Tissue factor pathway inhibitor: structure, biology and involvement in disease

Abstract

Tissue factor (TF)-initiated coagulation plays a significant role in the pathophysiology of many diseases, including cancer and inflammation. Tissue factor pathway inhibitor (TFPI) is a plasma Kunitz-type serine protease inhibitor, which modulates initiations of coagulation induced by TF. In a factor (F) Xa-dependent feedback system, TFPI binds directly and inhibits the TF-FVII/FVIIa complex. Normally, TFPI exists in plasma both as a full-length molecule and as variably carboxy-terminal truncated forms. TFPI also circulates in complex with plasma lipoproteins. The levels and the dual inhibitor effect of TFPI on FXa and TF-FVII/FVIIa complex offers insight into the mechanisms of various pathological conditions triggered by TF. The use of selective pharmacological inhibitors has become an indispensable tool in experimental haemostasis and thrombosis research. In vivo administration of recombinant TFPI (rTFPI) in an experimental animal model prevents thrombosis (and re-thrombosis after thrombolysis), reduces mortality from E. coli-induced-septic shock, prevents fibrin deposition on subendothelial human matrix and protects against disseminated intravascular coagulation (DIC). Thus, TFPI may play an important role in modulating TF-induced thrombogenesis and it may also provide a unique therapeutic approach for prophylaxis and/or treatment of various diseases. In this review, we consider structural and biochemical aspects of the TFPI molecule and detail its inhibitory mechanisms and therapeutic implications in various disease conditions.

Proteomics and Deep Sequencing Comparison of Seasonally Active Venom Glands in the Platypus Reveals Novel Venom Peptides and Distinct Expression Profiles

“…The platypus serpin does not belong to the Kunitz family of serine protease inhibitors found in snake and anemone venoms, but instead is a member of MEROPS inhibitor family 14, clan ID. These proteins function in proteolytic cascades, including blood clotting and inflammation (43), and cause irreversible "suicide inhibition" when they bind to their protease substrate (44).…”

Coagulation Abnormalities in Acute Pancreatitis

“…The third natural anticoagulant is tissue factor pathway inhibitor (TFPI), a Kunitz-type serine protease inhibitor that is produced by monocytes, macrophages, the liver, as well as endothelial cells (Lwaleed & Bass, 2006). It is stored mainly in three different regions of the body: in circulation, in the cytoplasm of platelets, and bound to the endothelium (DelGiudice & White, 2009).…”

Increased plasminogen activator inhibitor-1, decreased tissue factor pathway inhibitor, and unchanged thrombin-activatable fibrinolysis inhibitor levels in patients with primary hyperparathyroidism

“…Both endothelial cells and platelets produce TFPI (42). Low TFPI is a risk factor for a first venous thrombosis, recurrent venous thromboembolism, and stroke (31,43,44). To our knowledge, plasma TFPI Ag levels have not been investigated in patients with PHPT.…”