Post-mortem study of the association between cardiac iron and fibrosis in transfusion dependent anaemia.

Background: Heart failure related to cardiac siderosis remains a major cause of death in transfusion dependent anaemias. Replacement fibrosis has been reported as causative of heart failure in siderotic cardiomyopathy in historical reports, but these findings do not accord with the reversible nature of siderotic heart failure achievable with intensive iron chelation.

Methods: Ten whole human hearts (9 beta-thalassemia major, 1 sideroblastic anaemia) were examined for iron loading and fibrosis (replacement and interstitial).

Deferiprone-induced agranulocytosis: 20 years of clinical observations.

Use of the iron chelator deferiprone for treatment of iron overload in thalassemia patients is associated with concerns over agranulocytosis, which requires weekly absolute neutrophil counts (ANC). Here, we analyze all episodes of agranulocytosis (n = 161) and neutropenia (n = 250) during deferiprone use in clinical trials (CT) and postmarketing surveillance programs (PMSP). Rates of agranulocytosis and neutropenia in CT were 1.

Development of a new disease severity scoring system for patients with non-transfusion-dependent thalassemia.

Background: Patients with non-transfusion-dependent thalassemia (NTDT) present with a spectrum of disease severities. Since there are multiple pathophysiologies in such patients, tailoring treatment remains essential. Therefore, one simple, reliable tool would be beneficial to assess disease severity and tailor therapy, particularly for internal medicine specialists who may treat a variety of NTDT patients with a multitude of complications.

Second international round robin for the quantification of serum non-transferrin-bound iron and labile plasma iron in patients with iron-overload disorders.

Non-transferrin-bound iron and its labile (redox active) plasma iron component are thought to be potentially toxic forms of iron originally identified in the serum of patients with iron overload. We compared ten worldwide leading assays (6 for non-transferrin-bound iron and 4 for labile plasma iron) as part of an international inter-laboratory study. Serum samples from 60 patients with four different iron-overload disorders in various treatment phases were coded and sent in duplicate for analysis to five different laboratories worldwide.

Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels.

We report genome-wide association study results for the levels of A1, A2 and fetal hemoglobins, analyzed for the first time concurrently. Integrating high-density array genotyping and whole-genome sequencing in a large general population cohort from Sardinia, we detected 23 associations at 10 loci. Five signals are due to variants at previously undetected loci: MPHOSPH9, PLTP-PCIF1, ZFPM1 (FOG1), NFIX and CCND3.

IFNL3 polymorphisms and HCV infection in patients with beta thalassemia.

Unlabelled: BACKGROUND AND RATIONALE FOR THE STUDY: Genome-wide association studies have identified host genetic variation to be critical for spontaneous clearance and treatment response in patients infected with hepatitis C virus. Recently, the role of the IFNL3 polymorphisms in influencing the spontaneous clearance of HCV, the response to interferon and the progression of liver fibrosis, was also demonstrated in patients with thalassemia major infected by genotype 1b. In the present study we retrospectively analyzed 368 anti-HCV positive patients with beta-thalassemia at two Italian major centers in Cagliari and Torino.

A genetic score for the prediction of beta-thalassemia severity.

Clinical and hematologic characteristics of beta(β)-thalassemia are determined by several factors resulting in a wide spectrum of severity. Phenotype modulators are: HBB mutations, HBA defects and fetal hemoglobin production modulators (HBG2:g.-158C>T polymorphism, HBS1L-MYB intergenic region and the BCL11A).

EMQN Best Practice Guidelines for molecular and haematology methods for carrier identification and prenatal diagnosis of the haemoglobinopathies.

Haemoglobinopathies constitute the commonest recessive monogenic disorders worldwide, and the treatment of affected individuals presents a substantial global disease burden. Carrier identification and prenatal diagnosis represent valuable procedures that identify couples at risk for having affected children, so that they can be offered options to have healthy offspring. Molecular diagnosis facilitates prenatal diagnosis and definitive diagnosis of carriers and patients (especially 'atypical' cases who often have complex genotype interactions).

Efficacy and safety of deferiprone for the treatment of pantothenate kinase-associated neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation (NBIA): results from a four years follow-up.

Objective: To evaluate the long-term effect of Deferiprone (DFP) in reducing brain iron overload and improving neurological manifestations in patients with NBIA.

Methods: 6 NBIA patients (5 with genetically confirmed PKAN), received DFP solution at 15 mg/kg po bid. They were assessed by UPDRS/III and UDRS scales and blinded video rating, performed at baseline and every six months.

Brazilian Thalassemia Association protocol for iron chelation therapy in patients under regular transfusion.

In the absence of an iron chelating agent, patients with beta-thalassemia on regular transfusions present complications of transfusion-related iron overload. Without iron chelation therapy, heart disease is the major cause of death; however, hepatic and endocrine complications also occur. Currently there are three iron chelating agents available for continuous use in patients with thalassemia on regular transfusions (desferrioxamine, deferiprone, and deferasirox) providing good results in reducing cardiac, hepatic and endocrine toxicity.

Prevalence and risk factors for pulmonary arterial hypertension in a large group of β-thalassemia patients using right heart catheterization: a Webthal study.

Background: Pulmonary arterial hypertension (PAH) remains a concern in patients with β-thalassemia major (TM) and intermedia (TI); however, studies evaluating its prevalence and risk factors using systematic confirmation on right heart catheterization are lacking.

Methods And Results: This was a multicenter cross-sectional study of 1309 Italian β-thalassemia patients (mean age 36.4±9.

Impact of heart magnetic resonance imaging on chelation choices, compliance with treatment and risk of heart disease in patients with thalassaemia major.

This study aimed to verify the impact of heart magnetic resonance imaging on chelation choices and patient compliance in a single-institution cohort as well as its predictive value for heart failure and arrhythmias. Abnormal cardiac T2* values determined changes in treatment in most subjects. Heart T2* was confirmed to be highly predictive over 1 year for heart failure and arrhythmias.

Complexity of the alpha-globin genotypes identified with thalassemia screening in Sardinia.

α-Thalassemia commonly results from deletions or point mutations in one or both α-globin genes located on chromosome 16p13.3 giving rise to complex and variable genotypes and phenotypes. Rarely, unusual non-deletion defects or atypical deletions down-regulate the expression of the α-globin gene.

In vivo activation of the human δ-globin gene: the therapeutic potential in β-thalassemic mice.

β-thalassemia and sickle cell disease are widespread fatal genetic diseases. None of the existing clinical treatments provides a solution for all patients. Two main strategies for treatment are currently being investigated: (i) gene transfer of a normal β-globin gene; (ii) reactivation of the endogenous γ-globin gene.

Deferasirox effectively reduces iron overload in non-transfusion-dependent thalassemia (NTDT) patients: 1-year extension results from the THALASSA study.

Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload that requires chelation to levels below the threshold associated with complications. This can take several years in patients with high iron burden, highlighting the value of long-term chelation data. Here, we report the 1-year extension of the THALASSA trial assessing deferasirox in NTDT; patients continued with deferasirox or crossed from placebo to deferasirox.

Cardiovascular function and treatment in β-thalassemia major: a consensus statement from the American Heart Association.

This aim of this statement is to report an expert consensus on the diagnosis and treatment of cardiac dysfunction in β-thalassemia major (TM). This consensus statement does not cover other hemoglobinopathies, including thalassemia intermedia and sickle cell anemia, in which a different spectrum of cardiovascular complications is typical. There are considerable uncertainties in this field, with a few randomized controlled trials relating to treatment of chronic myocardial siderosis but none relating to treatment of acute heart failure.

Assessment and management of iron overload in β-thalassaemia major patients during the 21st century: a real-life experience from the Italian WEBTHAL project.

We conducted a cross-sectional study on 924 β-thalassaemia major patients (mean age 30·1 years) treated at nine Italian centres using the WEBTHAL software, to evaluate real-life application of iron overload assessment and management standards. Serum ferritin <2500 ng/ml was a risk factor for never having liver iron concentration (LIC) measurement, while absence of cardiac disease and siderosis were risk factors for a delay in LIC measurement >2 years. Patients who never had a cardiac MRI (CMR) T2* measurement were <18 years, had iron intake ≤0·4 mg/kg per day, or a serum ferritin <2500 ng/ml.

Deferasirox demonstrates a dose-dependent reduction in liver iron concentration and consistent efficacy across subgroups of non-transfusion-dependent thalassemia patients.

The 1-year THALASSA study enrolled 166 patients with various non-transfusion-dependent thalassemia (NTDT) syndromes, degrees of iron burden and patient characteristics, and demonstrated the overall efficacy and safety of deferasirox in reducing liver iron concentration (LIC) in these patients. Here, reduction in LIC with deferasirox 5 and 10 mg/kg/day starting dose groups is shown to be consistent across the following patient subgroups-baseline LIC/serum ferritin, age, gender, race, splenectomy (yes/no), and underlying NTDT syndrome (β-thalassemia intermedia, HbE/β-thalassemia or α-thalassemia). These analyses also evaluated deferasirox dosing strategies for patients with NTDT.

Natural history of hepatitis C in thalassemia major: a long-term prospective study.

Background: Transfusion-acquired hepatitis C virus (HCV) remains an important problem among patients with thalassemia. In this study, we evaluated the natural history of post-transfusional hepatitis C in thalassemia major, paying special attention to spontaneous viral clearance, to factors influencing the chronicity rate and fibrosis progression.

Design And Methods: A prospective study to evaluate the incidence and etiology of transfusion-related hepatitis was started in 1980.

Seventy-five genetic loci influencing the human red blood cell.

Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait.