Multiple hematological side effects have been reported to result from treatment with psychoactive phenothiazines. These reported toxicities include leucopenia, granulocytopenia, thrombocytopenia, agranulocytosis, and bone marrow aplasia. The physiological mechanism causing these potentially life-threatening blood dyscrasias is unknown. Recently, we discovered that phenothiazines exhibit antagonistic properties towards the VLA-4 integrin, an adhesion molecule that is responsible for homing and retention of hematological stem/progenitor cells (HSPCs) in the bone marrow. After administration of thioridazine we detected rapid mobilization of HSPCs into the peripheral blood. We propose that in patients receiving phenothiazines over a prolonged time period, continuous mobilization of stem cells out of the stem cell niche, results in a disorder of hematopoiesis. Furthermore, we also postulate that such cytopenias are caused by a loss of the niche environment, which is known to be essential for stem cell maintenance.
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