Tissue Factor Pathway Inhibitor: Then and Now^[*]

 

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Abstract

Tissue factor pathway inhibitor (TFPI) is the major physiological regulator of tissue factor (TF)-induced blood coagulation. TFPI inhibits the TF-activated factor VII (FVIIa) complex in an activated factor X (FXa)-dependent manner, helping to control thrombin generation and ultimately fibrin formation. The importance of TFPI is demonstrated in models of hemophilia where lower levels of FVIII or FIX are insufficient to overcome its inhibitory effect, resulting in a bleeding phenotype. There are two major isoforms in vivo; TFPIα contains three Kunitz-type inhibitory domains (designated K1, K2, and K3), is secreted by endothelial cells and requires protein S to enhance its anticoagulant activity. In contrast, TFPIβ contains only the K1 and K2 domains, but it is attached to the endothelial surface via a glycosylphosphatidylinositol anchor. This review will initially provide a brief history of the major discoveries related to TFPI, and then discuss new insights into the physiology of TFPI, including updates on its association with protein S and FV, as well as the current understanding of its association with disease.

^* This article is dedicated to Robert (Bob) Oostryck. In 1992, while a Senior Lecturer in Hematology at Curtin University at Curtin University of Technology, Bob asked M.J.A., who was then an undergraduate student interested in research, “Why do hemophiliacs bleed?” The explanation of a lack of factor VIII or factor IX was not only superficially correct, but it also did not take into account the important physiological effects of tissue factor pathway inhibitor (TFPI). Bob was our first mentor, a great teacher, and now friend, who ignited a passion for research and an interest in TFPI that we both still share. Although now retired, Bob retains a keen interest in all things related to coagulation, TFPI, and hemostasis.

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