Essential Thrombocythemia – Clinical Significance, Diagnosis and Treatment: Mutations in Familial Thrombocythemias

Familial, in most cases autosomal dominant, but also recessive or rarely X-chromosomally inherited forms of essential thrombocythemia (ET) should be recognized and classified as a further, rather heterogeneous entity. Within this group of ET, mutations in the thrombopoietin (Tpo) gene locus, typically in the 5’ untranslated region, were identified in a series of patients. These mutations lead to increased translation efficiency of Tpo mRNA and thus to overproduction of Tpo (1). Hematocrit and white blood count are characteristically normal. Familial thrombocythemias can also be due to mutations in the Tpo receptor (TpoR/c-Mpl). Mutations in the transmembrane domain of TpoR are associated with increased activation of intracellular signal pathways (2). In contrast, mutations in the extracellular binding domain of TpoR lead to disturbed regulation of Tpo concentrations in plasma. The reduced absorption of Tpo to mutated Tpo receptors on the platelets results in increased circulating Tpo concentrations and causes overstimulation of megakaryopoiesis (3). However, Tpo or TpoR mutations can be ruled out in more than half of familial thrombocythemias, and therefore other factors must be of pathophysiological relevance. In children and adolescents with familial forms of ET platelet counts are lower (< 1500/nL) than in non-familial forms. Splenomegaly and thrombotic or hemorrhagic complications are very rare. Treatment is only considered for such complications, with preference increasingly being given to anagrelide for the reasons described by Grieshammer et al.