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Combined factor VII/protein C deficiency results in intrauterine coagulopathy in mice.

Abstract
To determine whether an additional loss of the coagulation factor VII (FVII) gene influenced the coagulopathy observed in protein C gene-deficient (PC(-/-)) embryos and neonates, we crossed mice doubly heterozygous for the factor VII (FVII(+/-)) and protein C (PC(+/-)) genes to produce offspring possessing the 9 predicted genotypic combinations. FVII(-/-)/PC(-/-) embryos, although present at their expected Mendelian frequency, displayed a phenotype that had not been observed in either the FVII or PC singly deficient embryos. At E12.5 days postcoitum (dpc), FVII(-/-)/PC(-/-) embryos demonstrated an intra- and extravascular coagulopathy that progressed with substantial concomitant hemorrhage and peripheral edema by E17.5dpc, resulting in mortality immediately after birth. FVII(+/-)/PC(-/-) embryos showed a less severe phenotype, suggesting a gene dosage effect. The lack of rescue of PC(-/-) embryos and neonates and augmented coagulopathy resulting from an additional heterozygous or homozygous FVII deficiency are probably due to increased factor Xa and thrombin generation, resulting from loss of FVIIa-dependent tissue factor pathway inhibitor function and the absence of control at the levels of factors Va and VIIIa. The presence of fibrin in embryos in the absence of fetal FVII suggests that significant clot-generating potential exists outside of the embryonic factor VII-dependent pathway.
AuthorsJ C Chan, I Cornelissen, D Collen, V A Ploplis, F J Castellino
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 105 Issue 7 Pg. 897-903 (Apr 2000) ISSN: 0021-9738 [Print] United States
PMID10749569 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Topics
  • Animals
  • Crosses, Genetic
  • Embryonic and Fetal Development
  • Factor VII Deficiency (complications, genetics)
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein C Deficiency (complications, genetics)
  • Uterine Diseases (etiology)

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