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

Abstract

Congenital amegakaryocytic thrombocytopenia (CAMT) is a very rare bone marrow failure syndrome presenting with isolated hypomegakaryocytic thrombocytopenia at birth developing into a pancytopenia during the first years of life. Bone marrow transplantation is the only curative therapy for this disease so far. Thrombopoietin (TPO) is the most important hematopoietic growth factor for the regulation of megakaryopoiesis and thrombopoiesis. We investigated TPO production and reactivity in CAMT patients. TPO plasma levels were high like in other forms of thrombocytopenia due to ineffective megakaryopoiesis. However, we found a defective reactivity to TPO: Neither hematopoietic progenitor cells in the bone marrow nor platelets from the peripheral blood did respond to TPO. Flow cytometric investigations demonstrated a lack of expression of the TPO receptor c-Mpl on the surface of platelets. Accordingly, 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.