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

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 fact or VII (FVII+/-) and protein C (PC+/-) genes to produce offspring possessin g the 9 predicted genotypic combinations. FVII-/-/PC-/- embryos, although p resent at their expected Mendelian frequency, displayed a phenotype that ha d not been observed in either the FVII or PC singly deficient embryos. At E 12.5 days postcoitum (dpc), FVI-/-/PC-/- embryos demonstrated an intra- and extravascular coagulopathy that progressed with substantial concomitant he morrhage and peripheral edema by E17.5dpc, resulting in mortality immediate ly after birth. FVII+/-/PC-/- embryos showed a less severe phenotype, sugge sting a gene dosage effect. The lack of rescue of PC-/- embryos and neonate s and augmented coagulopathy resulting from an additional heterozygous or h omozygous FVII deficiency are probably due to increased factor Xa and throm bin generation, resulting from loss of FVIIa-dependent tissue factor pathwa y 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 e mbryonic factor VII-dependent pathway.