LOW-LEVELS OF TISSUE FACTOR ARE COMPATIBLE WITH DEVELOPMENT AND HEMOSTASIS IN MICE

Tissue factor (TF) expression is associated with life-threatening thro mbosis In a variety of human diseases, including sepsis, cancer, and a therosclerosis. Recently, it was shown that inactivation of the murine TF (mTF) gene results in embryonic lethality, To date, despite extens ive studies on the regulation of the TF promoter in vitro, no studies have examined the cis-acting regulatory elements that control TF gene expression in vivo. Here we report that a human TF (hTF) minigene cont aining the human TF promoter and human TF cDNA directed a low level (s imilar to 1% relative to mouse TF) of both constitutive and. LPS-induc ible human TF expression in transgenic mice. Importantly, the human TF minigene rescued the embryonic lethality of murine TF null embryos, s uggesting that human TF substituted for murine TF during embryogenesis . Rescued mice (mTF(-/-), hTF(+)), which expressed low levels (similar to 1%) of TF activity, developed normally with no signs of a bleeding diathesis, suggesting that low TF expression can maintain hemostasis compatible with normal survival. These studies establish a novel mouse model system that can be used to examine the regulation of the human TF gene in vivo and the impact of low TF levels on the hemostatic bala nce in various thrombotic diseases.