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, evidence suggests that LPS can influence coagulation, in part through activation
of the contact 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 the ability of LPS to activate
coagulation factor XII (FXII). While monomeric LPS can modulate FXII activity, only
aggregated forms of LPS (e.g., micelles) function as a procoagulant surface, initiating
contact activation. This review synthesizes current knowledge on LPS structural heterogeneity
and explores how the biophysical properties of LPS 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 structures—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.
Keywords
lipopolysaccharide - contact pathway - factor XII - thromboinflammation - supramolecular
structure
