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

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

Research output: Contribution to journalArticle

158 Scopus citations

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 primates. In 2 carotid artery injury models (FeCl3 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 plateletrich 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.

Original languageEnglish (US)
Pages (from-to)3981-3989
Number of pages9
JournalBlood
Volume116
Issue number19
DOIs
StatePublished - Nov 11 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Cheng, Q., Tucker, E. I., Pine, M. S., Sisler, I., Matafonov, A., Sun, M. F., White-Adams, T. C., Smith, S. A., Hanson, S. R., McCarty, O. J. T., Renné, T., Gruber, A., & Gailani, D. (2010). A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo. Blood, 116(19), 3981-3989. https://doi.org/10.1182/blood-2010-02-270918