Placental Vascular Defects and Embryonic Lethality Triggered by TFPIα Deficiency in Factor V Leiden Mice.

Abstract

BACKGROUND: TFPI (tissue factor pathway inhibitor) inhibits the initiation of blood coagulation. TFPIα (TFPI alpha isoform), the only alternatively spliced TFPI isoform in platelets, is abundant in placenta and uniquely inhibits prothrombinase (FXa [activated factor X]-FVa [activated factor V]). This inhibitory activity is reduced when prothrombinase is assembled with FVL (factor V Leiden). METHODS: Effects of TFPIα () and platelet (;-Cre) specific knockout alleles were characterized in FVL () mice to examine the physiological effects of the TFPIα-FV interaction. RESULTS: Genotype frequencies were assessed and revealed thatmice survive to adulthood. However,homozygosity with even a singleallele resulted in embryonic lethality during mid-gestation development regardless of maternal FVL status. In contrast,-Cremice were at expected frequencies at weaning, indicating that platelet TFPIα loss alone did not cause mid-gestation lethality inmice. Histological analyses showed no fibrin deposition in embryonic or extraembryonic tissues but revealed placental vasculature defects ingenotypes. Treatment with the direct thrombin inhibitor dabigatran partially rescued the lethality and corrected placental defects, implicating excessive thrombin generation as a factor indemise. CONCLUSIONS: These findings suggest that TFPIα and its inhibition of prothrombinase play an important role in placental angiogenesis and embryonic survival.