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.
