Platelets in sickle cell disease: biomarkers, mediators, and lessons from clinical trials

Sickle cell disease (SCD) is an inherited hemolytic disorder characterized by a mutation in β-globin, resulting in hemoglobin polymerization, red blood cell rigidity, and a persistently activated endothelium that promotes thromboinflammation. Platelets are recognized as central mediators of this thromboinflammatory milieu, integrating signals from hemostatic and innate immune pathways. In this review, we summarize the disease-specific mechanisms by which platelets are activated in SCD, including G-protein coupled receptor signaling, C-type lectin-like receptor-2 (CLEC-2)/glycoprotein VI-Bruton tyrosine kinase pathways, and responses to damage-associated molecular patterns such as free heme, and how these processes amplify leukocyte recruitment, inflammasome activation, and vascular occlusion. We highlight emerging platelet-associated biomarkers that correlate with disease severity and acute complications, including platelet-leukocyte aggregates, P-selectin, podoplanin-CLEC-2 signaling, and inflammatory cytokine pathways. Finally, we evaluate clinical trial data targeting platelet pathways, from early aspirin studies to more recent trials of P2Y purinoceptor-12 inhibitors and selectin-blocking agents, noting both the promise and limitations of these approaches. Together, these findings underscore the multifaceted contribution of platelets to SCD pathophysiology, and point toward ongoing questions regarding whether platelets primarily serve as biomarkers of disease activity or represent modifiable therapeutic targets capable of reducing the clinical burden of SCD.