title: A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo.
abstract: Mice lacking factor XII (fXII) or factor XI (fXI) are resistant to experimentally-induced thrombosis, suggesting fXIIa activation of fXI contributes to thrombus formation in vivo. It is not clear whether this reaction has relevance for thrombosis in pri mates. In 2 carotid artery injury models (FeCl(3) and Rose Bengal/laser), fXII-deficient mice are more resistant to thrombosis than fXI- or factor IX (fIX)-deficient mice, raising the possibility that fXII and fXI function in distinct pathways. Antibody 14E11 binds fXI from a variety of mammals and interferes with fXI activation by fXIIa in vitro. In mice, 14E11 prevented arterial occlusion induced by FeCl(3) to a similar degree to total fXI deficiency. 14E11 also had a modest beneficial effect in a tissue factor-induced pulmonary embolism model, indicating fXI and fXII contribute to thrombus formation even when factor VIIa/tissue factor initiates thrombosis. In baboons, 14E11 reduced platelet-rich thrombus growth in collagen-coated grafts inserted into an arteriovenous shunt. These data support the hypothesis that fXIIa-mediated fXI activation contributes to thrombus formation in rodents and primates. Since fXII deficiency does not impair hemostasis, targeted inhibition of fXI activation by fXIIa may be a useful antithrombotic strategy associated with a low risk of bleeding complications.
authors.affiliation: Department of Pathology, Vanderbilt University, Nashville, TN 37232-6305, USA.
authors.forename: Qiufang
authors.initials: Q
authors.lastname: Cheng
authors.forename: Erik I
authors.initials: EI
authors.lastname: Tucker
authors.forename: Meghann S
authors.initials: MS
authors.lastname: Pine
authors.forename: India
authors.initials: I
authors.lastname: Sisler
authors.forename: Anton
authors.initials: A
authors.lastname: Matafonov
authors.forename: Mao-Fu
authors.initials: MF
authors.lastname: Sun
authors.forename: Tara C
authors.initials: TC
authors.lastname: White-Adams
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Smith
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Hanson
authors.forename: Owen J T
authors.initials: OJ
authors.lastname: McCarty
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
authors.forename: András
authors.initials: A
authors.lastname: Gruber
authors.forename: David
authors.initials: D
authors.lastname: Gailani
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000209:etiology; D002415:Cats; D004195:Disease Models, Animal; D004285:Dogs; D005172:Factor XI / Q000037:antagonists & inhibitors / Q000502:physiology*; D005173:Factor XI Deficiency / Q000097:blood / Q000235:genetics / Q000503:physiopathology; D005175:Factor XII Deficiency / Q000097:blood / Q000235:genetics / Q000503:physiopathology; D015956:Factor XIIa / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D048530:Papio anubis; D010314:Partial Thromboplastin Time; D011655:Pulmonary Embolism / Q000097:blood / Q000209:etiology; D011817:Rabbits; D013045:Species Specificity; D013927:Thrombosis / Q000097:blood* / Q000209:etiology*
chemical_list: D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D005172:Factor XI; D015956:Factor XIIa