Factor V Inhibits PAR2-Mediated Lethal Inflammation

Abstract 3360

The Leiden polymorphism (Arg506Gln) in human blood coagulation factor V (fV) is the most prevalent genetic risk factor for venous thrombosis. We have now shown that heterozygous carriers, but not homozygous carriers, exhibit a robust survival advantage in murine models of lethal infection with gram-positive and gram-negative bacterial pathogens. FV Leiden augments the thrombin-mediated formation of activated protein C (aPC) and thereby enables the aPC-mediated inhibition of a specific component of the overall inflammatory response of myeloid immune cells. This specific, aPC-inhibited inflammatory response was mediated by the induction of tissue factor (TF) expression, assembly of the ternary TF-VIIa-Xa complex, and the EPCR-dependent activation of Protease Activated Receptor 2 (PAR2) by the ternary TF complex. The inhibition of inflammation-induced, PAR2-dependent gene expression by APC required factor V, protein S, and Protease Activated Receptor 3. This anti-inflammatory bioactivity of purified, plasma-derived or recombinant fV was not expressed by the fV Leiden variant. Thus, in heterozygous fV Leiden individuals, aPC levels are increased by fV Leiden, while wild type fV enhances aPC's beneficial actions on innate immune cells. This explains why heterozygous carriers are protected from sepsis mortality by aPC, whereas homozygous Leiden carriers do not respond to endogenous or therapeutically administered aPC. FV Leiden hence emerges as a unique example of a balancing and evolutionary selectable polymorphism, whose balanced nature is the consequence of beneficial, cooperative interactions of the variant fV Leiden allele that augments generation of aPC and the normal fV allele that is necessary for the protective effects of aPC.