Cellular expression and biological activities of alternatively spliced forms of tissue factor pathway inhibitor

Abstract

Purpose of review-Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein that inhibits tissue factor-factor VIIa (TF-fVIIa) and factor Xa (fXa). Recent studies revealed distinct cellular expression patterns for TFPI and TFPI and spurred additional experiments to define unique functions for these alternatively spliced TFPI isoforms.Recent findings-TFPI is produced by endothelial cells, localizes to an intracellular granule, and is released following cellular stimulation with thrombin or heparin. TFPI also is produced by megakaryocytes and released from activated platelets. Platelet TFPI limits clot growth following vessel injury and alters bleeding in hemophilia, suggesting that its primary physiological role is modulation of clot development. TFPI is made by endothelial cells, localizes to the endothelium surface, and is not in platelets. TFPI is an effective inhibitor of TF-mediated cellular migration and may act to dampen the adverse effects of intravascular TF expressed during inflammation.Summary-Knowledge of TFPI isoform expression and activity provides new insights into the biochemical regulation of TF-mediated thrombotic and inflammatory disease. Recent findings have therapeutic implications for use of recombinant TFPI to treat severe sepsis in communityacquired pneumonia or to achieve improved engraftment of hematopoietic stem cells, and for development of TFPI-blocking pharmaceuticals to treat hemophilia.

Expression of Human Tissue Factor Pathway Inhibitor on Vascular Smooth Muscle Cells Inhibits Secretion of Macrophage Migration Inhibitory Factor and Attenuates Atherosclerosis in ApoE −/− Mice

“…The hTFPI fusion protein used in ApX4 represents a hybrid of the 2 main isoforms of TFPI (α and β; physiological TFPIα and TFPIβ, mouse and human) are generated by alternative splicing and differ in their C-terminal structure and cellular localization. 23 TFPIα is a secreted protein with 3 tandem Kunitz-type domains (K1-K3) and a basic C-terminus, whereas TFPIβ has K1 and K2 domains and a glycosylphosphatidylinositol anchor membrane attachment. TFPIβ inhibits TF-mediated thrombin generation better than either TFPIα or a soluble truncated form of TFPI (TFPI-160) similar to TFPIβ, suggesting that cell surface association plays an important role in efficient inhibition of TF.…”

Defective fibrin deposition and thrombus stability in Bambi−/− mice are mediated by elevated anticoagulant function

“…In humans, full‐length TFPIα is primarily secreted into the plasma, where it circulates at low concentrations (0.1‐0.2 nM). Conversely, the shorter TFPIβ remains GPI‐linked to the endothelial cell surface . Both isoforms inhibit TF‐FVIIa in a FXa‐dependent manner, with TFPIα likely being more important for regulating hemostasis on platelet surfaces, whereas TFPIβ probably functions primarily on the endothelial cell surface to which it is attached .…”

TFPI inhibits lectin pathway of complement activation by direct interaction with MASP‐2

“…However, the inhibitory capacity of TFPI on L activation was in similar molar range as C1-inh, which is a well-known inhibitor with weak inhibitory capacity in the presence of a complement activator. Notably, TFPI levels in plasma do not reflect the total amount of TFPI that may be relevant in vivo, since most TFPI is produced by endothelial cells [9]. Under certain (inflammatory) conditions TFPI expression is decreased, for example, during sepsis [10] which could likely increase the LP activation.…”