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Lethal Perinatal Thrombosis in Mice Resulting From the Interaction of Tissue Factor Pathway Inhibitor Deficiency and Factor V Leiden

Background—Factor V Leiden (FVL) is a common genetic risk factor for thrombosis in humans. The incomplete penetrance of FVL suggests important contributions from other genetic or environmental modifying factors. Variation in the expression of tissue factor pathway inhibitor (TFPI) has also been proposed as a risk factor for venous thrombosis and has been shown to enhance the prothrombotic effect of FVL in vitro. Methods and Results—To examine the potential in vivo interaction between Tfpi and FvL, we analyzed crosses between mice carrying FvL and a deficiency of TFPI. The FvQ/Q, Tfpi+/− genotype was nearly completely fatal in the early perinatal period. Increased fibrin deposition was observed in multiple organs from the FvQ/Q, Tfpi+/− fetuses, suggesting disseminated thrombosis. Conclusions—These observations demonstrate the prothrombotic effect of modest variations in the level of TFPI expression and suggest that TFPI could be an important genetic modifier for the thrombosis associated with FVL in humans.