Inhibition of contact-mediated activation of factor XI protects baboons against S aureus–induced organ damage and death

Abstract

Staphylococcus aureus infections can produce systemic bacteremia and inflammation in humans, which may progress to severe sepsis or septic shock, even with appropriate antibiotic treatment. Sepsis may be associated with disseminated intravascular coagulation and consumptive coagulopathy. In some types of mouse infection models, the plasma coagulation protein factor XI (FXI) contributes to the pathogenesis of sepsis. We hypothesize that FXI also contributes to the pathogenesis of sepsis in primates, and that pharmacological interference with FXI will alter the outcome of Staphylococcus aureus–induced lethality in a baboon model. Pretreatment of baboons with the anti-FXI antibody 3G3, a humanized variant of the murine monoclonal 14E11 that blocks FXI activation by FXIIa, substantially reduced the activation of coagulation, as reflected by clotting times and plasma complexes of coagulation proteases (FXIIa, FXIa, FIXa, FXa, FVIIa, and thrombin) with serpins (antithrombin or C1 inhibitor) following infusion of heat-inactivated S aureus. 3G3 treatment reduced fibrinogen and platelet consumption, fibrin deposition in tissues, neutrophil activation and accumulation in tissues, cytokine production, kininogen cleavage, cell death, and complement activation. Overall, 3G3 infusion protected the structure and function of multiple vital organs, including lung, heart, liver, and kidney. All treated animals reached the end point survival (7 days), whereas all nontreated animals developed terminal organ failure within 28 hours. We conclude that FXI plays a role in the pathogenesis of S aureus–induced disseminated intravascular coagulation and lethality in baboons. The results provide proof of concept for future therapeutic interventions that may prevent sepsis-induced organ failure and save lives in certain forms of sepsis.

The contact pathway and sepsis

“…In nonhuman primate studies, inhibition of FXII‐ and FXII‐mediated activation of FXI have both been shown to blunt the cytokine response and improve measurable physiologic outcomes after inoculation with live or heat‐inactivated bacterium …”

“…More recent nonhuman primate work by Silasi et al investigated the effects of the monoclonal anti‐FXI antibody 3G3, a humanized variant of the mouse anti‐FXI antibody 14E11 discussed above, in baboons with S. aureus bacteremia. Baboons challenged with an infusion of heat‐inactivated S. aureus were randomized to pretreatment with 3G3 30 minutes before the bacterial infusion or to an untreated control arm.…”

“…Postmortem analysis showed no microvascular thrombi in the lungs, kidneys, and livers of 3G3‐treated baboons. These findings indicated that inhibition of FXI attenuates the consumptive coagulopathy of sepsis in a primate model without inducing bleeding …”

“…Baboons treated with 3G3 also had delayed and less severe increase in lactate dehydrogenase and circulating nucleosome levels, reflecting reduced cell death in comparison with controls. The 3G3‐treated baboons had normal organ appearance on histopathologic evaluation, compared to extensive organ damage in untreated animals …”

The non‐coding RNome after splenectomy

“…We consider that (a) the ncRNA expression after splenectomy could be used to detect the splenectomized patients at risk for sepsis and (b) the splenectomized patients at risk for OPSI could improve our understanding of sepsis-a disease for which clinicians are still in search for a cure. 27,28 2 | ME THODS…”