Standard treatment of adrenocortical carcinoma (ACC) comprises adrenolytic therapy with mitotane. Prolongation of bleeding time has previously been observed based on a series of 7 patients (Haak et al. 1991). As patients with ACC frequently undergo surgery for local recurrence or metastases, we have studied the effect of mitotane on coagulation in 44 patients with ACC before and/or during treatment with mitotane (total sample size n=62).
Platelet aggregation was performed with standard light transmission aggregometry using platelet rich plasma. Major components of the extrinsic and intrinsic coagulation cascade pathways were determined by routine coagulation testing using the Dade Behring BCS analyzer system or manual ELISA testing. In vitro bleeding time was detected as PFA-100 measurement.
During mitotane therapy, a successive decrease in platelet aggregation occurred that was closely correlated with mitotane levels. This effect was most pronounced for ADP-induced platelet aggregation (Pearson r=0.77; P<0.001) and induction with collagen (r=0.47; P=0.002), but less so for challenge with epinephrine (r=0.25; P=0.1), and ristocetin (r=0.18; P=0.2). Platelet counts, in vitro bleeding time, global plasmatic coagulation and von Willebrand parameters remained unaffected. With mitotane levels above 10 mg/l, 18 out of 19 patients had pathologic ADP-induced platelet aggregation.
In conclusion, in a large series of patients with ACC we show impaired agonist-induced platelet aggregation strongly dependent on plasma mitotane levels. Routine in vitro bleeding time is not suitable to detect this platelet defect and to assess bleeding risk. ADP-induced platelet aggregometry testing prior to surgery is recommended to determine mitotane-induced bleeding risk. Further studies should investigate the potential role of prophylactic administration of DDAVP to improve platelet function.
03 - 07 May 2008
European Society of Endocrinology