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

Purpose of reviewIn humans, tissue factor pathway inhibitor (TFPI) exists in two alternatively spliced isoforms, TFPI alpha and TFPI beta. TFPI alpha 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. TFPI beta 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 findingsRecent data have underscored the importance of TFPI alpha function and its reliance on its cofactors, protein S and FV-short, in influencing haemostatic control as well as bleeding and thrombotic riskSummaryTFPI alpha is likely the most important pool of TFPI in modifying the risk of thrombosis and bleeding. TFPI alpha forms a trimolecular complex with FV-short and protein S in plasma. FV-short expression levels control the circulating levels of TFPI alpha, whereas protein S exerts essential cofactor mediated augmentation of it anticoagulant function.