Biology of tissue factor pathway inhibitor

Abstract

Recent studies of the anticoagulant activities of the tissue factor (TF) pathway inhibitor (TFPI) isoforms, TFPIα and TFPIβ, have provided new insight into the biochemical and physiological mechanisms that underlie bleeding and clotting disorders. TFPIα and TFPIβ have tissue-specific expression patterns and anticoagulant activities. An alternative splicing event in the 5′ untranslated region allows for translational regulation of TFPIβ expression. TFPIα has 3 Kunitz-type inhibitor domains (K1, K2, K3) and a basic C terminus, whereas TFPIβ has the K1 and K2 domains attached to a glycosylphosphatidyl inositol–anchored C terminus. TFPIα is the only isoform present in platelets, whereas endothelial cells produce both isoforms, secreting TFPIα and expressing TFPIβ on the cell surface. TFPIα and TFPIβ inhibit both TF–factor VIIa–dependent factor Xa (FXa) generation and free FXa. Protein S enhances FXa inhibition by TFPIα. TFPIα produces isoform-specific inhibition of prothrombinase during the initiation of coagulation, an anticoagulant activity that requires an exosite interaction between its basic C terminus and an acidic region in the factor Va B domain. Platelet TFPIα may be optimally localized to dampen initial thrombin generation. Similarly, endothelial TFPIβ may be optimally localized to inhibit processes that occur when endothelial TF is present, such as during the inflammatory response.

Concizumab, an anti‐tissue factor pathway inhibitor antibody, induces increased thrombin generation in plasma from haemophilia patients and healthy subjects measured by the thrombin generation assay

“…One potential target for alternative treatment strategies is tissue factor pathway inhibitor (TFPI), the primary inhibitor of the initiation of coagulation. It binds and inhibits factor VIIa (FVIIa) in complex with tissue factor (TF), and factor Xa (FXa), with the overall effect of reduced thrombin generation and decreased blood coagulation [1,6].…”

Catalytically inactive Gla-domainless factor Xa binds to TFPI and restores ex vivo coagulation in hemophilia plasma

“…2,3 Indeed, when the intrinsic tenase pathway leading to factor Xa (FXa) activation is blocked due to FVIII or FIX deficiency, a small amount of FXa can be generated by the extrinsic tenase (FVIIa/tissue factor), but it is immediately neutralized by binding of TFPI through its Kunitz 2 (K2) domain while the Kunitz 1 (K1) domain of TFPI subsequently binds to FVIIa, inhibiting the tenase. 4,5 Our team has postulated an original anti-TFPI strategy, Gla-domainless factor Xa (GD-FXa), deprived of its membrane binding domain, and we have validated the proof of concept of this approach. Indeed, GD-FXa reconstituted thrombin generation in plasmas from hemophiliacs.…”

A preliminary estimation of tissue factor pathway inhibitor (TFPI) and protein C in patients with intracranial tumors

“…Eighty-five percent of TFPI circulating in the blood is inactive and connected with lipoproteins, and 15% of TFPI occurs in an active form which rapidly inhibits TF/VIIa complex. 1,4 It has been shown that TFPI infusion suppresses thrombosis, which has been induced in experimental animals by TF or endotoxin. On the other hand, tissue factor pathway inhibitor deficiency leads to the thrombotic process.…”

“…On the other hand, tissue factor pathway inhibitor deficiency leads to the thrombotic process. [4][5][6] Protein C (PC) is an important component of the inhibition system associated with endothelium. PC activation requires binding to 2 receptors present on the surface of endothelial cells; thrombomodulin and endothelial protein C receptor (EPCR).…”