Essential thrombocythaemia (ET) is a chronic myeloproliferative syndrome due to sustained proliferation of megakaryocytes, which results in elevated numbers of circulating platelets, thrombotic or haemorrhagic episodes and occasional leukaemic transformation. The cause of ET is unknown. Hereditary thrombocythaemia (HT) with autosomal-dominant transmission has been described with manifestations similar to those of sporadic ET. As the thrombopoietin gene (THPO) encodes a lineage-restricted growth factor with profound stimulatory effects on megakaryopoiesis and platelet production, we tested the hypothesis that HT results from a mutation in the human THPO gene. In a Dutch family with eleven affected individuals, the thrombopoietin protein (TPO) concentrations in serum were consistently elevated in individuals with HT. We derived an intragenic CA marker for the human THPO gene and performed linkage analysis in fourteen informative meioses in this family. This resulted in a lod score of 3.5 at theta=0. A G-->C transversion was found in the splice donor site of intron 3 of the THPO gene in all affected family members. This mutation leads to THPO mRNAs with shortened 5'-untranslated regions (UTR) that are more efficiently translated than the normal THPO transcripts. We conclude that a splice donor mutation in THPO leads to systemic overproduction of TPO and causes thrombocythaemia.
SummaryIn 2 groups of non surgical patients with venous thrombosis (V. T.) the fibrinogen turnover rate was determined in addition to scanning of the legs.In the first group of 13 patients with clinical signs of V. T. the Tx/2 of 131I-fibrinogen was shorter than in a normal group. In the second group of 10 patients with V. T., diagnosed only by local scanning of the legs using 125I-fibrinogen, the T72 was also shortened.Because of the longer half life time of the 125I-label, observations can be carried out during a period of 20 days, so that 125I-fibrinogen is preferable to 131I-fibrinogen. Of 33 elderly patients treated for congestive heart failure a positive leg scan was observed in 15. Treatment with intravenously injected heparin immediately interferes with further accumulation of radioactivity and corrects the shortened TVa to normal values, in contrast to treatment with oral anticoagulants.
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