DÄ internationalArchive4/2008Essential Thrombocythemia – Clinical Significance, Diagnosis and Treatment: Mutations in Familial Thrombocythemias

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

Dtsch Arztebl Int 2008; 105(4): 71. DOI: 10.3238/arztebl.2008.0071c

Dame, C

LNSLNS 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.
DOI: 10.3238/arztebl.2008.0071c

Prof. Dr. med. Christof Dame
Klinik für Neonatologie
Campus Virchow-Klinikum
Charité – Universitätsmedizin Berlin
Augustenburgerplatz 1, 13353 Berlin, Germany
christof.dame@charite.de
1.
Wiestner A, Schlemper RJ, van der Maas AP, Skoda RC: An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia. Nat Genet 1998; 18: 49–52. MEDLINE
2.
Ding J, Komatsu H, Wakita A et al.: Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Blood 2004; 103: 4198–200. MEDLINE
3.
Moliterno AR, Williams DM, Gutierrez-Alamillo LI, Salvatori R, Ingersoll RG, Spivak JL: Mpl Baltimore: a thrombopoietin receptor polymorphism associated with thrombocytosis. Proc Natl Acad Sci USA 2004; 101: 11444–7. MEDLINE
1. Wiestner A, Schlemper RJ, van der Maas AP, Skoda RC: An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia. Nat Genet 1998; 18: 49–52. MEDLINE
2. Ding J, Komatsu H, Wakita A et al.: Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Blood 2004; 103: 4198–200. MEDLINE
3. Moliterno AR, Williams DM, Gutierrez-Alamillo LI, Salvatori R, Ingersoll RG, Spivak JL: Mpl Baltimore: a thrombopoietin receptor polymorphism associated with thrombocytosis. Proc Natl Acad Sci USA 2004; 101: 11444–7. MEDLINE

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