Regulation of coagulation by tissue factor pathway inhibitor: Implications for hemophilia therapy

Tissue factor pathway inhibitor (TFPI) is an alternatively spliced anticoagulant protein that primarily dampens the initiation phase of coagulation before thrombin is generated. As such, TFPI's actions are localized to cells expressing TF and to sites of injury, where it is an important regulator of bleeding in hemophilia. The major splice isoforms TFPI alpha and TFPI beta localize to different sites within and surrounding the vasculature. Both forms directly inhibit factor Xa (FXa) via their Kunitz 2 domain and inhibit TF-FVIIa via their Kunitz 1 domain in a tight complex primarily localized to cells. By forming complexes localized to distinct cellular microenvironments and engaging additional cell surface receptors, TFPI alters cellular trafficking and signaling pathways driven by coagulation proteases of the TF pathway. TFPI alpha, which circulates in complex with FV and protein S, also serves an inhibitor of FXa independent of the TF initiation complex and prevents the formation of an active prothrombinase. This regulation of thrombin generation in the context of vessel injury is effectively blocked by antibodies to Kunitz 2 domain of TFPI and exploited as a therapy to restore efficient hemostasis in hemophilia.

Automated summary

Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein that inhibits the initiation phase of coagulation. TFPI acts at cells expressing tissue factor (TF) and at sites of injury, regulating bleeding in hemophilia. It has different isoforms that inhibit factor Xa and TF-FVIIa, and by forming complexes with cellular receptors, TFPI alters cellular trafficking and signaling pathways. Antibodies to TFPI's Kunitz 2 domain can effectively block thrombin generation in vessel injury and be used in hemophilia treatment.