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

Joyce C Y Chan, Peter Carmeliet, Lieve Moons, Elliot Rosen, Zhong Fu Huang, George J. Broze, Désiré Collen, Francis J. Castellino

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Abstract

Mice doubly heterozygous for a modified tissue factor pathway inhibitor (TFPI) allele (tfpi(δ)) lacking its Kunitz-type domain-1 (TFPI(+/δ)) and for a deficiency of the factor VII gene (FVII(+/-)) were mated to generate 309 postnatal and 205 embryonic day 17.5 (E17.5) offspring having all the predicted genotypic combinations. Progeny singly homozygous for the tfpi(δ) modification but with the wild-type fVII allele (FVII(+/+)TFPI(δ/δ)), and mice singly homozygous for the fVII deficiency and possessing the wild-type tfpi allele (FVII(-/-)TFPI(+/+)), displayed previously detailed phenotypes (i.e., a high percentage of early embryonic lethality at E9.5 or normal development with severe perinatal bleeding, respectively). Surprisingly, mice of the combined FVII(-/-)TFPI(δ/δ) genotype were born at the expected mendelian frequency but suffered the fatal perinatal bleeding associated with the FVII(-/-) genotype. Mice carrying the FVII(+/-)/TFPI(δ/δ) genotype were also rescued from the lethality associated with the FVII(+/+)/TFPI(δ/δ) genotype but succumbed to perinatal consumptive coagulopathy. Thus, the rescue of TFPI(δ/δ) embryos, either by an accompanying homozygous or heterozygous FVII deficiency, suggests that diminishment of FVII activity precludes the need for TFPI-mediated inhibition of the FVIIa/tissue factor coagulation pathway during embryogenesis. Furthermore, the phenotypes of these combined deficiency states suggest that embryonic FVII is produced in mice as early as E9.5 and that any level of maternal FVII in early-stage embryos is insufficient to cause a coagulopathy in TFPI(δ/δ) mice.

Original languageEnglish (US)
Pages (from-to)475-482
Number of pages8
JournalJournal of Clinical Investigation
Volume103
Issue number4
StatePublished - Feb 1999
Externally publishedYes

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Factor VII Deficiency
Alleles
Genotype
lipoprotein-associated coagulation inhibitor
Embryonic Structures
Hemorrhage
Phenotype
Thromboplastin

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Chan, J. C. Y., Carmeliet, P., Moons, L., Rosen, E., Huang, Z. F., Broze, G. J., ... Castellino, F. J. (1999). Factor VII deficiency rescues the intrauterine lethality in mice associated with a tissue factor pathway inhibitor deficit. Journal of Clinical Investigation, 103(4), 475-482.

Factor VII deficiency rescues the intrauterine lethality in mice associated with a tissue factor pathway inhibitor deficit. / Chan, Joyce C Y; Carmeliet, Peter; Moons, Lieve; Rosen, Elliot; Huang, Zhong Fu; Broze, George J.; Collen, Désiré; Castellino, Francis J.

In: Journal of Clinical Investigation, Vol. 103, No. 4, 02.1999, p. 475-482.

Research output: Contribution to journalArticle

Chan, JCY, Carmeliet, P, Moons, L, Rosen, E, Huang, ZF, Broze, GJ, Collen, D & Castellino, FJ 1999, 'Factor VII deficiency rescues the intrauterine lethality in mice associated with a tissue factor pathway inhibitor deficit', Journal of Clinical Investigation, vol. 103, no. 4, pp. 475-482.
Chan, Joyce C Y ; Carmeliet, Peter ; Moons, Lieve ; Rosen, Elliot ; Huang, Zhong Fu ; Broze, George J. ; Collen, Désiré ; Castellino, Francis J. / Factor VII deficiency rescues the intrauterine lethality in mice associated with a tissue factor pathway inhibitor deficit. In: Journal of Clinical Investigation. 1999 ; Vol. 103, No. 4. pp. 475-482.
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