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Hemolacria is a rare condition that causes a person to produce tears that are partially composed of blood. It can be a presenting feature of certain ocular and systemic conditions. Here, the authors describe an interesting case of a 12-year-old boy with an underlying beta-thalassemia trait, who presented with a 2-day history of bilateral blood-stained tears, and an episode of epistaxis. Ocular examination was normal, and syringing showed no nasolacrimal duct blockage. Systemic examination was unremarkable. Laboratory investigations confirmed type 2 von Willebrand disease. Management of hemolacria remains a clinical challenge given the rare occurrence of the disease. In this case report, the authors discuss the differential diagnosis and management approach to hemolacria., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Many studies determined the demographic and ethnic border of patients with beta (β)-thalassemia mutations and their migration. The effective way to health care policy of β-thalassemia is to prevent homozygote births and reduce the severity of the disease. The objectives of this study contributed to investigating the molecular and serologic characteristics of β-thalassemia patients in Iraq. Peripheral blood samples were collected from 97 β-thalassemia patients and 32 healthy control subjects. Quantitative sandwich enzyme-linked immunosorbent assay was performed to measure serum ferritin, 25-hydroxy vitamin D, and 8-hydroxydeoxyguanosine (8-OHdG) levels. Further, the β-globin mutation detection assay involving an extensive screening of β-globin mutations by direct Sanger DNA sequencing and gap-PCR was performed to detect the Δ619 deletion mutation. The results revealed that compared with the control subjects, the β-thalassemia patients showed significantly decreased vitamin D levels and significantly increased serum ferritin and 8-OHdG levels (all, P<0.001). Molecular analysis detected 9 types of mutations in the β-thalassemia patients, only 2 of which, namely IVS II-1 G>A and IVS 1-5 G>C, have been previously reported in Iraqi studies, whereas the remaining 7, namely IVS-II-666 C>T, CD2 CAT>CAC, IVS-II-850 G>A, IVS-II-16 GT, have never been reported in the Iraqi population. This study showed that the serum ferritin and 8-OHdG levels were significantly higher, and the serum 25-hydroxy vitamin D levels were significantly lower in the β-thalassemia patients than in the control subjects. Moreover, the results revealed seven newly identified mutations among Iraqi β-thalassemia patients and 2 previously reported mutations.

Objective: Deferasirox is a once-daily oral iron-chelation agent approved by the US Food and Drug Administration in November 2005. The authors aimed to evaluate efficacy, safety, and satisfaction of patients regarding twice-daily dose of deferasirox in patients with thalassemia who are resistant to once-daily regimen., Methods: In this historical cohort multicenter study, 34 patients with beta-thalassemia major resistant or intolerant to once-daily dose of deferasirox (35 mg/kg/d) were investigated in 2016. Patients were registered at 3 thalassemia referral centers in Shiraz, southern Iran and Tehran, the capital of Iran. All patients were followed for 1 year and monitored by regular physical examination, laboratory data, serum ferritin levels, and heart and liver T2 magnetic resonance imaging., Results: Mean age of thalassemia patients was 25.6±8.1 (8 to 40) years, including 22 female individuals and 12 male individuals. Serum ferritin levels significantly decreased during the study period (2021±955 at baseline vs. 1228±894 at the end of the study, P<0.001). Liver T2 magnetic resonance imaging of the patients demonstrated a significant improvement during the study. 73.3% of patients showed normal values at the end of study compared with 28.1% at the baseline (P<0.001). Drug side effects were reported only in 2 patients (5.8%) including 1 patient with abdominal pain and 1 with leukopenia and thrombocytopenia., Conclusions: It seems that deferasirox can be used with increased dose and twice daily with acceptable efficacy in unresponsive or intolerant thalassemia patients to once-daily dose. Close monitoring of the patients is necessary to detect and manage any possible adverse events.

Objective: It is well known that increased oxidative stress leads to tissue damage in beta-thalassemia (β-thal) patients. Thiols are one of the most important antioxidant agents, and thiol/disulfide (SH/SS) homeostasis is a novel oxidative stress marker. This study aimed to investigate the relationship of thiol levels, SH/SS homeostasis, and ischemia-modified albumin (IMA) in patients with β-thal., Materials and Methods: A hundred transfusion-dependent β-thal patients and 41 healthy controls were included in the study., Results: Native thiol, total thiol, disulfide, catalase, and IMA levels were significantly higher in the β-thal group compared with the control group (P<0.02). There were no correlation between serum ferritin level and SH/SS homeostasis, and weak positive correlations were found between serum ferritin and IMA (r=0.242, P=0.022)., Conclusions: Our study results suggest that antioxidant systems try to compensate for peroxidative damage in the patients' group and serum IMA level was found increased because of increased oxidative status. To the best of our knowledge, there has been no report evaluating plasma dynamic SH/SS homeostasis in β-thal patients.

Background: B-thalassemia carrier state or thalassemia minor confers cardiovascular protection through favorable lipidemic and blood pressure profile. However, its impact on inflammatory status-a common denominator of the above conditions-has not been addressed., Methods: We investigated a wide range of inflammatory markers [white blood cell (WBC) count, homocysteine, C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, plasminogen, fibronectin, plasminogen activator inhibitor-1 (PAI-1), and uric acid] in a large cohort of 15 805 newly diagnosed hypertensive patients (8299 men, 7506 women); 626 of them (4.0%) had thalassemia minor., Results: The levels of WBC, homocysteine, CRP, SAA, fibrinogen, and PAI-1 were significantly lower in thalassemia minor patients, but not of plasminogen, fibronectin, and uric acid. In multivariate linear regression analyses, the lower values of WBC (<0.001), CRP (<0.001), homocysteine (<0.001), fibrinogen (<0.001), and PAI-1 (0.008), but not of SAA, were independently associated with thalassemia minor. The interaction between thalassemia minor and body mass index had a significant impact only on WBC and CRP (P for the interaction 0.010 and 0.005, respectively), whereas the interaction between thalassemia minor and sex had a significant impact only on fibrinogen (P for the interaction 0.007)., Conclusion: Thalassemia minor is followed by a favorable inflammatory profile that may contribute to the overall better cardiovascular health of the carriers.

Background and Aim: Thalassemia screening instructions in Iran categorizes couples with mean corpuscular volume (MCV)=75 to 80, mean corpuscular hemoglobin (MCH)=26 to 27, hemoglobin A2 (HbA2)<3.5, and hemoglobin fetal (HbF)<3 indices as low-risk couples, and therefore further genetic testing is not obligatory. This study examined the possibility of classifying couples with MCH<26 and MCV≥80 indices in the low-risk group when their HbF was <3 and HbA2 was <3.2., Methodology: This was a cross-sectional study. The data included results from cell blood count and HbA2 prenatal diagnosis (PND) and HbF tests taken by 22 health care centers in Esfahan province, central Iran, throughout the years 2012-2016. The inclusion criterion was the registering of MCV, MCH, and PND results of the participants. From the 5804 participants, 5624 individuals were included in the study., Results: The sensitivity and specificity of the screening program were 99.7 and 53.12, respectively. Ten cases (0.18%) with thalassemia trait had indices MCV≥80 and MCH≥26 including 3 cases (0.05%) with concurrent α and β-thalassemia mutations and 7 cases (0.12%) with HbS mutations. Altogether, 553 subjects (9.83%) had MCV≥80 and MCH<26 indices, and only 1 case (0.018%) was found with β-thalassemia mutations (codon8 (-AA)/WT genotype)., Conclusions: Subjects with MCV≥80, MCH<26, HbA2<3.2, and HbF<3 cell blood count indices could be grouped as low-risk couples if normal HbA2 and HbF values are considered. The results of this study also indicate that there is a chance of missing concurrent α and β-thalassemia or HbS hemoglobinopathies in the current screening program given the fact that genetic testing is not considered for couples with MCV and MCH in the low-risk range. HbF testing could be conducted to prevent these missing cases.

Objective: The aim of this study was to evaluate the vitamin D-PTH axis in thalassemia major (TM) in relation to hepatic siderosis liver iron content., Design and Participants: In this case-controlled observational study, vitamin D-PTH axis was studied in 158 TM and 84 age and ethnicity-matched healthy nonthalassemic controls attending University College Hospital, London. Patients were classified as 25-hydroxy vitamin D (25-OHD) insufficient and sufficient if the value was less than or greater than 50 nmol/L, respectively. 25-OHD data were evaluated in relation to markers of iron load in TM., Results: In TM, 25-OHD insufficiency was 8-fold higher than the control group (odds ratio [OR], 8.1; 95% confidence interval [CI], 4.3-15.0; P<0.001). Similarly, serum PTH (P<0.001), calcium (P<0.001), and phosphate levels (P<0.05) were also significantly lower in TM compared with the controls. In TM, serum ferritin of >2500 μg/L (OR, 5.3; 95% CI, 2.3-12.3; P<0.01), liver iron of >7 mg/g dry weight (OR, 8.8; 95% CI, 3.5-10.3; P<0.001), and serum alanine aminotransferase of >50 IU/L (OR, 9.7; 95% CI, 4.0-23.5; P<0.001) were independent risk factors for low 25-OHD levels., Conclusions: Our results suggest that TM had a 8-fold higher risk of 25-OHD insufficiency compared with the controls. This was likely to be associated with hepatic hemosiderosis.

Background: Glycosylated hemoglobin (HbA1c) has been a well-recognized marker of glucose homeostasis among thalassemics. Recently some studies have proposed the role of fructosamine as a better marker as compared with HbA1c. Hence, the study was carried out to find out which marker holds promise among Indian beta-thalassemic children., Methods: In this case-control study, 60 diagnosed cases of beta-thalassemia major and equal number of normal controls who were ≥8 years of age were enrolled. HbA1c, fructosamine, and fasting insulin levels were measured in all. Oral glucose tolerance test was done as a gold standard and the measured parameters were compared., Results: HbA1c was significantly higher in cases (7.10% [±0.47%]) than in controls (5.15% [±0.19%]) (P<0.001). Thalassemics with abnormal glucose tolerance had higher HbA1c level (7.34% [±0.57%]) than those with normal glucose tolerance (7.05% [±0.43%]) (P=0.05). Insulin resistance was noticed among thalassemics with abnormal glucose tolerance as compared with their normal counterparts (P=0.04). No significant difference was found in fructosamine levels between cases (239.80 [±31.80] μmol/L) and controls (234.10 [±21.34] μmol/L) (P=0.25) or between thalassemics with abnormal glucose tolerance (243.92 [±21.94] μmol/L) and their normal counterparts (238.77 [±33.93] μmol/L) (P=0.62)., Conclusions: The use of HbA1c as a diagnostic marker for diabetes in hemolytic anemias has to be done with caution as its baseline values are higher in them. Despite this finding, HbA1c continues to be a good marker for worsening glucose homeostasis in thalassemics as higher values were found in thalassemics with abnormal glucose tolerance compared with their normal counterparts. The present study did not find any relationship of fructosamine levels with impaired glucose tolerance in beta-thalassemia.

This study aimed to study the differences in Raman spectra of red blood cells (RBCs) among patients with β-thalassemia and controls using laser tweezers Raman spectroscopy (LTRS) system.A total of 33 patients with β-thalassemia major, 49 with β-thalassemia minor, and 65 controls were studied. Raman spectra of RBCs for each sample were recorded. Principal component analysis (PCA), one-way analysis of variance (ANOVA), and independent-sample t test were performed.The intensities of Raman spectra of β-thalassemia (major and minor) RBCs were lower than those of controls, especially at bands 1546, 1603, and 1619 cm. The intensity ratio of band 1546 cm to band 1448 cm demonstrated that there was a significant difference between the spectra of β-thalassemia major (mostly below 2.15) and those of controls. The spectra of controls could be well distinguished from those of β-thalassemia major using PCA. After normalization, the spectra of two different genotypes with β/β mutations mainly overlapped, while those with β/β mutations had lower intensity at bands 1546, 1603, and 1619 cm.The present study provided Raman characteristics of RBCs in patients with β-thalassemia major and supported the use of LTRS as a method for screening β-thalassemia major. The recognition rate for β-thalassemia minor needs to be further improved.

Objectives: Iron-burden-induced arrhythmia and heart failure are among the leading causes of morbidity and mortality in β-thalassaemia major patients. T2* cardiac magnetic resonance remains the only reliable noninvasive method for the heart iron excess assessment. We explored the role of single nucleotide polymorphisms involved in vitamin D metabolism, transport and activity and in deferasirox (DFX) metabolism on cardiac iron burden., Patients and Methods: One hundred and five β-thalassaemia patients, treated with DFX, were enrolled in the present study. Drug plasma Ctrough was measured by a high-performance liquid chromatography-ultraviolet method. Allelic discrimination was carried out using the real-time PCR., Results: CYP1A1*1189 CC, ABCG2 421 GA, CYP24A1 8620 GG and VDR TaqI CC single nucleotide polymorphisms influenced T2* values. Age, serum ferritin, ABCG2 421 GA, ABCG2 1194 +928 TC/CC, CYP24A1 22776 TT and VDR TaqI TC/CC were retained in linear regression model., Conclusion: Our results suggested, for the first time, the role of DFX and vitamin D pharmacogenetics on cardiac iron overload.

Complications like impaired glucose tolerance and diabetes mellitus due to iron overload need early identification in thalassemia. We studied the proportion of insulin resistance in thalassemia major patients on chronic transfusion, identified insulin resistance using homeostasis model assessment of insulin resistance (HOMA-IR) and triglyceride glucose (TYG) index, compared them and validated TYG index. In total, 73 thalassemia patients on regular transfusion for 3 years with serum ferritin >1500 ng/mL were studied. Serum ferritin, fasting blood glucose, triglycerides, and insulin levels were measured, HOMA-IR, and TYG index calculated and analyzed. Mean fasting glucose, triglyceride, and serum insulin values were 104 mg/dL, 164.18 mg/dL, and 19.6 m IU/mL, respectively. Mean serum ferritin was 5156 ng/mL. Insulin resistance was prevalent in one third of thalassemia patients and showed increase with age and serum ferritin. Insulin resistance by HOMA-IR was 32% as against 16% by TYG index with a cut-off value of 4.3. Using receiver operating charecteristic curve analysis, it was found that, by lowering the value of TYG index to 4.0215, sensitivity improved to 78.3% (from 39.13%) with specificity of 70%. Hence, we recommend a newer lower cut-off value of 4.0215 for TYG index for better sensitivity and specificity in identifying insulin resistance.

Objective: To assess the prevalence of impaired glucose tolerance in β-thalassemia major and correlate it with chelation therapy., Materials and Methods: Sixty-seven subjects with β-thalassemia major, aged 1 to 20 years, were enrolled in our prospective cohort. Clinical details were recorded. Baseline oral glucose tolerance test, serum insulin, C peptide, and insulin resistance were measured. The biochemical profile was repeated after 6 months., Results: The mean age of subjects was 7.43±4.48 years. Eight (11.9%) subjects had impaired fasting glucose, 7 (10.4%) had impaired glucose tolerance, and 1 (1.4%) subject had diabetes at baseline. Subjects with abnormal glucose profile had longer disease duration (95% confidence interval [CI] of difference=-6.64 to -0.68; P=0.019) and higher fasting blood glucose (95% CI of difference=-32.1 to -10.5; P=0.001) and serum ferritin (95% CI of difference=-219.8 to -3.4; P=0.001) than normoglycemic subjects. Insulin resistance and serum ferritin showed significant increase at 6 months (P<0.001 and P=0.001, respectively). Patients on deferiprone alone significantly improved glucose homeostasis on follow-up than those on desferrioxamine or combination therapy of desferrioxamine and deferiprone (P<0.05)., Conclusions: Prolonged disease duration and higher serum ferritin adversely affects glucose homeostasis in thalassemic children. Deferiprone was the most effective chelator to improve glucose homeostasis in chronically transfused thalassemics.

Background: β-Thalassemia major patients with higher total drug levels [deferasirox (DEFR) plus its iron complex] do not yield better serum ferritin (SF) control. This study aimed to determine the concentrations of DEFR and its iron complex (Fe-[DEFR]2) in thalassemia patients to predict the chelation efficacy in terms of SF and cardiac T2* values., Methods: Patients' steady-state drug levels at trough (Ctrough) and 2 hours postdose (C2h) were determined. Because iron deposition may cause changes in the hepatic metabolism of amino acids, the concentrations of 40 amino acids in plasma were also assayed at 2 hours postdose., Results: A total of 28 patients either dosing daily or twice daily were recruited. After a 1-month DEFR maintenance therapy, 38.8% and 30% of patients from groups of once-daily and twice-daily, respectively, had a plasma DEFR-iron complex formation ratio higher than 0.05 [High Chelation Ratio, (HCR)]. After a 6-month follow-up, those patients who had a HCR (n = 10) at C2h showed more favorable median changes in SF and cardiac T2* values (-388.0, +10.1) than those with a low DEFR-iron complex formation ratio (Low Chelation Ratio; n = 18; +10.5; +4.5) compared with the baseline. The levels of plasma L-arginine, L-alanine, L-glycine, L-norleucine, and L-serine were significantly lower in patients with the low Chelation Ratio condition than the levels in HCR patients., Conclusions: This therapeutic drug monitoring study revealed that a DEFR-iron complex formation ratio at C2h might be an applicable indicator of the efficacy of long-term DEFR iron chelation therapy. A better iron-control response to DEFR was observed in the patients with HCRs. The trends for the ratio might have value in dose-setting and need to be validated in a larger cohort.

The present study was conducted to compare the coagulation factors between splenectomized and nonsplenectomized thalassemia intermedia (TI) patients as well as a healthy control group. A total of 60 splenectomized and 60 nonsplenectomized TI patients and 60 healthy controls participated in this case-control study. The level of homocysteine, protein C and S, antithrombin III, factors V and VIII, fibrinogen, and D-dimer were measured in all groups. Our results indicated a significant reduction of protein C and S and fibrinogen in TI patients compared with healthy controls (P<0.001), as well as factor V activity (P=0.009). Also a significant elevation of D-dimer (P=0.006) and factor VIII activity (P=0.001) was observed. There was no significant difference considering homocysteine and antithrombin III level among patients and healthy controls. Also our results demonstrated that there was no significant difference considering the homeostatic parameters (except D-dimer activity) between splenectomized and nonsplenectomized TI patients after adjustment for age. In conclusion, reduction of protein C and S, fibrinogen, and factor V activity and elevation of D-dimer levels and factor VIII activity was observed in TI patients compared with healthy controls. It seems that splenectomy has little significant effect on concentration of hemostatic factors except for D-dimer activity.

Few studies have investigated the quality of life of children with thalassemia in the Middle East or Mediterranean region, especially Iraq. Therefore, this study was performed to assess the health-related quality of life (HRQoL) of patients with β-thalassemia major compared with healthy children and adolescents in the same age group and to evaluate the effects of different iron chelators on HRQoL measurements. A case-control study was performed on patients with β-thalassemia major registered at the Center for Hereditary Blood Diseases in Basra from February 2012 through July 2013. The group included children and adolescents aged 2 to 17 years old. HRQoL was assessed using the Pediatric Quality of Life (PedsQL) Generic Core Scale questionnaire, version 4.0, for children 2 to 12 years old and the Short Form-36 health survey questionnaire, version 2 (SF-36v2), for children and adolescents aged 13 to 17 years old. A total of 209 age-matched and sex-matched children and adolescents were included in the control group. The study did not find a significant difference in PedsQL scores among different age groups or different iron chelators, whereas there were significant differences in all of the SF-36v2 domains, with the best quality of life observed in the deferasirox group, followed by the deferoxamine group and the combined therapy group (P<0.05). The use of deferasirox among patients aged 13 to 17 years old was associated with higher SF-36v2 scores than in the other groups (P<0.05). However, for younger patients, the PedsQL scores were not significantly different for different iron chelators. The use of oral deferasirox significantly improved the quality of life of adolescents with β-thalassemia major. However, this effect was less prominent among patients aged 2 to 12 years old.

Iron overload is an ineluctable complication in chronically transfused children warranting accurate assessment to avoid related morbidity. We investigated longitudinally the relationships between ferritin levels and hepatic and cardiac T2* magnetic resonance imaging (MRI) in a cohort of chronically transfused children receiving chelation therapy. Thirty children with sickle cell anemia (SCA) and 7 with thalassemia major (TM) chelated similarly by deferasirox were analyzed. Sex ratio, age, median duration of transfusion programs (5 y; range, 2 to 14 y), median transfusion iron intake 0.54 mg/kg/d (range, 0.27 to 0.74 mg/kg/d), and median ferritin level (1550 mg/L; range, 184 to 6204 mg/L) were comparable in TM and SCA. A significant relation was found between ferritin level and transfusion iron intake (P<0.001) despite chelation therapy. Analysis of 73 hepatic T2* MRI performed yearly demonstrated severe hepatic iron overload (≥14 mg/g) in 38.3% cases and a strong relationship between serum ferritin level and liver iron content both in SCA and TM (P<0.001). Analysis of 55 cardiac T2* MRI measurements found no cardiac overload in patients with SCA. Cardiac iron overload was moderate in 4 cases and severe in 1 case of TM. In almost half the cases, ferritin trend correctly predicted hepatic iron trend, both in patients with SCA and TM but failed to predict cardiac iron trend, notably in TM patients. Despite chelation therapy, iron burden in chronically transfused patients remains a threat. Ferritin levels are associated with liver iron overload in chelated children with SCA and TM, but iron burden should be best monitored with MRI whenever the setting allows it.

Thalassemia major (TM) results in hemolytic anemia, an increase in intestinal iron absorption, and occurrence of iron loading due to erythrocyte transfusion; the disease is characterized by oxidative damage in major organs. Oxidative stress leads to vascular endothelial damage and forms the basis for serious cardiovascular diseases. Pentraxin-3 (PTX-3) is one of the markers of vascular endothelial damage that increases in response to the oxidative stress, which can be used as an early diagnostic marker for inflammation. This study's purpose is to define the relation between PTX-3 and the vascular endothelial damage that increases with oxidative stress in thalassemia patients. Our study included 35 TM patients, 30 β-thalassemia minor patients, and 30 healthy children. As a result of our study, in TM patients, a positive relation was detected between the PTX-3 levels and the total oxidative stress, triglyceride, and very low-density lipoprotein values, whereas a negative relation was detected with the total antioxidant capacity and high-density lipoprotein values. This result shows that as oxidant stress increases, PTX-3 levels also increase; very low-density lipoprotein and triglyceride contribute to the endothelial damage occurring with oxidative stress. As a result, it was concluded that vascular endothelial damage in thalassemia patients can be evaluated through the serum PTX-3 level.

Background: Thalassemia major (TM) is a chronic disease requiring regular transfusions that may result in generalized iron loading, such as in the heart, the liver, endocrine organs, and the lungs. We aimed to determine pulmonary function abnormalities in children with TM in our center., Patients and Methods: In this study, pulmonary function tests (PFTs) of 49 patients with TM who received regular blood transfusion and had no history of chronic respiratory disease were evaluated. The relationship between PFTs and the age, the body surface area, pretransfusional hemoglobin, and serum ferritin was evaluated., Results: Among the β-TM patients included in this study, 61% were male and 39% were female, with a mean age of 10.8±3 years (range, 5 to 17 y). The patients' mean level of ferritin was 3873±2011 ng/dL (range, 676 to 9476 ng/dL). A reduced forced vital capacity (FVC) was found in 33 patients (67%). A reduced forced expiratory volume in 1 second (FEV1) was found in 15 patients (30%). A forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratio of >80% was found in all patients. The peak expiratory flow (PEF) was decreased in 23 patients (46.9%). The forced mid-expiratory flow between 25% and 75% of the exhaled vital capacity (MEF25%-75%) was decreased in 5 patients (10%). FVC and FEV1 values in patients with a high ferritin level (>2500 ng/dL) were decreased compared with patients with a low ferritin level (<2500 ng/dL) (P=0.04, 0.03). FVC, FEV1, and PEF parameters were negatively correlated with the age and the body surface area. Age was a predictor of FVC (β=-0.450, P<0.001), FEV1 (β=-0.419, P<0.001), and PEF (β=-0.505, P<0.001), and hemoglobin was a predictor of FEV1/FVC (β=0.366, P=0.01) and MEF25%-75% (β=0.323, P=0.003)., Conclusions: Our results concluded that the respiratory system should be evaluated by PFTs even in asymptomatic patients with high serum ferritin levels during the adolescent period annually to prevent the squeal of pulmonary disease in TM. Patients who have abnormal PFTs should be reevaluated for compliance with chelation therapy and the transfusion program.

Objective: To heighten awareness of increased postoperative thromboembolic complications in patients with β-hemoglobinopathies., Patient: A 42-year-old African American woman with previously undiagnosed β-hemoglobinopathies suffers from sensorineural hearing loss caused by bacterial meningitis and undergoes bilateral cochlear implantation., Intervention(s): Diagnostic: hemoglobin electrophoresis. Therapeutic: cochlear implantation, anticoagulation., Main Outcome Measure(s): Risk of thromboembolic event., Results: Five days after surgery, the patient developed pulmonary embolism and infarct in the right lower lobe, which was treated with a 4-month course of anticoagulation. Hemoglobin electrophoresis showed that the patient had a previously undiagnosed rare β-hemoglobinopathy known as sickle/β+ thalassemia., Conclusion: β-Hemoglobinopathies are associated with a higher incidence of thromboembolism; thus, they should be managed aggressively to prevent or treat perioperative thrombosis.

Normal hemoglobin is made of a tetramer of 2 α-globin and 2 β-globin polypeptide chains. Deletions in the β-globin gene cluster can range from a few hundred base pairs to loss of the entire cluster resulting in rare, but clinically significant, thalassemias. One such entity is εGγAγδβ0-thalassemia, a condition that presents within the first few weeks of life as a Coombs-negative hemolytic anemia and is not identified on routine newborn screening or hemoglobin electrophoresis.

Objective: To compare red blood cell hematology among fetuses at risk of homozygous β-thalassemia disease at mid-pregnancy., Materials and Methods: Eighty-six fetuses, 18 to 22 gestational weeks, at risk of homozygous β-thalassemia disease undergoing cordocentesis between December 2010 and June 2012 were recruited in the study. Red blood cell parameters were measured and final diagnosis of thalassemia status was based on fetal hemoglobin typing by high performance liquid chromatography technique and DNA analysis. The fetuses were categorized into 3 groups as normal β-globin genotype, β-thalassemia trait, and homozygous β-thalassemia disease., Results: Mean maternal age and mean gestational age were 26.56±6.36 and 19.12±1.06 weeks, respectively. The prevalence of fetuses with homozygous β-thalassemia disease, β-thalassemia trait, and normal β-globin genotype fetuses were 29.07% (25 cases), 20.93% (18 cases), and 50% (43 cases), respectively. All of red blood cell parameters were not significantly different among the 3 groups of fetuses. No affected fetus had anemia during mid-pregnancy., Conclusion: No significant difference in red blood cell parameters among unaffected and affected fetuses with homozygous β-thalassemia disease was found.

β-thalassemia is characterized by impaired β-chain synthesis leading to ineffective erythropoiesis, severe anemia, and a need for blood transfusion. Presence of Xmn I polymorphism (-158 C-T nucleotide change) in γ-globin gene is associated with a higher fetal hemoglobin and a lesser clinical severity. This prospective study attempted to find out the effect of hydroxyurea (HU) on β-thalassemia patients in the presence or absence of Xmn I polymorphism. A total of 143 consecutive β-thalassemia patients received HU (16 mg/kg/d). Sixty-four (44.7%) had Xmn I polymorphism (either homozygous or heterozygous). Patients were evaluated at a median duration of 3 years (range, 6 mo to 9 y). Responders became transfusion independent after 6 months, partial responders had a least 50% reduction in transfusion requirement and nonresponders had no significant reduction. Of the 64 patients with Xmn I polymorphism, 44 (69%) showed response (P<0.01), whereas in those who lacked Xmn I polymorphism (n=79), only 17 (21%) were responders. This study showed that the presence of Xmn I polymorphism in β-thalassemia is a predictor of response to HU and highlights the possibility of managing this subset of patients without blood transfusion.

Aims: Classical carriers of β-thalassaemia are identified by a raised HbA2 level. Earlier studies indicated that the Filipino β-deletion has high raised HbA2 levels. The introduction of automated high performance liquid chromatography (HPLC) for thalassaemia screening is an important advance in technology for haematology laboratories. The BioRad Variant II Hb analyser is a common instrument used to quantify HbA2 levels in thalassaemia screening. This study aimed to determine HbA2 levels in carriers of Filipino β-mutation using the BioRad Variant II Hb analyser., Methods: The Filipino β-deletion was identified using gap-polymerase chain reaction (PCR) in the parents of transfusion dependent β-thalassaemia patients who were homozygous for the Filipino β-deletion in the indigenous population of Sabah, Malaysia. Hb subtypes were quantified on the BioRad Variant II Hb analyser. Concurrent α-thalassaemia was identified by multiplex gap-PCR for deletions and amplification refractory mutation system (ARMS)-PCR for non-deletional mutations., Results: The mean HbA2 level for Filipino β-thalassaemia trait was 5.9 ± 0.47 and with coinheritance of α-thalassaemia was 6.3 ± 0.44 (-α heterozygous) and 6.7 ± 0.36 (-α homozygous). The HbA2 levels were all >4% in keeping with the findings of classical β-thalassaemia trait and significantly higher than levels seen in non-deletional forms of β-thalassaemia., Conclusion: The HbA2 level measured on the BioRad Variant II Hb analyser was lower than the level in the first description of the Filipino β-thalassaemia. β-thalassaemia trait with coinheritance of α-thalassaemia (-α) is associated with significantly higher HbA2 level.

This study reports on a 65-year-old female patient with controlled comorbidity, who was diagnosed with gastrointestinal stromal tumours following regular monitoring of renal cysts. After the surgical treatment, coadjuvant treatment with imatinib was initiated. After a few months, the patient complained of angor and asthenia and the diagnosis of anaemic syndrome was made on the basis of blood test results. We studied the causes of the anaemia (maturation factors and other causes of secondary anaemia) and it led to the diagnosis of vitamin B12 deficiency. Treatment with vitamin B12 supplementation was initiated. With the correction of the vitamin levels with supplementation, the symptoms improved. Thalassaemia led to the misdiagnosis of vitamin B12 deficiency because of the lower mean corpuscular volume levels.

Deferasirox (DFX) is a relatively new iron chelator approved by the US Food and Drug Administration for treatment of children >2 years of age. Prospective studies in Asian Indian children are limited. The β-thalassemia patients receiving regular transfusions in the thalassemia ward of an advanced pediatric center were included in this study. Monitoring of side effects was carried out by assessing monthly transaminases and serum creatinine levels. Hemoglobin levels were determined before blood transfusion. Thirty patients of transfusion-dependent thalassemia were eligible for the final analysis. The male:female ratio was 3.3:1, and ages ranged from 2.0 to 21 years. The serum ferritin (SF) level at the start of therapy was 2657.7±1414.6 (mean±SD). The mean dose of DFX was 21.57 mg/kg/d (range, 17.2 to 27.2 mg/kg/d). Common side effects noted were gastrointestinal manifestations in 5 (16.6%) and skin rash in 2 (6.6%) patients. There was an increase in serum creatinine in 2 patients, and treatment was interrupted in 1. Reversible cytopenia was observed in 1 patient. In 13/30 patients, an initial increase in SF was observed. A decrease in SF levels compared with initial value was seen in only 8 patients at a follow-up of 24 months, at a median dose of 28.8 mg/kg/d. Thus, DFX is a relatively safe oral iron chelator that can be used in Asian Indians, with gastrointestinal problems like diarrhea and abdominal pain as the most common side effects. Treatment requires individualization with careful dose escalation and proper monitoring.

The occurrence of multiple abnormalities of α, β, δ, and γ globin genes may lead to unusual and complex phenotypes when they arise simultaneously in the same individual. Here, we report the findings of an African American boy who coinherited 3 heterozygous globin gene abnormalities: the unstable β-globin chain variant; hemoglobin (Hb) Showa-Yakushiji [β110(G12) Leu→Pro], the δ-globin chain variant; HbB2 [δ16(A13) Gly→Arg] and α-thalassemia (α-thal); (α-/αα). Hb Showa-Yakushiji had been previously described in Japanese, Indian, and European populations. We report its first occurrence in a child of African ancestry who presented with anemia not responsive to iron and an incomplete β-thalassemia minor phenotype. Although the clinical and laboratory features of Hb Showa-Yakushiji mimic those of a β-thalassemia, the coinheritance of the δ-globin chain variant Hb B2 suppressed the relative increase in Hb A2 usually observed in heterozygotes for the Hb Showa-Yakushiji mutation. Protein-based methods detected only a trace amount of HbB2 and failed to reveal presence of Hb Showa-Yakushiji and α-thal. The latter were only identified through DNA analyses. The diagnostic difficulties, molecular characteristics, and genotype/phenotype correlations of this novel complex hemoglobinopathy syndrome are reviewed.

Summary: Iron deficiency anemia (IDA) and beta-thalassemia trait (beta-TT) are the most common microcytic anemia. Kinds of discrimination indices have been established as simple, fast, and inexpensive means since 1970s. This study evaluates the validity of 12 indices in differentiation between IDA and beta-TT for Chinese children. The 12 discrimination indices were red blood cell (RBC) count, RBC distribution width, Mentzer Index, Green and King Index, RBC distribution width Index, England and Fraser Index, Shine and Lal Index, Srivastava Index, Ricerca Index, Ehsani Index, Sirdah Index, and Huber-Herklotz-Index. A total of 300 children (beta-TT, n=127 and IDA, n=173) were enrolled in the study. We calculated the sensitivity and specificity, positive and negative predictive values, and Youden's index for each index. We also established new cut-off values by receiver operating characteristic curves. Green and King Index showed the highest reliability, as it had the largest area under the curve (AUC=0.947), whereas Srivastava Index and Shine and Lal Index showed the lowest reliability (AUC=0.679 and 0.532, respectively). We concluded Green and King Index, Ricerca Index, and England and Fraser Index could be used in discrimination between IDA and beta-TT in Chinese children.

Bone disease in beta-thalassemia major (betaTM) remains poorly understood. Receptor activator of nuclear factor-kappabeta ligand (RANKL) regulates osteoclast formation and function. RANKL activity is balanced by interaction with its receptor (RANK) and binding to osteoprotegerin (OPG). L-Carnitine (LC) enhances osteoblastic activity by furnishing fuel. This study hypothesized that abnormal bone metabolism in betaTM involves imbalanced RANKL/OPG and LC/free fatty acids (FFAs) metabolism. Sixty-nine transfusion-dependent betaTM patients and 15 healthy controls were enrolled. One group of patients (n=34) received desferrioxamine (DFO) and the other (n=35) did not. Serum OPG, soluble RANKL (sRANKL), FFAs, LC [total LC (TC), free LC (FC), and esterified LC (EC)], calcium, and inorganic phosphate were measured by specific immuno and colorimetric assays; bone mineral density was examined by dual x-ray absorptiometry. Patients showed lower levels of OPG, TC, FC, EC and higher levels of sRANKL, sRANKL/OPG ratio, and FFAs than controls. Patients on DFO showed lower levels of OPG, TC, FC and higher levels of sRANKL, sRANKL/OPG ratio, and FFAs than those without chelation. In patients, sRANKL correlated negatively with TC and OPG and FC correlated positively with OPG and negatively with sRANKL, sRANKL/OPG ratio, and FFAs. In conclusion, altered bone metabolism owing to imbalanced osteoclastic bone resorption versus constructive osteoblastic activities in betaTM pediatric patients could be due to abnormal sRANKL-OPG and LC-FFAs systems that were worsened by DFO.

Introduction: Homozygous beta-thalassemia major (hbeta-TM) is an autosomal recessive hemoglobinopathy with prominent endocrine complications. Our aims were to evaluate reproductive hormones, hypothalamic-pituitary-ovarian axis, and fertility in female patients with hbeta-TM., Patients and Methods: One hundred forty-four female patients with hbeta-TM, aged 18 years or above were enrolled in the study. Seventy-four age-matched healthy female volunteers served as controls. Two blood samples were drawn from each subject at 20-minute intervals for the determination of the resting levels of the following hormones: luteinizing hormone, follicle-stimulating hormone, estradiol, insulin-like growth factor-1, and insulin-like growth factor binding protein-3. The hypothalamic-pituitary-ovarian axis was also assessed using the gonadotropin-releasing hormone test. Menstruation status and growth rate were also noted. Puberty was assessed in both groups by Tanner classification., Results: The mean age of puberty in the control group and hbeta-TM patients was 10.8+/-1.2 and 16.4+/-2.2 years, respectively (P=0.01). The mean age of menarche was 11.4+/-1.3 and 16.8+/-2.1 years in control subjects and patients with thalassemia, respectively (P=0.01). Of studied subjects with hbeta-TM, 61 (42.4%) were short in stature (height below the third percentile and below -2 SD scores). The baseline and peak levels of luteinizing hormone, follicle-stimulating hormone, and estradiol after gonadotropin-releasing hormone test in thalassemic group were significantly lower than in the control group., Conclusions: Further interventional studies are warranted to better clarify the treatment options to attain normal puberty and sexual maturation in patients with thalassemia.

Background: The goal of this study was to determine the predictive value of cardiac T2* magnetic resonance for heart failure and arrhythmia in thalassemia major., Methods and Results: We analyzed cardiac and liver T2* magnetic resonance and serum ferritin in 652 thalassemia major patients from 21 UK centers with 1442 magnetic resonance scans. The relative risk for heart failure with cardiac T2* values <10 ms (compared with >10 ms) was 160 (95% confidence interval, 39 to 653). Heart failure occurred in 47% of patients within 1 year of a cardiac T2* <6 ms with a relative risk of 270 (95% confidence interval, 64 to 1129). The area under the receiver-operating characteristic curve for predicting heart failure was significantly greater for cardiac T2* (0.948) than for liver T2* (0.589; P<0.001) or serum ferritin (0.629; P<0.001). Cardiac T2* was <10 ms in 98% of scans in patients who developed heart failure. The relative risk for arrhythmia with cardiac T2* values <20 ms (compared with >20 ms) was 4.6 (95% confidence interval, 2.66 to 7.95). Arrhythmia occurred in 14% of patients within 1 year of a cardiac T2* of <6 ms. The area under the receiver-operating characteristic curve for predicting arrhythmia was significantly greater for cardiac T2* (0.747) than for liver T2* (0.514; P<0.001) or serum ferritin (0.518; P<0.001). The cardiac T2* was <20 ms in 83% of scans in patients who developed arrhythmia., Conclusions: Cardiac T2* magnetic resonance identifies patients at high risk of heart failure and arrhythmia from myocardial siderosis in thalassemia major and is superior to serum ferritin and liver iron. Using cardiac T2* for the early identification and treatment of patients at risk is a logical means of reducing the high burden of cardiac mortality in myocardial siderosis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00520559.

A 10-year-old white boy presented clinically with thalassemia major facies, pallor, jaundice, and hepatomegaly. Investigation revealed the patient has hemoglobin (Hb) Lufkin concurrent with beta(0) thalassemia. DNA sequencing of the beta globin gene confirmed a GGC to a GAC mutation at codon 29 (gly to asp) for Hb Lufkin on the patient and also revealed a beta(0) thalassemia mutation, IVS-1-1 (G to A), on both the patient and his mother. Both parents lack the Hb Lufkin mutation. Molecular studies, human leukocyte antigen, and red blood cells phenotypic studies indicate spontaneous mutation of Hb Lufkin in this patient.

Objective: The present study was undertaken to evaluate left ventricular function in patients with beta-thalassemia major with special reference to pulsed wave tissue Doppler imaging., Methods: The present study compared 30 diagnosed cases of beta-thalassemia major (mean age: 9.43+/-2.78 y) with 30 age-sex-matched healthy controls (mean age: 8.3+/-2.83 y) for left ventricular function assessment using following parameters: ejection fraction, mitral valve E/A ratio and E deceleration time (Edec), isovolumic relaxation time, and E/Eann ratio. Serum ferritin levels were also measured., Results: There was significant increase in E/Eann (9.46+/-1.5 vs. 6.16+/-2.4, P<0.0001) and significant prolongation of Edec (177.66+/-40.73 vs. 138.5, P<0.001) and isovolumic relaxation time (40.2+/-14.89 vs. 36.67+/-5.12, P<0.05) in cases as compared with controls. However, there was no significant difference in ejection fraction value (65.55+/-8.98 vs. 63.87+/-16.35) and E/A ratio (2.0386+/-0.73 vs. 2.119+/-0.92). Serum ferritin levels although increased significantly in cases (8370.85+/-2660.35), no correlation could be established between increased serum ferritin and progressive diastolic dysfunction (r=0.148, P=0.258)., Conclusions: Diastolic dysfunction precedes systolic dysfunction in patients with beta-thalassemia major as assessed by Edec and E/Eann ratio.

Cardiac symptoms and premature death from cardiac causes are still suggested to be a major problem in thalassemic patients. One of the main reasons for the cardiovascular events in thalassemia major (TM) patients has suggested having iron overload, in addition to other reasons such as hypoxia, abnormal lipoproteins levels, atherosclerotic conditions, etc. This study aims to investigate whether the periodontal health has an impact on the blood lipid levels. Twenty-four TM patients and sex-matched controls (C) enrolled to this study. The measurements of the periodontal parameters (gingival index, plaque index, bleeding on probing, probing depth, and clinical attachment level) were recorded. Besides, in venous blood samples the lipid profile was investigated. All of the periodontal parameters were significantly higher in TM group than in C group (P<0.05). Triglyceride and cholesterol/high density lipoprotein ratio had significant positive correlations with the periodontal parameters (P<0.05). Multiple regression analyses present significant associations between gingival index, plaque index scores, and the cholesterol/high density lipoprotein ratio (P<0.001). Our study results showed that the lipid profile of TM patients might be affected by their periodontal health. Further studies are needed to determine the lipid profile involvement magnitude and the cardiovascular disease risk caused by the periodontal health of TM patients.

A serious problem in thalassemia major is growth impairment for which several possible etiologies have been proposed. Sixty-seven patients with thalassemia were randomly enrolled into the study, divided into 2 groups with and without growth failure and the correlation between growth failure and the following parameters was evaluated: age, sex, serum ferritin level, serum zinc and copper concentrations, serum copper-zinc ratio, regularity of blood transfusion, and the regularity and duration of chelation therapy. Among all studied parameters, only age, duration, and type of chelation therapy and age of beginning chelation therapy were significantly different between the 2 groups. Binomial multivariate logistic regression showed that the only significant independent correlation was between age and growth failure. A 1-year increase in age is associated with a 1.57-fold increase in the risk of growth impairment. The results of this study indicated that a temporally cumulative damage to growth-mediating mechanisms except those considered here is responsible for growth failure in thalassemia major.

Objectives: Increased iron stores have been implicated in the association with increased risk of cardiovascular events. We evaluated whether the abdominal aortic stiffness was altered in the patients with beta-thalassemia major in relation with body iron load., Methods: Sixty-two (32 males and 30 females) beta-thalassemia major patients aged 16.47 +/- 4.8 years were enrolled into the study. Healthy 52 subjects matched for age and sex were recruited as controls. In all subjects, hemoglobin, fasting glucose, cholesterol, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol levels were measured. The average serum ferritin level and liver iron concentration (LIC) were assessed in thalassemia patients. Left ventricular function and mass were evaluated echocardiographically and aortic strain (S), pressure strain elastic modulus (Ep), and normalized Ep (Ep*), aortic distensibility (DIS), and beta stiffness index (beta index) were calculated in all subjects., Results: There was no statistically significant difference between the study and control groups in sex, mean age, body mass index, heart rate, and systolic blood pressure (P > 0.05). However, pulse pressure and left ventricular mass index (LVMI) were found higher in thalassemia major patients compared with the control group. In beta-thalassemia major patients S (0.21 +/- 0.027 vs. 0.26 +/- 0.017, P < 0.0001) and DIS (1.07 +/- 0.25 vs. 1.56 +/- 0.37, P < 0.0001) were significantly lower compared with the control group. However, Ep (196.9 +/- 44.86 vs. 134.20 +/- 29.10, P < 0.0001), Ep* (3.26 +/- 0.98 vs. 2.04 +/- 0.60, P < 0.0001), and beta index (2.44 +/- 0.58 vs. 1.61 +/- 0.37, P < 0.0001) were significantly higher in beta-thalassemia patients than controls. There was a statistically significant negative correlation between LIC and S, DIS. There was also negative correlation between LVMI and S. However, there was a statistically significant positive correlation between LIC and Ep, Ep*., Conclusions: Increased abdominal aortic stiffness was detected in beta-thalassemia major patients and this increase in arterial stiffness correlated with LIC and LVMI.

Globin chain imbalance and tissue hypoxia are important determinants of the clinical severity of thalassemias. Phenotypic expression may be further modified by interactions between alpha- and beta-thalassemia defects. We retrospectively and prospectively studied the clinical and hematologic features in children and adults with hemoglobin (Hb) E trait/Hb H disease (SEA/Paksé) (seven cases) and Hb E trait/Hb H disease (SEA/Constant Spring) (29 cases) and found that they had similar presentations. The severity of these two intermediate thalassemic manifestations ranged from very mild to severe. Severe anemia developed in accordance with very high fever, whereupon the range of Hb and hematocrit (Hct) levels declined to 5.2-5.8 g/dL and 13%-19%, respectively. In one case, during a hemoconcentrated state as occurs in dengue hemorrhagic fever, the Hb and Hct were 10 g/dL and 31%; the latter rose to 35% after fluid therapy. In some patients, the range of Hb and Hct levels was constantly low (4.3-5.8 g/dL and 15%-19%, respectively). (If dengue hemorrhagic fever is misdiagnosed, a fatal outcome may occur for thalassemic patients.) After a hemodiluted condition as in acute post-streptococcal glomerulonephritis, the respective Hb and Hct were 5.4 g/dL and 19%. These observations suggest that the instability of Hb E, especially during fever, may play an important role in the clinical manifestations of Hb E trait/Hb H disease with Hb Paksé and with Hb Constant Spring.

Purpose of Review: This review provide an update on antenatal screening and diagnosis of thalassaemia disorders., Recent Findings: The topics covered are the effectiveness of antenatal screening programmes for thalassaemia, its prenatal diagnosis, molecular basis and laboratory findings, ultrasound screening for haemoglobin Bart's disease, and non-invasive prenatal diagnosis of thalassaemia., Summary: Universal antenatal screening for thalassaemia carriers should be implemented in populations with a high prevalence of this condition. The appropriate measure to screen for alpha and beta thalassaemias remains mean cell haemoglobin (<27 pg) or mean corpuscular volume (<80 fl). A haemoglobin pattern and iron profile should follow if the red cell indices are low. In a population where alpha thalassaemia is prevalent, it is advisable to check the partner's mean cell haemoglobin or mean corpuscular volume as well. Further cascades of investigations will depend on these results and the prevalence of other haemoglobinopathies in that population. Invasive prenatal diagnosis remains the gold standard for diagnosis in high-risk couples. Provided expertise is available, ultrasound measurement of the cardiothoracic ratio appears a good screening tool for alpha thalassaemia major. Non-invasive prenatal diagnosis by identification of a paternal mutation in maternal plasma, although currently at the experimental stage, may be an option in the future.

Unlabelled: In this case report, we report a patient with a placenta accreta and thalassemia intermedia undergoing cesarean delivery. There are no data regarding the use of cell salvage in patients with thalassemia. During the course of her surgery, she lost approximately 9000 mL of blood. Of this blood, 2250 mL of concentrated red cells were collected, washed, and returned to the patient. During processing, increased hemolysis was noted in the effluent line of the cell salvage machine, which resolved by increasing the wash volume. The patient's postoperative course was uneventful. This case would suggest that cell salvage in patients with thalassemia can be performed safely; however, further study is warranted., Implications: This case report details the safe administration of cell salvage in a patient with beta thalassemia undergoing cesarean delivery. Cell salvage is the collection, washing, and re-administration of blood lost during surgery. This process has not been previously reported in a patient with this type of blood disease.

Objective: To determine the prevalence and risk factors of hypogonadotropic hypogonadism in transfusion-dependent patients with thalassemia., Patients and Methods: The authors examined 29 patients with thalassemia major aged 15 years or older. Luteinizing hormone-releasing hormone tests were performed and beta-thalassemia mutations were analyzed by direct sequencing., Results: The prevalence of hypogonadotropic hypogonadism was 72%. Failure of puberty was observed in 5 of 11 (45%) boys and 7 of 18 (39%) girls. Arrested puberty was noted in two boys (18%) and five girls (28%). Ten girls (56%) did not menstruate, two (11%) had regular menstrual cycles, one (6%) had irregular menstrual cycles, and five (28%) developed secondary amenorrhea. Twenty-one and eight patients had the beta 0/beta 0 and beta 0/beta+ hematologic phenotypes, respectively. beta 0-thalassemia mutation alleles involved IVS II-654 (C-T), codons 41/42 (-TCTT), codons 27/28 (+C), and codons 17 (A-T). beta+-thalassemia mutations alleles were -28 (A-G) and HbE (codons 26(GAG-AAG)). Hematologic phenotype (odds ratio, 28.50; P = 0.002) was the only risk factor identified in the logistic regression analysis., Conclusions: In patients with thalassemia major, genetic differences may influence their susceptibility to hypogonadotropic hypogonadism, possibly as a result of differences in the amounts of blood transfused and/or their vulnerability to free radical damage. The hematologic phenotype is a main determinant of the severity of thalassemia major; hence, it may influence the need for and frequency of blood transfusion and the patient's iron-overload status.

Purpose: To investigate the frequency of high erythrocyte count (red blood cell count >or=5.0 x 106/microL) in infants and young children with iron deficiency anemia and to document the differences in hematologic parameters at diagnosis and during iron therapy in IDA patients with and without a high erythrocyte count., Patients and Methods: A total of 140 infants and young children aged 6 to 48 months with nutritional IDA without a history of any bleeding disorder were the subjects of this study. The patients were divided into three groups according to the severity of anemia. Group A1 children had Hb values 8.0 g/dL or less (severe anemia); group A2, 8.1 to 10.0 g/dL (moderate anemia); and group A3, 10.1-11.0 g/dL (mild anemia). All children received oral iron (3-5 mg/kg per day) for 12 weeks. Complete blood counts were done weekly during treatment., Results: A total of 36 of the 140 patients (26%) had a high erythrocyte count. Of the 140 patients, 37 were in group A1, 80 in A2, and 23 in A3. The frequency of high erythrocyte count was 11%, 23%, and 61% in groups A1, A2, and A3, respectively. The patients with a high erythrocyte count had significantly higher Hb and Hct but significantly lower mean corpuscular volume and mean corpuscular hemoglobin (MCH) values than those with a low erythrocyte count (n = 104). A continuous elevation in the erythrocyte count has been observed in patients with a high red cell count, as in those with a low red cell count, after the institution of iron therapy., Conclusions: A high erythrocyte count is a common feature of iron deficiency anemia in infants and young children, with an increasing frequency from severe to moderate to mild anemia. High erythrocyte count cannot be regarded as a reliable preliminary parameter in differentiating iron deficiency from thalassemias in infants and children aged up to 48 months.

This report describes the sustained response of an Iranian girl with homozygous beta(0) thalassemia (IVS-II-1G-->A) to hydroxyurea (HU) and recombinant erythropoietin (rEPO). Since the start of this regimen 7 years ago, she has been transfusion-independent and her hemoglobin is maintained between 9.5-11.0 gm/dL. She is maintaining consistent growth around the 10th percentile for age and enjoys a good quality of life. She has not had any therapy-related adverse effects. This experience suggests that therapy with HU and rEPO may be useful long-term in some patients with beta thalassemia.

Background: Increased iron store has been linked to risk of cardiovascular disease. Structural alterations of arteries in beta-thalassemia major patients and in vitro functional disturbance of vascular endothelial cells by thalassemic serum have been described. We sought to determine whether arterial stiffness and endothelial function are altered in vivo., Methods and Results: Thirty thalassemia patients (16 male) aged 22.2+/-7.4 years were recruited. Left ventricular (LV) mass and function were assessed echocardiographically. Carotid and brachioradial artery stiffness was assessed by stiffness index and pulse-wave velocity (PWV), respectively. Brachial artery endothelial function was assessed by vascular response to reactive hyperemia (flow-mediated dilation [FMD]) and sublingual glyceryl trinitrate. These indexes were compared with those of 30 age- and sex-matched controls. None of the patients had LV systolic or diastolic dysfunction. When compared with controls, patients had greater absolute (113.8+/-38.0 versus 109.0+/- 32.6 g, P=0.04) and indexed (82.4+/-17.5 versus 66.7+/-12.7 g/m(2), P<0.001) LV mass, carotid artery stiffness index (8.1+/-3.5 versus 5.5+/-1.6, P<0.001), and brachioradial PWV (8.9+/-2.4 versus 7.9+/-1.7 m/s, P= 0.03). Their FMD was impaired (3.5+/-3.3% versus 8.8+/-3.9%, P<0.001), whereas glyceryl trinitrate- mediated dilation was preserved (17.9+/-7.6% versus 16.3+/-6.1%, P=0.40). Both stiffness index and PWV correlated inversely with magnitude of FMD (r=-0.40, P=0.03; r=-0.41, P=0.03) and positively with indexed LV mass (r=0.50, P=0.005; r=0.40, P=0.027). Nonetheless, no significant correlation existed between ferritin level and carotid stiffness, PWV, or FMD., Conclusions: Increased arterial stiffness, endothelial dysfunction, and LV hypertrophy occur in patients with beta-thalassemia major, which may result in reduction of mechanical efficiency of the heart.

Newborn screening for hemoglobinopathies rarely produces a fetal hemoglobin only result; it is most consistent with beta-thalassemia major, although other diagnoses are possible. The authors describe two unrelated African-American babies born in North Carolina whose newborn screening revealed fetal hemoglobin only. Both had a relatively benign clinical and hematologic picture. Molecular analyses indicated that both children are compound heterozygotes for beta-thalassemia and pancellular (deletional) hereditary persistence of fetal hemoglobin, a rare and apparently benign condition. Accurate interpretation of the fetal hemoglobin only result on newborn screening requires thorough evaluation, including family studies and molecular analysis.

Purpose: To determine the prevalence of hypoparathyroidism in transfusion-dependent patients with beta-thalassemia., Patients and Methods: A total of 28 transfusion-dependent patients with beta-thalassemia were interviewed, and their serum calcium, phosphate, magnesium, and intact parathyroid hormone levels were checked. Serum ferritin levels were measured to monitor the effect of chelation therapy. Blood urea nitrogen, creatinine, total protein, and albumin were measured in patients with undetectable or low intact parathyroid hormone levels., Results: The prevalence of hypoparathyroidism was 10.7% (3/28). Mean age at diagnosis was 18 years. The serum ferritin levels of patients with hypoparathyroidism were 1,032, 2,102, and 7,680 microg/L. Only one patient had clinical symptoms of hypocalcemia. All three of the patients with hypoparathyroidism had hypogonadism, and 66.7% (2/3) of the patients had insulin-dependent diabetes mellitus., Conclusions: Hypoparathyroidism in transfusion-dependent patients with beta-thalassemia seems to be accompanied by other endocrinopathies. Serum ferritin may not have been a reliable indicator of iron overload in the three patients with hypoparathyroidism. Severe iron overload would easily explain these multiple endocrinopathies. This pattern is commonly seen in iron-overloaded patients with thalassemia elsewhere.

Purpose: India bears a major burden of homozygous beta-thalassemia. Hemoglobin (Hb) E/beta-thalassemia has been described mainly among Bengalis in Eastern India. Ethnic groups in northeastern India have among the highest known gene frequency for Hb E. However, there are few reports of Hb E/beta-thalassemia from these ethnic groups. This study aims to determine whether the paucity of reports of Hb E/beta-thalassemia from this region are because of underdiagnosis or complete elimination of beta-thalassemia by Hb E., Populations and Methods: The published literature concerning Hb E, beta-thalassemia, and the syndrome of Hb E/beta-thalassemia in Indid, Tibeto-Burman, and Austro-Asiatic ethnic groups in northeast India was analyzed to determine the gene frequency of Hb E and beta-thalassemia for different ethnic groups. The expected cases of Hb E/beta-thalassemia were calculated using the Hardy-Weinberg law., Results: The Bodo-Kachari have a gene frequency of 0.50 for Hb E, the highest anywhere in the world. There are, however, no reports of beta-thalassemia in this group. Among ethnic groups in which prevalence of Hb E and beta-thalassemia are known, there is a vast discrepancy between the reported number of cases of Hb E/beta-thalassemia and the number predicted by Hardy-Weinberg law. Thus, there are only seven cases of Hb E/beta-thalassemia from northeast India reported in the literature as opposed to 67,332 predicted cases., Conclusion: A potentially large pool of unsuspected Hb E/beta-thalassemia cases exist in northeast India. The significance of this finding and possible contributory factors are discussed.

Whereas hemoglobin (Hb) E-beta thalassemia is recognized as probably the most common serious hemoglobinopathy worldwide, its natural history remains poorly defined. The interaction of hemoglobin E and beta-thalassemia result in a wide spectrum of clinical disorders, some indistinguishable from thalassemia major and some milder and not transfusion-dependent. Partially as a result of this wide range of phenotypes, clear guidelines for approaches to transfusion and to iron-chelating therapy for patients with Hb E-beta thalassemia have not been developed. By contrast, data that have accumulated during the past 10 years in patients with beta-thalassemia permit a quantitative approach to the management of iron overload and provide guidelines for the control of body iron burden in individual patients treated with iron-chelating therapy. These guidelines may be applicable to patients with Hb E-beta thalassemia. Preliminary evidence from our studies of iron loading in affected patients with Hb E-beta thalassemia in Sri Lanka suggest that this disorder may be associated with variable, but accelerated, gastrointestinal iron absorption, and that the iron loading associated with chronic transfusions in patients with Hb E-beta thalassemia is similar to that observed in patients with beta-thalassemia. These data, in the only cohort of patients with Hb E-beta thalassemia to have undergone quantitative assessment of body iron burden, suggest that the principles that guide assessment of iron loading and initiation of chelating therapy in patients with beta-thalassemia may be generally applicable to those with Hb E-beta thalassemia. Further quantitative studies in both nontransfused and transfused patients will be necessary to permit firm conclusions.

Hemoglobin (Hb) F levels are high and variable in Hb E/beta-thalassemia, ranging from 10% to 80%. The high levels are secondary to expansion of the erythron with ineffective erythropoiesis and selection in favor of cells able to make more gamma-globin. The variability in levels reflects the complex processes involved in Hb F production. Important determinants include age, alpha-thalassemia, and genetic determinants of gamma-chain synthesis. Overall, percentage of Hb F correlates with total hemoglobin levels and decreases steadily with age. alpha-thalassemia is associated with a lower percentage of Hb F levels but a higher total hemoglobin level in Hb E/beta-thalassemia.