Tissue factor pathway inhibitor gene disruption

Tissue factor pathway inhibitor (TFPI) is a trivalent Kunitz-type plasma proteinase inhibitor that regulates the initiation of coagulation by producing activated factor X (FXa)-dependent feedback inhibition of the catalytic complex of FVIIa and tissue factor (TF). The second Kunitz domain of TFPI binds and inhibits FXa, whereas the first Kunitz domain is responsible for the inhibition of FVIIa in the TF-FVIIa complex. To define further the physiological role of TFPI, gene targeting was used to disrupt exon 4 encoding the first Kunitz domain of TFPI in the mouse TFPI gene. Mice heterozygous for TFPI gene disruption, TFPI(K1)/((+/-)), have plasma TFPI activity ~50% that of wild-type mice based on a functional assay that measures TF-FVIIa inhibition, and have a normal phenotype. Sixty per cent of TFPI(K1)/((-/-)) mice die between embryonic days 9.5 and 11.5 with signs of yolk sac haemorrhage. Organogenesis is normal in TFPI(K1)/((-/-)) animals that progress beyond embryonic day 11.5, but haemorrhage, particularly in the central nervous system and tail, is evident during later gestation, and none of the TFPI(K1)/((-/-)) mice survive to the neonatal period. The presence of immunoreactive fibrin(ogen) in the liver and intravascular thrombi is consistent with the notion that unregulated TF-FVIIa action and a consequent consumptive coagulopathy underlies the bleeding diathesis in these older embryos. Human TFPI-deficient embryos may suffer a similar fate as an individual with TFPI deficiency has not been identified.