Summary
Patients with sepsis or after major surgery have decreased plasma levels of the anticoagulant
protein antithrombin. In such patients elevated levels of interleukin-6 (IL-6) are
present and this interleukin is known to induce positive and negative acute phase
responses. To investigate the possibility that antithrombin acts as a negative acute
phase response-protein we performed studies on the human hepatoma cell line HepG2
in vitro and baboons in vivo. HepG2 cells were treated with recombinant human IL-6,
ILß3, or combinations of the latter two, and tested for production of antithrombin,
fibrinogen and prealbumin (transthyretin). This treatment resulted in a dose dependent
increase in fibrinogen concentration (with a maximum effect of 2.8-2.9-fold) and a
dose dependent decrease in prealbumin (with a maximum effect of 0.6-0.7-fold) and
antithrombin concentrations (with a maximum effect of 0.6-0.8-fold). Simultaneous
treatment of the HepG2 cells with IL-6 (1,000 pg/ml or 2,500 pg/ml) and IL-1β (25
pg/ml), provided more extensively decreased prealbumin (0.8 and 0.6-fold, respectively)
and antithrombin concentration (0.7 and 0.6-fold, respectively) compared to the single
interleukin treatment at these concentrations. Baboons treated with 2 µg IL-6 · kg
body-weight-1 · day1 showed increased plasma CRP levels (59-fold, p <0.05) and decreased prealbumin (0.9-fold,
p <0.05) and antithrombin (0.8-fold, p <0.05) plasma levels, without evidence for
coagulation activation. Our results indicate that antithrombin acts as a negative
acute phase protein, which may contribute to the decreased antithrombin plasma levels
observed after major surgery or in sepsis.
