The effect of daunomycin on platelets in vitro

Daunomycin (rubidomycin, daunorubicin), an anthracycline antimetabolite used in the therapy of acute leukemia, is highly toxic to both normal and malignant cells. Treatment with daunomycin may produce thrombocytopenia and bleeding which have been attributed to bone marrow toxicity. We have examined daunomycin to determine if a direct drug effect on platelet structure and function could contribute to a hemorrhagic diathesis in some patients on therapy. Normal citrated platelet-rich plasma was reacted in vitro with daunomycin and/or collagen with structural assessment by phase and electron microscopy and functional studies by platelet aggregation, [2-14C]5-hydroxytryptamine release studies and assays for released cytoplasmic marker enzyme, lactic dehydrogenase, in the supernatant fluid. High [greater than 0.04 mg/ml (greater than 0.07 mM)] concentrations of daunomycin were associated with structural changes, specifically by platelet swelling, vacuole formation and mitochondrial swelling with interruption of the trilaminar membrane. Platelets, exposed to low doses of daunomycin, 0.001 to 0.01 mg/ml (0.00177-0.0177 mM) of platelet-rich plasma, were dysfunctional with decreased aggregation with collagen and decreased [2-14C]5-hydroxytryptamine release. These studies indicate that daunomycin has a direct effect on platelets in vitro which may explain certain instances of bleeding observed in some patients undergoing therapy.