Factor VII deficiency rescues the intrauterine lethality in mice associated with a tissue factor pathway inhibitor deficit

Mice doubly heterozygous for a modified tissue factor pathway inhibitor (TF PI) allele (tfpi(delta)) lacking its Kunitz-type domain-1 (TFPI+/delta) and for a deficiency of the factor VII gene (FVII+/-) were mated to generate 3 09 postnatal and 205 embryonic day 17.5 (E17.5) offspring having all the pr edicted genotypic combinations. Progeny singly homozygous for the tfpi(delt a) modification but with the wild-type fVII allele (FVII+/+/TFPIdelta/delta , and mice singly homozygous for the fVII deficiency and possessing the wil d-type tfpi allele (FVII-/-/TFPI+/+), displayed previously detailed phenoty pes (i.e., a high percentage of early embryonic lethality at E9.5 or normal development with severe perinatal bleeding, respectively). Surprisingly, m ice of the combined FVII-/-/TFPIdelta/delta genotype were born at the expec ted mendelian frequency but suffered the fatal perinatal bleeding associate d with the FVII-/- genotype. Mice carrying the FVII+/-/TFPIdelta/delta geno type were also rescued from the lethality associated with the FVII+/+/TFPId elta/delta genotype but succumbed to perinatal consumptive coagulopathy. Th us, the rescue of TFPIdelta/delta embryos, either by an accompanying homozy gous or heterozygous FVII deficiency, suggests that diminishment of FVII ac tivity precludes the need for TFPI-mediated inhibition of the FVIIa/tissue factor coagulation pathway during embryogenesis. Furthermore, the phenotype s of these combined deficiency states suggest that embryonic FVII is produc ed in mice as early as E9.5 and that any level of maternal FVII in early-st age embryos is insufficient to cause a coagulopathy in TFPIdelta/delta mice .