Studies on megakaryopoiesis in patients with myelodysplasia and idiopathic thrombocytopenic purpura

In this thesis mechanisms of thrombocytopenia (a low number of platelets) in patients with myelodysplastic syndromes (MDS) or idiopathic thrombocytopenic purpura (ITP) were investigated. Thrombocytopenia can cause serious bleeding complications and elucidation of the underlying pathophysiology of thrombocytopenia in these disorders may lead to new treatment strategies. MDS are a heterogeneous group of bone marrow disorders, in which abnormalities of hematopoietic stem cells result in a decreased production of blood cells, including platelets. In ITP the thrombocytopenia develops because autoantibodies are formed against antigens on platelets leading to increased platelet destruction. In a large subgroup of ITP patients these antibodies also induce a reduced platelet production. In this thesis we provide evidence that premature cell death of megakaryocytes, the bone marrow cells that produce platelets, contributes to the reduced platelet production in both ITP and MDS. The types of cell death in ITP and MDS megakaryocytes, however, are different. The mechanisms for these forms of cell death are not fully elucidated. We show that in ITP factors which are present in the plasma, most likely the antibodies, can induce cell death in megakaryocytes. In MDS intrinsic abnormalities of megakaryocytes are important. External factors, such as signals from the bone marrow microenvironment, may also affect the cell death process in the hematopoietic precursor cells. This was suggested from our study on MDS erythroblasts (precursor cells of red cells). The level of cell death and presence of other abnormalities in these erythroblasts depended on the presence or absence of the bone marrow microenvironment. Finally, we observed that successful prednisone therapy can reverse the cell death abnormalities in ITP megakaryocytes. In keeping with these findings we also found that ITP patients with a decreased platelet production respond better to prednisone therapy than patients with a normal or increased production