Interleukin 12 induces activation of fibrinolysis and coagulation in humans

Interleukin 12 (IL-12) has potential efficacy in malignant, infectious and allergic diseases. Its side-effects include activation of coagulation and f ibrinolysis, as documented in chimpanzees. We assessed the coagulative and fibrinolytic response in 18 patients with renal cell carcinoma after subcut aneous injection of 0.5 mug/kg recombinant human IL-12. IL-12 induced a fib rinolytic response in 17 patients (94%): plasmin-alpha2-anti-plasmin comple xes (PAPc) increased from 11.8 +/- 6.6 nmol/l (mean +/- SD) to a maximum of 18.8 +/- 7.4 nmol/l at 72 h. Baseline levels of tissue plasminogen activat or (tPA) and plasminogen-activator inhibitor-I (PAI) were elevated in eight and 14 patients respectively. tPA increased from 12.6 +/- 5.2 ng/ml to a m aximum of 19.0 +/- 6.7 ng/ml at 72 h. PAI decreased from 111 +/- 69 ng/ml t o a minimum of 65 +/- 53 ng/ml at 8 h, thereafter remaining below baseline. Elevation of PAPc correlated with elevation of tPA and reduction of PAI. A coagulative response occurred in nine patients (50%): thrombin-anti-thromb in III complexes increased from 29 +/- 53 ng/ml to a maximum of 460 +/- 322 ng/ml at 12 h. Patients with and without a coagulative response had simila r levels of recombinant human IL-12, interferon-gamma or tumour necrosis fa ctor-alpha. We conclude that IL-12 can activate both fibrinolysis and coagu lation in a significant proportion of patients with cancer. The time-frame and sequence of these activation processes differ from those known for othe r cytokines.