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

146 Citations (Scopus)

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
Pages (from-to)3981-3989
Number of pages9
JournalBlood
Volume116
Issue number19
DOIs
Publication statusPublished - 11 Nov 2010
Externally publishedYes

Fingerprint

Factor XIIa
Factor XI
Thrombosis
Chemical activation
Factor XII
Thromboplastin
Primates
Factor XII Deficiency
Factor XI Deficiency
Carotid Artery Injuries
Rose Bengal
Factor VIIa
Factor IX
Papio
Mammals
Hemostasis
Pulmonary Embolism
Grafts
Rodentia
Lasers

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Cheng, Q., Tucker, E. I., Pine, M. S., Sisler, I., Matafonov, A., Sun, M. F., ... 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

A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo. / Cheng, Qiufang; Tucker, Erik I.; Pine, Meghann S.; Sisler, India; Matafonov, Anton; Sun, Mao Fu; White-Adams, Tara C.; Smith, Stephanie A.; Hanson, Stephen R.; McCarty, Owen J T; Renné, Thomas; Gruber, András; Gailani, David.

In: Blood, Vol. 116, No. 19, 11.11.2010, p. 3981-3989.

Research output: Contribution to journalArticle

Cheng, Q, Tucker, EI, Pine, MS, Sisler, I, Matafonov, A, Sun, MF, White-Adams, TC, Smith, SA, Hanson, SR, McCarty, OJT, Renné, T, Gruber, A & Gailani, D 2010, 'A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo', Blood, vol. 116, no. 19, pp. 3981-3989. https://doi.org/10.1182/blood-2010-02-270918
Cheng Q, Tucker EI, Pine MS, Sisler I, Matafonov A, Sun MF et al. A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo. Blood. 2010 Nov 11;116(19):3981-3989. https://doi.org/10.1182/blood-2010-02-270918
Cheng, Qiufang ; Tucker, Erik I. ; Pine, Meghann S. ; Sisler, India ; Matafonov, Anton ; Sun, Mao Fu ; White-Adams, Tara C. ; Smith, Stephanie A. ; Hanson, Stephen R. ; McCarty, Owen J T ; Renné, Thomas ; Gruber, András ; Gailani, David. / A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo. In: Blood. 2010 ; Vol. 116, No. 19. pp. 3981-3989.
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