RAPID COMMUNICATION Tissue Factor Pathway Inhibitor Gene Disruption Produces Intrauterine Lethality in Mice

Tissue factor pathway inhibitor (TFPI) is a multivalent Kurhage. The extent of structural abnormalities within the yolk sac vascular system appears to mirror the condition of the nitz-type proteinase inhibitor that directly inhibits factor Xa and, in a factor Xa–dependent fashion, produces feedback embryo, suggesting that the embryonic and extra-embryonic tissues are both responding to same insult, presumably inhibition of the factor VIIa/TF catalytic complex responsible for the initiation of coagulation. To further define the physiocirculatory insufficiency. Organogenesis is normal in TFPIK1 null animals that progress beyond E11.5, but hemorrhage, logic role of TFPI, gene-targeting techniques were used to disrupt exon 4 of the TFPI gene in mice. This exon encodes particularly in the central nervous system and tail, is evident during later gestation and none of the TFPIK1(Ï/Ï) mice surKunitz domain-1 of TFPI, which is required for factor VIIa/ TF inhibition. In mice heterozygous for TFPI gene-disruption, vive to the neonatal period. The presence of immunoreactive fibrin(ogen) in the liver and intravascular thrombi is consisTFPIK1("/Ï), an altered form of TFPI lacking Kunitz domain1, circulates in plasma at a concentrationÒ40% that of wildtent with the notion that unregulated factor VIIa/TF action and a consequent consumptive coagulopathy underlies the type TFPI. TFPIK1("/Ï) animals have plasma TFPI activity Ò50% that of wild-type mice, based on a functional assay bleeding diathesis in these older embryos. Human TFPI-deficient embryos may suffer a similar fate because an individthat measures factor VIIa/TF inhibition, and have a normal phenotype. Sixty percent of TFPIK1(Ï/Ï) mice die between ual with TFPI deficiency has not been identified. q 1997 by The American Society of Hematology. embryonic days E9.5 and E11.5 with signs of yolk sac hemor-