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Objectives Apoptosis plays a key role in systemic lupus erythematosus (SLE) pathogenesis, promoting autoimmunity, inflammation and cardiovascular disease. In SLE, platelets are morphologically altered and actively participate in complement activation and immune crosstalk. Given their central role at the interface of inflammation, coagulation and thrombosis and their susceptibility to autoantibody targeting, platelets may represent an integrated pathogenic component in SLE. We aimed to investigate whether platelets from patients with SLE exhibit signs of apoptosis and activation, and to explore their potential contribution to impaired clearance.Methods Consecutive patients with SLE (n=133; 90% female; mean age 50 ± 14 years) were clinically characterized, and platelet-rich plasma was collected upon informed consent. Platelets were analyzed by flow cytometry for mitochondrial membrane depolarization (δψm, TMRE), caspase-3 activation, and surface exposure of phosphatidylserine (PtdSer), detected by Annexin V. Surface sialic acid (detected by Sambucus nigra agglutinin, SNA) and platelet P-selectin/CD62P expression were also assessed as markers of activation and clearance signaling. Results from patients with SLE were compared with platelets from healthy controls (n=45) using Mann Whitney test (Graphpad Prism v10.6.1).Results Clinical characterization showed SLEDAI-2K, median (IQR): 2 (0–4). Flow cytometry displayed a higher proportion of P-selectin (CD62P) positive platelets in patients with SLE, lower TMRE signal (indicating mitochondrial depolarization), increased proportions of cells with cleaved caspase-3, enhanced surface PtdSer exposure, and reduced surface sialic acid (reflected by decreased SNA binding), compared with controls ( figure 1)Abstract PO:06:163 Figure 1Increased activation and signs of platelet apoptosis in SLE Flow cytometry of platelets from SLE patients showed A) increased depolarization of mitochondrial membrane; Caspase 3 activation and expression phosphatidylserine (PtdSer) and B) higher levels of platelets expressing P-selectin/CD62P and decreased levels of SNA suggesting lower surface levels of sialic acid. HC = healthy control. SNA=Sambucus Nigra Agglutinin.Conclusions Our findings demonstrate enhanced platelet apoptosis and activation in SLE. The combination of increased PtdSer exposure and reduced surface sialic acid indicates disturbed platelet homeostasis and impaired clearance. Given that platelets are the most abundant circulating cells after erythrocytes, apoptotic platelets may substantially contribute to defective clearance and immune activation in SLE. The observed upregulation of P-selectin confirms ongoing platelet activation despite low disease activity and supports a role in platelet-complement and platelet-leukocyte interactions. Future studies will determine the clinical implications of these findings, including the contribution of apoptotic platelets to thrombocytopenia, overall disease activity, and thrombosis.