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Background: Platelet activation and subsequent thrombus formation is a well‐defined process to maintain vascular integrity upon tissue damage. However, platelets are also activated by an array of inflammatory stimuli, including microbial infection. Further, circulating platelets contain intracellular IgG that are released upon activation.

Aim: We aimed to elucidate the physiologic function of platelet‐derived IgGs and their effect on viral infections.

Methods: IgG levels, subclass and light chain distributions were quantified by ELISA. For neutralization assays, CMV‐infected HUVECs were perfused with platelets or plasma of anti‐CMV IgG seropositive or seronegative donors before quantification of infection by IF or qPCR. IgG content of neonatal Fc‐receptor (FcRn)‐deficient or wild‐type murine megakaryocytes (MK) was measured by flow cytometry.

Results: Human platelets can store and release anti‐IAV and anti‐CMV IgG. Platelets from anti‐CMV IgG seropositive but not seronegative donors potently neutralized in vitro CMV‐infection under microvascular shear stress. In spite of containing approximately 100‐fold less IgG, platelets were equally efficient at neutralization as plasma from the same donor. Platelets were not enriched for a specific IgG subclass, nor for a specific kappa or lambda light chain. As MKs contain FcRn, sequestration of IgG might occur in the shared microenvironment of MKs and plasma cells. Indeed, MK FcRn was partially responsible for IgG uptake and may thus rescue IgG from degradation after endocytosis.

Conclusion: Our data show that platelets have the potential to mediate potent IgG‐mediated antiviral effects directly at foci of infection, indicating that platelet activation may represent a novel mechanism for focused serological immunity.