Activation of coagulation factor (F) XI promotes multi-organ failure in rodent models of sepsis and in a baboon model of lethal systemic inflammation induced by infusion of heat-inactivated Staphylococcus (S.) aureus. Here we employed the anticoagulant FXII-neutralizing antibody 5C12 to verify the mechanistic role of FXII in this baboon model. Compared to untreated controls, repeated 5C12 administration before and at 8h and 24h after bacterial challenge prevented the dramatic increase in circulating complexes of contact system enzymes FXIIa, FXIa and kallikrein with antithrombin or C1 inhibitor, and prevented cleavage and consumption of high-molecular-weight kininogen. Activation of several coagulation factors and fibrinolytic enzymes were also prevented. D-dimer levels showed profound increase in untreated but not in the treated animals. The antibody also blocked the increase in plasma biomarkers of inflammation and cell damage, including tumor necrosis factor, interleukin (IL)-1β, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, nucleosomes, and myeloperoxidase. Based on clinical presentation and circulating biomarkers, inhibition of FXII prevented fever, terminal hypotension, respiratory distress and multi-organ failure. All animals receiving 5C12 had milder and transient clinical symptoms and were asymptomatic at day 7, while untreated controls suffered irreversible multi-organ failure and had to be euthanized within 2 days after the bacterial challenge. This study confirms and extends our previous finding that at least two enzymes of the contact activation complex, FXIa and FXIIa, play critical roles in the development of an acute and terminal inflammatory response in baboons challenged with heat-inactivated S. aureus.
Robert Silasi, Ravi Shankar Keshari, Girija Regmi, Cristina Lupu, Constantin Georgescu, Joe H Simmons, Michael Wallisch, Tia C L Kohs, Joseph J Shatzel, Sven R Olson, Christina Lorentz, Cristina Puy, Erik I Tucker, David Gailani, Sidney Strickland, Andras Gruber, Owen McCarty, Florea Lupu