The role of microparticle-associated endothelial protein C receptor in disseminating activated protein C function. (360G-Wellcome-077950_Z_05_Z)

Activated protein C (APC) was recently shown to significantly reduce the relative risk of death in patients with severe sepsis. The mechanisms of its protective effects are not fully understood and treatment carries serious bleeding risks. In treated patients, we have made the novel observation that APC induces endothelial microparticle release into the circulation. The microparticles contain APC bound to its endothelial receptor to enable expression of anticoagulant activity. We hypothesise that this mechanism of disseminating APC could be harnessed into more efficient strategies for delivering APC to cell surfaces to prevent overlying thrombus formation and protect endothelial cell integrity, especially under inflammatory conditions. We therefore propose to examine for these effects in vitro and in vivo using clinical samples from patients and a mouse model of sepsis, through gene microarrays, flow cytometric, functional, histological and electron microscopic studies. The potential benefits of such an approach would includeo Improved understanding of the mechanisms underlying the protective effects