Congenital amegakaryocytic thrombocytopenia: an intrinsic hematopoietic stem cell defect.

Serial studies of bone marrow (BM) hematopoiesis using clonogenic assays were performed in an infant with congenital amegakaryocytic thrombocytopenia. Initially, when the only hematological abnormality was isolated thrombocytopenia, the number of clonogenic BM hematopoietic progenitors was comparable to controls, including the number of megakaryocyte precursors. As the disease evolved into aplastic anemia over an 11-month period, the peripheral blood counts declined, and colony numbers from four classes of BM progenitors--termed BFU-E, CFU-GM, CFU-Mix, and CFU-Meg--also declined in parallel. When added to the marrow cultures, patient's plasma was not inhibitory to either control or to patient's BM colony growth. Similarly, no cellular inhibition of hematopoiesis was observed when patient's BM was cultured after depleting the sample of T lymphocytes and after adding the T lymphocytes back. Furthermore, stromal cells established from short-term and long-term cultures of patient's BM showed normal proliferative activity and yielded a "fertile" marrow microenvironment for patient's and control BM colony growth. Our data suggest that the central problem in congenital amegakaryocytic thrombocytopenia is an intrinsic hematopoietic stem cell defect, rather than an abnormality of the marrow milieu. The findings are consistent with either a progressive, quantitative attrition of progenitors or their inability to proliferate into colonies in vitro and into differentiated, functional cells in vivo.