title: Interleukin 12 induces activation of fibrinolysis and coagulation in humans.
abstract: Interleukin 12 (IL-12) has potential efficacy in malignant, infectious and allergic diseases. Its side-effects include activation of coagulation and fibrinolysis, as documented in chimpanzees. We assessed the coagulative and fibrinolytic response in 18 patients with renal cell carcinoma after subcutaneous injection of 0.5 microg/kg recombinant human IL-12. IL-12 induced a fibrinolytic response in 17 patients (94%): plasmin-alpha2-anti-plasmin complexes (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 activator (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 maximum of 19.0 +/- 6.7 ng/ml at 72 h. PAI decreased from 111 +/- 69 ng/ml to 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-thrombin 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 similar levels of recombinant human IL-12, interferon-gamma or tumour necrosis factor-alpha. We conclude that IL-12 can activate both fibrinolysis and coagulation in a significant proportion of patients with cancer. The time-frame and sequence of these activation processes differ from those known for other cytokines.
authors.affiliation: Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Department of Medical Oncology, Rotterdam, The Netherlands. jportiel@worldonline.nl
authors.forename: J E
authors.initials: JE
authors.lastname: Portielje
authors.forename: W H
authors.initials: WH
authors.lastname: Kruit
authors.forename: A J
authors.initials: AJ
authors.lastname: Eerenberg
authors.forename: M
authors.initials: M
authors.lastname: Schuler
authors.forename: A
authors.initials: A
authors.lastname: Sparreboom
authors.forename: C H
authors.initials: CH
authors.lastname: Lamers
authors.forename: R L
authors.initials: RL
authors.lastname: Bolhuis
authors.forename: G
authors.initials: G
authors.lastname: Stoter
authors.forename: C
authors.initials: C
authors.lastname: Huber
authors.forename: C
authors.initials: C
authors.lastname: Hack
mesh_terms: D000328:Adult; D000368:Aged; D000990:Antithrombin III / Q000032:analysis; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy*; D005260:Female; D005341:Fibrinolysin / Q000032:analysis; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000097:blood / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis; D011994:Recombinant Proteins / Q000097:blood / Q000494:pharmacology; D013917:Thrombin / Q000032:analysis / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D000979:alpha-2-Antiplasmin / Q000032:analysis
chemical_list: D015415:Biomarkers; D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000979:alpha-2-Antiplasmin; D018664:Interleukin-12; D007371:Interferon-gamma; D000990:Antithrombin III; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin