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

Robert Silasi, Ravi Shankar Keshari, Cristina Lupu, Walter Janse Van Rensburg, Hala Chaaban, Girija Regmi, Aleksandr Shamanaev, Joseph J. Shatzel, Cristina Puy, Christina U. Lorentz, Erik Tucker, David Gailani, Andras Gruber, Owen McCarty, Florea Lupu

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)658-669
Number of pages12
JournalBlood advances
Volume3
Issue number4
DOIs
StatePublished - Feb 26 2019

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    Silasi, R., Keshari, R. S., Lupu, C., Van Rensburg, W. J., Chaaban, H., Regmi, G., Shamanaev, A., Shatzel, J. J., Puy, C., Lorentz, C. U., Tucker, E., Gailani, D., Gruber, A., McCarty, O., & Lupu, F. (2019). Inhibition of contact-mediated activation of factor XI protects baboons against S aureus-induced organ damage and death. Blood advances, 3(4), 658-669. https://doi.org/10.1182/bloodadvances.2018029983