Abstract
Tissue factor pathway inhibitor (TFPI) is the major physiological regulator of tissue
factor (TF)-induced blood coagulation. TFPI inhibits the TF-activated factor VII (FVIIa)
complex in an activated factor X (FXa)-dependent manner, helping to control thrombin
generation and ultimately fibrin formation. The importance of TFPI is demonstrated
in models of hemophilia where lower levels of FVIII or FIX are insufficient to overcome
its inhibitory effect, resulting in a bleeding phenotype. There are two major isoforms
in vivo; TFPIα contains three Kunitz-type inhibitory domains (designated K1, K2, and
K3), is secreted by endothelial cells and requires protein S to enhance its anticoagulant
activity. In contrast, TFPIβ contains only the K1 and K2 domains, but it is attached
to the endothelial surface via a glycosylphosphatidylinositol anchor. This review
will initially provide a brief history of the major discoveries related to TFPI, and
then discuss new insights into the physiology of TFPI, including updates on its association
with protein S and FV, as well as the current understanding of its association with
disease.
Keywords
tissue factor - thrombosis - protein S - hemophilia - factor V
