Platelet heterogeneity in disease: the many and the diverse?

ABSTRACT: Platelets in peripheral blood critically drive clot formation in health and disease. Previously considered to uniformly respond to vascular injury and inflammatory cues, recent studies have highlighted that circulating platelets exhibit marked heterogeneity, with distinct populations contributing differentially to hemostasis, thrombosis, and inflammation. In this review, we highlight platelet diversity as a consequence of origin (ie, megakaryocyte diversity), circulatory age (ie, young vs aged platelets), and, specifically, as both a sequela of and a contributing factor to cardiovascular and inflammatory diseases. This diversity includes reticulated platelets (RPs), newly released from the bone marrow, RNA-rich, and highly prothrombotic, vs aged platelets, which exhibit altered receptor expression and proinflammatory rather than hemostatic features. We further describe how platelet subsets actively shape disease progression. Hyperreactive RPs drive arterial thrombosis, whereas procoagulant platelets amplify fibrin formation in venous thromboembolism. In chronic inflammation, interactions of immune-responsive platelets with leukocyte subsets facilitate their recruitment and impact on polarization, but can also promote endothelial dysfunction and immune hyperactivation, perpetuating thromboinflammatory dysregulation. Moreover, platelet phenotypes are dynamically regulated by disease states, with systemic inflammation, altered shear forces, and metabolic stress influencing platelet turnover, activation thresholds, and functional specialization. Recognizing platelet heterogeneity in disease pathogenesis could provide new opportunities for precision medicine, potentially allowing stratification of thrombotic risk and differential tailoring of antiplatelet and anti-inflammatory therapies.