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Thromb Haemost
DOI: 10.1055/a-2632-3100
Cellular Haemostasis and Platelets

Distinct Platelet Phenotype and Reactivity in Individuals with Permanent Atrial Fibrillation Treated with Direct Oral Anticoagulants: A Pilot Study

Marzia Miglionico   *
1   Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
,
Francesca Maiorca   *
2   Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
,
Annamaria Sabetta
2   Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
,
Ludovica Lombardi
2   Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
,
Tania D'amico
1   Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
,
Alessandro Cincione
2   Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
,
Giovanni Buoninfante
2   Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
,
Marin Pecani
1   Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
,
Marco Proietti
3   Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
4   Division of Subacute Care, IRCCS Istituti Clinici Scientifici Maugeri, Milan, Italy
,
Giulio Francesco Romiti 
2   Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
5   Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom
,
Roberto Cangemi
2   Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
,
Stefania Basili
2   Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
,
Valeria Raparelli
2   Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
,
Lucia Stefanini
2   Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
6   Istituto Pasteur Italia - Fondazione Cenci-Bolognetti, Rome, Italy
› Author Affiliations
Funding The study was supported by Sapienza University Research Project 2023 (code: RG123188B4CD04C9) to L.S. and co-financed by the Next Generation EU (DM 1557 11.10.2022), in the context of the National Recovery and Resilience Plan, Investment PE8—Project Age-It: “Ageing Well in an Ageing Society.” The views and opinions expressed are only those of the authors and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be held responsible for them. G.F.R. is supported by a grant issued by Sapienza University of Rome (AR22419077BB6154).
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Abstract

Background

Atrial fibrillation (AF) is linked to an elevated risk of thromboembolic events. Despite the use of guideline-recommended direct anticoagulants (DOACs), a significant proportion of AF patients show a residual risk of thromboembolic events, driven by mechanisms that are not fully understood.

Objective

We conducted a pilot study to characterize the platelet function in DOACs-treated AF patients, to explore whether an association between platelets and the residual thromboembolic risk exists.

Methods

Within the Age-It project of the National Recovery and Resilience Plan, we examined by flow cytometry the platelet phenotype, reactivity, and mitochondrial function and quantified 12 inflammatory cytokines of individuals with DOACs-treated permanent AF without a history of stroke (n = 18, 66 ± 13 years, 39% females), compared with an age-, sex-, and comorbidity-matched control group without AF (n = 18, 65 ± 11 years, 39% females).

Results

Unstimulated circulating platelets of DOACs-treated AF displayed a low-adhesive phenotype compared with matched controls. Upon stimulation, platelets of DOACs-treated AF were hyporeactive to ADP and PAR1 stimulation, but hyper-reactive to GPVI stimulation (adjusted p < 0.01). The lower responsiveness to ADP correlated with increased plasmatic concentrations of IFN-γ (r = − 0.539; p < 0.05) and TNF-α (r = − 0.472; p < 0.05). The higher reactivity to GPVI associated with an increased mitochondrial function, which positively correlated with TNF-α levels.

Conclusion

Individuals with AF treated with DOACs exhibit low-grade inflammation and an altered platelet reactivity, suggesting a potential mechanism behind their residual thromboembolic risk. Further well-powered studies are warranted to test whether the observed platelet phenotype is implicated with the residual thromboembolic events in DOACs-treated AF patients.

Keywords

platelet physiology - cardiology - coagulation inhibitors - platelet glycoproteins

Data Availability Statement

The data supporting the findings of this study are available upon request from the corresponding author.


Authors' Contribution

M.M. enrolled patients, analyzed and interpreted the data, and contributed to the final manuscript; F.M. performed experiments, analyzed and interpreted the data, and contributed to the final manuscript; A.S. and L.L. performed the experiments and analyzed the data; T.D., A.C, G.B., and M.P. enrolled the study participants, collected clinical data, and stratified the patients; M.P., G.F.R., R.C., S.B, and V.R. designed the study, recruited the patients, and critically revised the manuscript; L.S. coordinated the study, analyzed and interpreted the data, and wrote the manuscript.


* These authors contributed equally to this study.


Supplementary Material



Publication History

Received: 27 December 2024

Accepted: 10 June 2025

Accepted Manuscript online:
11 June 2025

Article published online:
24 June 2025

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