The multifaceted role of platelets in systemic sclerosis: beyond haemostasis!

Systemic sclerosis (SSc) is characterized by early and persistent vascular injury, immune dysregulation, and fibrosis, with a growing recognition of an excess thrombotic burden that cannot be fully explained by traditional cardiovascular risk factors. Increasing experimental and clinical evidence positions platelets as mediators at the interface of vasculopathy, inflammation, and coagulation in systemic sclerosis. This review addresses emerging platelet-driven mechanisms that extend platelet function beyond haemostasis and highlight their role as intravascular messengers capable of propagating damage across organs.

Recent literature demonstrates that platelets in SSc exhibit a persistently activated and primed phenotype, driven by endothelial injury, aberrant platelet-collagen interactions, inflammation-mediated priming, and defective platelet clearance. Activated platelets interact dynamically with immune cells, particularly neutrophils, promoting neutrophil extracellular trap formation and immunothrombosis through pathways involving HMGB1, P-selectin-PSGL-1, and GPVI. Platelet-derived mediators, including CXCL4, serotonin, PDGF, and extracellular vesicles, enable the dissemination of inflammatory and profibrotic signals, thereby contributing to endothelial dysfunction, immune activation, and fibrotic remodelling in distant vascular beds. Clinical studies increasingly link platelet activation markers with distinct disease subsets and major organ complications.

Collectively, these findings identify platelets as key orchestrators and conveyors of immunothrombosis and thromboinflammation in SSc. Improved understanding of platelet-driven signalling networks may inform risk stratification and support the development of targeted antithrombotic or immunomodulatory strategies, although robust evidence for disease-modifying antiplatelet interventions remains limited.