TFPI

TFPI, tissue factor pathway inhibitor, is a natural anticoagulant that limits initiation of blood coagulation by inhibiting the tissue factor–VIIa catalytic complex and factor Xa. It is a small secreted glycoprotein belonging to the Kunitz-type serine protease inhibitors and is expressed mainly by endothelial cells, with additional expression in placenta and some other tissues. In humans, TFPI exists in two gene families: TFPI and TFPI2. The TFPI gene encodes TFPI-1, which is produced as secreted TFPI-α and a GPI-anchored TFPI-β isoform on the endothelium. The TFPI2 gene encodes TFPI-2, a distinct protein with two Kunitz domains that is expressed in a variety of tissues, including the extracellular matrix.

Mechanistically, the first Kunitz domain of TFPI inhibits the TF–VIIa complex, while the second domain inhibits factor Xa, thereby reducing thrombin generation. The interaction with lipoproteins and phospholipid surfaces influences its activity and distribution in plasma; TFPI circulates largely bound to LDL and HDL particles, and endothelial surface–associated TFPI can regulate local initiation of coagulation.

Regulation of TFPI expression is responsive to inflammatory mediators and lipid status, and TFPI activity can be altered in various disease states. Clinically, TFPI contributes to the balance between bleeding and thrombosis, and abnormalities in TFPI levels or function can influence thrombotic risk. Because of its central role in dampening tissue factor–driven coagulation, TFPI has been explored as a target or therapeutic agent in anticoagulation strategies, although clinical use remains limited.