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.
Keywords
FXII deficiency - targeted gene replacement - bradykinin generation - vasoactivity
- reproduction - intrinsic coagulation pathway - contact activation