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. 2025 Aug 31:ehaf694.
doi: 10.1093/eurheartj/ehaf694. Online ahead of print.

Reticulated platelets in coronary artery disease: a multidimensional approach unveils prothrombotic signalling and novel therapeutic targets

Kilian Kirmes  1   2 , Jiaying Han  1   2 , Melissa Klug  1   2   3 , Conor J Bloxham  1   4 , Olena Babyak  4 , Judith Bernett  3 , Lis Arend  3 , Quirin Manz  3 , Leonora Raka  3   4 , Leon Schwartz  3 , Markus Hoffmann  3   5 , Marc Rosenbaum  6   7 , Jürgen Ruland  6   7 , Octavia-Andreea Ciora  3 , Zakaria Louadi  8 , Olga Tsoy  8 , Khalique Newaz  8 , Jessica Modica  9   10 , Carola Conca Dioguardi  10   11 , Clelia Peano  10   11 , Michaela Müller  3 , Donato Santovito  2   12 , Giacomo Viggiani  1 , Stephanie Kühne  4 , Moritz von Scheidt  2 , Leo Nicolai  2   13 , Tianjiao Wu  13 , Jan Baumbach  8 , Mauro Chiarito  9 , Karl-Ludwig Laugwitz  1   2 , Gianluigi Condorelli  9 , Philip W J Raake  4 , Markus List  3   14 , Isabell Bernlochner  1   2 , Dario Bongiovanni  4   9
Affiliations

Reticulated platelets in coronary artery disease: a multidimensional approach unveils prothrombotic signalling and novel therapeutic targets

Kilian Kirmes et al. Eur Heart J. .

Abstract

Background and aims: Reticulated platelets (RPs), hyperreactive and RNA-rich, are associated with increased risk of cardiovascular events and suboptimal response to antiplatelet therapy in coronary artery disease (CAD). However, the underlying mechanisms remain poorly defined. This study aimed to characterise the molecular and functional phenotype of RPs in CAD and assess their potential as therapeutic targets.

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 to 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.

Keywords: GPVI; coronary artery disease; mass cytometry; reticulated platelets; thrombocytes; transcriptomics.

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