Interleukin-2 induces activation of coagulation and fibrinolysis: resemblance to the changes seen during experimental endotoxaemia.
The administration of Interleukin-2 (IL-2) causes the release or generation of other cytokines such as tumour necrosis factor (TNF) which, by disturbing the anticoagulant properties of the endothelium, may induce a procoagulant state in patients receiving this drug. We therefore evaluated the effects of IL-2 on coagulation and fibrinolysis in 14 patients receiving 12 or 18 x 10(6) IU/m2/d of IL-2 given as a 15 min infusion for 5 d. Blood samples were drawn at short intervals after the first IL-2 infusion. The parameters were analysed by way of analysis for repeated measures (F tests rather than t tests). During the first day, thrombin-antithrombin (TAT) complexes started to increase 2 h after the IL-2 infusion, reaching peak levels at 4 h (n = 14; 11.2 +/- 6.4 micrograms/l v 49.8 +/- 49.2 micrograms/l, P < 0.01). Plasma alpha 2 antiplasmin (PAP) complexes showed a similar pattern rising from a mean baseline value of 17.5 +/- 7.6 nmol/l to 66.8 +/- 47.7 nmol at 4 h (P < 0.01). In four patients the peak of PAP preceeded that of TAT. Tissue plasminogen activator (tPA) rose from a mean baseline value of 4.9 +/- 3.7 micrograms/l to 26.3 +/- 13.5 micrograms/l at 4 h (P < 0.01). Plasminogen-activator-inhibitor-1 (PAI-1) levels increased from 59 +/- 35 micrograms/l to 113 +/- 39 micrograms/l at 6 h (P < 0.01). tPA PAI-1 complexes increased from 0.15 +/- 0.07 to 0.69 +/- 0.21 nmol/l at 6 h (P < 0.01). Our study indicates that IL-2 activates the coagulation and fibrinolytic systems in vivo. The changes resemble the perturbations observed after endotoxin/TNF administration. These abnormalities may play a role in the side-effects induced by IL-2 therapy.
Baars
J W
JW
Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands.
de Boer
J P
JP
Wagstaff
J
J
Roem
D
D
Eerenberg-Belmer
A J
AJ
Nauta
J
J
Pinedo
H M
HM
Hack
C E
CE
D000328:Adult; D000368:Aged; D000933:Antifibrinolytic Agents / Q000032:analysis; D000990:Antithrombin III / Q000032:analysis; D001777:Blood Coagulation / Q000276:immunology*; D004731:Endotoxins / Q000097:blood* / Q000276:immunology; D005260:Female; D005341:Fibrinolysin / Q000032:analysis; D005342:Fibrinolysis / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010447:Peptide Hydrolases / Q000032:analysis; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis; D011994:Recombinant Proteins / Q000494:pharmacology*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000032:analysis; D000979:alpha-2-Antiplasmin
D000933:Antifibrinolytic Agents; D004731:Endotoxins; D007376:Interleukin-2; D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; D000979:alpha-2-Antiplasmin; C046193:antithrombin III-protease complex; C037742:plasmin-plasmin inhibitor complex; D000990:Antithrombin III; D010447:Peptide Hydrolases; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin