Reticulated platelets in coronary artery disease: a multidimensional approach unveils prothrombotic signalling and novel therapeutic targets.
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Kirmes Kilian, Han Jiaying, Klug Melissa, Bloxham Conor J, Babyak Olena, Bernett Judith, Arend Lis, Manz Quirin, Raka Leonora, Schwartz Leon, Hoffmann Markus, Rosenbaum Marc, Ruland Jürgen, Ciora Octavia-Andreea, Louadi Zakaria, Tsoy Olga, Newaz Khalique, Modica Jessica, Conca Dioguardi Carola, Peano Clelia, Müller Michaela, Santovito Donato, Viggiani Giacomo, Kühne Stephanie, von Scheidt Moritz, Nicolai Leo, Wu Tianjiao, Baumbach Jan, Chiarito Mauro, Laugwitz Karl-Ludwig, Condorelli Gianluigi, Raake Philip W J, List Markus, Bernlochner Isabell, Bongiovanni Dario
Аннотация
METHODS: 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-platelet 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.
RESULTS: 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.
CONCLUSIONS: 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.