Tissue Factor Pathway Inhibitor: Multiple Anticoagulant Activities for a Single Protein

Abstract

Tissue factor (TF) pathway inhibitor (TFPI) is an anticoagulant protein that inhibits early phases of the procoagulant response. Alternatively spliced isoforms of TFPI are differentially expressed by endothelial cells and human platelets and plasma. The TFPIβ isoform localizes to the endothelium surface where it is a potent inhibitor of TF-factor VIIa complexes that initiate blood coagulation. The TFPIα isoform is present in platelets. TFPIα contains a stretch of 9 amino acids nearly identical to those found in the B-domain of factor V that are well conserved in mammals. These amino acids provide exosite binding to activated factor V, which allows for TFPIα to inhibit prothrombinase during the initiation phase of blood coagulation. Endogenous inhibition at this point in the coagulation cascade was only recently recognized and has provided a biochemical rationale to explain the pathophysiological mechanisms underlying several clinical disorders. These include the east Texas bleeding disorder that is caused by production of an altered form of factor V with high affinity for TFPI and a paradoxical procoagulant effect of heparins. In addition, these findings have led to ideas for pharmacological targeting of TFPI that may reduce bleeding in hemophilia patients.

Keywords: factor V; factor VII; hemophilia A; lipoprotein-associated coagulation inhibitor; thromboplastin.

Figure 1

The blood coagulation pathway is a series of sequential proteolytic reactions that can be separated into intrinsic and extrinsic pathway. A) When TFPI is present, it dampens activation of clotting through the extrinsic pathways by serving as a fXa-dependent inhibitor of TF-fVIIa and of prothrombinase. Under these conditions, hemostasis occurs through activation of fIX by TF-VIIa, which amplifies fXa generation such that TFPI inhibition of clotting is overcome. B) When TFPI activity is blocked, sufficient thrombin can be generated for hemostasis without requiring amplification by fVIII/fIX, thereby providing the rationale for developing inhibitors of TFPI to treat hemophilia.