During sepsis, the early innate response and inflammatory cytokine cascade are associated with activation of the coagulation cascade. Acute hypercoagulability can contribute to lethal sequela of vascular thrombosis, tissue ischemia, and organ failure. We investigated if amitriptyline (AMIT), an antidepressant drug with a number of anti-inflammatory effects, could ameliorate sepsis in a murine model of sepsis—cecal ligation and puncture (CLP). We hypothesized that AMIT treatment would reduce inflammation and mitigate sepsis-induced coagulopathy. Coagulation was measured using thromboelastometry and ferric chloride-induced carotid artery thrombosis. Our findings demonstrate a dynamic early hypercoagulability, followed by delayed hypocoagulability in septic mice. However, septic mice treated with AMIT were unaffected by these coagulation changes and exhibited a coagulation profile similar to sham mice. TNFα was markedly elevated in septic mice, but decreased in AMIT-treated mice. Exogenous administration of recombinant TNFα in naive mice recapitulated the acute sepsis-induced hypercoagulability profile. After sepsis and endotoxemia, peritoneal macrophages were the predominant source of TNFα expression. AMIT treatment significantly decreased macrophage TNFα expression and blunted M1 polarization. Altogether, during polymicrobial sepsis, AMIT treatment suppressed macrophage TNFα expression and the M1 phenotype, mitigating an initial hypercoagulable state, and protecting septic mice from delayed hypocoagulability. We propose that AMIT treatment is a promising therapeutic approach in the treatment of sepsis-associated coagulopathy and prevention of acute thromboembolic events or delayed bleeding complications.
*Division of Research, Department of Surgery, University of Cincinnati, Cincinnati, Ohio
†Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Address reprint requests to Charles C. Caldwell, PhD, Division of Research, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0558. E-mail: email@example.com
Received 7 July, 2017
Revised 21 July, 2017
Accepted 23 March, 2018
This work was presented at the 40th Annual Shock Society Conference, on June 5, 2017. The first author was selected to receive a Travel Award.
The authors report no conflicts of interest.
Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com).