Tissue factor pathway inhibitor - cofactor-dependent regulation of the initiation of coagulation

Abstract

Purpose of review: In humans, tissue factor pathway inhibitor (TFPI) exists in two alternatively spliced isoforms, TFPIα and TFPIβ. TFPIα consists of three Kunitz domains (K1, K2 and K3) and a highly basic C-terminal tail. K1 inhibits the tissue factor-activated factor VII complex, K2 specifically inhibits activated factor X, K3 is essential for interaction with its cofactor, protein S, and the basic C-terminus is binds factor V-short (FV-short) with high affinity. TFPIβ consists of K1 and K2 that is glycosylphosphatidylinositol anchored directly to cell surfaces. This review explores the structure/function of TFPI and its cofactors (protein S and FV-short), and the relative contributions that different TFPI isoforms may play in haemostatic control.

Recent findings: Recent data have underscored the importance of TFPIα function and its reliance on its cofactors, protein S and FV-short, in influencing haemostatic control as well as bleeding and thrombotic risk.

Summary: TFPIα is likely the most important pool of TFPI in modifying the risk of thrombosis and bleeding. TFPIα forms a trimolecular complex with FV-short and protein S in plasma. FV-short expression levels control the circulating levels of TFPIα, whereas protein S exerts essential cofactor mediated augmentation of it anticoagulant function.

Box 1

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FIGURE 1

Anticoagulant function of TFPI. (a) TFPIα consists of three Kunitz domains (K1–K3) and a basic C-terminus. Following exposure of TF, the TF–FVIIa complex activates FX. TFPIα K2 inactivates FXa in a rate limiting step (1). Thereafter, TFPI–FXa inhibits TF–FVIIa to form an inactive quaternary complex. (b) The alternatively spliced TFPIβ consists of two Kunitz domains (K1–K2) coupled to the cell surface via a GPI-anchor. TFPIβ inhibits FXa and TF-FVIIa in a two-stage mechanism similar to TFPIα. (c) TFPIα forms a high affinity trimolecular complex with FV-short and protein S. TFPIα binds the acidic region of FV-short via its basic C-terminus. TFPIα and protein S do not normally interact in the absence of phospholipid surfaces. However, once bound to FV-short protein S binds with high affinity to TFPIα. This trimolecular complex has high affinity to phospholipid surfaces, which augments TFPIα anticoagulant function. GPI, glycosylphosphatidylinositol; TFPI, tissue factor pathway inhibitor; TF, tissue factor; FVII, factor VII.