Expression of tissue factor pathway inhibitor by endothelial cells and platelets.

Tissue factor pathway inhibitor (TFPI) is a potent anticoagulant protein that abrogates the activity of the tissue factor-factor VIIa catalytic complex that activates blood coagulation in vivo. The importance of TFPI in the regulation of blood coagulation is emphasized by how its activity is modulated in human disease. Decreased TFPI activity contributes to the development of both arterial and venous thrombosis and has been implicated in the thrombotic events occurring in women using oral contraceptives and in patients with paroxysmal nocturnal hemoglobinuria. Both endothelial cells and platelets produce TFPI. Our laboratory is interested in the mechanisms for expression of TFPI on the surface of these cells to better understand how TFPI prevents intravascular thrombosis. Studies of cultured endothelial cells and human placenta have demonstrated that TFPI associates with the cell surface through a glycosyl phosphatidyinositol (GPI)-anchor in a manner that is not dependent on GAGs or altered by heparin. TFPI is not directly bound to the GPI-anchor; instead it appears to bind tightly to a GPI-anchored protein. This GPI-anchored protein appears to be necessary for proper trafficking of TFPI to the cell surface. An alternatively spliced form of TFPI, TFPIbeta, is a truncated form of TFPI that is directly attached to a GPI-anchor. However, it is not clear that human endothelial cells produce TFPIbeta. Platelets produce TFPI but not TFPIbeta. TFPI is expressed on the platelet surface following dual activation with collagen plus thrombin, but not through a GPI-anchor. Studies using mouse models of TFPI deficiency are currently being conducted in our laboratory to determine if distinct physiological functions of endothelial and platelet TFPI exist in vivo.