title: Fibrinolysis, thrombocytopenia, and coagulation abnormalities complicating high-dose interleukin-2 immunotherapy.
abstract: High-dose interleukin-2 (IL-2) immunotherapy can cause hypotension, respiratory distress, interstitial edema, and thrombocytopenia, similar to endotoxic shock. We have observed that IL-2 has no direct effect on coagulation factors in vitro, but it has been observed to alter the coagulant properties of vascular endothelium. Accordingly, we investigated the possibility that IL-2 infusions initiate plasma fibrinolysis and disseminated intravascular coagulation (DIC). We studied the clinical course, platelet count, and coagulation profile in response to IL-2 infusion in seven patients, two with metastatic melanoma and five with metastatic renal cell carcinoma. Every patient experienced hemodynamic instability and thrombocytopenia, and one patient suffered an unusual complication, mesenteric thrombosis. No patient had appreciable changes in the prothrombin time or the partial thromboplastin time, nor did factors V or VIII decline in the two patients observed. In four patients examined, we found decreased titers of Hageman factor (factor XII), high molecular weight kininogen, prekallikrein, and plasma thromboplastin antecedent, as if these had been consumed by reactions of the intrinsic pathway of thrombin formation. Circulating D-dimer fragments were found in the plasma of every patient at some point during each infusion cycle, and we observed decreased titers of plasminogen in the four patients just mentioned, suggesting that IL-2 infusions initiated fibrinolysis. Taken together, the clotting factor derangements and related toxicity phenomena cannot be ascribed firmly to DIC. Activation of the intrinsic (contact) system of coagulation, however, may provide one link between the vascular endothelial surface alterations caused by IL-2 infusions and the development of the systemic toxicity that resembles septic shock.
authors.affiliation: Division of Urology, Metrohealth Medical Center, Cleveland, Ohio.
authors.forename: J D
authors.initials: JD
authors.lastname: Fleischmann
authors.forename: W B
authors.initials: WB
authors.lastname: Shingleton
authors.forename: C
authors.initials: C
authors.lastname: Gallagher
authors.forename: O D
authors.initials: OD
authors.lastname: Ratnoff
authors.forename: A
authors.initials: A
authors.lastname: Chahine
mesh_terms: D000328:Adult; D000368:Aged; D001778:Blood Coagulation Disorders / Q000139:chemically induced*; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects*; D007376:Interleukin-2 / Q000009:adverse effects*; D008875:Middle Aged; D010976:Platelet Count / Q000187:drug effects; D013921:Thrombocytopenia / Q000139:chemically induced*
chemical_list: D007376:Interleukin-2