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Analysis of the mechanism of anagrelide-induced thrombocytopenia in humans
EM Mazur, AG Rosmarin, PA Sohl, JL Newton and A Narendran
Department of Medicine, Miriam Hospital, Providence, RI 02906.
Anagrelide is a new therapeutic compound recently demonstrated to have a
rapid and selective thrombocytopenic effect in humans. The effects of
anagrelide were evaluated in plasma clot and liquid suspension cultures of
optimally stimulated normal human peripheral blood megakaryocyte
progenitors in order to determine the mechanism of its thrombocytopenic
activity. In plasma clot cultures, at clinically relevant, therapeutic
concentrations (5 to 50 ng/mL), anagrelide exerted no significant
inhibitory effect on megakaryocyte colony numbers or colony size. Only at
anagrelide concentrations of 10 to 500 times therapeutic doses did
anagrelide inhibit megakaryocyte colony development: an anagrelide
concentration of 5 micrograms/mL reduced colony numbers by 57% and colony
size by 31%. In contrast, lower, therapeutic anagrelide concentrations
exerted profound effects in liquid culture on megakaryocyte cytoplasmic
maturation, size, and DNA content. When present for the entire 12-day
culture duration, anagrelide induced left- shifted megakaryocyte maturation
and reduced both megakaryocyte ploidy and megakaryocyte diameter.
Anagrelide, at concentrations of 5 to 50 ng/mL, shifted the modal cultured
megakaryocyte morphologic stage from III to II, reduced the model ploidy
value from 16N to 8N, and decreased the mean megakaryocyte diameter by up
to 22%, from 27.6 microns to 21.6 microns. Megakaryocyte diameter was
significantly reduced in most instances, even when analyzed as a function
of morphologic stage. When anagrelide was added to the cultures after 6-
and 9-day delays (during the final 6 and 3 days, respectively, of culture),
similar inhibitory effects on megakaryocyte maturation stage and ploidy
distribution were observed. However, the magnitude of the left-shift in
ploidy appeared to be less as the duration of anagrelide exposure was
reduced. Conversely, megakaryocyte diameter was not significantly affected
by the shorter 3- and 6-day anagrelide exposures. These data indicate that
therapeutic concentrations of anagrelide influence primarily the
postmitotic phase of megakaryocyte development, decreasing platelet
production by reducing megakaryocyte size and ploidy, as well as by
disrupting full megakaryocyte maturation. Inhibition of megakaryocyte
diameter appears to require more prolonged anagrelide exposure than
inhibition of maturation stage and ploidy. The molecular mechanisms
responsible for the inhibitory effects of anagrelide on
megakaryocytopoiesis remain to be defined.
Volume 79,
Issue 8,
pp. 1931-1937,
04/15/1992
Copyright © 1992 by The American Society of Hematology
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