A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo.

Cheng Q, Tucker EI, Pine MS, Sisler I, Matafonov A, Sun MF, White-Adams TC, Smith SA, Hanson SR, McCarty OJ, Renné T, Gruber A, Gailani D
Blood. 2010 116 (19): 3981-9

PMID: 20634381 · PMCID: PMC2981546 · DOI:10.1182/blood-2010-02-270918

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.

MeSH Terms (23)

Animals Antibodies, Monoclonal Anticoagulants Carotid Artery Thrombosis Cats Disease Models, Animal Dogs Factor XI Factor XI Deficiency Factor XIIa Factor XII Deficiency Humans In Vitro Techniques Male Mice Mice, Inbred BALB C Mice, Knockout Papio anubis Partial Thromboplastin Time Pulmonary Embolism Rabbits Species Specificity Thrombosis

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