Β-thalassemia Intermedia Research Articles

A New β0 Frameshift Mutation, HBB: c.44delT (p.Leu14ArgfsX5), Identified in an Argentinean Family Associated with Secondary Genetic Modifiers of β-Thalassemia

β-Thalassemia intermedia (β-TI) patients present with a wide spectrum of phenotypes depending on the presence of primary, secondary, and tertiary genetic modifiers which modulate, by different mechanisms, the degree of imbalance between α and β chains. Here we describe a new β0 frameshift mutation, HBB: c.44delT (p.Leu14ArgfsX5), identified in four members of a family, associated with secondary genetic modifiers in three of them. The different genotype present in this family was suspected after hematological analysis and thorough observation of blood smears highlighting their importance in the identification of β-TI patients among members of the same family.

Prevalence of hepatitis C virus infection among thalassemia patients: a perspective from a multi-ethnic population of Pakistan

ObjectiveTo evaluate current situation regarding the prevalence of hepatitis C virus (HCV) in thalassemic patients visiting a thalassemia centre in Rawalpindi District, Pakistan for supportive therapy. MethodsSerum samples were screened for hepatitis B surface antigen and anti-HCV by using commercially available ELISA kit. Micro-plate reader was used to perform analysis based on the absorbance/cut-off ratios. Samples were considered positive or negative. Results from ELISA were analyzed statistically. ResultsA total of 95 subjects were observed to have β-thalassemia major (96%) and β-thalassemia intermedia (4%). Among these, 47 (49%) were detected positive for anti-HCV antibodies and three for hepatitis B surface antigen. All recruited subjects were observed for therapy/medication behavior and clinical complications. About 83 (87%) patients were on chelation therapy, and overall complications (hepatomegaly, splenomegaly and splenectomy) were observed in 81% individuals. The distribution of disease status (thalassemia and hepatitis) was not significantly associated with gender, age, origin, province, socio-economic status and parental marriage type (P>0.05). The distributions of ferritin levels, therapy/medication and complications were assessed across demographic variables. Thalassemic subjects were distributed with respect to their sporadic and familial presentations. Among the familial cases (n=35), a total of 93 subjects were found to be affected. Parity was scored for the index cases, and majority belonged to second parity (29%), followed by first and third parities (25% and 15%, respectively). The sibship size was increasing with increasing parity level. ConclusionsAlthough standardized blood screening procedures are supposed to be implemented, higher prevalence of HCV in thalassemic patients requires greater attention in Pakistan. Furthermore, a poor compliance regarding iron chelation therapy has been observed in this study.

Expression of CD55 on Red Blood Cells of β-Thalassemia Patients

CD55 is a complement regulatory protein expressed by cells to protect them from bystander lysis by complement. It prevents the formation of C3/C5 convertase. In β-thalassemia (β-thal), the defective hemoglobin (Hb) production makes red blood cells (RBCs) lyse early and frequently. Loss of CD55 expression in those patients compromises the complement regulatory function, thereby accelerating RBC lysis. In this study, we aimed to evaluate the expression of CD55 on erythrocytes of β-thal patients. Flow cytometry analysis of CD55 was conducted on RBCs of 21 β-thalassemia major (β-TM) patients, 11 β-thalassemia intermedia (β-TI) patients and 10 healthy volunteers. The results showed a significant decrease in CD55 expression in β-TM (57.5 ± 16.7%), while there was a slight decrease in β-TI patients (81.8 ± 3.8%) in comparison with that of the normal controls (88.7 ± 0.8%). The diminished expression of CD55 was not accompanied by decrease in CD59 expression in β-thal patients (97.2 ± 2.3%). This could suggest a mechanism (could be genetic) responsible for low CD55 expression. It may be related to defective Hb genes in thalassemia, but it does not relate to cell membrane changes.

Novel Βeta (β)-Thalassemia Mutation in Turkish Children.

Beta (β)-thalassemia is the most frequently observed hereditary blood disorder in the world. It is characterized by deficiency of hemoglobin β-globin gene and is also a profoundly heterogeneous both at the molecular and clinical level. In the case of β-thalassemia, there is reduced (β(+) type) or absent (β(o) type) synthesis of thebeta chains ofhemoglobin. β-Thalassemia clinically occurs in three main forms: major, intermedia and minor according to requirement of transfusion. The objective of this study was to evaluate β-thalassemia mutations in 89 patients ranging from 2monthsto 16years of age, who enrolled to Medical School Research and Training Hospital, Gaziantep University. The direct DNA sequence analysis was performed for mutation scanning of β-globin gene. 89 children with β-Thalassemia including all types were analyzed, 16 different β-thalassemia mutations were detected. We have also identified a novel mutation (HBB.c.-80delT, rs397509430) in the promoter region (-30 TATA box) of β-globin gene, and clinical data of patient having novel mutation was given. The β-Thalassemia mutations were determined as β-Thalassemia major type in 42 patients (47.19%), β-Thalassemia intermedia in 4 (4.49%), β-Thalassemia minor in 43, (48.31%) patients. The most frequent mutation was IVS I-110 G>A, followed by IVS I-1 G>A, IVS I-6 T>C, IVS II-1 G>A, respectively.

β-Thalassemia Intermedia: A Bird's-Eye View.

Beta-thalassemia is due to a defect in the synthesis of the beta-globin chains, leading to alpha/beta imbalance, ineffective erythropoiesis, and chronic anemia. The spectrum of thalassemias is wide, with one end comprising thalassemia minor, which consists of a mild hypochromic microcytic anemia with no obvious clinical manifestations, while on the other end is thalassemia major, characterized by patients who present in their first years of life with profound anemia and regular transfusion requirements for survival. Along the spectrum lies thalassemia intermedia, a term developed to describe patients with manifestations that are neither mild enough nor severe enough to be classified in the spectrum’s extremes. Over the past decade, our understanding of β-thalassemia intermedia has increased tremendously with regards to molecular information as well as pathophysiology. It is now clear that β-thalassemia intermedia has a clinical presentation as well as complications associated with the disease that are different from those of β-thalassemia major. This review is designed to tackle issues related to β-thalassemia intermedia from the basic definition of the disease to paramedical issues, namely the quality of life in these patients. Genetics and pathophysiology are revisited, as well as the complications specific to this disease. These complications include effects on several organ systems, including the cardiovascular, hepatic, endocrine, renal, brain, and skeletal systems. Extramedullary hematopoiesis is also discussed in this article. Risk factors are highlighted and cutoffs are identified to minimize morbidities in β-thalassemia intermedia. Several treatment modalities are considered by shining a light on the pros and cons of each modality, as well as the role of special pharmacological agents in the progress of the disease and its morbidities. Finally, health-related quality of life is discussed in these patients with a direct comparison to the more severe β-thalassemia major.

Adipocytokine concentrations in children with different types of beta-thalassemia

Background. Beta-thalassemia is an inherited blood disorder. It results from the impaired production of β-globin chains, leading to a relative excess of alpha-globin chains. Clinical severity separates this disease into three main subtypes: β- thalassemia major, β-thalassemia intermedia and β-thalassemia minor, the former two being clinically more significant. Inflammatory processes may play an important role in some of the complications of thalassemia. Adipose tissue is one of the most important endocrine and secretory organs that release adipocytokines like adiponectin, resistin and visfatin. Aim. The aim of our study was to analyze adipocytokine concentrations (adiponectin, resistin and visfatin) in different types of β-thalassemia patients and determine any possible correlations with disease severity. Methods. We recruited 29 patients who were transfusion-dependent β-thalassemia-major patients, 17 patients with β-thalassemia intermedia, 30 β-thalassemia minor patients. The control group consisted of 30 healthy children. Anthropometric measurements, complete blood count, biochemical parameters, serum concentrations of adiponectin, resistin, visfatin were performed for all subjects. Results. Resistin and visfatin concentrations were significantly higher in β-thalassemia minor patients than in controls. Adiponectin, resistin and visfatin concentrations were significantly higher in both β-thalassemia intermedia and major patients than in controls. The concentrations of adiponectin, resistin and visfatin were significantly higher in both β-thalassemia intermedia and major patients than in β-thalassemia minor patients. There was no significant difference between β-thalassemia intermedia and β-thalassemia major patients for adipocytokines concentrations. Conclusion. We speculate that these adipocytokines may play a role in the development of complications in β-thalassaemia.

Harvesting autologous stem cells from a patient with red blood cell abnormalities of β‐thalassemia intermedia

Autologous stem cell transplants in patients with hemoglobinopathies are limited. Previous reports used granulocyte-colony-stimulating factor (G-CSF) for mobilization of stem cells; there are no reported cases undergoing plerixafor mobilization. We report such a patient, providing guidance for peripheral blood stem cells collection when aberrant red blood cells (RBCs) disrupt normal separation. A patient with β-thalassemia intermedia and hereditary persistence of fetal hemoglobin presented for peripheral blood stem cell collection for autologous transplant for myeloma. He underwent splenectomy for anemia secondary to hemoglobinopathy and chemotherapy, ceasing RBC transfusions. The patient was mobilized using plerixafor after collection with G-CSF failed. Collections were performed using an apheresis system, processing 24 L daily. Peripheral blood and apheresis product CD34 determinations were performed daily. On Day 1, the product yield was 0.04 × 10(6) CD34 cells/kg, less than expected based on white blood cell count and CD34-positive cells. Peripheral blood smear showed nucleated RBCs and RBC morphologic abnormalities. Changes in instrument variables were made after consultation with Terumo BCT to adjust for variable distribution of mononuclear and stem cells during centrifugation. Collecting stem cells at a deeper location and centrifuging faster improved collection, and a cumulative total of 4.40 × 10(6) CD34 cells/kg was achieved after four collections. The patient underwent tandem autologous transplantation and engrafted within 12 to 13 days of each transplant. Adjustments in apheresis variables allowed successful collection of peripheral blood stem cells from a patient with RBC anomalies of β-thalassemia that interfered with standard stem cell harvesting.

Serum Angiogenin Level in Sickle Cell Disease and Beta Thalassemia Patients

Introduction: Angiogenesis has been investigated in different kinds of anemia. However, its role as a marker of angiogenesis has not been investigated in thalassemia or sickle cell disease (SCD). Objectives: We aimed to investigate serum angiogenin level in children and adolescents with beta thalassemia or SCD and its relation to possible risk factors of angiogenesis. Materials and Methods: This study included; 32 β-thalassemia major (β-TM) patients aged 14.2 ± 3.8 years, 20 β-thalassemia intermedia (β-TI) patients aged 14.3 ± 4.8 years, 20 SCD patients aged 14.1 ± 2.4 years; 8 with (HbSS) and 12 with sickle thalassemia (HbS/β-thalassemia) and 35 age and sex-matched controls. Data collected regarding; age, sex, disease duration, blood transfusion frequency, transfusion index, chelation type and duration, CBC, Hb electrophoresis, serum ferritin and serum angiogenin level (by ELISA). Results: Angiogenin level was significantly higher in patients with SCD [250 (100–300) pg/mL] compared to β-TM [180 (140–230) pg/mL] and controls [89 (80–103) pg/mL] (P < .001) especially those with HbSS (P = .06). There was a significant negative correlation between serum angiogenin and age of patients, age of onset and duration of chelation in β-TM (P < .01, P < .001, P = .003) and β-TI (P = .009, P = .03, P < .001) and with serum ferritin in β-TI group (r = −0.573, P = .008). In SCD, angiogenin level was negatively correlated with both frequency of blood transfusion (r = −0.731, P < .001) and duration of hydroxyurea therapy (P = .017). Conclusions: High angiogenin level detected among patients with SCD may be negatively influenced by regular blood transfusion and hydroxyurea therapy, while; early onset of chelation therapy may decrease angiogenin level in β-TM.

The Spectrum of Ocular Alterations in Patients with β-Thalassemia Syndromes Suggests a Pathology Similar to Pseudoxanthoma Elasticum

To determine the prevalence and spectrum of ocular fundus abnormalities in patients with β-thalassemia and to investigate risk factors for their development. Cross-sectional, observational study. A total of 255 patients with β-thalassemia major (TM) and β-thalassemia intermedia (TI) were consecutively recruited and investigated. Patients underwent best correct visual acuity, indirect ophthalmoscopy, and fundus photography, including fundus autofluorescence (FAF) and near-infrared reflectance imaging using a confocal scanning laser ophthalmoscope (cSLO). Hematologic parameters were determined, including mean ferritin levels, aspartate amino transferase, alanine amino transferase, calcium, pre-transfusion hemoglobin, history of splenectomy, and liver iron concentration. Factors associated with the ocular phenotype were assessed using logistic regression. Ocular phenotype as determined by clinical examination and used multimodal imaging. A total of 153 patients (60.0%) affected by TM and 102 patients (40.0%) affected by TI participated, of whom 216 (84.7%) were receiving iron-chelating therapy. Ocular fundus abnormalities characteristic of pseudoxanthoma elasticum (PXE) were detected by cSLO in 70 of 255 patients (27.8%) and included peau d'orange (19.6%), angioid streaks (12.9%), pattern dystrophy-like changes (7.5%), and optic disc drusen (2.0%). Pseudoxanthoma elasticum-like changes were more frequent in patients with TI (P<0.001). Patients with PXE-like fundus changes were older than patients without these fundus changes (P<0.001). In both patients with TI and TM, age (P = 0.001) and splenectomy (P = 0.001) had the strongest association with presence of PXE-like fundus changes in multivariate analyses. A total of 43 of 255 patients (16.9%) showed increased retinal vascular tortuosity independently of the PXE-like fundus changes, which was associated with aspartate amino transferase (P = 0.036), hemoglobin (P = 0.008), and ferritin levels (P = 0.005). Pseudoxanthoma elasticum-like fundus changes are a frequent finding in patients with β-thalassemia. In TI, these changes increase with duration or severity of the disease. This particular ocular phenotype suggests an ocular pathology similar to PXE. Retinal vascular tortuosity may be an additional disease manifestation independent of the PXE-like syndrome. Patients with long-standing disease requiring iron-chelating treatment and a history of splenectomy need regular ophthalmic checkups because they are at risk of developing PXE-like fundus changes and potentially of subsequent choroidal neovascularization.

Study of thyroid function in Egyptian children with β-thalassemia major and β-thalassemia intermedia

Thyroid dysfunction is a known complication of transfusion-dependent β-thalassemia. However, information on its frequency and risk factors among Egyptian Children is still unclear. We aimed to determine the frequency of functional thyroid abnormalities among young patients with β-thalassemia and compare the thyroid function status among patients with β-thalassemia major (TM) and β-thalassemia intermedia (TI). This was a cross-sectional study that included 52 β-thalassemia children [27 boys and 25 girls; 34 (65.4%) with TM and 18 (34.6%) with TI]. Their mean age was 16.0±1.91 (range: 12-18) years. Thyroid function and iron load status were assessed by measurement of free tetraiodothyronine, free triiodothyronine, thyroid stimulating hormone (TSH), and serum ferritin concentrations. Serum TSH of the studied cases ranged from 0.28 to 25 μIU/ml with a mean of 4.5±4.8 μIU/ml. None of the studied cases had overt primary hypothyroidism and the frequency of subclinical hypothyroidism was 19.2%. No risk factors for thyroid dysfunction could be identified among our cases. The thyroid profile was comparable in TM and TI patients (P>0.05) and the frequency of subclinical hypothyroidism among TM cases was 20.6% and it was comparable to the 16.7% found among TI patients (P>0.05). No correlations were found between TSH, serum ferritin, chelation therapy, and frequency of blood transfusion. Both TM and TI patients are at risk for subclinical thyroid failure regardless of their iron overload status. Early evaluation of thyroid function in β-thalassemia children and thyroid replacement therapy for subclinical hypothyroidism should be introduced in the treatment protocols.

A Deletion Of About 11kb Starting From 0.5 Kb 5' To The β-Globin Gene Reactivates Foetal Haemoglobin and Leads To β Thalassemia Intermedia When Associated To a β-Zero Thalassemic Mutation

Background and Aims Thalassemia intermedia is characterized by severe but not transfusion dependent anemia secondary to seriously decreased production of hemoglobin (Hb). In the majority of cases, thalassemia intermedia concerns β-globin gene pathology. The molecular basis of thalassemia intermedia is heterogeneous. Here we describe a case of an adopted child native of Myanmar suffering from β-thalassemia intermedia which was proved to be secondary to a β-zero thalassemia associated with a not yet described deletional form of HPFH. Patient, Material and Methods Male child born in 1994 with Hb varying between 50 and 60 g/l, with Hb A2 of 2.1% and Hb F of 97.9%. No α-thalassemia or α-gene triplication was found. Sequencing of β-globin gene put in evidence the IVS-I-1 (G&gt;T) or c.92+1G&gt;T mutation in a “homozygous” state. This mutation is known to produce a β-zero thalassemia. The patient was treated with hydroxyurea as well as with erythropoietin and the Hb value was improved up to 86 g/l with normal leucocytes and platelets count. No transfusion was given during this period of treatment. Because the clinical phenotype was not typical for β-thalassemia major homozygous for the above mentioned mutation, we analyzed β-globin cluster looking for the presence of a possible deletion responsible for Hb F activation. Patient’s DNA was extracted with commercial columns from peripheral blood cells. Analysis of deletion in the beta cluster was performed by MLPA (Multiplex Ligation Probe Analysis) MRC-Holland P-102 probe mix. The data obtained were analyzed with the Coffyanalyzer software. The exact size of the deletion was determined by PCR with the primers: DelHBB_F: 5’-AGGCTTGGCTCCTGTTTAGT-3’, DelHBB_R: 5’-TGAGAG CTGCTGAGTTGTGT-3’ Results A heterozygous deletion in the beta-globin cluster has been detected by MLPA. This deletion was located between the coordinated 5,237,089 and 5,251,133 on chromosome 11 - (GRCh37/hg19 Assembly). The deletion starts about 0.5 kb 5’ upstream the HBB gene, between HBB and HBD genes, and ends about 9 kb downstream the 3’ end of HBB gene. The density of the MLPA probes is not sufficient to determinate the exact size of the deletion (between 14.3kb and 9.6 kb). A PCR using the primers DelHBB_F and DelHBB_R determined the size of this deletion to around 11kb. Conclusions Our molecular biology studies confirmed our clinical suspicion of association of HPFH with β-zero thalassemia. In fact, we put in evidence a not yet described (to our knowledge) 11kb deletion, which is very similar to the 12.6kb deletion of the Dutch β-zero thalassemia (Br J Haematol 67:369;1987) and to the Asian Indian 10.3kb deletion described by Craig et al (Br J Haematol 82:735;1992). Our deletion starts between δ and β-globin gene, almost 0.5 kb upstream of the β-gene, and goes about 9 kb downstream of 3’ end of the β-gene. The exact borders of the deletion are currently under investigation by PCR and appropriate primers. The pathophysiology of reactivation of γ-globin genes in our case is not yet known. We raise the following hypothesis: does this deletion bring an enhancer located 3’ to β-globin gene, close enough to the γ-genes, so that transcription of these genes continues after birth? In vitro studies in expression systems (constructs) are currently performed to elucidate the exact mechanism of γ-globin activation. Disclosures: No relevant conflicts of interest to declare.

Therapeutic superiority and safety of combined hydroxyurea with recombinant human erythropoietin over hydroxyurea in young β‐thalassemia intermedia patients

To assess the efficacy and safety of combined hydroxyurea (HU) and recombinant human erythropoietin (rHuEPO) in β-thalassemia intermedia (TI) patients compared with single HU therapy. An interventional prospective randomized study registered in the ClinicalTrials.gov (NCT01624038) was performed on 80 TI patients (≤ 18 yr) divided into group A (40 patients received combined HU and rHuEPO) and group B (40 patients received single HU therapy). Baseline serum EPO levels were measured, and both groups were followed up for a mean period of 1 yr with regular assessment of transfusion requirements, blood pressure, ferritin, liver and renal functions, hemoglobin, and HbF. Quality of life (QoL) was assessed at the start and end of the study. Transfusion frequency and index were significantly decreased, while QoL was increased in group A compared with group B where 85% of patients showed improvement on combined therapy compared with 50% of patients on HU. Hemoglobin and HbF were significantly increased in both TI groups; however, this was more evident in group A than in group B. Also, 37.5% of patients in group A became transfusion-independent compared with 15% in group B. EPO levels were negatively related to increments of hemoglobin and HbF. Splenectomized patients and those with initial HbF% >40% had the best response to combined therapy. No serious adverse events necessitating discontinuation of therapy in both groups. HU was effective in management of TI; however, combination with rHuEPO gave a superior therapeutic effect resulting in the best clinical and hematological responses without adverse events.

Association between clinical expression and molecular heterogeneity in β-thalassemia Tunisian patients

Beta-thalassemia is the most frequent hereditary blood disorder in Tunisia because of its geographic localization and history. This pathology is characterized by a complex multisystem process with genetic and biochemical interactions. The aim of this work was to establish phenotype/genotype association through studying the distribution and the relationship between β-thalassemia and α-thalassemia mutations and three polymorphic markers: the C → T polymorphism at -158 of the Gγ gene, the RFLP haplotype and the repeated sequence (AT)xTy in the β globin silencer, in two groups of β-thalassemia major and β-thalassemia intermedia (TI) patients. Statistical analysis has shown that moderate expression seen in TI patients was significantly associated to β(+) -87 (C → G), -30 (T → A) and IVSI-6 (T → C) mutations, haplotypes VIII, IX and Nb and to XmnI polymorphism. The regression analysis of combined genotypes (mutation/XmnI/RFLP haplotype) revealed that they contribute to justify 17.1 % of clinical expression diversity (p < 0.05). Among the studied genotypes the XmnI polymorphism seems to be the most determinant modulating factor, followed by the β-thalassemia mutation and RFLP haplotype. Our findings highlight the heterogeneity of molecular background of β-thalassemia that would be responsible of clinical variability.

Diagnostic value of real-time elastography in the assessment of hepatic fibrosis in patients with liver iron overload

ObjectiveThe objective of our prospective monocentric work was to determine the diagnostic value of real-time elastography (RTE) in the assessment of liver fibrosis in patients with iron overload, using transient elastography (TE) as reference standard. MethodsSixty-seven consecutive patients with MRI detectable iron overload (T2*<6.3ms) were enrolled. TE and RTE were performed on the same day as MRI. Elastograms were acquired by an experienced operator and analyzed by calculating the elastic ratio between perihepatic soft tissues and liver parenchyma. An elliptical ROI of 1cm2 (Z1) was positioned in the liver parenchyma and a smaller elliptical ROI of 2mm2 (Z2) was positioned in a homogeneously soft (red) region of the diaphragm, which was considered as internal control to calculate the elastic ratio Z2/Z1. ResultsSeven patients were excluded because of invalid TE or RTE examinations. The remaining 60 patients were 57% males and 43% females (mean age: 42 [21–76] years), including 37 homozygous-β-thalassemics, 13 patients with β-thalassemia intermedia, 6 with primary hemochromatosis, and 4 with myelodysplastic syndrome. Increasing elastic ratios were significantly correlated with increasing TE values (r=0.645, 95% CI 0.468–0.772, P<0.0001). The mean elastic ratios for each METAVIR group were as follows: F0/1=1.9±0.4; F2=2.2±0.4; F3=2.9±0.5; F4=3.2±0.4. The diagnostic accuracy of RTE for F≥2 evaluated by AUC-ROC analysis was 0.798 (95% CI 0.674–0.890). The diagnostic accuracy of RTE for F≥3 was 0.909 (95% CI 0.806–0.968). At a cut-off≥2.75, RTE showed a sensitivity of 70% (95% CI 45.7–88.1) and a specificity of 97.5% (95% CI 86.8–99.9). ConclusionsIn patients with MRI-detectable liver iron-overload RTE allows to discriminate between F0/1–F2 and F3–F4 with a reasonable diagnostic accuracy.

β- And α-Thalassemia Intermedia in Basra, Southern Iraq

Hemoglobinopathies are common in Iraq and β-thalassemia major (β-TM) is a leading health problem in Basra, Southern Iraq. However, β- and α-thalassemia intermedia (β- and α-TI) have not been so well studied. This is a descriptive study of 152 consecutive β- and α-TI patients registered at the Centre for Hereditary Blood Diseases (CHBD) in Basra, Southern Iraq from October 1 2010 through June 30 2012 including age at diagnosis, blood transfusions and complications. β-Thalassemia intermedia was found in 80 (52.6%) patients with a mean age at diagnosis of 7.10 ± 8.0 years. This was significantly different from that of Hb H (β4) disease (12.95 ± 14.8 years), p <0.05. Patients with β-TI received significantly more blood transfusions (3.39 ± 3.85)/year compared to those with Hb H disease (1.07 ± 1.39)/year, p <0.05.Short stature, extramedullary erythropoiesis, pulmonary hypertension and iron overload were significantly higher among patients with β-TI compared to those with Hb H disease, p <0.05. Iron overload is a significant risk factor for growth retardation among patients with Hb H and β-TI. While age is a significant risk factor for osteoporosis in both types of thalassemia intermedia.Both α- and β-thalassemia (α- and β-thal) have been reported in Basra. Although β-TI is associated with a more severe disease than α-TI, both are associated with considerable complications. Thus, genetic studies are needed to determine the types of mutation producing β-TI and the exact α-thal determinants producing Hb H disease as they are important in the prediction of the phenotype severity.

Leg ulcers in patients with β‐thalassaemia intermedia: a single centre's experience

Leg ulcers in β-thalassaemia intermedia (TI) patients are a relatively common occurrence that have an 8% prevalence. Both the pathophysiology and treatment of this condition have not been well-elucidated. This is mainly because of the rarity of the disease and the lack of well-structured studies. The goal of this study was to better explore the risk factors for the development of this condition along with the treatment options available. We present 11 such cases that have occurred in 6 β-TI patients over the course of 19years who are followed up at the Chronic Care Center of Lebanon. Our patient population comprised three men and three women aged between 25 and 58, most of whom had iron overload and with an average lifetime haemoglobin ranging between 49g/L and 77g/L. Most of the patients were treated with blood transfusions with varying degrees of success. Nonetheless, some received Hydroxyurea, granulocyte macrophage colony-stimulating factor (GM-CSF) or topical antibiotics. Our results show that chelation therapy, hydroxyurea use and blood transfusions are beneficial in the treatment of this condition. Whether foetal haemoglobin is directly related to the development of the ulcers is not clear based on our results. Larger studies are needed to better explore the risk factors that predispose patients to this condition.

Utility Of The Multivariate Approach In Predicting β-Thalassemia Intermedia Or β-Thalassemia Major Types In Iranian Patients

Recently, five genetic modifiers [β-globin mutations, coinheritance of α-thalassemia (α-thal), XmnI polymorphism and single nucleotide polymorphisms (SNPs) in the BCL11A and HBS1L-MYB loci] were used to predict the β-thal major (β-TM) or β-thal intermedia (β-TI) types in 106 French patients with 83.2% accuracy. The dichotomous grouping was based on the age when the patient received his/her first transfusion (4 years). Here, a similar study was conducted in a cohort of 306 Iranian β-thal patients having distinct β-globin mutations and minor allele frequencies of key SNPs in these loci. Multivariate regression analyses and a simple scoring system were used to predict the β-TM/β-TI types using three scenarios: 1) when considering only the severe β-TM and the mild β-TI cases, 2) using clinical parameters for β-thal typing, and 3) using age at first transfusion as the basis for classification. Using these scenarios, the β-thal types could be correctly predicted in 77.6, 75.5 and 68.0% of cases, respectively.

Overview of the Clinico-Laboratory Profile and Therapeutic Alternatives among Egyptian Patients with β-Thalassemia Intermedia : A Single Center Experience

Overview of the Clinico-Laboratory Profile and Therapeutic Alternatives among Egyptian Patients with β-Thalassemia Intermedia : A Single Center Experience

Non-transfusion-dependent thalassemias

Non-transfusion-dependent thalassemias include a variety of phenotypes that, unlike patients with beta (β)-thalassemia major, do not require regular transfusion therapy for survival. The most commonly investigated forms are β-thalassemia intermedia, hemoglobin E/β-thalassemia, and α-thalassemia intermedia (hemoglobin H disease). However, transfusion-independence in such patients is not without side effects. Ineffective erythropoiesis and peripheral hemolysis, the hallmarks of disease process, lead to a variety of subsequent pathophysiologies including iron overload and hypercoagulability that ultimately lead to a number of serious clinical morbidities. Thus, prompt and accurate diagnosis of non-transfusion-dependent thalassemia is essential to ensure early intervention. Although several management options are currently available, the need to develop more novel therapeutics is justified by recent advances in our understanding of the mechanisms of disease. Such efforts require wide international collaboration, especially since non-transfusion-dependent thalassemias are no longer bound to low- and middle-income countries but have spread to large multiethnic cities in Europe and the Americas due to continued migration.

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. Greater reductions in LIC were achieved in patients dose-escalated at Week 24 from deferasirox 10 mg/kg/day starting dose to 20 mg/kg/day. Patients who received an average actual dose of deferasirox >12.5–≤17.5 mg/kg/day achieved a greater LIC decrease compared with the ≥7.5–≤12.5 mg/kg/day and >0–<7.5 mg/kg/day subgroups, demonstrating a dose–response efficacy. LIC reduction across patient subgroups was generally consistent with the primary efficacy analysis with a similar safety profile. Am. J. Hematol. 88:503–506, 2013. © 2013 Wiley Periodicals, Inc.