Effects of anagrelide on megakaryopoiesis and platelet production.

Possible pathomechanisms regarding the thromboreductive effect of anagrelide (ANA) include decrease in the megakaryocyte cell mass or life span of platelets, interference with maturation, and stimulation of apoptosis and proliferation. Finally, a fibrogenic effect has been reported in patients with high-risk essential thrombocythemia (ET). Based on scrutinized evaluations, including immunohistochemistry and morphometry performed on representative bone marrow (BM) biopsies, ANA was found to exert a significant influence on the endoreduplicative activity of megakaryopoiesis, with an arrest of maturation at lower ploidy stages causing a predominance of precursors. This result confirms and greatly extends former investigations that also failed to document a decrease in quantity or enhancement of apoptosis. Moreover, a comparative study on the putative mutagenic capacity of hydroxyurea (HU) versus ANA treatment reveals that both agents generate a left-shifting of megakaryocytes. However, HU creates conspicuously expressed maturation defects consistent with dysplastic changes of megakaryopoiesis, and therefore supports concerns about the possible leukemogenic potential of this drug. On the other hand, in follow-up examinations of BM specimens, ANA failed to show a stimulation of myelofibrosis in ET, provided diagnosis was established according to the World Health Organization criteria.