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Inherited thrombocytopenias
Congenital amegakaryocytic thrombocytopenia
Born with severe thrombocytopenia but normal sized platelets, patients with congenital amegakaryocytic thrombocytopenia lack mature megakaryocytes in the bone marrow. Evolution to critical multi-lineage aplasia occurs before adulthood.47,48 In the majority of cases, AR mutations in the MPL gene make the cells incapable of binding thrombopoietin; as a result circulating throm- bopoietin levels are very high.47 Nonsense mutations with a complete loss of Mpl give rise to a severe form (type I) while missense mutations and the presence of residual Mpl may give a milder form of the disease (type II). The mutations lead to a loss of thrombopoietin binding or on rare occasions, altered receptor recycling. In culture, megakaryocytes from the patients with congenital amegakaryocytic thrombocytopenia fail to form colonies. The mutations can also affect stem cell maintenance. Disease severity depends on the extent of the interference with JAK2/STAT and MAPK signaling pathways, with there being residual signaling in type II disease. HSC trans- plantation has been the treatment of choice.48 Progression to aplastic anemia or myelodysplastic syndrome is a risk. Rare homozygous mutations in the THPO gene with loss of thrombopoietin production or an inability to bind to Mpl can also lead to bone marrow aplasia. Note that because of the largely hepatic origin of thrombopoietin, these patients are unsuitable for bone marrow transplan- tation.48 Conversely, both MPL and THPO gain-of-func- tion mutations are a source of familial thrombocytosis.
Wiskott-Aldrich syndrome
Wiskott-Aldrich syndrome (WAS) is an X-linked disor- der described by Alfred Wiskott in 1937 and Robert Aldrich in 1954. The syndrome is characterized by severe immunodeficiency, thrombocytopenia and small platelets. The clinical spectrum includes eczema, infections, autoim- mune hemolytic anemia and cancer; bleeding is mostly mild but can be severe if the platelet count is very low and can prove fatal.49 Hemizygous mutations in the WAS gene abrogate expression or alter function of WAS protein: the protein has multiple roles in the early stages of actin poly- merization and in signal transduction with virtually all hematopoietic lineages affected.50,51 Megakaryocytes of WAS patients form proplatelets prematurely and shed platelets ectopically in the marrow.52 There is also a peripheral component to the thrombocytopenia with cir- culating autoantibodies and platelet destruction in the spleen making WAS a rare inherited thrombocytopenia in which splenectomy is still performed. Patients lacking WAS protein have a worse phenotype than those with residual amounts; milder forms are known as X-linked thrombocytopenia. Allogeneic HSC transplantation, first performed for WAS over 40 years ago, has a good progno- sis for severe cases with a high risk of bleeding and also benefits immunodeficiency.53 In the absence of matched donors gene therapy using a lentiviral vector encoding functional WAS protein is a promising alternative, even if full normalization of the platelet count is not achieved.54
Familial platelet disorders with predisposition to myeloid or lymphoid malignancies
Defects of transcription factors are a major source of inherited thrombocytopenias (Figure 1). Those that inter-
fere with the early stages of megakaryocyte maturation are often accompanied by a risk of developing myeloid or lymphoid malignancies and this was first shown for AD thrombocytopenia caused by mutations of RUNX1.55-57 The thrombocytopenia is mild and platelet volume increases are modest, but platelet function is defective and a reduced dense granule secretion contributes to the most- ly mild bleeding. Disease-causing variants occur across the gene with emphasis on the Runt homology domain that mediates DNA-binding and dimerization with the core binding factor (CBFAb), a complex essential for regulated proliferation and differentiation of HSC and normal megakaryopoiesis as well as suppression of erythroid gene expression. RUNX1 mutations interfere with ploidy and prolong the expression of the cytoskeletal protein MYH10, whose natural loss triggers the switch from mito- sis to endomitosis; the result is an abundance of immature megakaryocytes that fail to differentiate properly.21 Furthermore, RUNX1 directly or indirectly regulates the synthesis of a number of platelet proteins thereby altering the function of those platelets that are affected. Decreased DNA repair, a pro-inflammatory environment and the prolonged life of HSC predispose patients to acute myeloid leukemia and related conditions. Most of the genetic variants act through haploinsufficiency but, signif- icantly, those that act in a dominant negative manner have a higher probability of causing malignancy.57
Myeloid malignancies and myelodysplastic syndromes are also a risk for patients with mutations in the 5’ untranslated region of ANKRD26, which are associated with mostly moderate thrombocytopenia, mild bleeding and normal sized platelets (a condition also known as thrombocytopenia 2, THC2).58-60 Unexplained findings in some patients are a low density of a2b1 integrin, decreased numbers of platelet a-granules and large, partic- ulate structures formed of ubiquitinated proteins or pro- teasomes. As for mutations of RUNX1, patients with ANKRD26 mutations have downregulated megakary- ocyte maturation leading to an abundance of cells with hypolobulated nuclei. Mechanistically, mutations of the 5’ untranslated region of ANKRD26 prevent downregulation of this gene by RUNX1 and FLI1, leading to increased ANKRD26 protein with a lack of repression in the termi- nal stages of megakaryopoiesis.60 Extramedullary hematopoiesis, a characteristic of inherited hemolytic ane- mia, and myeloproliferative and myelodysplastic syn- dromes, was reported in a case with ANKRD26-related thrombocytopenia.61 It should be noted that THC2 also includes the Ser/Thr kinase MASTL without a tendency for malignancy, dealt with in a later section.
Mutations of ETV6 lead to AD thrombocytopenia and a predisposition to acute lymphoblastic leukemia.62 ETV6 is a tumor repressor gene with close links with FLI1. Red cell macrocytosis is said to accompany the thrombocytopenia in some families. An early study involving 130 families with suspected inherited thrombocytopenias identified ETV6 gene variants in seven of them; four of the family members had developed B-cell acute lymphoblastic leukemia during childhood.63 Thrombocytopenia was moderate as was the bleeding tendency; platelet size was normal but platelet spreading on fibrinogen was defective. Megakaryocytes in culture produced fewer proplatelets. Mutations within the consensus ETS DNA binding sites of ETV6 resulted in reduced nuclear localization and tran- scriptional repression with cytoskeletal genes especially
haematologica | 2020; 105(8)
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