Familial thrombocythaemia – a distinct entity from essential thrombocythaemia

Familial thrombocythaemia (FT) includes a group of predominantly autosomal dominant conditions due to various mutations in the thrombopoietin (THPO), myeloproliferative leukaemia virus oncogene (MPL), or Janus kinase 2 (JAK2) genes. These disorders differ from essential thrombocythaemia (ET), one of the classical, Philadelphia chromosome breakpoint cluster region-Abelson tyrosine-protein kinase 1 (BCR-ABL1)-negative myeloproliferative neoplasms (which are a group of diseases characterised by vascular and bleeding complications and risk of fibrotic or leukaemic transformation.) Of the three common drivers responsible for ET [JAK2, calreticulin (CALR) and MPL), MPL is responsible for <5% of ET cases. In this issue, Al-Harbi et al. describe a cohort of 64 patients with familial thrombocythaemia due to four different MPL mutations. The cohort described in this paper is young, with a median age of 20 years (Table I) and approximately ~40% of subjects being aged ≤14 years. While ET is the most common classical myeloproliferative neoplasm in young patients, it is classically a disease of older patients, with a median age in the 50’s. The median platelet count in this cohort was 707 5 9 10/l; two older cohorts of MPL-mutated ET patients had higher median counts (749 and 949 9 10/l). The majority of patients in this cohort had the c.317C>T (Pro106Leu) mutation, which has previously been reported in patients with familial thrombocythaemia. Only one patient in this cohort had a thrombotic event, and this occurred after organ transplant. Thrombotic events have been reported in patients with familial thrombocythaemia harbouring the MPL Ser505Asn mutation. While there is a clear association between JAK2 mutation and thrombosis, the relationship between MPL mutations and thrombotic events is less well defined. Various series report rates of thrombosis in patients with MPL-mutated ET ranging from 0% to 40%. A portion of the patients in this cohort (11%) were treated with cytoreductive therapy with hydroxyurea, yet there are no clear guidelines for management of familial thrombocythaemia nor any data suggesting platelet count is associated with thrombotic risk. Management of ET is dependent on risk stratification, and cytoreductive therapy is generally not recommended in younger patients without JAK2 mutation and no other indications for cytoreduction (such as acquired von Willebrand disease or thrombosis). Alternatively, aspirin is often used for patients with ET with vascular symptoms, and 32% of this cohort received aspirin. While this paper was a retrospective analysis, it is reassuring that no patients were identified to have myelofibrotic or leukaemic progression. Development of marrow fibrosis and decreased survival has been reported in patients with familial thrombocythaemia and MPL Ser505Asn mutation. Progression to post-ET myelofibrosis or acute leukaemia has been reported in patients with MPL-mutated ET, and some series report poorer outcomes with MPL-mutated ET, which may be due to mischaracterisation of pre-myelofibrosis as ET. Given the difference in prognosis, it is important to distinguish between ET and FT. Obtaining a detailed family history and characterising the specific MPL mutation involved can help with this distinction, and when haematological complications or uncertainty are present, a bone marrow evaluation can help aid in the diagnosis of ET. One of the most interesting aspects of this cohort is the role of the tribal system and its relevance for genetic disease. There are numerous tribes in Saudi Arabia and tribal affiliation is often maintained through intra-tribal and Correspondence: Nicole Kucine, Pediatrics, Weill-Cornell Medical College, New York, NY, USA. E-mail: nik9015@med.cornell. edu commentary