Tissue factor (TF) of blood coagulation plays a pivotal role in mediating cellular initiation of blood coagulation, by activating factor VII to factor Vila. A role of TF in hemostasis and thrombogenesis following vascular injury or inflammation is suggested by (he induction of TF expression in endothelial cells and in cells of the monocyte lineage, following activation by proinflammatory cytokines or growth factors. TF might, however, also participate in other biological processes including embryogenesis, tumorigenesis, sepsis, atherosclerosis, brain function and kidney disease. The exact in vivo role of TF, and its requirement for interaction with factor VII, in these processes remains, however, to be furhter defined. In order to examine the role of TF in vivo, the rnurine TF gene was disrupted by targeted replacement of the TF promoter, the first exon and part of the second exon by the neoR gene. Genolyping of 350 offspring from heterozygous TF deficient (TF+/- ) breeding pairs resulted in one viable homozygous TF deficient (TF-/-) offspring that survived a few hours after birth. TF-/- embryos generally died in utero around 10.5 days post coitum (dpc) as a result of defective extraembryonic vessel development. Most notably, the large collecting vessels that connect the yolk sac with the embryo were present in 73/100 (73%) TF+/+ yolk sac sections but in 0/54 (0%) TF-/- yolk sac sections (p<0.05 vs TF+/+). The presence of the TF mRNA and protein in the visceral endoderm cells of the yolk sac was identified by RTPCR, immunostaining and procoagulant assay. No factor VIIimmunoreactivity was observed in the yolk sac or embryo at 9.5 dpc, and <1% of recombinant human factor VII was recovered within 1.3.5 dpc embryos after intravenous injection in a pregnant female mouse, suggesting that TF might exert its role during early embryogenesis independently of factor VII.
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