A Report on the Education, Employment and Marital Status of Thalassemia Patients from a Tertiary Care Center in the Middle East.

Very few reports in the literature have focused on the psychosocial status of patients with thalassemia. The aim of this study was to report on the education, employment, and marital status of thalassemia patients in Lebanon and potential influencing factors. A total of 228 patients from the Chronic Care Center, Hazmieh, Lebanon, were incorporated for the data analysis. Demographic, social, and clinical variables were collected. Statistical analysis was performed using the Pearson χ2 test, Fisher Exact test, and binary logistic regression. In this sample, 54.4% were employed, and 45.6% not employed. Of those employed, 65.3% were male, 62.9% single or divorced, 77.4% splenectomized. University level was reached by 26.3% subjects, 7.9% reached high school level, and 32.5% have a level less than high school. Multivariate analysis revealed higher education was most likely attained by males [odds ratio (OR) = 2.23, 95% confidence interval (95% CI): 0.23-0.86] and those with no heart disease and no joint disease (OR = 27.5, 95% CI: 2.80-270 and OR = 3.40, 95% CI: 0.90-12.7, respectively). For employment, a lower average ferritin was associated with current employment. Neither the type of thalassemia nor transfusion status or type of chelation therapy corresponded with higher education or employment status. In conclusion, this is one of the few studies in the literature to look at education, employment, and marital status of thalassemia patients. Such information is essential to develop effective psychosocial support plans for our thalassemia patients.

Common fetal hemoglobin variants in Lebanese patients bearing the codon 29 beta gene mutation associated with different thalassemia phenotypes.

Beta-thalassemia can present with a wide spectrum of phenotypes determined by the coinheritance of α-thalassemia, hereditary persistence of fetal hemoglobin, and polymorphic variants in the BCL11A, HMIP, and HBB clusters. The codon 29 (cd29) mutation in the beta gene has been associated with a broad diversity of thalassemia phenotypes, possibly through genetic modifiers determining the genotype-phenotype relationship. In this study, we evaluated the effect of 10 single nucleotide polymorphisms (SNPs) on ß-thalassemia severity in a group of 21 Lebanese patients bearing the cd29 mutation. Hematological parameters and clinical characteristics were evaluated according to transfusion dependence. The proportions and absolute concentrations of HbF were found to be higher in non-transfusion-dependent (NTD) patients than in transfusion-dependent (TD) ones. Iron parameters were found to be higher in TD patients. The SNPs that were evaluated included the XmnI-158 polymorphism in the HBG gene and SNPs in the BCL11A and HMIP loci. It was noted that individuals homozygous or heterozygous for the effect allele in the BCL11A and HMIP SNPs had higher HbF levels, lower ferritin concentrations, and lower liver iron content and were less likely to be transfusion dependent. Our results showed that HbF production variants may have an important impact on the severity of ß-thalassemia, which might provide a severity prediction tool that can help in the anticipation of patients' phenotypes and therefore in future therapeutic decision making.

Long-term safety and efficacy of deferasirox in young pediatric patients with transfusional hemosiderosis: Results from a 5-year observational study (ENTRUST).

BACKGROUND: Children with red blood cell disorders may receive regular transfusions from an early age and consequently accumulate iron. Adequate iron chelation therapy can prevent organ damage and delayed growth/development. Deferasirox is indicated for treatment of pediatric patients with chronic iron overload due to transfusional hemosiderosis; however, fewer than 10% of patients in the registration studies were aged 2 to less than 6 years. PROCEDURE: Deferasirox, a once-daily oral iron chelator, was evaluated in young pediatric patients with transfusional hemosiderosis during the observational 5-year ENTRUST study. Patients aged 2 to less than 6 years at enrollment received deferasirox according to local prescribing information, with the primary objective of evaluating safety, specifically renal and hepatic function. Serum ferritin was observed as a surrogate efficacy parameter. RESULTS: In total, 267 patients (mean age 3.2 years) predominantly with ß-thalassemia (n = 176, 65.9%) were enrolled. Mean ± standard deviation deferasirox dose was 25.8 ± 6.5 mg/kg per day over a median of 59.9 months. A total of 145 patients (54.3%) completed 5 years' treatment. The proportion of patients with two or more consecutive postbaseline measurements (≥7 days apart) of serum creatinine higher than age-adjusted upper limit of normal (ULN) and alanine aminotransferase more than five times the ULN was 4.4% (95% confidence interval [CI]: 2.1-7.9) and 4.0% (95% CI: 1.8-7.4), respectively. Median serum ferritin decreased from 1,702 ng/ml at baseline to 1,127 ng/ml at 5 years. There were no new safety signals. CONCLUSIONS: Safety and efficacy of deferasirox in young pediatric patients in this long-term, observational study in everyday clinical practice were consistent with the known deferasirox profile.

One-year results from a prospective randomized trial comparing phlebotomy with deferasirox for the treatment of iron overload in pediatric patients with thalassemia major following curative stem cell transplantation.

BACKGROUND: Iron overload is well documented in patients with ß-thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre- and immediate post-HSCT transfusions. PROCEDURE: This is a prospective, randomized, 1-year clinical trial that compares the efficacy and safety of the once-daily oral iron chelator deferasirox versus phlebotomy for the treatment of iron overload in children with ß-thalassemia major following HSCT. RESULTS: Patients (aged 12.4 years) received deferasirox (n = 12, 10 mg/kg/day starting dose) or phlebotomy (n = 14, 6 ml/kg/2 weeks) for 1 year. In two and five patients, deferasirox dose was increased to 15 and 20 mg/kg/day, respectively. Magnetic resonance imaging (MRI)-assessed liver iron concentration (LIC) decreased with deferasirox (mean 12.5 ± 10.1 to 8.5 ± 9.3 mg Fe/g dry weight [dw]; P = 0.0005 vs. baseline) and phlebotomy (10.2 ± 6.8 to 8.3 ± 9.2 mg Fe/g dw; P = 0.05). LIC reductions were greater with deferasirox than with phlebotomy for patients with baseline serum ferritin 1,000 ng/ml or higher (-8.1 ± 1.5 vs. -3.5 ± 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and non-transferrin-bound iron also decreased significantly. In two patients with severe cardiac siderosis, a clinically relevant improvement in myocardial T2* was seen, following phlebotomy and deferasirox therapy (n = 1 each). Adverse effects with deferasirox were skin rash, gastrointestinal upset, and increased liver function tests (all n = 1), while those for phlebotomy were difficulty with venous access (n = 4) and distress during procedure (n = 1). Parents of 13/14 children receiving phlebotomy wished to switch to deferasirox, with 1/14 being satisfied with phlebotomy. CONCLUSIONS: Deferasirox treatment or phlebotomy reduces iron burden in pediatric patients with ß- thalassemia major post-HSCT, with a manageable safety profile.

Priapism, an emerging complication in ß-thalassemia intermedia patients.

The increase in survival rate of ß-thalassemia (ß-thal) patients allowed for the appearance and manifestation of several complications in almost every organ system. Priapism in ß-thal patients is rarely reported in the literature. We herein report and investigate the occurrence of two cases of priapism in two young patients with ß-thal intermedia (ß-TI). The potential mechanisms are due to either a cellular mechanism involving a thrombus obstructing the efferent venules of the corpora cavernosa leading to priapism, or a recently elucidated functional mechanism that causes alteration of nitric oxide (NO) response of the penis, ultimately causing priapism. This should incite clinicians for a close follow-up and monitoring of high risk patients who are susceptible to developing priapism.

Preventing thalassemia in Lebanon: successes and challenges in a developing country.

Thalassemia continues to be a major health burden. The chronicity of the disease and the high cost of life-long treatment make prevention strategies crucial in the management of this disease. In this article, we revisit different successful prevention strategies, and underline the Lebanese model. The Chronic Care Center (CCC), Beirut, is the only specialized center in Lebanon for the treatment and prevention of thalassemia. The current number of patients registered up to August 2013 was 724, representing cases from all over Lebanon. In 1994, the center launched a national prevention program following the World Health Organization (WHO) recommendations. The major activities of the program include awareness campaigns, screening for thalassemia carriers in the general population and high risk groups, registry of new cases and follow-up on the mandatory premarital law (established at the same time). Screening programs showed a carrier rate of around 2.3% in the general population, and 4.0-41.0% in high risk groups. The major pitfall in the law is that only persons with a mean corpuscular volume (MCV) of >70.0 fL are asked to perform further hemoglobin (Hb) testing. A significant decrease in the number of new cases of thalassemia patients in Lebanon reflects the efforts deployed in the prevention of the disease. However, some limitations are faced in reaching a complete eradication of the disease, mainly due to the fact that abortion is illegal and due to pitfalls and incorrect implementation of the premarital law.

A killer revealed: 10-year experience with beta-thalassemia intermedia.

OBJECTIVES: Patients with beta-thalassemia intermedia tend to present later in life with milder anemia than beta-thalassemia major patients. The incidence of mortality and its causes in this patient population remains unknown. We aim to reveal the incidence and most common causes of death in this population. METHODS AND RESULTS: We reviewed the charts of all of the beta-thalassemia intermedia patients who had been followed at the Chronic Care Center in Hazmieh, Lebanon during a 10-year period. A total of 18 patients out of 127 had died during the follow-up period giving a cumulative 10-year mortality incidence of 14%. The most common causes of cardiac deaths were due to renal and cardiac causes. DISCUSSION: Most causes of death have been linked to the high levels of iron coupled with anemia present in this patient population. Many of deaths could be prevented by adequate treatment. CONCLUSION: Larger studies with more comprehensive data capture on risk factors of mortality in this patient population are called for.

A randomized phase I/II trial of HQK-1001, an oral fetal globin gene inducer, in ß-thalassaemia intermedia and HbE/ß-thalassaemia.

ß-thalassaemia intermedia (BTI) syndromes cause haemolytic anaemia, ineffective erythropoiesis, and widespread complications. Higher fetal globin expression within genotypes reduces globin imbalance and ameliorates anaemia. Sodium 2,2 dimethylbutyrate (HQK-1001), an orally bioavailable short-chain fatty acid derivative, induces γ-globin expression experimentally and is well-tolerated in normal subjects. Accordingly, a randomized, blinded, placebo-controlled, Phase I/II trial was performed in 21 adult BTI patients (14 with HbE/ß(0) thalassaemia and seven with ß(+)/ß(0) thalassaemia intermedia, to determine effective doses for fetal globin induction, safety, and tolerability. HQK-1001 or placebo were administered once daily for 8 weeks at four dose levels (10, 20, 30, or 40 mg/kg per day), and subjects were monitored for laboratory and clinical events. Pharmacokinetic profiles demonstrated a t(1/2) of 10-12 h. Adverse events with HQK-1001 treatment were not significantly different from placebo treatment. The 20 mg/kg treatment doses increased median HbF above baseline levels by 6·6% and 4·4 g/l (P < 0·01) in 8/9 subjects; total haemoglobin (Hb) increased by a mean of 11 g/l in 4/9 subjects. These findings identified a safe oral therapeutic which induces fetal globin in BTI. Further investigation of HQK-1001 with longer dosing to definitively evaluate its haematological potential appears warranted.

Glomerular hyperfiltration and proteinuria in transfusion-independent patients with ß-thalassemia intermedia.

BACKGROUND/AIMS: Renal manifestations have been described in ß-thalassemia major and were attributed to transfusional iron overload and chelation therapy. Patients with the milder phenotype, ß-thalassemia intermedia (TI), remain largely transfusion and iron chelation independent while enduring a chronic hemolytic anemia and primary iron overload. Data on renal function in patients with TI is lacking. METHODS: In this cross-sectional study of 50 TI patients, we evaluated the association of estimated glomerular filtration rate (eGFR) and urinary protein to creatinine (UPr/UCr) ratio with relevant patient, disease and laboratory indices. RESULTS: The median age of patients was 28 years (44% males). The eGFR was >90 ml/min/1.73 m(2) in all patients, with a median value of 142.3 ml/min/1.73 m(2). The median UPr/UCr ratio was 213.2 mg/g. There was a negative correlation between age and eGFR, while the UPr/UCr ratio correlated positively with markers of anemia, hemolysis and iron overload. A total of 24 (48%) patients had evidence of glomerular hyperfiltration, while 7 (14%) had proteinuria (UPr/UCr ratio >500 mg/g). Patients with proteinuria were characterized by elevated liver iron concentration (>7 mg Fe/g dry weight), non-transferrin-bound iron levels and nucleated red blood cell counts. CONCLUSIONS: A considerable proportion of TI patients show evidence of abnormally elevated eGFR, with a declining trend towards advancing age. The occurrence of proteinuria is associated with anemia, hemolysis and iron toxicity.

Brain positron emission tomography in splenectomized adults with ß-thalassemia intermedia: uncovering yet another covert abnormality.

Covert brain infarction is an emerging concern in patients with ß-thalassemia intermedia (TI). We have recently observed a high prevalence (60%) of silent brain infarction on brain magnetic resonance imaging (MRI) in 30 splenectomized adults with TI. In this work, we further evaluate cerebral involvement in the same 30 patients using fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scanning. The median age was 32 years (range, 18-54 years) with a male to female ratio of 13:17. Nineteen patients (63.3%) had evidence of decreased neuronal function on PET-CT. Involvement was mostly left sided, multiple, and most commonly in the temporal and parietal lobes. Elevated liver iron concentration, beyond 15 mg Fe/g dry weight, characterized patients with decreased neuronal function. The concordance rate between brain MRI and PET-CT for the detection of brain abnormality was only 36.7% (Kappa 0.056, P = 0.757), highlighting that both modalities reveal different types of brain pathology. Decreased neuronal function is a common finding in patients with TI and is associated with iron overload. Moreover, the addition of PET-CT to MRI identifies a greater proportion of TI patients with silent neuroimaging abnormalities.

Prevalence of depression and anxiety in adult patients with ß-thalassemia major and intermedia.

OBJECTIVE: To evaluate and compare the prevalence and risk factors for anxiety and depression in adults with beta-thalassemia major (TM) and intermedia (TI). METHOD: A cross-sectional study of TI and TM patients at a Chronic Care Center in Lebanon. A total of 80 patients agreed to participate (32 TI (median age 24 years) and 48 TM (median age 23 years)). The Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI) questionnaires were used to assess the depression and anxiety levels of patients, respectively. Data on patient demographics, clinical complications, and socioeconomic status were also collected. RESULTS: Patients with TM had a significantly longer median duration with a known thalassemia diagnosis than patients with TI (p < 0.001). A considerable proportion of patients had depression (35.0%), State (S)-anxiety (22.5%) or Trait (T)-anxiety (36.2%). Patients with TI had a higher median S-anxiety score compared with TM (p = 0.035), although the median T-anxiety and depression scores were similar. On linear regression analysis, the significant association between the thalassemia diagnosis (TM versus TI) and S-anxiety score (beta: 5.740; 95% CI: 0.201 to 11.278; p = 0.042) was no longer observed upon adjustment for the co-variate duration with a known thalassemia diagnosis (beta: 3.162; 95% CI: -2.949 to 9.274; p = 0.306). CONCLUSIONS: A considerable proportion of adult patients with TM and TI show evidence of depression and anxiety. Patients with TI are more liable to state anxiety than TM patients of a similar age, which is attributed to a shorter duration of living with a thalassemia diagnosis.

Risk factors for pulmonary hypertension in patients with ß thalassemia intermedia.

BACKGROUND: Pulmonary hypertension (PHT) is a common yet poorly understood complication of ß thalassemia intermedia (TI). METHODS: We herein evaluated risk factors for PHT in TI, through comparing 64 TI patients with evidence of PHT by symptomatology and echocardiography (Group I) to age- and sex-matched TI patients without PHT (Group II). Retrieved data included demographics, laboratory parameters, clinical characteristics, and received treatments that may influence PHT development; and reflected the period prior to PHT occurrence in Group I. RESULTS: The mean age of Group I patients at development of PHT was 37.3±10.6years; with 44% being males. Among studied parameters, Group I patients were more likely to be splenectomized (4.9-times), transfusion-naive (3.5-times); hydroxyurea-naive (2.6-times), or iron chelation-naive (2.3-times); and have nucleated red blood cell count ≥300×10(6)/l (2.59-times) or a previous history of thromboembolic events (3.69-times). CONCLUSION: TI patients who eventually develop PHT may be identified early on by being splenectomized, having high nucleated red blood cell counts and a previous history of thromboembolism. Prospective clinical trials that evaluate the efficacy, safety, and cost effectiveness of transfusion, iron chelation, and hydroxyurea therapy in preventing PHT in TI are invited.

Brain magnetic resonance angiography in splenectomized adults with ß-thalassemia intermedia.

BACKGROUND: Hypercoagulability and venous thromboembolism are common in patients with ß-thalassemia intermedia (TI), especially in the splenectomized adult. Although arterial involvement is not commonly reported, we have recently observed a high prevalence (60%) of silent brain infarction on brain MRI in 30 splenectomized adults with TI. The pathophysiology of these white matter lesions remains unknown. METHODS: In this prospective work, we evaluated magnetic resonance angiography (MRA) scans of the same cohort of 30 patients. Data collected were the presence or absence of vascular lesions, their locations, and severity. Correlations between MRA abnormality and patients/disease characteristics were evaluated. Comparisons between MRA and previous MRI findings were made. RESULTS: Of 29 evaluable patients, 8 (27.6%) had evidence of arterial stenosis on MRA. The majority of lesions had mild narrowing and mostly involved the internal carotid artery. Five patients (17.2%) had evidence of aneurysms. Low total hemoglobin and high non-transferrin-bound iron levels independently characterized patients with evidence of stenosis on MRA. Among the 18 patients with silent brain infarction on MRI, three had evidence of stenosis on MRA with only one patient having lesions that could explain the silent infarcts. CONCLUSIONS: Cerebral vasculopathy is common in splenectomized adults with TI. However, large-vessel disease does not explain the occurrence of silent brain infarction. The combined use of MRA and MRI better identifies splenectomized TI adults with neuroimaging abnormalities.

Health-related quality of life in adults with transfusion-independent thalassaemia intermedia compared to regularly transfused thalassaemia major: new insights.

BACKGROUND: In patients with ß thalassaemia intermedia (TI), the milder anaemia and transfusion independence imply better health-related quality of life (HR-QoL). However, the unbalanced pathophysiology of the disease allows for several serious clinical complications to manifest, which may have a negative impact on HR-QoL. METHODS: This was a cross-sectional study on adult patients with transfusion- and iron chelation-independent TI and ß thalassaemia major (TM) attending the Chronic Care Center, Hazmieh, Lebanon. A total of 80 patients agreed to participate in the study [32 TI (median age 24 yr) and 48 TM (median age 23 yr)]. The RAND SF-36 survey was used to assess HR-QoL. Data on patient demographics, clinical complications and socioeconomic status were collected. RESULTS: Patients with TI and TM were comparable with age and gender, but patients with TM had a significantly longer median duration with a known thalassaemia diagnosis. Patients with TI had a higher proportion of multiple complications. Socioeconomic parameters were comparable, except for patients with TI being more commonly married. The mean Total, Physical Health and Mental Health Scores were significantly lower in patients with TI compared to TM, indicating poorer HR-QoL. There was a statistically significant positive correlation between the duration with a known thalassaemia diagnosis and a higher Mental Health Score (r(s) = 0.73, P = 0.020). The mean Physical Health Score was significantly lower in patients with multiple clinical complications compared to patients with single or no complications (P = 0.012). Associations remained independently significant at multivariate analysis. CONCLUSION: Patients with transfusion-independent TI have lower HR-QoL compared to TM patients. At a comparable age, the shorter duration since diagnosis and the multiplicity of complications may explain these findings.

Myocardial infarction in a 28-year-old thalassemia intermedia patient.

A 28-year-old Lebanese thalassemia intermedia (TI) patient with homozygous IVS1-110 mutation sustained atypical chest pain of 1 day's duration. The EKG reading revealed ST segment elevation in the chest leads V(1) to V(5). Coronary angiography showed 2 plaques in the left anterior descending coronary artery. He underwent subsequent angioplasty with stenting of the left anterior descending coronary artery. An extensive thrombophilia profile was negative. He was started on medication, and his medical condition improved and chest pain ceased. This is the first case report of myocardial infarction in a TI patient among thalassemics. We propose that such cases will emerge more frequently as our population ages, keeping in mind a possible thrombotic mechanism.