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Background: Thrombotic events constitute a major cause of morbidity and mortality in the general population and are disproportionately frequent in patients with connective tissue diseases (CTD), large- (LVV) and small-vessel vasculitis (SVV). In these diseases, multiple factors, including accelerated atherosclerosis, inflamed endothelium, dysfunctional coagulation cascade, pro-coagulant antibodies might concur to increase the risk of ischemia [1]. Platelets and granulocytes constitute the bulk corpuscular fraction of innate immune mediators in blood and take part in immunothrombosis [2, 3] besides accelerating and sustaining inflammation. Markers of platelet/granulocyte activation and/or thrombogenicity might correlate with thrombotic risk in patients with autoimmune diseases.
Objectives: To evaluate the diagnostic performance of markers of platelet and neutrophil activation/thrombogenicity in patients with CTD, LVV and SVV followed up for thrombotic events.
Methods: From 2006 to 2017, 122 patients (n=98 women) with CTD (systemic lupus erythematosus, n=24; systemic sclerosis, n=50), LVV (giant cell arteritis, n=12; Takayasu arteritis, n=21), and SVV (n=15) were consecutively enrolled and followed up until December 2024. Demographics, disease-specific clinical and treatment features and the prevalence of general cardiovascular risk factors were recorded for all patients. Thrombotic events, defined as arterial, venous or small vessel thromboses (including coronary artery disease and stroke) [4], occurring after enrollment were also recorded. The percentage of platelets, platelet-derived extracellular vesicles (pltEV), monocytes and neutrophils expressing tissue factor (TF) was measured by flow cytometry. We also quantitated the fraction of platelet expressing P-selectin. Cox regression analysis was used to determine potential risk factors for thrombosis and receiver operating characteristics (ROC) curves to define potential diagnostic cut-offs. Data are expressed as median (interquartile range, IQR) or number (percentage) unless otherwise specified.
Results: At enrollment, patients had a median (IQR) age of 50 (40-64) years and a 7 (3-15)-year disease duration. Median follow-up was 9 (8-15) years. During follow-up, 16 patients (13%) died and 19 (16%) had at least one thrombotic event, 11 of whom (58%) following a previous event before enrollment. In total, 60 patients were receiving anti-platelet and eight anticoagulant treatments at enrollment. Nonetheless, 12 of them had a further thrombotic event during follow-up. Patients with SVV had higher TF-positive platelets [52 (50-53)%; n=9] than patients with LVV [17(13-28)%; p<0.001; n=24] or CTD [30 (17-42)%; p=0.002; n=34]. Neutrophil TF was significantly more expressed in patients with SVV than LVV [35 (17-35)% vs 13 (9-19)%; p=0.016; n=27], while no differences were found with other disease groups. TF-positive neutrophil, platelet, pltEV and monocyte counts were not associated with thrombotic events. P-selectin-positive platelet count did not differ among groups. Patients with thrombotic complications showed higher P-selectin-positive platelets at enrollment [30 (22-40)%] than patients with no complications [21 (13-27)%; p=0.008]. P-selectin-positive platelet levels were associated with an increased risk of thrombotic events over time, even when diabetes, hypertension, smoke, dyslipidemia, exposure to estrogen-based contraceptives and concomitant anticoagulant or antiplatelet treatments were included as covariates [hazard ratio 1.06, (95% confidence interval: 1.01-1.11); p=0.014, n=73]. ROC curve analysis showed that P-selectin-positive platelet percentage could explain 77% of the total variability related to the occurrence of cardiovascular events, with a cut-off of 28.8% P-selectin-positive platelets being associated with optimal sensitivity (67%) and specificity (79%).
Conclusion: Thrombotic events are frequent in patients with autoimmune diseases and might not be sufficiently prevented by conventional antiplatelet/anticoagulant treatment. P-selectin-positive platelet count seems to be a possible predictor of long-term thrombotic risk and supports the development of dedicated treatment strategies aiming at preventing immunothrombosis due to aberrant platelet/leukocyte activation. Long-term validation studies are required to corroborate these data.
REFERENCES: [1] Ramirez GA, et al., Rheumatology (Oxford). 2019.
[2] Engelmann B, et al., Nat Rev Immunol. 2013.
[3] Maugeri N, et al., PLoS One. 2012.
[4] Miyakis S, et al., J Thromb Haemost. 2006.
Acknowledgements: This project is funded by the European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS. Project: PNRR-MR1-2022-12376638.
Disclosure of Interests: None declared.
© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (