Peptides Binding to Kunitz Domain 1 of Tissue Factor Pathway Inhibitor (TFPI) Inhibit All Functions of TFPI and Improve Thrombin Generation of Hemophilia Plasma

Abstract 2245 Blood coagulation is initiated by the tissue factor-factor VIIa (TF-FVIIa) complex which cleaves and activates coagulation factor X to Xa (FXa). Tissue factor pathway inhibitor (TFPI) controls this key process and thus plays a crucial role in maintaining the delicate balance of pro- and anticoagulant processes. Inhibition of TFPI in hemophilia plasma and in a rabbit model of hemophilia has been shown to improve coagulation and hemostasis (Nordfang et al., Thromb Haemost. 1991;66:464; Erhardsen et al., Blood Coagulation and Fibrinolysis 1995;6:388). TFPI is a Kunitz-type protease inhibitor that inhibits FXa and TF-FVIIa. TFPI is a slow, tight-binding FXa inhibitor which rapidly forms a loose FXa-TFPI complex that slowly isomerises to a tight FXa-TFPI* complex. The FXa-TFPI* complex inhibits TF-FVIIa by formation of a quaternary FXa-TFPI-TF-FVIIa complex.