Messengers of coagulopathy: complement-carrying extracellular vesicles in SARS-CoV-2 infection

SARS-CoV-2 disease (COVID-19) is increasingly recognized as a thromboinflammatory vascular disorder characterized by dysregulated complement activation, endothelial injury, and sustained hypercoagulability. This review examines emerging evidence that extracellular vesicles act as key intermediaries linking complement activation to coagulation in acute and postacute COVID-19 infection.

Recent studies demonstrate that extracellular vesicles released from platelets, endothelial cells, and neutrophils are markedly increased in COVID-19 and exhibit a combined procoagulant and complement-active phenotype. Sub-lytic complement attack, particularly membrane attack complex (MAC) deposition, triggers phosphatidylserine exposure and extracellular vesicle shedding, generating vesicles that support thrombin generation and propagate complement activity in the circulation. Extracellular vesicle-associated complement components, including C1q, C3 fragments, MASP2, and preassembled MACs, promote tissue factor decryption, platelet activation, and assembly of the prothrombinase complex, establishing a self-amplifying thromboinflammatory loop. Proteomic profiling further reveals compartment-specific extracellular vesicle signatures, with systemic extracellular vesicles enriched in complement and coagulation pathways. Importantly, complement-bearing and tissue factor-bearing extracellular vesicles persist beyond acute infection and are increasingly implicated in postacute sequelae of COVID-19.

Extracellular vesicles serve as mobile platforms integrating complement activation with coagulation, providing a mechanistic framework for acute and chronic immunothrombosis in COVID-19. Targeting extracellular vesicle-mediated complement-coagulation crosstalk may offer novel diagnostic and therapeutic opportunities.