title: [Anagrelide-induced changes of megakaryopoiesis during therapy of chronic myeloproliferative disorders with thrombocythemia].
abstract: Thrombocythemia in the course of chronic myeloproliferative disorders like chronic idiopathic myelofibrosis (cIMF) and of course essential thrombocythemia (ET), are characterized by life-threatening complications. In a number of clinical trials the recently introduced drug Agrylin((R)) has proven to be very effective. The normalization of the platelet count was related to an interference with megakaryocyte maturation leading to a left-shifting of this cell lineage and/or a reduced proliferation. However, until now no systematic study has been performed on the relationship between development of megakaryopoiesis and proliferative activity. In this investigation we included 10 patients with cIMF and 5 patients with ET that had received Agrylin((R)) for a period ranging between 6 and 70 months. Following therapy this cohort revealed a decrease in the platelet count from 1,104x10(9)/l at diagnosis to 485x10(9)/l. In this context we focused on an immunohistochemical and morphometric analysis of the CD61(+) megakaryopoiesis involving also endomitotic reduplication, by applying a double-immune incubation technique with the proliferating cell nuclear antigen (PCNA). Moreover, we determined the changes of fiber density during observation time. According to our results, the thrombocytopenic effect of Agrylin((R)) is based on an arrest in the dynamics of megakaryocyte maturation towards large (mature) platelet-shedding (polyploid) cells. This pathomechanism causes a significant increase in the number of promegakaryoblasts and megakaryoblasts. On the other hand, the total amount of CD61(+) megakaryocytic cells is not increased. Related to the peculiar cell biology of endomitotic reduplication during the maturation process and its different periods alloted to each single step, PCNA activity (late G1- and S-phase of the cell cycle) is found to be enhanced in the megakaryocyte precursors. Finally, no significant influence of Agrylin((R)) on the evolution of myelofibrosis is detectable and there is a general improvement of hematological data especially in cIMF.
authors.affiliation: Zentrum für Pathologie, Universität zu Köln, Joseph-Stelzmann-Strasse 9, 50924 Köln, Germany. j.thiele@uni-koeln.de
authors.forename: J
authors.initials: J
authors.lastname: Thiele
authors.forename: H M
authors.initials: HM
authors.lastname: Kvasnicka
authors.forename: A
authors.initials: A
authors.lastname: Schmitt-Gräff
mesh_terms: D001792:Blood Platelets / Q000473:pathology; D002908:Chronic Disease; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D008533:Megakaryocytes / Q000187:drug effects / Q000473:pathology*; D009196:Myeloproliferative Disorders / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D010976:Platelet Count; D018809:Proliferating Cell Nuclear Antigen / Q000097:blood; D011799:Quinazolines / Q000627:therapeutic use*; D012016:Reference Values; D012189:Retrospective Studies; D013922:Thrombocytosis / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D034061:Thrombopoiesis / Q000187:drug effects*
chemical_list: D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D011799:Quinazolines; C021139:anagrelide