Anagrelide-induced bone marrow changes during therapy of chronic myeloproliferative disorders with thrombocytosis. an immunohistochemical and morphometric study of sequential trephine biopsies.
OBJECTIVE
Anagrelide is an agent with a significant platelet-lowering activity in humans. Contrasting the wealth of clinical data, bone marrow (BM) changes during therapy have been relatively rarely studied; information is particularly lacking regarding specific features of megakaryocytopoiesis.


METHODS
A study was performed on 15 patients with essential thrombocythemia and early stage chronic idiopathic myelofibrosis presenting with an elevated platelet count. These patients received anagrelide for 25 months resulting in a significant improvement of thrombocytosis. Evaluations were carried out by morphometry on sequential BM biopsies following enzyme- and immunohistochemical stainings that also included those for proliferative capacity and apoptosis.


RESULTS
No significant change in proliferation or apoptosis was recognizable during anagrelide treatment. The most conspicuous alterations were those of the CD61+ megakaryocytopoiesis. Megakaryocytopoiesis revealed an increase in promegakaryoblasts together with an enhancement of proliferating cell nuclear antigen activity. This feature is in keeping with an inhibitory effect on endoreduplication implying an arrest of polyploidization and maturation into platelet-shedding large megakaryocytes. On the other hand, a significant increase in the number of megakaryocytes was not detectable. Anagrelide failed to exert a stimulating influence on the progression of myelofibrosis or on the amount of CD34+ progenitor cells. Regarding angiogenesis, there was no increase in the density of BM vessels, but distension of the vascular lumina corresponded with a vasodilatory effect.


CONCLUSIONS
Anagrelide exerts a significant effect on endoreduplicative activity of megakaryocytes consistent with an inhibition of maturation and therefore, generates a relative predominance of precursor cells but fails to stimulate myelofibrosis.
Thiele
Juergen
J
Institute of Pathology, University of Cologne, Germany. j.thiele@uni-koeln.de
Kvasnicka
Hans Michael
HM
Fuchs
Nina
N
Brunnbauer
Kerstin
K
Volkwein
Nina
N
Schmitt-Graeff
Annette
A
D000328:Adult; D000368:Aged; D001706:Biopsy; D001792:Blood Platelets / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology*; D002908:Chronic Disease; D004341:Drug Evaluation; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000150:complications / Q000188:drug therapy*; D010976:Platelet Count; D011799:Quinazolines / Q000494:pharmacology*; D012189:Retrospective Studies; D013922:Thrombocytosis / Q000188:drug therapy* / Q000209:etiology
D011799:Quinazolines; C021139:anagrelide