Spanish registry of hemoglobinopathies and rare anemias (REHem-AR): demographics, complications, and management of patients with ß-thalassemia.

INTRODUCTION: The increase in the number of patients with hemoglobinopathies in Europe in recent decades highlights the need for more detailed epidemiological information in Spain. To fulfil this need, the Spanish Society of Pediatric Hematology and Oncology (SEHOP) sponsored the creation of a national registry of hemoglobinopathies known as REHem-AR (Spanish Registry of Hemoglobinopathies and Rare Anemias). Data from the transfusion-dependent (TDT) and non-transfusion-dependent (NTDT) ß-thalassemia cohorts are described and analyzed. METHODS: We performed an observational, multicenter, and ambispective study, which included patients of any age with TDT and NTDT, registered up to December 31, 2021. RESULTS: Among the 1741 patients included, 168 cases of thalassemia were identified (103 TDT and 65 NTDT-patients). Survival at 18 years was 93% for TDT and 100% for NTDT. Regarding management, 80 patients with TDT (77.7%) and 23 patients with NTDT (35.4%) started chelation treatment during follow-up, with deferasirox being the most widely used. A total of 76 patients within the TDT cohort presented at least 1 complication (73.8%), the most frequent being hemosiderosis and osteopenia-osteoporosis. Comparison of both cohorts revealed significant differences in the diagnosis of hepatic hemosiderosis (p = 0.00024), although these were not observed in the case of cardiac iron overload (p = 0.27). DISCUSSION: Our registry enabled us to describe the management of ß thalassemia in Spain and to analyze the morbidity and mortality of the cohorts of patients with TDT and NTDT. Complications related to iron overload in TDT and NTDT account for most of the morbidity and mortality of the disease, which is associated with a considerable social, psychological, and economic impact, although cardiac, osteopathy and endocrinological complications requiring more attention. The convenience and simplicity of online registries make it possible to homogenize variables and periodically update data, thus providing valuable information on these diseases.

Efficacy and safety in patients with haemophilia A switching to octocog alfa (BAY 81-8973): Final results of the global real-world study, TAURUS.

OBJECTIVES: To report the final results of the 2-year TAURUS study, assessing weekly prophylaxis dosing regimens of octocog alfa (Kovaltry®/BAY 81-8973) used in standard clinical practice in patients with moderate-to-severe haemophilia A. METHODS: TAURUS (NCT02830477) is a phase 4, multinational, prospective, non-interventional, single-arm study in patients of any age with moderate or severe haemophilia A (≤5% factor [F]VIII activity). TAURUS was designed to primarily investigate weekly prophylaxis dosing regimens used in standard clinical practice. Annualised bleeding rates (ABRs), treatment satisfaction and adherence, and safety were also assessed. RESULTS: Of 302 patients included in the full analysis set, 84.4% (n = 255) maintained their octocog alfa prophylaxis baseline regimen throughout the study, with a majority of patients (76.5%, n = 231) on two times or three times weekly regimens at the end of the observation period (≥1-≤2 years). ABRs, treatment satisfaction, and adherence remained stable during the observation period. Octocog alfa was well tolerated and there were no new or unexpected adverse events. CONCLUSIONS: These data show that a smooth transition is observed when switching to octocog alfa from a previous FVIII treatment, with no safety issues and stable bleeding rates in a real-world setting of patients with moderate-to-severe haemophilia A.

Tapering of the thrombopoietin receptor agonist in paediatric patients with chronic immune thrombocytopenia: Is it possible?

It is not clear if platelet responses are sustained after thrombopoietin receptor agonist (ar-TPO) withdrawal in paediatric patients. A multicentre retrospective observational study was performed in children with chronic immune thrombopenia (cITP) to describe ar-TPO tapering and withdrawal in patients who had achieved a sustained complete response to ar-TPOs. Ten patients (eltrombopag n = 6, romiplostim n = 4) were included. Treatment withdrawal was performed after a mean tapering time of 7.6 months. Two patients relapsed (median follow-up time of 24 months). Slow tapering and withdrawal of ar-TPOs can be safely performed in cITP paediatric patients after achieving a sustained complete response.

Secondary immune thrombocytopenia in children: Characteristics and outcome of a large cohort from two Spanish centres.

AIM: To evaluate the incidence and outcome of secondary immune thrombocytopenia (ITP) in a large cohort of paediatric Spanish patients. METHODS: A retrospective observational study was conducted in two paediatric University hospitals in Spain between 2009 and 2019, which included children from 4 months to 18 years old diagnosed with ITP. Data were recorded from clinical charts: gender, age at diagnosis, coexisting condition and associated characteristics, outcome and treatment. RESULTS: Secondary ITP was diagnosed in 87 out of 442 patients (19.6%). Post-immunisation ITP was seen in younger children. The onset of secondary ITP to autoimmune diseases (AD) and immunodeficiencies (ID) was at an older age and had more tendency to be insidious, and platelet level was higher than primary ITP. Mean time from ITP onset to AD diseases or ID diagnosis was 1.2 and 2.6 years, respectively. Whereas the cumulative incidence of remission was significantly higher in post-immunisation and post-viral infection (compared with primary ITP patients), it was worse in AD and ID patients. CONCLUSIONS: Identification of secondary ITP is important as it predicts outcome. Most of them are diagnosed at ITP onset, but AD diseases and ID should be ruled out periodically as they are usually identified later.

High Mutational Heterogeneity, and New Mutations in the Human Coagulation Factor V Gene. Future Perspectives for Factor V Deficiency Using Recombinant and Advanced Therapies.

Factor V is an essential clotting factor that plays a key role in the blood coagulation cascade on account of its procoagulant and anticoagulant activity. Eighty percent of circulating factor V is produced in the liver and the remaining 20% originates in the α-granules of platelets. In humans, the factor V gene is about 80 kb in size; it is located on chromosome 1q24.2, and its cDNA is 6914 bp in length. Furthermore, nearly 190 mutations have been reported in the gene. Factor V deficiency is an autosomal recessive coagulation disorder associated with mutations in the factor V gene. This hereditary coagulation disorder is clinically characterized by a heterogeneous spectrum of hemorrhagic manifestations ranging from mucosal or soft-tissue bleeds to potentially fatal hemorrhages. Current treatment of this condition consists in the administration of fresh frozen plasma and platelet concentrates. This article describes the cases of two patients with severe factor V deficiency, and of their parents. A high level of mutational heterogeneity of factor V gene was identified, nonsense mutations, frameshift mutations, missense changes, synonymous sequence variants and intronic changes. These findings prompted the identification of a new mutation in the human factor V gene, designated as Jaén-1, which is capable of altering the procoagulant function of factor V. In addition, an update is provided on the prospects for the treatment of factor V deficiency on the basis of yet-to-be-developed recombinant products or advanced gene and cell therapies that could potentially correct this hereditary disorder.

BAY 81-8973 prophylaxis and pharmacokinetics in haemophilia A: Interim results from the TAURUS study.

OBJECTIVES: To report interim data from TAURUS, a study assessing real-world prophylactic treatment with unmodified, full-length recombinant FVIII BAY 81-8973 (Kovaltry® ; Bayer) indicated for haemophilia A. METHODS: TAURUS (NCT02830477) is an international, open-label, prospective, non-interventional, single-arm study with a one-year observation period (target N = 350). Patients have moderate or severe haemophilia A (FVIII ≤5% or ≤1%) and ≥50 exposure days to any FVIII product. Clinician- and patient-reported outcomes are captured on previous product use, changes in prophylaxis dose and dosing frequency, FVIII consumption, reported bleeding rates, treatment satisfaction and adherence, pharmacokinetic (PK) data (if available) and safety data. RESULTS: At cut-off, baseline data were available from 160 patients (89 had ≥6 months of follow-up data). Most patients had severe haemophilia A (85%), infused BAY 81-8973 ≥ 3×/wk (59%) and experienced a median number of total bleeds of 2.0 (non-annualised; 246 days median documentation period). Good levels of treatment satisfaction (Hemo-SATA,P ) and adherence (VERITAS-Pro) were maintained. TAURUS demonstrated a favourable PK profile of BAY 81-8973 in comparison with other standard half-life rFVIIIs and supported the WAPPS PopPK model. No patients developed inhibitors. CONCLUSIONS: TAURUS data demonstrate effective prophylaxis with BAY 81-8973 in the real world without compromising patient satisfaction or adherence.

Unraveling the effect of silent, intronic and missense mutations on VWF splicing: contribution of next generation sequencing in the study of mRNA.

Large studies in von Willebrand disease patients, including Spanish and Portuguese registries, led to the identification of >250 different mutations. It is a challenge to determine the pathogenic effect of potential splice site mutations on VWF mRNA. This study aimed to elucidate the true effects of 18 mutations on VWF mRNA processing, investigate the contribution of next-generation sequencing to in vivo mRNA study in von Willebrand disease, and compare the findings with in silico prediction. RNA extracted from patient platelets and leukocytes was amplified by RT-PCR and sequenced using Sanger and next generation sequencing techniques. Eight mutations affected VWF splicing: c.1533+1G>A, c.5664+2T>C and c.546G>A (p.=) prompted exon skipping; c.3223-7_3236dup and c.7082-2A>G resulted in activation of cryptic sites; c.3379+1G>A and c.7437G>A) demonstrated both molecular pathogenic mechanisms simultaneously; and the p.Cys370Tyr missense mutation generated two aberrant transcripts. Of note, the complete effect of three mutations was provided by next generation sequencing alone because of low expression of the aberrant transcripts. In the remaining 10 mutations, no effect was elucidated in the experiments. However, the differential findings obtained in platelets and leukocytes provided substantial evidence that four of these would have an effect on VWF levels. In this first report using next generation sequencing technology to unravel the effects of VWF mutations on splicing, the technique yielded valuable information. Our data bring to light the importance of studying the effect of synonymous and missense mutations on VWF splicing to improve the current knowledge of the molecular mechanisms behind von Willebrand disease. clinicaltrials.gov identifier:02869074.

Multirefractory primary immune thrombocytopenia; targeting the decreased sialic acid content.

Patients with multirefractory immune thrombocytopenia (ITP) have limited treatment options. Recent data suggest that specific anti-platelet antibodies may cause destruction of platelets by favoring platelet loss of sialic acid. In this multicenter study 35 patients with ITP, including 16 with multirefractory disease, were analyzed for antiplatelet-antibodies, thrombopoietin (TPO) levels, and platelet desialylation. In selected cases, responses to a novel treatment strategy using oseltamivir were tested. We found that antibodies against GPIbα were overrepresented in multirefractory patients compared to responders (n = 19). In contrast to conventional ITP patients, multirefractory patients exhibited a significant increased platelet activation state (granule secretion) and desialylation (RCA-1 binding) (p < 0.05), and a trend toward higher plasma TPO concentrations. The decreased sialic acid content seemed to be restricted to platelet glycoproteins, since other plasma proteins were not hypoglycosylated. A total of 10 patients with multirefractory ITP having remarkable loss of platelet terminal sialic acids were given oseltamivir phosphate. When the antiviral drug was combined with TPO receptor agonists (TPO-RAs) or with immunosuppressant drugs, platelet responses were observed in 66.7% of patients. All responding patients presented with antibodies reactive only against GPIbα. These findings suggest that desialylation may play a key pathogenic role in some multirefractory ITP patients, and provide diagnostic tools for the identification of such patients. Furthermore, we show that sialidase inhibitor treatment in combination with therapies that help to increase platelet production can induce sustained platelet responses in some patients with anti-GPIbα -mediated thrombocytopenia that have failed previous therapies.

Paediatric patients with acute leukaemia and KMT2A (MLL) rearrangement show a distinctive expression pattern of histone deacetylases.

Histone deacetylase inhibitors (HDACi) had emerged as promising drugs in leukaemia, but their toxicity due to lack of specificity limited their use. Therefore, there is a need to elucidate the role of HDACs in specific settings. The study of HDAC expression in childhood leukaemia could help to choose more specific HDACi for selected candidates in a personalized approach. We analysed HDAC1-11, SIRT1, SIRT7, MEF2C and MEF2D mRNA expression in 211 paediatric patients diagnosed with acute leukaemia. There was a global overexpression of HDACs, while specific HDACs correlated with clinical and biological features, and some even predicted outcome. Thus, some HDAC and MEF2C profiles probably reflected the lineage and the maturation of the blasts and some profiles identified specific oncogenic pathways active in the leukaemic cells. Specifically, we identified a distinctive signature for patients with KMT2A (MLL) rearrangement, with high HDAC9 and MEF2D expression, regardless of age, KMT2A partner and lineage. Moreover, we observed an adverse prognostic value of HDAC9 overexpression, regardless of KMT2A rearrangement. Our results provide useful knowledge on the complex picture of HDAC expression in childhood leukaemia and support the directed use of specific HDACi to selected paediatric patients with acute leukaemia.

Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): comprehensive genetic analysis by next-generation sequencing of 480 patients.

Molecular diagnosis of patients with von Willebrand disease is pending in most populations due to the complexity and high cost of conventional molecular analyses. The need for molecular and clinical characterization of von Willebrand disease in Spain prompted the creation of a multicenter project (PCM-EVW-ES) that resulted in the largest prospective cohort study of patients with all types of von Willebrand disease. Molecular analysis of relevant regions of the VWF, including intronic and promoter regions, was achieved in the 556 individuals recruited via the development of a simple, innovative, relatively low-cost protocol based on microfluidic technology and next-generation sequencing. A total of 704 variants (237 different) were identified along VWF, 155 of which had not been previously recorded in the international mutation database. The potential pathogenic effect of these variants was assessed by in silico analysis. Furthermore, four short tandem repeats were analyzed in order to evaluate the ancestral origin of recurrent mutations. The outcome of genetic analysis allowed for the reclassification of 110 patients, identification of 37 asymptomatic carriers (important for genetic counseling) and re-inclusion of 43 patients previously excluded by phenotyping results. In total, 480 patients were definitively diagnosed. Candidate mutations were identified in all patients except 13 type 1 von Willebrand disease, yielding a high genotype-phenotype correlation. Our data reinforce the capital importance and usefulness of genetics in von Willebrand disease diagnostics. The progressive implementation of molecular study as the first-line test for routine diagnosis of this condition will lead to increasingly more personalized and effective care for this patient population.

National registry of hemoglobinopathies in Spain (REPHem).

BACKGROUND: Although highly prevalent throughout the world, the accurate prevalence of hemoglobinopathies in Spain is unknown. PROCEDURE: This study presents data on the national registry of hemoglobinopathies of patients with thalassemia major (TM), thalassemia intermedia (TI), and sickle cell disease (SCD) in Spain created in 2014. Fifty centers reported cases retrospectively. Data were registered from neonatal screening or from the first contact at diagnosis until last follow-up or death. RESULTS: Data of the 715 eligible patients were collected: 615 SCD (497 SS, 64 SC, 54 SBeta phenotypes), 73 thalassemia, 9 CC phenotype, and 18 other variants. Most of the SCD patients were born in Spain (65%), and 51% of these were diagnosed at newborn screening. Median age at the first diagnosis was 0.4 years for thalassemia and 1.0 years for SCD. The estimated incidence was 0.002 thalassemia cases and 0.03 SCD cases/1,000 live births. Median age was 8.9 years (0.2-33.7) for thalassemia and 8.1 years (0.2-32.8) for SCD patients. Stroke was registered in 16 SCD cases. Transplantation was performed in 43 TM and 23 SCD patients at a median age of 5.2 and 7.8 years, respectively. Twenty-one patients died (3 TM, 17 SCD, 1 CC) and 200 were lost to follow-up. Causes of death were related to transplantation in three patients with TM and three patients with SCD. Death did not seem to be associated with SCD in six patients, but nine patients died secondary to disease complications. Overall survival was 95% at 15 years of age. CONCLUSIONS: The registry provides data about the prevalence of hemoglobinopathies in Spain and will permit future cohort studies and the possibility of comparison with other registries.

Evans Syndrome as First Manifestation of Primary Immunodeficiency in Clinical Practice.

BACKGROUND: Evans syndrome (ES) is a rare immune disorder in children, manifested by simultaneous or sequential autoimmune cytopenias (ACs) of unknown cause and having a chronic course with periods of exacerbation and remission. Some primary immunodeficiencies (PIDs) may present with autoimmune manifestations without infections, masking suspicion of them. The PIDs that can typically manifest as ES are autoimmune lymphoproliferative syndrome and common variable immunodeficiency (CVID). MATERIALS AND METHODS: Review of clinical charts and laboratory results of pediatric patients followed-up in the outpatient clinic of PID with a diagnosis of ES and humoral immunodeficiency. RESULTS: Three pediatric patients, a boy and 2 girls, presented with corticosteroid-dependent ES. In the diagnostic approach, autoimmune lymphoproliferative syndrome was ruled out, and during follow-up, patients showed laboratory signs of humoral immune deficiency and were diagnosed with CVID. After initiating the recommended treatment for CVID with AC, patients improved without new exacerbations. CONCLUSIONS: These cases highlight the importance of detection of possible PID in the context of ES and the establishment of CVID treatment to control AC.

Influence of new antiretrovirals on hematological toxicity in HIV-exposed uninfected infants.

UNLABELLED: Maternal combined antiretroviral therapy (cART) successfully prevents HIV mother-to-child transmission but also causes hematological toxicity in the HIV-exposed uninfected (HEU) infant. We performed a single-center prospective observational study. Hematological toxicity during the first year of life (at 3 and 6 weeks, and 3, 6, and 12 months) was compared between HEU infants born in two different time periods: P1 (2000-2001) and P2 (2007-2013). Mother-infant pairs in P1 (n = 55) and P2 (n = 48) mainly differed in maternal ethnic origin, HIV route of transmission, and cART regimens. Anemia and neutropenia were both less common in P2 than P1, albeit not significantly. Earlier normalization of red blood cell mean corpuscular volume levels in P2 infants suggests that current cART maternal regimens and shorter neonatal prophylaxis are less toxic. Leukocyte, lymphocyte, and platelet counts remained within normal values during follow-up, without differences between groups. CONCLUSION: New cART regimens have had very little impact on the hematological toxicity in HEU infants. WHAT IS KNOWN: • Antiretroviral drugs during pregnancy and the neonatal period very effectively prevent mother-to-child transmission of HIV infection. • Hematological toxicity has been widely reported among HIV-exposed uninfected children. What is New: • In HIV-exposed uninfected children, hematological toxicity is still mainly caused by exposure to zidovudine. • New antiretroviral drugs have very little impact on hematological toxicity among HIV-exposed uninfected children.

Thrombin Generation Profile Using ST-Genesia after PEG-asparaginase in Pediatric Patients with Acute Lymphoblastic Leukemia.

BACKGROUND: Venous thromboembolism (VTE) etiology in children with acute lymphoblastic leukemia (ALL) is multifactorial. The use of global assays of hemostasis as a thrombin generation test (TGT) is useful to individualize VTE risk in adult patients. This prospective cohort study aimed to evaluate the usefulness of an automated TGT to evaluate VTE risk during ALL treatment in children. METHODS: TGT (automated analyzer ST Genesia; ThromboScreen) and pro- and anticoagulant plasma proteins were analyzed during ALL treatment in pediatric patients following LAL-SEHOP-PETHEMA-2013 guidelines. Results were compared with a series of pediatric normal controls and evaluated according to pegylated asparaginase PEG-ASP administration and to VTE risk factors. RESULTS: The study included 67 patients: males n = 35, B-ALL (n = 60). None had a VTE during the evaluated period. Compared to healthy controls, the normalized endogenous thrombin potential (N-ETP) ratio in patients was higher and ETP inhibition (ETP-inh) was lower, especially after PEG-ASP administration. Plasmatic protein C and protein S levels decreased after PEG-ASP administration, but antithrombin mean level did not. A bivariant analysis showed that ETP-inh was lower in patients >10 years old (p = 0.05) and in those with non-O blood type (p = 0.005). A linear mixed model also showed a higher TGT prothrombotic profile in patients with inherited thrombophilia. CONCLUSION: TGT could be a biomarker of a high VTE risk in ALL pediatric patients. Non-O blood group and inherited thrombophilia were associated with a significantly higher thrombotic profile, and an increased profile was also observed after administration of PEG-ASP.

Gaining Insights into Inherited Bleeding Disorders of Complex Etiology in Pediatric Patients: Whole-Exome Sequencing as First-Line Investigation Tool.

INTRODUCTION: Investigation of the molecular basis of inherited bleeding disorders (IBD) is mostly performed with gene panel sequencing. However, the continuous discovery of new related genes underlies the limitation of this approach. This study aimed to identify genetic variants responsible for IBD in pediatric patients using whole-exome sequencing (WES), and to provide a detailed description and reclassification of candidate variants. MATERIAL AND METHODS: WES was performed for 18 pediatric patients, and variants were filtered using a first-line list of 290 genes. Variant prioritization was discussed in a multidisciplinary team based on genotype-phenotype correlation, and segregation studies were performed with available family members. RESULTS: The study identified 22 candidate variants in 17 out of 18 patients (94%). Eleven patients had complete genotype-phenotype correlation, resulting in a diagnostic yield of 61%, 5 (28%) were classified as partially solved, and 2 (11%) remained unsolved. Variants were identified in platelet (ACTN1, ANKRD26, CYCS, GATA1, GFI1B, ITGA2, NBEAL2, RUNX1, SRC, TUBB1), bleeding (APOLD1), and coagulation (F7, F8, F11, VWF) genes. Notably, 9 out of 22 (41%) variants were previously unreported. Variant pathogenicity was assessed according to the American College of Medical Genetics and Genomics guidelines and reclassification of three variants based on family segregation evidence, resulting in the identification of 10 pathogenic or likely pathogenic variants, 6 variants of uncertain significance, and 6 benign or likely benign variants. CONCLUSION: This study demonstrated the high potential of WES in identifying rare molecular defects causing IBD in pediatric patients, improving their management, prognosis, and treatment, particularly for patients at risk of malignancy and/or bleeding due to invasive procedures.

Management of Urgent Bleeding in Patients with Hemophilia A: Focus on the Use of Emicizumab.

Management of patients with hemophilia A (HA) requires the knowledge and experience of specialized health care professionals. However, these patients may need to be attended in emergencies, outside the referral hospital, where health care professionals do not know about hemophilia and/or new innovative treatments. This study aimed to develop a simple and practical algorithm that could be used in emergency situations by nonspecialized treaters in HA and bleeding with or without factor VIII (FVIII) inhibitors under emicizumab prophylaxis. A group of experts agreed on a simple algorithm, easy to operate, adapted from previous international guidelines, and based on their clinical experience. The proposed algorithm starts with identifying the patient, confirming the diagnosis of HA, prophylaxis with emicizumab, and/or use of other treatments. After stabilizing the patient and stratifying the bleeding risk, the patient is managed according to the presence/absence of FVIII inhibitors. Patients without FVIII inhibitors should receive FVIII concentrate. Dose and follow-up depend on bleeding localization and severity. Patients with FVIII inhibitors should preferably receive recombinant activated factor VII as bypass agent. A basic coagulation assay, FVIII assessment, and FVIII inhibitors detection assays are necessary in an emergency. However, these tests should be interpreted with caution and appropriately chosen, as emicizumab may alter the results. The management of patients with HA is challenging in emergency situations, especially if they are treated with new agents. Nonspecialized in coagulopathies health care professionals have limited understanding of the disease, highlighting the need for an algorithm to assist them in making informed decisions.

Prospective surveillance study of blood stream infections associated with central venous access devices (port-type) in children with acute leukemia: an intervention program.

The use of intensive chemotherapy and central devices has improved patients survival, but it is associated with catheter-related blood-stream infections (CRBSI). An educational program was instituted for preventing CRBSI occurrence in acute leukemia pediatric patients having totally implanted central devices. The Centers of Disease Control and Prevention criteria were used as definition for CRBSI. Data collected were age, sex, diagnosis, chemotherapy, inpatient versus outpatient, microbiological data, risk factors, social risk score, and treatment performed. CRBSI rate decreased from 6.7 to 3.7/1000 catheter-days with preventive measures (P=0.05). A further decrease to 1.5/1000 catheter-days was reached after the intensification of the educational program (P=0.01). Severe neutropenia at the time of catheter insertion was related to CRBSI and to infection recurrence (P<0.05). Most of the episodes occurred during induction chemotherapy. Thirty-six CRBSI episodes occurred in 25 of 73 patients. The most frequent microorganism isolated was Staphylococcus spp. Antibiotherapy was successful in 83.3% of episodes. Six patients needed a central venous access device replacement. Our intervention program was successful to decrease the CRBSI rates and its intensification allowed a further decrease, approaching reported rates in this setting. Severe neutropenia at the time of central venous access device insertion was related to CRBSI occurrence and recurrence.

Individualizing primary prophylaxis in patients with hemophilia A and B, adherence and new products.

The purpose of prophylaxis in hemophilic patients is to prevent bleeding. The latest guidelines of the World Hemophilia Federation recommend that all patients with a severe hemorrhagic phenotype should receive prophylactic treatment, defined as the regular administration of therapeutic products (either factor concentrates or nonfactor replacement treatments). These products are aimed at preserving hemostasis and preventing bleeding, especially into joints. The guidelines also stipulate that prophylaxis should allow patients with hemophilia to lead healthy and active lives, participating in most physical and social activities, similar to the nonhemophilic population.

Mycophenolate mofetil for autoimmune cytopenias in children: high rates of response in inborn errors of immunity.

Second-line treatments of autoimmune cytopenias (AC) are not well-defined in children. Mycophenolate mofetil (MMF) is an immunosuppressant agent that has been demonstrated to be safe and effective in this setting. A retrospective observational study was conducted in 18 children with prolonged AC who received MMF, in order to describe clinical and biological markers of response. The overall response rate of MMF at 20-30 mg/kg per day was 73.3%. All patients with Evans syndrome (n = 9) achieved complete response. Among the patients with monolineage AC (n = 9), those with an underlying inborn errors of immunity (IEI), tended to respond better to MMF. No biological markers related to treatment response were found. Rather, lymphocyte subpopulations proved useful for patient selection as a marker suggestive of IEI along with immunoglobulin-level determination.