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This study examined whether DAPTs provide vasculoprotective benefits in injured coronary microvessels, including in the setting of chronic hyperglycaemia. Mice were fed a normal (ND) or high-fat diet (HFD) for 16\u00a0weeks and treated with vehicle, aspirin plus ticagrelor, clopidogrel, prasugrel or cangrelor, anti-GPIb\u03b1 antibody, or dabigatran. Intravital imaging assessed platelet, neutrophil, and fibrin presence in the beating heart subjected to ischaemia\u2013reperfusion injury (IRI). Laser speckle contrast imaging evaluated overall ventricular perfusion, and infarct size was determined histologically. IRI increased platelet and neutrophil accumulation in coronary capillaries and reduced perfusion. DAPTs, particularly using prasugrel, and anti-GPIb\u03b1 reduced platelet numbers but increased neutrophil infiltration. Despite limited perfusion improvement, infarct size decreased. Fibrin deposition was also extensive and contributed to platelet recruitment, as shown using dabigatran. HFD-fed mice demonstrated markedly elevated thromboinflammatory cell accumulation. DAPT with prasugrel reduced platelet and neutrophil presence, but left a significant residual presence of both. Despite perfusion improvements, infarcts remained larger. Our data do not support a simple linear relationship between reduced platelet microthrombi, improved perfusion, and infarct limitation. Whilst early platelet inhibition confers cardioprotection independently of flow recovery in healthy mice, metabolic compromise uncouples microvascular flow from myocardial tissue survival. This may explain the diminished cardioprotective efficacy of DAPTs in patients with T2DM and supports exploring combination vasculoprotective therapies targeting multiple microvascular perturbations.<\/jats:p>","DOI":"10.1007\/s00395-026-01168-7","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T13:06:04Z","timestamp":1775135164000},"page":"351-370","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparing anti-platelet and anti-thrombin therapies in the ischaemia\u2013reperfusion injured coronary microcirculation of healthy and diabetic mice"],"prefix":"10.1007","volume":"121","author":[{"given":"Joanne L.","family":"Mitchell","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juma","family":"El-Awaisi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dean","family":"Kavanagh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernhard","family":"Nieswandt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert F.","family":"Storey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2960-7829","authenticated-orcid":false,"given":"Neena","family":"Kalia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"1168_CR1","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.vph.2015.02.006","volume":"71","author":"KF Alsharif","year":"2015","unstructured":"Alsharif KF, Thomas MR, Judge HM, Khan H, Prince LR, Sabroe I, Ridger VC, Storey RF (2015) Ticagrelor potentiates adenosine-induced stimulation of neutrophil chemotaxis and phagocytosis. 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