and coagulation pathway amplification on a background of heterogeneous ischemic and bleeding risk. Optimal antithrombotic therapy therefore varies across clinical settings, from acute coronary syndromes (ACS) to chronic coronary syndromes (CCS), ischemic stroke, peripheral artery disease (PAD), and atrial fibrillation (AF) associated with atherosclerotic disease. Contemporary European and North American guidelines endorse an increasingly individualized approach, moving away from rigid \u201cone-size-fits-all\u201d dual antiplatelet therapy (DAPT) duration and intensity and incorporating dual pathway inhibition with low-dose rivaroxaban plus aspirin in selected high-risk CCS and PAD patients. In ischemic stroke, short-course DAPT is confined to minor events and transient ischemic attacks, whereas long-term monotherapy remains standard, and the coexistence of AF typically shifts the balance toward oral anticoagulation. Across all scenarios, antithrombotic benefit must be weighed against bleeding, especially in elderly, frail, or comorbid patients. Evidence gaps remain substantial, particularly in patients with overlapping vascular territories, AF plus atherosclerotic disease, and after ischemic stroke of complex or mixed mechanisms. This narrative review summarizes current evidence and guideline-based strategies in major atherosclerotic settings, proposes a unifying conceptual framework, and highlights key uncertainties and research directions for truly personalized antithrombotic care.<\/jats:p>","DOI":"10.3390\/jcm15062325","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T11:14:14Z","timestamp":1773832454000},"page":"2325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Optimal Antithrombotic Regimens Across Atherosclerotic Vascular Beds: Toward Mechanism and Risk-Oriented Strategies"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0243-3673","authenticated-orcid":false,"given":"Pierre","family":"Sabouret","sequence":"first","affiliation":[{"name":"Heart Institute and Action Group, Piti\u00e9-Salp\u00e9tri\u00e8re, Sorbonne University, 75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2161-3066","authenticated-orcid":false,"given":"Domenico Mario","family":"Giamundo","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Policlinico Casilino, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Costa","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and of Morphological and Functional Images, University of Messina, 98122 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piera","family":"Capranzano","sequence":"additional","affiliation":[{"name":"Cardiology Division, Policlinico Hospital, University of Catania, 95124 Catania, 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Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1940-4258","authenticated-orcid":false,"given":"Ali","family":"Abdelaziz","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Alexandria University, Alexandria 5424041, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0615-0811","authenticated-orcid":false,"given":"Giulia","family":"Alagna","sequence":"additional","affiliation":[{"name":"Cardiology Department, San Biagio Hospital, ASL VCO Distretto Sanitario di Verbania, 28922 Verbania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6943-278X","authenticated-orcid":false,"given":"Felice","family":"Gragnano","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"},{"name":"Division of Cardiology, 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