Congenital Amegakaryocytic thrombocytopenia (CAMT) - a defect of the thrombopoietin receptor c-Mpl

Congenital amegakaryocytic thrombocytopenia (CAMT) is a very rare bone marr ow failure syndrome presenting with isolated hypomegakaryocytic thrombocyto penia at birth developing into a pancytopenia during the first years of lif e. Bone marrow transplantation is the only curative therapy for this diseas e so far. Thrombopoietin (TPO) is the most important hematopoietic growth f actor for the regulation of megakaryopoiesis and thrombopoiesis. We investi gated TPO production and reactivity in CAMT patients. TPO plasma levels wer e high like in other forms of thrombocytopenia due to ineffective megakaryo poiesis. However, we found a defective reactivity to TPO: Neither hematopoi etic progenitor cells in the bone marrow nor platelets from the peripheral blood did respond to TPO. Flow cytometric investigations demonstrated a lac k of expression of the TPO receptor c-MpI on the surface of platelets. Acco rdingly, we found mutations in the c-mpl gene, which are predicted to lead to a complete or at least partial loss of function of the TPO receptor. TPO is not only involved in the regulation of megakaryocytopoiesis but also in early hematopoiesis. This seems to be the reason for the general defect in hematopoiesis in CAMT leading to the development of pancytopenia.