Comparing different markers of tubular dysfunction in transfusion-dependent thalassemia patients.

BACKGROUND: Renal tubular dysfunction was reported in transfusion-dependent thalassemia (TDT) patients and ranges from mild to severe. The objectives of our study were identification of the best marker of early renal tubular dysfunction in TDT patients among the three most commonly used urinary biomarkers, named neutrophil gelatinase-associated lipocalin (NGAL), retinol-binding protein (RBP) and N-acetyl-D-glucosaminidase (NAG) and correlation of these biomarkers with different patient variables. METHODOLOGY: Sixty-one TDT patients and another 62 healthy children were enrolled in a cross-sectional study. Morning urine samples were taken for measurement of calcium, phosphorus, creatinine, microalbumin and markers of tubular dysfunction (NGAL, NAG and RBP). Urine NGAL/creatinine (UrNGAL/Cr), urine NAG/creatinine (UrNAG/Cr) and urine RBP/creatinine (UrRBP/Cr) ratios were used for accuracy. Patients were classified into 2 groups: group A, with tubular dysfunction and group b, without tubular dysfunction. RESULTS: Group A showed statistically significant higher UrNGAL/Cr (p < 0.001), UrRBP/Cr (p < 0.001) and UrNAG/Cr (p <0.001) than group B. In group A, microalbuminuria was detected only in 7 patients (28%) while it was detected in 12 patients (33.3%) in group B. By using ROC curve analysis, the diagnostic cutoff values for UrNGAL/Cr, UrRBP/Cr and UrNAG/Cr were 3713.38, 1614.85 and 56.56 ng/g, respectively. We found a statistically significant superiority of UrNGAL/Cr over UrRBP/Cr (p < 0.001) and UrRBP/Cr over UrNAG/Cr (p < 0.001). CONCLUSION: Evaluation of UrNGAL/Cr, UrRBP/Cr and UrNAG/Cr could early discriminate tubular dysfunction TDT patients from those with normal tubular function. UrNGAL/Cr is more accurate in early detection of tubular dysfunction when compared with the other two biomarkers.

Genotyping analysis of the MNS blood group system of thalassemia patients with alloantibodies in Iran.

BACKGROUND: Serological methods are unreliable for accurate determination of blood group antigens in multi-transfused thalassemia patients. The MNS blood group system has five high-frequency antigens. Many studies demonstrated that some antibodies including anti-S, anti-s, and anti-U may cause acute and delayed transfusion reactions and hemolytic disease of the fetus and newborn. This study aimed to determine the genotype of the MNS blood group in thalassemia patients with alloantibodies by molecular methods. MATERIAL AND METHODS: In this study, 104 blood samples from thalassemia patients were collected. The blood group phenotype for M, N, S and s antigens was determined by the tube hemagglutination method. MNS blood group genotyping was performed using PCR-SSP and DNA Sequencing methods. RESULTS: All patients were genotyped with a total of 6 pairs of primers. Discrepancies between genotype and phenotype were observed in 22 patients with S/s alleles and 2 patients with M/N alleles, however, there was full accordance between the results of SSP-PCR and DNA sequencing. The frequency of MNS blood group alleles was determined as follows: 25 % MNSs, 23 % MNss, 21 % MMSs, 9% MMSS, 9% MMss, 8% NNss, 2%MNSS, and NNSS, NNSs, MM genotypes at 1% each. CONCLUSION: In conclusion, molecular genotyping is more reliable than serological methods in multiple transfusion patients and can lead to a more compatible blood unit for transfusion in these patients.

Prevalence and prognostic impact of left ventricular non-compaction in patients with thalassemia.

A high incidence of isolated left ventricular non-compaction (LVNC) has been reported in previous studies on smaller cohorts of patients with thalassemia by cardiac MRI but the clinical impact of the finding is unknown. This prospective cohort study evaluates the prevalence and clinical implication of the finding. Prospective cohort study with enrollment of all consecutive cases with thalassemia referred for cardiac MRI from September 2007 to November 2014. The presence of LVNC was assessed according to the Petersen method and the Jacquier method, with the proposed changes by Fazio, Grothoff, and Chiodi. A clinical follow-up was performed in all patients. We included 560 patients with thalassemia (473 with thalassemia major and 87 with thalassemia intermedia: mean age 31.9 ± 10.6 years, male/female = 250/310). A total number of 1683 MRI tests were performed. A diagnosis of LVNC was determined according to adopted MR criteria in 44 patients (7.9%). Patients with LVNC had a significantly lower ejection fraction (52.68 ± 5.17% vs. 56.90 ± 6.34%; p = 0.0005) and greater indexed LV ESV (48.16 ± 10.03 ml/m2 vs. 40.02 ± 10.06 ml/m2; p = 0.0022). After a mean follow-up time was 5.1 years, no significant change of MR parameters was detected as well as no clinical adverse events. LVNC is relatively frequent in patients with thalassemia. However, it is not associated with a worsening of LV function and adverse events after a long-term follow-up.

Erythropoiesis and Iron Homeostasis in Non-Transfusion-Dependent Thalassemia Patients with Extramedullary Hematopoiesis.

BACKGROUND: Extramedullary hematopoiesis (EMH) is common in non-transfusion-dependent thalassemia (NTDT) patients. Clinical presentations of EMH vary as MRI screening is not feasible. Hence, serum biomarkers are used to predict the risk of EMH. MATERIALS AND METHODS: 52 NTDT patients, including 26 EMH (+) and 26 EMH (-), together with 26 healthy controls, were enrolled in this case-control study from 2013 to 2016. EMH was confirmed by computed tomography or MRI. Demographic, transfusion, genetic, laboratory, and liver iron concentration (LIC) data, as well as clinical complications, were analyzed. RESULTS: EMH (+) patients had significantly higher serum ferritin (SF), growth differentiation factor 15 (GDF15), and erythropoietin (EPO) levels compared with EMH (-) patients and controls. The levels of erythroferrone (ERFE), hepcidin, and sTfR did not differ significantly between EMH (+) and EMH (-) patients (p>0.05). In NTDT patients, serum ERFE was not related to SF, LIC, hepcidin, sTfR, EPO, GDF15, and Hb levels. GDF15, EPO concentrations, and GDF15 to sTfR and GDF15 to EPO ratios are able to determine the presence of EMH with considerable sensitivity and specificity. CONCLUSIONS: GDF15, EPO, and GDF15 to EPO and GDF15 to sTfR ratios are potential biomarkers for the early prediction of NTDT in patients who are at risk for EMH.

Review of disease-related complications and management in adult patients with thalassemia: A multi-center study in Thailand.

Disease-related complications and management are different among patients with thalassemia. This study was aimed to review the prevalence, clinical risk factors for the complications and the management in patients with thalassemia in Thailand. A multicenter cross-sectional study was conducted in patients with thalassemia aged ≥ 18 years old. Thalassemia-related complications and management were reviewed. The clinical parameters significantly associated with the complications were analyzed by logistic regression methods. The prevalence of thalassemia-related complications was 100% in patients with transfusion-dependent thalassemia (TDT) and 58.8% in patients with non-transfusion-dependent thalassemia (NTDT). Advanced age was statistically associated with extramedullary hematopoiesis in both TDT and NTDT patients. Splenectomy was a significant risk factor for pulmonary hypertension in both groups of patients. Severe iron overload started earlier in patients with TDT than NTDT and was associated with diabetes mellitus (adjusted odds ratio (AOR) = 6.2, p-value = 0.02). Disease-related complications are more prevalent in patients with TDT than patients with NTDT. Splenectomy and advanced age were important risk factors for developing major complications in both groups. Early screening and management for specific disease-related complications should be considered in patients with thalassemia according to their clinical risk factors.

Risk factors for heart disease in transfusion-dependent thalassemia: serum ferritin revisited.

Heart disease remains a leading cause of morbidity and mortality in transfusion-dependent thalassemia (TDT), which can be attributed to several factors but primarily develops in the setting of iron overload. This was a retrospective cohort study utilizing Webthal® patient data from five major centers across Italy. Patients without heart disease were followed-up for 10 years (2000-2010) and data were collected for demographics, splenectomy status, serum ferritin and hemoglobin levels, and comorbidities associated with heart disease. Among 379 patients analyzed (mean age 22.9 ± 5.1 years, 47.8% men), 44 (cumulative incidence: 11.6%) developed heart disease during the period of observation. Splenectomy (p = 0.002) and serum ferritin level (p < 0.001) were the only risk factors with significant association with heart disease. A serum ferritin threshold of ≥ 3000 ng/mL was the best predictor for the development of heart disease (86.4% sensitivity and 92.8% specificity, AUC: 0.912, 95% CI 0.852-0.971, p < 0.001). On multivariate analysis, only a serum ferritin level ≥ 3000 ng/mL remained significantly and independently associated with increased risk of heart disease (HR: 44.85, 95% CI 18.85-106.74), with a 5- and 10-year heart disease-free survival of 58 and 39%. The association between iron overload and heart disease in patients with TDT is confirmed, yet a new serum ferritin level of 3000 ng/mL to flag increased risk is suggested.

Effects of the iron chelator deferiprone and the T-type calcium channel blocker efonidipine on cardiac function and Ca2+ regulation in iron-overloaded thalassemic mice.

Although disturbance of cardiac Ca2+ regulation is involved in the pathophysiology of iron-overload cardiomyopathy, the obvious mechanisms involved in the dysregulation of iron-induced cardiac Ca2+ are unclear. Moreover, the roles of the iron chelator deferiprone and the T-type calcium channel blocker efonidipine on cardiac intracellular Ca2+ transients and Ca2+ regulatory proteins in thalassemic mice are still unknown. We tested the hypothesis that treatment with either deferiprone or efonidipine attenuated cardiac Ca2+ dysregulation and led to improved left ventricular (LV) function in iron-overloaded thalassemic mice. Wild-type (WT) mice and ß-thalassemic (HT) mice were fed with either a normal diet (ND) or a high iron-diet (FE) for 90 days. Then, the FE-fed mice were treated with either deferiprone (75 mg/kg/day) or efonidipine (4 mg/kg/day) for 30 days. ND-fed HT mice had an increase in T-type calcium channels (TTCC) and an increased level of sarcoplasmic reticulum Ca2+-ATPase (SERCA), compared with ND-fed WT mice. Chronic iron feeding led to an increase in TTCC and expression of SERCA proteins in FE-fed WT mice. Moreover, chronic iron overload led to increased plasma non-transferrin bound iron (NTBI) and cardiac iron deposition, impaired cardiac intracellular Ca2+ transients including decreased intracellular Ca2+ transient amplitude, rising rate and decay rate, as well as impaired LV function as indicated by a decreased %LV ejection fraction (%LVEF) in both WT and HT mice. Our findings showed that treatment with either deferiprone (DFP) or efonidipine (EFO) showed similar benefits in reducing plasma NTBI and cardiac iron deposition, and improving %LVEF from 84.3 (WT) to 89.3 (DFP) and 89.2 (EFO) treatment; and from 84.2 (HT) to 88.8 (DFP) and 89.5 (EFO) treatment, however there was no improvement in the regulation of cardiac Ca2+ in iron-overloaded thalassemic mice. These findings provide the understanding of the effects of these drugs on the iron-overloaded heart in thalassemic mice and suggest that an alternative intervention that could improve calcium regulation under this condition is needed to improve the therapeutic outcome. Moreover, whether the benefits of the TTCC blocker is via its inhibition of the TTCC alone or together with its ability to chelate iron are still unclear and need further investigation.

Deferiprone increases endothelial nitric oxide synthase phosphorylation and nitric oxide production.

Iron chelation can improve endothelial function. However, effect on endothelial function of deferiprone has not been reported. We hypothesized deferiprone could promote nitric oxide (NO) production in endothelial cells. We studied effects of deferiprone on blood nitrite and blood pressure after single oral dose (25 mg/kg) in healthy subjects and hemoglobin E/ß-thalassemia patients. Further, effects of deferiprone on NO production and endothelial NO synthase (eNOS) phosphorylation in primary human pulmonary artery endothelial cells (HPAEC) were investigated in vitro. Blood nitrite levels were higher in patients with deferiprone therapy than those without deferiprone (P = 0.023, n = 16 each). Deferiprone increased nitrite in plasma and whole blood of healthy subjects (P = 0.002 and 0.044) and thalassemia patients (P = 0.003 and 0.046) at time 180 min (n = 20 each). Asymptomatic reduction in diastolic blood pressure (P = 0.005) and increase in heart rate (P = 0.009) were observed in healthy subjects, but not in thalassemia patients. In HPAEC, deferiprone increased cellular nitrite and phospho-eNOS (Ser1177) (P = 0.012 and 0.035, n = 6) without alteration in total eNOS protein and mRNA. We conclude that deferiprone can induce NO production by enhancing eNOS phosphorylation in endothelial cells.

Fertility and Pregnancy in Women with Transfusion-Dependent Thalassemia.

As more women with transfusion-dependent thalassemia are seeking pregnancy, ensuring the best outcomes for both the mother and baby requires concerted, collaborative efforts between practitioners and the family. Proactive counseling, early fertility evaluation, recent developments in reproductive technology, and optimal management of iron overload, have resulted in more successful pregnancies and the birth of healthy newborns. With advances in technology for prenatal screening and increased awareness to perform screening for hemoglobinopathies, healthy pregnancy outcomes have become the expectation. Topics that require further study include management that allows fertility preservation, improved non-invasive prenatal diagnosis methods for affected fetuses, the use of chelation therapy during pregnancy, and indications for and duration of anticoagulation.

Increased sympathovagal imbalance evaluated by heart rate variability is associated with decreased T2* MRI and left ventricular function in transfusion-dependent thalassemia patients.

Early detection of iron overload cardiomyopathy is an important strategy for decreasing the mortality rate of patients with transfusion-dependent thalassemia (TDT). Although cardiac magnetic resonance (CMR) T2* is effective in detecting cardiac iron deposition, it is costly and not generally available. We investigated whether heart rate variability (HRV) can be used as a screening method of iron overload cardiomyopathy in TDT patients. HRV, evaluated by 24-h Holter monitoring, non-transferrin bound iron (NTBI), serum ferritin, left ventricular (LV) ejection fraction (LVEF), and CMR-T2* were determined. Patients with a cardiac iron overload condition had a significantly higher low frequency/high frequency (LF/HF) ratio than patients without a cardiac iron overload condition. Log-serum ferritin (r = -0.41, P=0.008), serum NTBI (r = -0.313, P=0.029), and LF/HF ratio (r = -0.286, P=0.043) showed a significant correlation with CMR-T2*, however only the LF/HF ratio was significantly correlated with LVEF (r = -0.264, P=0.043). These significant correlations between HRV and CMR-T2* and LVEF in TDT confirmed the beneficial role of HRV as a potential early screening tool of cardiac iron overload in thalassemia patients, especially in a medical center in which CMR T2* is not available. A larger number of TDT patients with cardiac iron overload are needed to confirm this finding.

Glomerular and Tubular Functions in Children and Adults with Transfusion-Dependent Thalassemia.

This study aimed at assessing renal functions in patients with transfusion-dependent thalassemia (TDT). Fifty patients and 30 controls were enrolled in this prospective study. Serum levels of electrolytes and albumin were measured by a spectrophotometer. Serum levels of cystatin-C and urinary levels of ß2-microglobulin were measured by nephelometric method. Thirty-eight patients were receiving deferasirox and 8 were on deferiprone. Serum electrolytes and albumin levels of the patients were found to be within normal ranges. Urinary ß2-microglobulin and serum cystatin-C levels were significantly higher in patients than controls. They did not significantly differ between the subgroup of patients on deferiprone and the control group, whereas they were found to be higher in patients using deferasirox compared to controls. Urinary ß2-microglobulin levels significantly increased in patients who were receiving high-dose deferasirox compared to those who were receiving a daily dose of 15-20 mg/kg or controls. Subclinical renal injury may be present in TDT patients.

Thalassaemia.

Inherited haemoglobin disorders, including thalassaemia and sickle-cell disease, are the most common monogenic diseases worldwide. Several clinical forms of α-thalassaemia and ß-thalassaemia, including the co-inheritance of ß-thalassaemia with haemoglobin E resulting in haemoglobin E/ß-thalassaemia, have been described. The disease hallmarks include imbalance in the α/ß-globin chain ratio, ineffective erythropoiesis, chronic haemolytic anaemia, compensatory haemopoietic expansion, hypercoagulability, and increased intestinal iron absorption. The complications of iron overload, arising from transfusions that represent the basis of disease management in most patients with severe thalassaemia, might further complicate the clinical phenotype. These pathophysiological mechanisms lead to an array of clinical manifestations involving numerous organ systems. Conventional management primarily relies on transfusion and iron-chelation therapy, as well as splenectomy in specific cases. An increased understanding of the molecular and pathogenic factors that govern the disease process have suggested routes for the development of new therapeutic approaches that address the underlying chain imbalance, ineffective erythropoiesis, and iron dysregulation, with several agents being evaluated in preclinical models and clinical trials.

Flow cytometric osmotic fragility test: Increased assay sensitivity for clinical application in pediatric hematology.

BACKGROUND: Osmotic fragility test (OFT) is widely considered as a sensitive indicator of red blood cells' sensitivity to the hypotonic solution. It is often used as a screening test for the diagnosis of hereditary spherocytosis (HS). Nowadays, the osmotic fragility test based on flow cytometric analysis (FCM OF) is widely used in laboratory practice. The purpose of this study was to optimize the assay sensitivity and to validate its clinical application in the diagnostic screening of childhood anemias. METHODS: The study was conducted on 175 children suffering from various types of anemia (including 30 children with proven hereditary spherocytosis, HS) and 16 healthy subjects. All children were aged between 3 months and 17 years, including 94 boys and 97 girls. FCM OF was performed on every subject according to two different analysis time patterns (hemolysis was analyzed for 214 or 300 s) using Cytomics FC500 flow cytometer. RESULTS: Significant higher sensitivity was demonstrated by the tests carried out according to the longer analysis time pattern (90.0 vs. 83.33%). The level of specificity of both the analysis patterns was similar. When an extended analysis time was used, the percentage of red cell survival levels in HS patients were significantly lowered compared to the same cases analyzed with shorter incubation times and all other non-HS anemic cases (9.31 ± 4.69 vs. 35.59 ± 15.30%, P < 0.05). During the shorter analysis time, the values obtained were 13.76 ± 7.92% for HS and 48.18 ± 19.04% for non-HS, P < 0.0001. The 300-s test is very useful in distinguishing thalassemia patients from patients with other types of anemias (94.74% sensitivity and 90.12% specificity) and provided the values of remaining red blood cells as 70.46 ± 12.29% for thalassemia and 27.16 ± 13.01% for nonthalassemia subjects, P < 0.0001. CONCLUSION: Flow cytometric osmotic fragility test with a longer (300-s) analysis time demonstrated an increased sensitivity in detecting HS in anemic children. © 2017 International Clinical Cytometry Society.

A Comparison Of Skeletal Age Of Thalassaemic Patients Of 9-15 Years With Chronological Age By Radiography.

BACKGROUND: Thalassemia is inherited disorder characterized by haemolytic anaemia, due to complete absence or reduced ß-globin chain synthesis, stimulating pathological bone marrow overstimulation and altered erythropoiesis. The change in bone mass ultimately results into miss interpretation of bone age once assed from x-ray radiograph. The aims compare skeletal age of thalassaemic children of 9-15 years with chronological age by x-ray wrist bones. METHODS: This was cross sectional analytical study; the study was conducted in conjunction with Fatimid Hospital Peshawar Pakistan and Out Patients Department (OPD) of paediatrics for minor illness (other than Thalassemia) Khyber Teaching Hospital August 2014 to January 2015. A total 156 samples were selected convenient sampling to make comparison of bone age and chronological age between thalassaemic children (age 9-15years) and age sex matched normal control. A structure data collection check list was used to collect data X-ray findings (bone age). SPSS 20 was used for statistical analysis. RESULTS: The results showed a total of 156 children with their mean age 11.9±2.2, male were 97 (62.2%) and females 59 (37.8%). Out of thalassaemic (n=76) majority 49 (62.8%) were male as compared to female 29 (37.2%). The mean chorological age among both of group were not significantly different (p=0.67). However, the bone age was significantly different from each other (p=0001). Pearson's correlation analysis revealed that was strong correlation between erupt teeth and bone age (r=0.462, p=0.0001). CONCLUSION: Skeletal age assessment was found to be suboptimal along with chronological age in children and adolescents suffering from thalassemia.

Serum Levels of S100b and NSE Proteins in Patients with Non-Transfusion-Dependent Thalassemia as Biomarkers of Brain Ischemia and Cerebral Vasculopathy.

Patients with non-transfusion-dependent thalassemia (NTDT) are at risk of developing brain ischemia. Transcranial Doppler (TCD) has been established as a useful screening tool of cerebrovascular disease in patients with sickle cell disease. Proteins neuron specific enolase (NSE) and S100B are biomarkers that reflect CNS injury. The purpose of this study is to evaluate cerebral vessel vasculopathy and brain damage in NTDT patients using non-invasive methods as TCD and measurement serum levels of NSE and S100B. We included in our study 30 patients with NTDT, aged between 8 and 62 years old (mean: 29.4, median: 32) who presented in our Unit for regular follow-up. We performed in all patients a non-imaging TCD examination and have measured serum S100, NSE and lactate dehydrogenase (LDH) levels. We investigated the possible correlation between TCD results and S100B, NSE and LDH levels as well as between NSE-LDH and S100B-LDH levels by regression analysis. We found a statistically significant relationship for both NSE, S100B with LDH. We also found a statistically significant relationship for S100B and time-averaged mean velocity (TAMV)/peak velocity of left middle cerebral artery (MCA), NSE and pulsatility index (PI)/resistive index (RI) of the left posterior cerebral artery (PCA). TCD results correlated with biomarkers for brain ischemia. This finding enhances the role of TCD as a screening tool for brain ischemia in patients with NTDT.

Portal vein aneurysm in thalassaemia.

Arterial aneurysms are more common than visceral venous aneurysms. Portal vein aneurysms being the most common type of visceral venous aneurysms. Here, we present an 18-year-old young woman with thalassaemia major, who presented with headache, palpitation, shortness of breath and a recent increase in blood transfusion rate. On clinical examination, she had hepatosplenomegaly. Ultrasonography revealed hepatosplenomegaly with fusiform dilatation of extrahepatic portal vein, which was confirmed to be portal vein aneurysm on contrast enhanced CT. Though portal vein aneurysms were previously thought to be rare, recently they are increasingly diagnosed with the use of cross-sectional imaging. Recognition of this finding can help to avoid potential confusion with other periportal cystic masses of different aetiologies, especially on sonography.

Investigational drugs in phase I and phase II clinical trials for thalassemia.

INTRODUCTION: Regular transfusion and iron chelation are the current treatment of severe forms of thalassemia. As a consequence of this demanding supportive treatment, there are several unmet therapeutic needs. Due to a deeper understanding in the pathophysiology of thalassemia, new therapeutic strategies have been developed that are now in pre-clinical and clinical trials. Areas covered: Activin receptor ligand traps (luspatercept and sotatercept), drugs targeting ineffective erythropoiesis, showed encouraging results in Phase I and II clinical trials. A phase III clinical trial is currently ongoing. Ruxolitinib, a Jak2 inhibitor, has been tested to limit stress erythropoiesis in a phase II clinical trial. In addition, improvement in iron chelation has been developed. Moreover, several trials of gene therapy are currently active in different countries with different lentiviral vectors. Expert opinion: The most promising molecules are the activin receptor ligand traps. Together with gene therapy these could be an alternative to bone marrow transplant, aiming towards a curative strategy. The main limit to gene therapy seems to be the conditioning regimen, thus an in vivo gene therapy would be more suitable. At pre-clinical level gene editing is showing extremely encouraging results.

Cardiac iron overload in chronically transfused patients with thalassemia, sickle cell anemia, or myelodysplastic syndrome.

The risk and clinical significance of cardiac iron overload due to chronic transfusion varies with the underlying disease. Cardiac iron overload shortens the life expectancy of patients with thalassemia, whereas its effect is unclear in those with myelodysplastic syndromes (MDS). In patients with sickle cell anemia (SCA), iron does not seem to deposit quickly in the heart. Our primary objective was to assess through a multicentric study the prevalence of cardiac iron overload, defined as a cardiovascular magnetic resonance T2*<20 ms, in patients with thalassemia, SCA, or MDS. Patient inclusion criteria were an accurate record of erythrocyte concentrates (ECs) received, a transfusion history >8 ECs in the past year, and age older than 6 years. We included from 9 centers 20 patients with thalassemia, 41 with SCA, and 25 with MDS in 2012-2014. Erythrocytapharesis did not consistently prevent iron overload in patients with SCA. Cardiac iron overload was found in 3 (15%) patients with thalassemia, none with SCA, and 4 (16%) with MDS. The liver iron content (LIC) ranged from 10.4 to 15.2 mg/g dry weight, with no significant differences across groups (P = 0.29). Abnormal T2* was not significantly associated with any of the measures of transfusion or chelation. Ferritin levels showed a strong association with LIC. Non-transferrin-bound iron was high in the thalassemia and MDS groups but low in the SCA group (P<0.001). Hepcidin was low in thalassemia, normal in SCA, and markedly elevated in MDS (P<0.001). Two mechanisms may explain that iron deposition largely spares the heart in SCA: the high level of erythropoiesis recycles the iron and the chronic inflammation retains iron within the macrophages. Thalassemia, in contrast, is characterized by inefficient erythropoiesis, unable to handle free iron. Iron accumulation varies widely in MDS syndromes due to the competing influences of abnormal erythropoiesis, excess iron supply, and inflammation.

Unusual Anemias.

Many processes lead to anemia. This review covers anemias that are less commonly encountered in the United States. These anemias include hemoglobin defects like thalassemia, bone marrow failure syndromes like aplastic anemia and pure red cell aplasia, and hemolytic processes such as paroxysmal nocturnal hemoglobinuria. The pathogenesis, diagnostic workup, and treatment of these rare anemias are reviewed.