Significance & Physiological Role of Tissue Factor Pathway Inhibitor (TFPI)

• Tissue Factor Pathway Inhibitor (TFPI) is located

• On Endothelial Cells (ECs)
• On Monocytes
• In Platelets 
• In plasma 

• Bulk of TFPI is associated with ECs

• Measurement of low TFPI in plasma doesn’t mean TFPI deficiency 
• TFPI associated with ECs → 4X ↑in TFPI upon Heparin injection
• Most of circulating TFPI is bound to lipoproteins & the C terminals are variably degraded  

• Physiological Role 

• TFPI inhibits FVIIa in a FXa-dependent manner
• TFPI binds to & directly inhibits TF-FVIIa-FXa complex → So, it effectively halts TF initiated activation of coagulation but only after sufficient FXa has been generated to propagate coagulation
• Plasma TFPI has reduced anticoagulant activity
• So, likely not very important anticoagulant role in vivo

• Therapeutic Role 

• TFPI binds to Heparan Sulphate on EC surface
• UFH or LMWH displace this bound TFPI → This released TFPI contributes to antithrombotic activities of these drugs

• Isoforms of TFPI

• Two isoforms exist 
• TFPIα
• TFPIβ 
• TFPIα has 3 Kunitz type protease inhibitory domains → K1, K2, K3 
• K1 domain inhibits FVIIa in a FXa dependent manner 
• K2 directly binds & inhibits FXa
• Protein S (PS) acts as cofactor in the formation of TFPI-FXa complex

Physiological Inhibitors of Coagulation System

There are many physiological inhibitors impacting various stages of coagulation system. Most important inhibitors with known physiology are enumerated as under: 

• Antithrombin 
• Protein C
• Protein S 
• Heparin
• Heparin cofactor II
• TFPI (Kunitz type inhibitor)
• PZ & PZ dependent inhibitor 
• 𝛂1-Antitrypsin
• 𝛂2-Antiplasmin
• α2-Macroglobulin
• Protease Nexin 2 
• C1-esterase inhibitor