Deficiency of tissue factor pathway inhibitor promotes atherosclerosis andthrombosis in mice

Background-Tissue factor initiates blood coagulation after atherosclerotic plaque disruption. Tissue factor pathway inhibitor (TFPI) inhibits tissue f actor activity and may reduce thrombus formation in this setting. We evalua ted the effect of heterozygous TFPI deficiency on the development of athero sclerosis and thrombosis in atherosclerosis-prone mice. Methods and Results-Mice with a combined heterozygous TFPI deficiency and h omozygous apolipoprotein E deficiency (TFPI+/-/apoE(-/-)) were generated by crossbreeding, and they were analyzed for atherosclerosis throughout the v ascular tree. Compared with mice with a normal TFPI genotype (TFPI+/+/apoE( -/-)), mice with a TFPI deficiency exhibited a greater atherosclerotic burd en involving the carotid and common iliac arteries. Staining for active tis sue factor within the plaque revealed more activity in TFPI+/-/apoE(-/-) mi ce compared with TFPI+/+/apoE(-/-) mice. Consistent with increased plaque t issue factor activity, the time to occlusive thrombosis after photochemical carotid plaque injury was significantly decreased in TFPI+/-/apoE(-/-) mic e. Conclusions-These observations indicate that TFPI protects from atheroscler osis and is an important regulator of the thrombosis that occurs in the set ting of atherosclerosis.