[Show abstract][Hide abstract] ABSTRACT: Anagrelide (ANA) and hydroxycarbamide (HC) are two distinct pharmacological agents used to treat thrombocythaemia associated with myeloproliferative disorders. Although both drugs have been in clinical use for a number of years, comparative studies of their selectivity and mode of action are still lacking. Here, we have evaluated the activities of ANA and HC on the growth and differentiation of human haematopoietic progenitor cells in liquid culture. Both drugs inhibited thrombopoietin-induced megakaryocytopoiesis in a dose-dependent manner, but with strikingly different potencies (IC(50)=26 nM for ANA and 30 muM for HC) and modes of action. Whereas HC inhibited cell proliferation, ANA acted primarily on the differentiation process. At doses that abrogated megakaryocytopoiesis, HC also inhibited the expansion of CD34(+) cells stimulated by stem cell factor, interleukin-3 and Flt-3 ligand and also induced apoptosis. Furthermore, HC inhibited erythroid and myelomonocytic cell growth, induced by erythropoietin or granulocyte-macrophage colony-stimulating factor, respectively. In contrast, ANA showed none of these additional effects. Taken together, these results demonstrate that ANA is a potent and selective inhibitor of megakaryocytopoiesis, having no significant activity against haematopoietic progenitor cell expansion or differentiation into other lineages. In contrast, the anti-megakaryocytopoietic activity of HC cannot be dissociated from its more general cytoreductive and cytotoxic actions.
[Show abstract][Hide abstract] ABSTRACT: Background: Cellular prion protein (PrPC) is a naturally occurring protein in normal individuals which adopts an abnormal conformation, termed scrapie prion protein (PrPSc) that is associated with disease. There is great concern that clinically asymptomatic variant Creutzfeldt–Jacob disease (vCJD) may transmit PrPSc in blood transfusion products. PrPC is widely expressed and has been found in human blood. The majority of cellular borne PrPC is associated with platelets (84%). Although PrPC mRNA has been demonstrated in platelets, the quantity is unknown and may not reflect the total PrPC present. Objective: To investigate the expression of PrPC in the megakaryocyte lineage. Methods: The expression of PrPC was studied in CD34+ cells, cultured megakaryocytes and platelets using electron microscopy, flow cytometry, semi-quantitative RT-PCR and immunofluorescence confocal microscopy. Results and conclusions: The expression of PrPC appeared to increase with differentiation and polyploidization in the megakaryocyte lineage. PrPC was located within platelet -granules and its source is likely to be from megakaryocyte precursors. If PrPSc has a similar distribution, these results have implications for the selection of blood donors and preparation of cell-depleted blood products.
Journal of Thrombosis and Haemostasis 06/2005; 3(6):1266 - 1273. · 6.08 Impact Factor