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However, the underlying mechanisms remain poorly defined. This study aimed to characterize the molecular and functional phenotype of RPs in CAD and assess their potential as therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>RPs and mature platelets (MPs) were isolated from CAD patients based on RNA content and CD41 expression. Paired RP vs MP comparisons were conducted within each donor. Transcriptomic profiling (RNA-seq) was integrated with high-dimensional proteomics (mass cytometry) and validated in independent cohorts. Functional studies, including flow cytometry-based platelet\u2013platelet binding, in vitro thrombosis, platelet spreading, and intracellular phospho-protein profiling, assessed the impact of PI3K and GPVI pathways. Results were curated in Platlas, an open-access interactive web resource.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 95 CAD patients, RPs exhibited elevated activation marker expression and enrichment of prothrombotic pathways compared with MPs. RNA-seq revealed upregulation of GP6, TBXA2R, and VWF transcripts, novel GPVI splicing, and RP-specific non-coding RNAs including novel circRNAs. Proteomic and functional assays confirmed heightened PI3K and GPVI signalling, with increased phosphorylation of AKT, PI3K, and SYK, and elevated reactive oxygen species production. RPs showed increased aggregation, spreading and greater recruitment in thrombus formation, which were significantly reduced by PI3K (LY294002) and GPVI (glenzocimab) inhibition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides the first mechanistic explanation for RP hyperreactivity, revealing a distinct molecular profile and identifying GPVI and PI3K inhibition as promising targets for tailored antiplatelet therapy in CAD patients with elevated RPs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehaf694","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T11:55:07Z","timestamp":1755777307000},"page":"4901-4917","source":"Crossref","is-referenced-by-count":12,"title":["Reticulated platelets in coronary artery disease: a multidimensional approach unveils prothrombotic signalling and novel therapeutic targets"],"prefix":"10.1093","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6940-0983","authenticated-orcid":false,"given":"Kilian","family":"Kirmes","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Rechts der Isar, Technical University of Munich , Munich ,","place":["Germany"]},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4158-4826","authenticated-orcid":false,"given":"Jiaying","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Rechts der Isar, Technical University of Munich , Munich ,","place":["Germany"]},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Klug","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Rechts der Isar, Technical University of Munich , Munich ,","place":["Germany"]},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance , Munich ,","place":["Germany"]},{"name":"Data Science in Systems Biology, TUM School of Life Sciences, Technical University of Munich , Freising ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1469-8174","authenticated-orcid":false,"given":"Conor J","family":"Bloxham","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Rechts der Isar, Technical University of Munich , Munich ,","place":["Germany"]},{"name":"Department of Internal Medicine I, University Hospital of Augsburg, Faculty 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