Platelet activation and bacterial interactions: linking immunothrombosis to infectious pathophysiology.

Platelets are anucleate blood cells traditionally recognized for their central role in hemostasis but are now appreciated as active sentinels of innate immunity. During bacterial infection, platelets sense pathogen-associated molecular patterns and immune complexes through toll-like receptors, FcγRIIA, complement receptors, and adhesive integrins. This recognition enables platelets to interact with leukocytes and endothelial cells and to release proinflammatory and procoagulant mediators. While these responses contribute to pathogen containment, they also promote thromboinflammation and microvascular thrombosis, a process collectively referred to as immunothrombosis. This review synthesizes knowledge on platelet interactions with gram-positive and gram-negative bacteria and delineates how these pathways converge on immunothrombosis in clinical settings such as infective endocarditis and sepsis. Gram-positive bacteria, including Staphylococcus aureus and Streptococcus spp, activate platelets through FcγRIIA signaling following IgG opsonization and through αIIbβ3 engagement via plasma protein bridges. In contrast, gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Neisseria meningitidis predominantly trigger inflammatory platelet activation through TLR4-dependent recognition of lipopolysaccharide. Activated platelets form aggregates with neutrophils and monocytes, promote neutrophil extracellular trap formation, and support tissue factor-dependent coagulation. Although localized immunothrombosis may be host-protective by restricting bacterial dissemination, dysregulated systemic platelet activation contributes to disseminated intravascular coagulation and organ failure. We discuss mechanistic and translational implications and argue for selective modulation of platelet immune signaling rather than global platelet inhibition. We outline priorities for biomarker-guided interventions, including circulating markers of platelet activation such as soluble P-selectin, soluble GPVI, and NETosis markers, aimed at preserving antimicrobial defense while limiting pathological thrombosis.