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: Qiufang Cheng, Erik I Tucker, Meghann S Pine, India Sisler, Anton Matafonov, Mao-Fu Sun, Tara C White-Adams, Stephanie A Smith, Stephen R Hanson, Owen J T McCarty, Thomas Renné, András Gruber, David Gailani
• Journal: Blood (Blood) Vol. 116 Issue 19 Pg. 3981-9 (Nov 11 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20634381 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Anticoagulants
• Factor XI
• Factor XIIa

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Anticoagulants (pharmacology)
• Carotid Artery Thrombosis (blood, etiology)
• Cats
• Disease Models, Animal
• Dogs
• Factor XI (antagonists & inhibitors, physiology)
• Factor XI Deficiency (blood, genetics, physiopathology)
• Factor XII Deficiency (blood, genetics, physiopathology)
• Factor XIIa (physiology)
• Humans
• In Vitro Techniques
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Papio anubis
• Partial Thromboplastin Time
• Pulmonary Embolism (blood, etiology)
• Rabbits
• Species Specificity
• Thrombosis (blood, etiology)