TISSUE FACTOR PATHWAY INHIBITOR GENE DISRUPTION PRODUCES INTRAUTERINELETHALITY IN MICE

Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type pr oteinase inhibitor that directly inhibits factor Xa and, in a factor X a-dependent fashion, produces feedback inhibition of the factor VIIa/T F catalytic complex responsible for the initiation of coagulation. To further define the physiologic role of TFPI, gene-targeting techniques were used to disrupt exon 4 of the TFPI gene in mice. This exon encod es Kunitz domain-1 of TFPI, which is required for factor VIIa/TF inhib ition. In mice heterozygous for TFPI gene-disruption, TFPIK1(+/-), an altered form of TFPI lacking Kunitz domain-1, circulates in plasma at a concentration similar to 40% that of wildtype TFPI. TFPIK1(+/-) anim als have plasma TFPI activity similar to 50% that of wild-type mice, b ased on a functional assay that measures factor VIIa/TF inhibition, an d have a normal phenotype. Sixty percent of TFPIK1(-/-) mice die betwe en embryonic days E9.5 and E11.5 with signs of yolk sac hemorrhage. Th e extent of structural abnormalities within the yolk sac vascular syst em appears to mirror the condition of the embryo, suggesting that the embryonic and extra-embryonic tissues are both responding to same insu lt, presumably circulatory insufficiency. Organogenesis is normal in T FPIK1, null animals that progress beyond E11.5, but hemorrhage, partic ularly in the central nervous system and tail, is evident during later gestation and none of the TFPIK1(-/-) mice survive to the neonatal pe riod. The presence of immunoreactive fibrin(ogen) in the liver and int ravascular thrombi is consistent with the notion that unregulated fact or VIIa/TF action and a consequent consumptive coagulopathy underlies the bleeding diathesis in these older embryos, Human TFPI-deficient em bryos may suffer a similar fate because an individual with TFPI defici ency has not been identified. (C) 1997 by The American Society of Hema tology.