Primary or essential thrombocytosis (ET) is a chronic myeloproliferative disorder that is characterized by sustained elevation of platelet count, megakaryocytic hyperplasia in the bone marrow and increased risk of thrombotic and hemorrhagic complications. Familial thrombocytosis is a rare syndrome, reported previously in several families with an autosomal dominant mode of inheritance. More recently the genetic basis of familial thrombocytosis has been described in four such kindreds, each with a distinct mutation in the thrombopoietin (TPO) gene resulting in markedly elevated plasma TPO levels in affected individuals. Here we report a kindred with familial thrombocytosis wherein affected members have normal plasma TPO levels. The proband is a 39 y.o. male who presented to our clinic carrying the diagnosis of ET. His platelet count was noted as high as 902,000/ul. Iron studies were normal. Bone marrow examination showed normal cytogenetics and the presence of megakaryocytic hyperplasia. The patient's symptoms of intermittent headache and paraesthesias resolved upon treatment with hydroxyurea and anagrelide. The proband's brother was diagnosed with ET in his 20's, and was started on anagrelide at age 33 when he developed headaches in the setting of a platelet count of 1,200,000/1. Investigation of additional family members revealed an elevated platelet count in the proband's father of 554,000/ul, suggesting an autosomal dominant pattern of inheritance. Plasma TPO levels of the proband, his affected brother, and 2 unaffected siblings were measured by ELISA. They were found to be 147, 134, 275, and 180 pg/ml respectively (controls: 102 and 151 pg/ml). We have begun to investigate whether a structural alteration in c-mpl, the cell surface receptor for TPO, is associated with the occurence of inherited thrombocytosis in this family through a dominant gain-of-function mutation. Genomic PCR and nucleotide sequence analysis of the intracellular domain of c-mpl does not reveal a mutation in the proband. Structural analysis of the remainder of c-mpl as well as TPO genes are in progress.
|Original language||English (US)|
|Issue number||11 PART II|
|State||Published - 2000|
ASJC Scopus subject areas
- Cell Biology