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Anagrelide platelet‐lowering effect is due to inhibition of both megakaryocyte maturation and proplatelet formation: insight into potential mechanisms
Author(s) -
Espasandin Y. R.,
Glembotsky A. C.,
Grodzielski M.,
Lev P. R.,
Goette N. P.,
Molinas F. C.,
Marta R. F.,
Heller P. G.
Publication year - 2015
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12850
Subject(s) - anagrelide , megakaryocyte , platelet , microbiology and biotechnology , chemistry , pharmacology , medicine , biology , essential thrombocythemia , progenitor cell , stem cell
Summary Background and Objectives Anagrelide represents a treatment option for essential thrombocythemia patients. It lowers platelet counts through inhibition of megakaryocyte maturation and polyploidization, although the basis for this effect remains unclear. Based on its rapid onset of action, we assessed whether, besides blocking megakaryopoiesis, anagrelide represses proplatelet formation ( PPF ) and aimed to clarify the underlying mechanisms. Methods and Results Exposure of cord blood‐derived megakaryocytes to anagrelide during late stages of culture led to a dose‐ and time‐dependent inhibition of PPF and reduced proplatelet complexity, which were independent of the anagrelide‐induced effect on megakaryocyte maturation. Whereas anagrelide was shown to phosphorylate cAMP ‐substrate VASP , two pharmacologic inhibitors of the cAMP pathway were completely unable to revert anagrelide‐induced repression in megakaryopoiesis and PPF , suggesting these effects are unrelated to its ability to inhibit phosphodiesterase ( PDE ) 3. The reduction in thrombopoiesis was not the result of down‐regulation of transcription factors which coordinate PPF , while the myosin pathway was identified as a candidate target, as anagrelide was shown to phosphorylate the myosin light chain and the PPF phenotype was partially rescued after inhibition of myosin activity with blebbistatin. Conclusions The platelet‐lowering effect of anagrelide results from impaired megakaryocyte maturation and reduced PPF , both of which are deregulated in essential thrombocythemia. These effects seem unrelated to PDE 3 inhibition, which is responsible for anagrelide′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 pharmacologic profile.