Tissue factor pathway inhibitor (TFPI) could be a novel target for the treatment of hemophilia, according to a new study published in the Journal of Thrombosis and Haemostasis.

The inhibition of TFPI can increase coagulation independently of clotting factors FVIII and FIX which could make it a treatment for both hemophilia A and hemophilia B. Since a therapy that targets TFPI bypasses these clotting factors, it could also be used in patients who have developed inhibitors to traditional treatments.

TFPI is an alternatively spliced anticoagulant protein that primarily inhibits the initiation of coagulation through a reduction in procoagulant stimuli before the generation of thrombin. Two main isoforms of TFPI are traditionally found in the body: TFPIα which is primarily located floating in the plasma and TFPIβ which is primarily localized to the surface of monocytes and endothelial cells.

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Three kunitz domains (K1, K2, and K3) are present in TFPIα while only the first 2 are present in TFPIβ. The K1 and K2 domains inhibit the tissue factor-factor VIIa (TF-FVIIa) catalytic complex involved in the coagulation pathway. TF-FVIIa activates FIX and FX causing the association of FXa and FVa which combine to convert prothrombin to thrombin.

The K3 domain of TFPIα also binds protein S that contains a Gla domain and helps to localize TFPIα to the surface of cell membranes and enhances its inhibition of FXa. TFPIβ contains an amino acid sequence that encodes a glycosylphosphatidylinositol cell-surface attachment that helps it bind strongly to the cell membrane and inhibit TF-FVIIa procoagulant activity.

“Within the intravascular space, TFPI exerts anticoagulant activity early in the coagulation cascade, before thrombin is generated, and at steps that do not require FVIII or FIX,” the authors said. “Inhibition of TFPI allows amplification of coagulation through pathways that bypass FVIII and FIX. Therefore, TFPI is an attractive target for management of hemophilia-related bleeding.”


Mast AE, Ruf W. Regulation of coagulation by tissue factor pathway inhibitor: implications for hemophilia therapy. J Thromb Haemost. Published online March 13, 2022. doi:10.1111/jth.15697