Lipopolysaccharide and coagulation factor XII: biophysics of contact activation in infection.

Abstract

Lipopolysaccharide (LPS), a key component of the outer membrane of Gram-negative bacteria, is well known for its role in triggering inflammation via innate immune receptors. However, emerging evidence reveals that LPS also directly activates the coagulation system, primarily through the contact activation pathway. Recent studies from our group and others demonstrate that the supramolecular organization and physicochemical properties of LPS-such as aggregate size, surface charge, and chemotype-critically determine its ability to activate coagulation factor XII (FXII). While monomeric LPS can modulate FXII activity, only aggregated forms of LPS (e.g., micelles) function as procoagulant surfaces, initiating contact activation. This review synthesizes current knowledge on LPS structural heterogeneity and explores how its biophysical properties govern supramolecular assembly in aqueous environments, ultimately dictating interactions with the contact activation pathway. We further discuss the possible mechanisms by which LPS-driven FXII activation contributes to thromboinflammatory disorders, including disseminated intravascular coagulation and sepsis-associated vascular leakage. Finally, we highlight novel therapeutic strategies-from FXIIa inhibitors to molecules that disrupt LPS supramolecular structure-as potential interventions to mitigate coagulation-driven pathology during bacterial infections. These insights not only reflect our growing understanding of infection-associated thrombosis but may also pave the way for targeted therapies in sepsis and other thromboinflammatory conditions.