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

Blood. 2010 Nov 11;116(19):3981-9. doi: 10.1182/blood-2010-02-270918. Epub 2010 Jul 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


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