Deciphering Platelet Transcriptomic Profiles in Antiphospholipid Syndrome: Insights into Their Role as Immunological Players

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder driven by antiphospholipid antibodies (aPLs), primarily characterized by recurrent thrombosis and pregnancy morbidity. Transcriptomic analyses of other immune compartments have provided insights into APS pathogenesis. However, despite the central role of platelets in APS pathophysiology, their transcriptomic features remain largely unexplored. We therefore aimed to characterize the platelet transcriptomic landscape in APS and identify key immune-thrombotic pathways. RNA sequencing and bioinformatic analyses of platelets from 43 APS patients, 20 asymptomatic aPL carriers, and 20 healthy controls revealed distinct proinflammatory transcriptional reprogramming, consistent with platelets as active thrombo-inflammatory hubs. APS platelets exhibited marked activation of innate immune (Toll-like and NOD-like receptors) and neutrophil pathways, which may contribute to disease propagation through a functional platelet–neutrophil axis. A 15-gene classifier (e.g., FCER1G, MAP4K4) discriminated APS from controls with high accuracy (Area Under the Curve 0.901–0.948). The classifier also highlighted molecular differences between APS and asymptomatic aPL carriers relevant to disease progression. Network analysis suggested that anti-β2-glycoprotein I antibodies were associated with unique coagulation–immunity modules, while arterial and venous thrombosis displayed divergent cytoskeletal-energetic and lipid-signaling signatures, respectively. Together, these findings suggest that platelets in APS acquire a distinct proinflammatory phenotype and function as key immunothrombotic interfaces, supporting disease stratification and platelet-derived diagnostic strategies.