Hypoprothrombinemia Associated with Interleukin-2 Therapy

Abstract

We noted that patients treated with high-dose interleukin (IL)-2 (600,000 IU/kg every 8 h by intravenous bolus) at our institution frequently developed prolongation of their prothrombin time (PT). We therefore performed a prospective study of coagulation function during IL-2 treatment. Since IL-2 treated individuals are known to develop cholestatic liver dysfunction, we hypothesized that the hypoprothrombinemia was due to deficiency of liver-synthesized clotting factors and could be prevented by vitamin K replacement. Alternating patients served as controls or received prophylactic subcutaneous subcutaneous vitamin K. While the nine control patients did not exhibit a significant increase (mean +/- SD) in PT (13.6 +/- 0.6 s pretreatment, 15.0 +/- 2.2 on day 4, and 15.0 +/- 2.5 on day 7, p = 0.77 by repeated measures analysis), three patients developed marked increases in PT (greater than 18 s). Changes in partial thromboplastin time (PTT) over this interval were also not statistically significant. Factor VII levels decreased in all patients from 106 +/- 22 to 59 +/- 16 and 52 +/- 26% on days 4 and 7 (p = 0.0002). Factor VII levels in four patients dropped below the lower limit of normal. Prophylactic treatment of seven patients with vitamin K on days 1-8 of the IL-2 therapy protocol resulted in diminished changes in PT and factor VII compared to control patients (p = 0.02 and 0.003 respectively). No vitamin K-treated patient developed PT or Factor VII levels significantly outside the normal range. Prophylactic vitamin K can prevent hypoprothrombinemia in patients treated with IL-2. This may be of importance in patients with decreased hepatic vitamin K stores, who may be at risk for bleeding complications.