Thrombopoietin (THPO) and the interaction with its receptor c-Mpl have a nonredundant role in platelet biogenesis and maintenance of the haematopoietic stem cell compartment in postnatal haematopoiesis.
Mutations of c-MPL can either result in loss-of-function and inherited thrombocytopenia (IT) or in gain-of-function and hereditary thrombocythaemia. Similarly, heterozygous gain-of-function mutations in THPO cause hereditary thrombocythaemia, a chronic myeloproliferative syndrome characterised by elevated numbers of circulating platelets, thrombotic or haemorrhagic episodes, and occasional leukaemic transformation. On the other hand, homozygous THPO loss-of-function mutations result in thrombocytopenia evolving in bi-tri lineage bone marrow aplasia of varying degree.
Until recently, loss-of-function mutations in c-MPL were the only known cause of congenital amegakaryocytic thrombocytopenia (CAMT), a disorder characterised by congenital hypomegakaryocytic thrombocytopenia and the development of further cytopenias during childhood until progression to generalised bone marrow aplasia. This severe aplasia is fatal unless children are treated with haematopoietic stem cell transplantation (HSCT).1 Of note, a proportion of patients with the clinical presentation of CAMT do not carry mutations in c-MPL, suggesting that the disease is genetically heterogeneous. It has been hypothesised that the patients with wild-type c-MPL have alterations in genes playing a role upstream or downstream of the receptor.1,2
Recent research showed that homozygous loss-of-function variants in THPO induce a phenotype similar to that caused by c-MPL mutations.3-5 In fact, patients present with hypomegakaryocytic thrombocytopenia with or without anaemia or neutropenia, which progresses to trilineage bone marrow aplasia. The only difference with patients affected with CAMT due to c-MPL mutation was that in these THPO-mutated subjects the HSCT was constantly unsuccessful.
Since the endogenous THPO is cleared from circulation by megakaryocytes and platelets, the serum or plasma THPO levels are markedly increased in all forms of bone marrow aplasia or hypoplasia, including CAMT due to c-MPL mutations.6-8 In contrast, the serum THPO concentration was not increased in patients with THPO-variants. These observations suggest that measurement of the serum THPO level could be useful to discriminate CAMT patients with c-MPL mutations from those with THPO-variants or other bone marrow failure syndromes.
THPO-mimetic drugs represent an appealing therapeutic option for the cytopenias caused by THPO mutations.9 Consistently, romiplostim was effective at increasing platelet count in all at-risk patients,4,5 as well as at increasing haemoglobin concentration and neutrophil count in subjects presenting with anaemia and/or neutropenia. Besides the haematological response, romiplostim induced remission of spontaneous bleeding and transfusion independence. Thus, recognising THPO-variants is essential for correct management and avoiding the use of invasive and unnecessary treatments, such as HSCT and immunosuppressive drugs.
Additionally, Noris et al.10 recently described a new, autosomal dominant form of IT caused by a THPO heterozygous variant leading to a truncated THPO protein, characterised by normal or slightly increased platelet size; affected subjects had no bleeding tendency and their thrombocytopenia was discovered incidentally. Unlike the homozygous THPO-variant, this innocuous disease has to be distinguished from the more severe autosomal dominant IT with normal platelet size deriving from mutations in ETV6, ANKRD26, and RUNX1, which predispose individuals to the development of haematological malignancies.