Pathophysiology of Hyperleukocytosis and ATRA Syndrome

The pathophysiology of hyperleukocytosis and ATRA syndrome is still not completely understood. ATRA syndrome is not due to leukostasis or thrombosis (or both) [34], and because its clinical signs are reminiscent of those observed in endotoxic shock and in adult respiratory distress syndrome (ARDS), a possible stimulatory effect of ATRA on cytokine expression by APL cells has been envisaged. Induction ofinterleukin (IL)-1 alpha and granulocyte colony-stimulating factor (G-CSF) secretion by APL cells under ATRA may contribute to hyperleukocytosis in vivo. On the other hand, the secretion of IL-1 alpha, IL-6, tumor necrosis factor (TNF) alpha, and IL-8—which are involved in leukocyte activation and adherence, and are implicated in the development of ARDS—could have a pathogenetic role in ATRA syndrome [112,113].

More recently, it has been shown that ATRA induced aggregation of NB4 cells (an APL cell line). This process was mediated by the adhesion molecules lymphocyte function-associated antigen (LFA)1 and intercellular adhesion molecule (ICAM)2 and was reversed by addition of methylprednisolone [114]. These findings suggest that modification of the adhesive properties of APL cells by ATRA could play a role in ATRA syndrome.

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