The molecular basis of congenital thrombocytopenias: insights into megakaryopoiesis.

Thrombocytopenia, defined as a platelet count less than 150,000 ml , is a common problem in clinical hematology. In most patients, the cause is secondary to an acquired autoimmune disorder, a systemic illness or infection, or an adverse drug effect. Inherited thrombocytopenias are relatively rare, but the identification of genetic mutations in patients with these disorders has contributed significantly to our understanding of the molecular basis of megakaryopoiesis and platelet production. Although laboratory models based on engineered cell lines or transgenic mice are useful in the evaluation of genetic changes that affect megakaryopoiesis, they are not always faithful representations of the human conditions. Therefore, studies from affected patients continue to be vital for our understanding of these diseases. The list of recognized syndromes of inherited thrombocytopenia is growing, reflecting our increased understanding of the variety of genes that regulate megakaryocyte development and the formation of platelets. Individual syndromes can be classified conceptually by grouping them into disorders with amegakaryocytosis, impaired megakaryocyte maturation, or more distal defects in platelet formation. Low platelets are usually the dominant feature, but abnormalities in other blood cell lineages may be present. In addition, features outside of the hematopoietic system may be associated, such as skeletal defects, hearing abnormalities, or renal dysfunction. Importantly, several of the inherited thrombocytopenias carry a risk of progression to aplastic anemia or leukemia and may occasionally present with these features if the preceding thrombocytopenic phase has not been detected. Disorders associated with amegakaryocytosis include congenital amegakaryocytic thrombocytopenia (CAMT), thrombocytopenia with absent radii (TAR), and amegakaryocytic thrombocytopenia with radioulnar synostosis (ATRUS). These children typically present at birth with severe thrombocytopenia, platelets of normal size, and a paucity of bone marrow megakaryocytes. If plasma levels of thrombopoietin (TPO), the primary cytokine regulating platelet production, are obtained they are elevated due to decreased uptake by the decreased megakaryocyte mass [1]. The prototypical disorder in this category is CAMT, in which patients have severely reduced megakaryocytes and platelets due to mutations in the TPO receptor c-Mpl [2]. Because of the complete lack of receptor-mediated uptake, elevated TPO levels are particularly prominent in CAMT. Although infants present with low platelets, they usually progress to complete bone marrow aplasia within a few years, providing evidence for a critical role for TPO in the maintenance of the hematopoietic stem cell [3]. Mice engineered to have homozygous deletion of c-Mpl are thrombocytopenic and have a reduced number of stem cells [4,5], but the mice do not develop pancytopenia even with prolonged monitoring (unpublished observation). The basis for this difference between humans and mice deficient in c-Mpl is not understood. Identified mutations of c-Mpl are scattered throughout the gene and are inherited in an autosomal recessive pattern, as heterozygous expression of a wild type receptor is adequate for normal thrombopoiesis. Mutations can be classified as type I, in which there is complete loss of the receptor due to a truncation or nonsense mutation, or type II, in which an amino acid substitution results in a receptor with some partial function [2]. This distinction is clinically significant as it appears that patient with type II mutations tend to have a higher initial platelet count and a slower course of progression to aplasia. Because of the expected development of marrow failure, it is recommended that patients with CAMT be trans-