MOLECULAR MARKERS OF HEMOSTATIC ACTIVATION AND INFLAMMATION FOLLOWINGMAJOR INJURY - EFFECT OF THERAPY WITH IFN-GAMMA

Interferon-gamma (IFN-gamma) has shown promise in treatment of injured patients, However, reactive states marked by immunologic and inflamma tory responses constitute a potential deleterious effect of IFN-gamma administration. IFN-gamma therapy has been associated with high levels of tumor necrosis factor-alpha (TNF-alpha), with potential enhancemen t of coagulopathy after injury, This study evaluated TNF-alpha product ion and markers of hemostatic activation in patients receiving IFN-gam ma therapy. Seventy-three patients, part of a larger multicenter trial , with severe injuries were randomized to IFN-gamma (100 mu g/day s.c. for 21 days) or placebo treatment. Enrollment criteria included injur y severity score (ISS) greater than or equal to 25 or significant bact erial contamination with ISS greater than or equal to 20, TNF-alpha an d other cytokine production was assessed at baseline and on days 3, 8, and 22 following injury, Markers of coagulation activation and fibrin olysis were also evaluated. Plasma TNF-alpha 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 fibri nolysis were elevated at all times studied following injury in both tr eatment and control groups but did not differ between patients receivi ng IFN and those receiving placebo, Activation of coagulation and fibr inolysis diminished in a time-related manner following injury. We conc lude that (1) IFN-gamma therapy at the dose employed was not associate d with a significant increase in TNF-alpha or other inflammatory cytok ine production beyond that seen in patients receiving placebo, (2) coa gulation and fibrinolytic markers were increased following injury but decreased significantly in surviving patients, and (3) no changes in c oagulation and fibrinolytic parameters were noted in relation to IFN-g amma therapy. These findings support previous observations that trauma is associated with hemostatic activation and that treatment of patien ts at the dose of IFN-gamma studied is safe in the setting of injury.