A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo.
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.
Cheng
Qiufang
Q
Department of Pathology, Vanderbilt University, Nashville, TN 37232-6305, USA.
Tucker
Erik I
EI
Pine
Meghann S
MS
Sisler
India
I
Matafonov
Anton
A
Sun
Mao-Fu
MF
White-Adams
Tara C
TC
Smith
Stephanie A
SA
Hanson
Stephen R
SR
McCarty
Owen J T
OJ
Renné
Thomas
T
Gruber
András
A
Gailani
David
D
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*
D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D005172:Factor XI; D015956:Factor XIIa