We describe the clinical, hematologic and genetic characteristics of a retrospective series of 126 subjects from 64 families with hereditary xerocytosis. Twelve patients from six families carried a KCNN4 mutation, five had the recurrent p.Arg352His mutation and one had a new deletion at the exon 7-intron 7 junction. Forty-nine families carried a PIEZO1 mutation, which was a known recurrent mutation in only one-third of the cases and private sequence variation in others; 12 new probably pathogenic missense mutations were identified. The two dominant features leading to diagnosis were hemolysis that persisted after splenectomy and hyperferritinemia, with an inconstant correlation with liver iron content assessed by magnetic resonance imaging. PIEZO1 -hereditary xerocytosis was characterized by compensated hemolysis in most cases, perinatal edema of heterogeneous severity in more than 20% of families and a major risk of post-splenectomy thrombotic events, including a high frequency of portal thrombosis. In KCNN4 -related disease, the main symptoms were more severe anemia, hemolysis and iron overload, with no clear sign of red cell dehydration; therefore, this disorder would be better described as a ‘Gardos channelopathy’. These data on the largest series to date indicate that PIEZO1 -hereditary xerocytosis and Gardos channelopathy are not the same disease although they share hemolysis, a high rate of iron overload and inefficient splenectomy. They demonstrate the high variability in clinical expression as well as genetic bases of PIEZO1 -hereditary xerocytosis. These results will help to improve the diagnosis of hereditary xerocytosis and to provide recommendations on the clinical management in terms of splenectomy, iron overload and pregnancy follow-up.

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Romiplostim and eltrombopag, the first thrombopoietic receptor-agonists with demonstrated efficacy against immune thrombocytopenia in prospective controlled studies, were recently authorized in most countries for adults with chronic immune thrombocytopenia. So far, no data are available about the potential contribution of switching from romiplostim to eltrombopag or vice versa in terms of efficacy or tolerance. Efficacies and tolerance profiles were evaluated for 46 patients who sequentially received both drugs, switching from one to the other. The reasons for switching were: lack of efficacy for 23 patients, platelet-count fluctuations for 11, side effects for 4, and 8 patients' preferences. For 50-80% of the patients, switching from romiplostim to eltrombopag or eltrombopag to romiplostim effectively impacted the platelet count, with fluctuations disappearing in 54% and side effects resolved in 100%. In 80% of the patients, the 2 thrombopoietic receptor-agonists achieved similar response patterns. Our results confirmed that switching from one thrombopoietic receptor-agonist to the other could be beneficial in clinical practice for patients with severe chronic immune thrombopenia who failed to respond or experienced adverse events to the first. (Clinical Trials.gov identifier: NCT01618734). A retrospective pilot evaluation of switching thrombopoietic receptor-agonists in immune thrombocytopenia Design and Methods PatientsAll patients followed by specialists in the network of National ITP Referral Centers who have been sequentially treated with the TPO-RAs, romiplostim and eltrombopag, were enrolled. Inclusion criteria were: 1) age 18 years or over; 2) primary ITP diagnosed according to the current definitions; 4,22 3) previous romiplostim and eltrombopag treatment, regardless of the switching sequence, with at least three months of follow up with each molecule. Patients treated for secondary ITP were excluded.The trial protocol was approved by the Henri-Mondor University Hospital Institutional Review Board and Ethics Committee; all patients received a written information form before screening and data analysis. Treatment designAccording to the European Medicines Agency authorization of the 2 TPO-RAs, patients received a weekly subcutaneous injection of romiplostim, usually started at 1 mg/kg/week, or daily oral eltrombopag, at a starting dose of 50 mg/day; the dose was then adjusted, as needed (up to a maximum 10 mg/kg/week and 75 mg/day, respectively) based on the patient's platelet count.Patients could continue to receive concurrent ITP therapies, including rescue interventions, defined as any agent administered to transiently increase the platelet count, e.g. IVIg, corticosteroids, anti-IgD and/or platelet transfusions. The need to increase the dose of concurrent ITP medication to levels above those used at baseline was also considered a rescue intervention. Assessments and outcome measuresThe following characteristics were recorded on a standardized form by the same investigator (MK): age, gender; and ITP ...