title: Factor XIIa regulates the structure of the fibrin clot independently of thrombin generation through direct interaction with fibrin.
abstract: 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.
authors.affiliation: Laboratory for Clinical Thrombosis and Haemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Joke
authors.initials: J
authors.lastname: Konings
authors.forename: José W P
authors.initials: JW
authors.lastname: Govers-Riemslag
authors.forename: Helen
authors.initials: H
authors.lastname: Philippou
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Mutch
authors.forename: Julian I
authors.initials: JI
authors.lastname: Borissoff
authors.forename: Peter
authors.initials: P
authors.lastname: Allan
authors.forename: Sumitra
authors.initials: S
authors.lastname: Mohan
authors.forename: Guido
authors.initials: G
authors.lastname: Tans
authors.forename: Hugo
authors.initials: H
authors.lastname: Ten Cate
authors.forename: Robert A S
authors.initials: RA
authors.lastname: Ariëns
mesh_terms: D001777:Blood Coagulation; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D004548:Elasticity; D015956:Factor XIIa / Q000378:metabolism*; D005337:Fibrin / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D006801:Humans; D011485:Protein Binding; D011516:Prothrombin / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*; D013927:Thrombosis / Q000378:metabolism / Q000473:pathology; D014783:Viscosity
chemical_list: D011516:Prothrombin; D005337:Fibrin; D015956:Factor XIIa; D013917:Thrombin