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

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 TFPIα and TFPIβ and spurred additional experiments to define unique functions for these alternatively spliced TFPI isoforms.

TFPIα is produced by endothelial cells, localizes to an intracellular granule, and is released following cellular stimulation with thrombin or heparin. TFPIα also is produced by megakaryocytes and released from activated platelets. Platelet TFPIα limits clot growth following vessel injury and alters bleeding in hemophilia, suggesting that its primary physiological role is modulation of clot development. TFPIβ is made by endothelial cells, localizes to the endothelium surface, and is not in platelets. TFPIβ is an effective inhibitor of TF-mediated cellular migration and may act to dampen the adverse effects of intravascular TF expressed during inflammation.

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 community-acquired pneumonia or to achieve improved engraftment of hematopoietic stem cells, and for development of TFPI-blocking pharmaceuticals to treat hemophilia.