FATAL EMBRYONIC BLEEDING EVENTS IN MICE LACKING TISSUE FACTOR, THE CELL-ASSOCIATED INITIATOR OF BLOOD-COAGULATION

Tissue factor (TF) is the cellular receptor for coagulation factor VII /VIIa and is the membrane-bound glycoprotein that is generally viewed as the primary physiological initiator of blood coagulation, To define in greater detail the physiological role of TF in development and hem ostasis, the TF gene was disrupted in mice, Mice heterozygous for the inactivated TF allele expressed approximately half the TF activity of wild-type mice but were phenotypically normal, However, homozygous TF- /- pups were never born in crosses between heterozygous mice, Analysis of mid-gestation embryos showed that TF-/- embryos die in utero betwe en days 8.5 and 10.5. TF-/- embryos were morphologically distinct from their TF+/+ and TF+/- littermates after day 9.5 in that they were Dal e, edematous, and growth retarded, Histological studies showed that ea rly organogenesis was normal, The initial failure in TF-/- embryos app eared to be hemorrhaging, leading to the leakage of embryonic red cell s from both extraembryonic and embryonic vessels, These studies indica te that TF plays an indispensable role in establishing and/or maintain ing vascular integrity in the developing embryo at a time when embryon ic and extraembryonic vasculatures are fusing and blood circulation be gins.