Anagrelide platelet‐lowering effect is due to inhibition of both megakaryocyte maturation and proplatelet formation: insight into potential mechanisms

Abstract

To cite this article: Espasandin YR, Glembotsky AC, Grodzielski M, Lev PR, Goette NP, Molinas FC, Marta RF, Heller PG. Anagrelide platelet-lowering effect is due to inhibition of both megakaryocyte maturation and proplatelet formation: insight into potential mechanisms. J Thromb Haemost 2015; 13: 631-42. effect of anagrelide results from impaired megakaryocyte maturation and reduced PPF, both of which are deregu-lated in essential thrombocythemia. These effects seem unrelated to PDE3 inhibition, which is responsible for anagrelide 0 s cardiovascular side-effects and antiplatelet activity. Further work in this field may lead to the potential development of drugs to treat thrombocytosis in myeloproliferative disorders with an improved pharmaco-logic profile.

Skewed megakaryopoiesis in human induced pluripotent stem cell‐derived haematopoietic progenitor cells harbouring calreticulin mutations

“…The non‐inferiority of anagrelide to hydroxycarbamide, another general cytoreductive agent used for ET patients, in preventing thrombotic complications and platelet‐lowering effects in ET patients was demonstrated in the ANAHYDRET study (Gisslinger et al , ). The precise mechanisms by which anagrelide reduces the blood platelet count are still unclear; however, it does not inhibit the JAK‐STAT signal pathway (Ahluwalia et al , ), but suppresses megakaryocyte maturation and proplatelet formation (Espasandin et al , ). In addition, 3‐HA, the active metabolite of anagrelide, has similar potency, efficacy, mode of action, and specificity to anagrelide for its platelet‐lowering effects.…”

Long‐term follow‐up of essential thrombocythemia patients treated with anagrelide: subgroup analysis according to JAK2/CALR/MPL mutational status

“…Anagrelide is a platelet‐lowering agent which acts by blocking megakaryocyte maturation, polyploidization and, as shown recently, proplatelet formation . Its clinical effectiveness in essential thrombocythemia (ET) was established by several centers .…”

Anagrelide and the Calr Mutation Allele Burden in Essential Thrombocythemia

“…While some emerging evidence suggests that driver mutation status may impact on the clinical response [5,6], the above observation is broadly in line with the finding that in essential thrombocythemia, anagrelide therapy also does not impact on the JAK2 V617F allele burden [7,8]. While interferon and JAK1/2 inhibitors are known to exert some of their effects through disruption of immune responses, the full mechanism of action of anagrelide remains unclear with the primary effect being inhibition of megakaryocyte maturation and proplatelet formation [9]. This inability to directly target the malignant clone may reflect the inability of anagrelide to induce molecular responses in essential thrombocythemia, if indeed deep responses are required for long-term survival.…”