Inhibition of factor XI activation attenuates inflammation and coagulopathy while improving the survival of mouse polymicrobial sepsis.

Abstract

Severe bacterial sepsis often leads to a systemic procoagulant and proinflammatory condition that can manifest as disseminated intravascular coagulation, septic shock, and multiple organ failure. Because activation of the contact proteases factor XII (FXII), prekallikrein, and factor XI (FXI) can trigger coagulation and inflammatory responses, the contact factors have been considered potential targets for the treatment of sepsis. However, the pathogenic role of contact activation in severe infections has not been well defined. We therefore investigated whether an anticoagulant antibody (14E11) that selectively inhibits prothrombotic FXI activation by activated FXII (FXIIa) modifies the course of bowel perforation-induced peritoneal sepsis in mice. Early anticoagulation with 14E11 suppressed systemic thrombin- antithrombin complex formation, IL-6, and TNF-α levels, and reduced platelet consumption in the circulation and deposition in the blood vessels. Treatment with 14E11 within 12 hours after bowel perforation significantly improved survival compared with vehicle treatment, and the saturating dose did not increase tail bleeding. These data suggest that severe polymicrobial abdominal infection induces prothrombotic FXI activation, to the detriment of the host. Systemic anticoagulation by inhibiting FXI activation or FXIIa procoagulant activity during sepsis may therefore limit the development of disseminated intravascular coagulation without increasing bleeding risks.

• Authors: Erik I Tucker, Norah G Verbout, Philberta Y Leung, Sawan Hurst, Owen J T McCarty, David Gailani, András Gruber
• Journal: Blood (Blood) Vol. 119 Issue 20 Pg. 4762-8 (May 17 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22442348 (Publication Type: Comparative Study, Evaluation Study, Journal Article)

Chemical References

• Antibodies, Monoclonal
• Anticoagulants
• Protein C
• Factor XIa

Topics

• Animals
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Anticoagulants (pharmacology, therapeutic use)
• Blood Coagulation Disorders (drug therapy, etiology, mortality, prevention & control)
• Coinfection (complications, drug therapy, mortality, pathology)
• Down-Regulation (drug effects)
• Factor XIa (antagonists & inhibitors, immunology)
• Immunotherapy
• Inflammation (etiology, pathology, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Protein C (pharmacology, therapeutic use)
• Sepsis (complications, drug therapy, mortality, pathology)
• Survival Analysis