Platelets as drivers of immunothrombosis in rheumatic diseases

Platelets are central players in inflammatory and thrombotic responses that drive the onset and progression of rheumatic diseases. In particular, they regulate immunothrombosis, a defence mechanism in which the immune and blood-clotting systems cooperate to contain infections or vascular damage. Although immunothrombosis can help to preserve blood-vessel integrity and promote healing, it becomes harmful when exaggerated or chronic. In rheumatic diseases, such as systemic lupus erythematosus, systemic sclerosis and antiphospholipid syndrome, immunothrombosis contributes to persistent inflammation, abnormal blood-clot formation and long-term damage to the small blood vessels. It has also been implicated in maintaining autoimmune responses to autoantigens released by neutrophils. Platelets are among the first responders to vascular injury and influence the activity of immune cells, particularly neutrophils, by promoting the formation of neutrophil extracellular traps. Platelets express proteins such as P-selectin and the damage-associated molecule high-mobility group box 1 (HMGB1), which have distinct and non-redundant roles, both via direct interactions locally at sites of vascular damage and systemically via the release of extracellular vesicles. Understanding how platelets contribute to vascular inflammation and clotting in autoimmune settings elucidates disease mechanisms and might lead to the identification of new therapeutic targets. This Review provides an overview of how platelets promote immunothrombosis in rheumatic disease. The authors discuss the different ways in which platelets and immunothrombosis can be targeted for therapeutic intervention.