Highlights:
The diagnosis of immune thrombocytopenia (ITP) may sometimes conceal more rare cases of inherited disorders of the platelet function, particularly in patients found to be resistant to steroids or splenectomy. On the whole, these last include a crowded list of dysfunctions, involving platelet surface constituents or intracellular components.2 Because two Tpo receptor agonists, eltrombopag and romiplostin, have been approved for chronic ITP adult patients unresponsive to glucocorticoids, intravenous immunoglobulin, or splenectomy,3 their potential use also in inherited thrombocytopenia is attractive.
Léon et al report the effects of romiplostim in the mouse model of inherited platelet dysfunction because of mutation of the myosin 9 gene (MYH9).1 So far, at least 45 mutations of MYH9 have been described, accounting for an ensemble of autosomal-dominant inherited diseases, grouped as MYH9-related diseases (MYH9-RD), all characterized by the presence of thrombocytopenia with giant platelets and Döhle body–like inclusions within leukocytes.4,5 These three alterations, also known as May-Hegglin anomaly, can variably associate with other phenotypic peculiarities, including presenile cataract, proteinuric nephropathy, and progressive sensorineural hearing loss.4,5 Depending on the entity, the bleeding tendency is extremely variable, ranging from asymptomatic individuals to patients experiencing severe hemorrhages: in the latter, however, no therapy other than platelet transfusion is so far available.
We have recently reported that patients with thrombocytosis because of the inherited MPLSer505Asn activating mutation have not only a significant risk of thrombosis, but also evolve to bone marrow fibrosis. In these patients there is an unequivocal association between fibrosis and aging, with progressive increase of reticulin fibers, which in some middle-age and in most elderly patients appears diffuse and surrounded by focal bundles of collagen.9 The problem of marrow fibrosis in ITP patients undergoing Tpo mimetic therapy is truly felt, so that monitoring of cell counts and the peripheral blood smear is recommended. If new morphologic abnormalities or cytopenias are noted or if there is a loss of response to treatment, a bone marrow biopsy with staining for reticulin and collagen should be performed.
A recent Italian trial has first reported that patients with MYH9 mutations significantly benefit from 6-week eltrombopag treatment, with increase of platelet count and disappearance of bleeding tendency in most of them.11 Whereas the experiences gathered so far in ITP patients indicate that Tpo-mimetic-induced fibrosis is reversible if drug therapy is discontinued, the irreversibility of marrow fibrosis associated with MPLSer505Asn mutation provides ground for reflection. In addition, data presented here by Léon and colleagues cast doubt that, under prolonged Tpo stimulation, patients with thrombocytopenia sustained by ineffective megakaryocytopoiesis would be predisposed to this complication.
bloodjournal.hematologylibrary.org/content/119/14/3194.full?ct
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