Factor Xa as an interface between coagulation and inflammation - Molecular mimicry of factor Xa association with effector cell protease receptor-1 induces acute inflammation in vivo

Coagulation proteases were tested in a rat model of acute inflammation, Subplantar injection of Factor Xa (10-30 mu g) produced a time- and dose-dependent edema in the rat paw, and potentiated carrageenin-induced edema. In contrast, the homologous protease Factor IXa was ineffective, This inflammatory response was recapitulated by the Factor Xa sequence (LFTRKL88)-F-83(G), which mediates ligand binding to effector cell protease receptor-1 (EPR-1), while a control scrambled peptide did not induce edema in vivo. Conversely, injection of the EPR-1-derived peptide S(123)PGKPGNQNSKNEPP(137) (corresponding to the receptor binding site for Factor Xa) inhibited carrageenin-induced rat paw edema, while the adjacent EPR-1 sequence (PPKKRERERSSHCYP150)-P-136 was without effect, EPR-l-Factor Xa-induced inflammation was characterized by fast onset and prominent perivascular accumulation of activated and degranulated mast cells, was inhibited by the histamine/serotonin antagonists cyproheptadine and methysergide, but was unaffected by the thrombin-specific inhibitor, Hirulog, These findings suggest that through its interaction with EPR-1, Factor Xa may function as a mediator of acute inflammation in vivo, This pathway may amplify both coagulation and inflammatory cascades, thus contributing to the pathogenesis of tissue injury in vivo.