Summary

A genetically-transmissible factor (F) XII-inactivated allele has been produced in mice by targeted replacement of exons 3–8 of the FXII gene with the neomycin resistance gene. Interbreeding of these mice provided offspring homozygous for two inactivated FXII alleles (FXII-/-). Male and female FXII-deficient mice bred normally in all genotypic combinations of the heterozygous and homozygous states,and the offspring survived to adulthood, suggesting that a total FXII deficiency does not affect embryonic development and survival. Neither FXII transcripts nor FXII antigen was found in various tissues of adult FXII -/- mice. No obvious unchallenged coagulopathies were present in FXII-/- adult mice, despite greatly prolonged activated partial thromboplastin times in this mouse cohort.FXII-/- mice were then used to assess the in vivo importance of the plasma FXII/prekallikrein/kininogen pathway in provision of resting plasma bradykinin (BK) levels and in generation of plasma BK stimulated by contact with an artificial surface, using a new and greatly improved plasma BK assay developed during these studies. It was found that approximately 50% of resting BK, and all of the contact-stimulated plasma BK, was provided by this FXII-dependent pathway, without a requirement for FXI.These results provide clear evidence that surface-stimulated BK production, in mice, is dependent on the activation of FXII.