The Potential to Enhance Hemostasis by Inhibiting Tissue Factor Pathway Inhibitor

Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein that inhibits tissue factors (TF) X and VIIa. As such, it is a major regulator of the extrinsic clotting pathway. Compounds that block TFPI activity, or “inhibit the inhibitor,” effectively restore hemostasis in animal models of hemophilia. These compounds are thought to act by allowing unfettered TF-mediated thrombin generation through the extrinsic pathway in a manner that bypasses the need for the intrinsic pathway proteins, factor VIII and factor IX. Improved understanding of TFPI tissue expression and function is needed to better recognize how pharmaceutical agents targeting TFPI alter biochemical and physiological mechanisms of blood coagulation. Several advances have been made recently. TFPI is an alternatively spliced protein with two primary isoforms, TFPIα and TFPIβ, which have distinct cellular expression patterns and anticoagulant functions. TFPIα is produced by endothelial cells, and appears to localize within an intracellular granule with release following stimulation with thrombin or heparin. TFPIα is also produced by megakaryocytes and is released from activated platelets. Platelet TFPIα limits clot growth following vascular injury and alters bleeding in a murine hemophilia model. Interestingly, the anticoagulant activity produced by platelet TFPIα appears to be isoform specific and not mediated through inhibition of TF. TFPIβ is made by endothelial cells, localizes to endothelium, and is not present in platelets. TFPIβ is an effective inhibitor of TF-mediated cellular migration and dampens the effects of TF-induced intravascular coagulation in mice. This new knowledge of TFPI isoform expression patterns and anticoagulant activities has important implications for the development of TFPI-blocking pharmaceuticals to treat hemophilia. The recent findings also provide new insights into the biochemical mechanisms that activate blood coagulation pathways and regulate TF-mediated thrombotic and inflammatory disease.