Molecular Markers of Hemostatic Activation and Inflammation Following Major Injury: Effect of Therapy with IFN-γ

Abstract

Interferon-γ (IFN-γ) has shown promise in treatment of injured patients. However, reactive states marked by immunologic and inflammatory responses constitute a potential deleterious effect of IFN-γ administration. IFN-γ therapy has been associated with high levels of tumor necrosis factor-α (TNF-α), with potential enhancement of coagulopathy after injury. This study evaluated TNF-α production and markers of hemostatic activation in patients receiving IFN-γ therapy. Seventy-three patients, part of a larger multicenter trial, with severe injuries were randomized to IFN-γ (100 μg/day s.c. for 21 days) or placebo treatment. Enrollment criteria included injury severity score (ISS) ≥ 25 or significant bacterial contamination with ISS ≥ 20. TNF-α and other cytokine production was assessed at baseline and on days 3, 8, and 22 following injury. Markers of coagulation activation and fibrinolysis were also evaluated. Plasma TNF-α and interleukin-6 (IL-6) levels were higher in IFN-treated relative to placebo-treated patients before and after IFN administration. Markers of coagulation and fibrinolysis were elevated at all times studied following injury in both treatment and control groups but did not differ between patients receiving IFN and those receiving placebo. Activation of coagulation and fibrinolysis diminished in a time-related manner following injury. We conclude that (1) IFN-γ therapy at the dose employed was not associated with a significant increase in TNF-α or other inflammatory cytokine production beyond that seen in patients receiving placebo, (2) coagulation and fibrinolytic markers were increased following injury but decreased significantly in surviving patients, and (3) no changes in coagulation and fibrinolytic parameters were noted in relation to IFN-γ therapy. These findings support previous observations that trauma is associated with hemostatic activation and that treatment of patients at the dose of IFN-γ studied is safe in the setting of injury.