Recent data indicate an important contribution of
coagulation factor (F)XII to in vivo
thrombus formation. Because
fibrin structure plays a key role in clot stability and
thrombosis, we hypothesized that FXII(a) interacts with
fibrin(
ogen) and thereby regulates clot structure and function. In plasma and purified system, we observed a dose-dependent increase in
fibrin fiber density and decrease in turbidity, reflecting a denser structure, and a nonlinear increase in clot stiffness with FXIIa. In plasma, this increase was partly independent of
thrombin generation, as shown in clots made in
prothrombin-deficient plasma initiated with
snake venom enzyme and in clots made from plasma deficient in FXII and
prothrombin. Purified FXII and α-FXIIa, but not β-FXIIa, bound to purified
fibrinogen and
fibrin with nanomolar affinity. Immunostaining of human carotid artery thrombi showed that FXII colocalized with areas of dense
fibrin deposition, providing evidence for the in vivo modulation of
fibrin structure by FXIIa. These data demonstrate that FXIIa modulates
fibrin clot structure independently of
thrombin generation through direct binding of the N-terminus of FXIIa to
fibrin(
ogen). Modification of
fibrin structure by FXIIa represents a novel physiologic role for the contact pathway that may contribute to the pathophysiology of
thrombosis.