Program: Oral and Poster Abstracts
Type: Oral
Session: 321. Blood Coagulation and Fibrinolytic Factors: Coagulation Proteins and Blood Vessels
RESULTS: In murine sepsis models of S.aureus-induced septic peritonitis, aPC-resistance of endogenous fV R504Q prevents marked disease stage-specific deleterious effects associated with aPC’s anticoagulant activity, but also abrogated the mortality-reducing benefits of therapy with the signaling-selective 5A-aPC variant that only exerts minimal anticoagulant activity towards activated fVa. In mice homozygous for the R504Q mutation (fVQQ mice), 5A-aPC failed to suppress inflammatory gene expression in the presence of fVR504Q. This finding was reproduced in an in vitro culture model of murine RAW cells and bone marrow-derived dendritic cells, in which thrombosis and thrombin generation play no role. Gene expression analyses and functional in vitro studies of LPS-induced inflammatory cell signaling showed that fV, as well as protein S were required for the aPC-mediated suppression of inflammatory tissue factor-PAR2 signaling3. Structure-function analyses of recombinant variants of aPC and fV showed that this anti-inflammatory cofactor function of protein S and fV involved the same structural features that underlie their accessory role for aPC’s anticoagulant function, but did not involve the degradation of activated fVa or fVIIIa.
CONCLUSION These findings reveal a novel biological function and mechanism of the protein C pathway in which protein S and the aPC-cleaved form of fV are cofactors for anti-inflammatory cell signaling by aPC in the context of endotoxemia and infection. This cofactor function is structurally related, but mechanistically distinct from the anticoagulant cofactor activities of protein S and fV. APC-resistance of fV thus emerges as a response modifier of the endogenous host response to infection, as well as the outcome of sepsis therapy with normal APC and signaling-selective variants thereof.
REFERENCES
1. Kerlin BA, Yan SB, Isermann BH, et al. Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. Blood. 2003;102(9):3085-3092.
2. Kerschen E, Hernandez I, Zogg M, Maas M, Weiler H. Survival advantage of heterozygous factor V Leiden carriers in murine sepsis. J Thromb Haemost. 2015;13(6):1073-1080.
3. Liang HP, Kerschen EJ, Hernandez I, et al. EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice. Blood. 2015.
Disclosures: Camire: Pfizer: Consultancy , Patents & Royalties , Research Funding ; Novo Nordisk: Research Funding ; Spark Therapeutics: Membership on an entity’s Board of Directors or advisory committees .
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