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1.  Beliefs about chelation among thalassemia patients 
Understanding patients’ views about medication is crucial to maximize adherence. Thalassemia is a congenital blood disorder requiring chronic blood transfusions and daily iron chelation therapy.
The Beliefs in Medicine Questionnaire (BMQ) was used to assess beliefs in chelation in thalassemia patients from North America and London in the Thalassemia Longitudinal Cohort (TLC) of the Thalassemia Clinical Research Network (TCRN). Chelation adherence was based on patient report of doses administered out of those prescribed in the last four weeks.
Of 371 patients (ages 5-58y, mean 24y), 93% were transfused and 92% receiving chelation (26% deferoxamine (DFO; a slow subcutaneous infusion via portable pump), 63% oral, 11% combination). Patients expressed high “necessity” for transfusion (96%), DFO chelation (92%) and oral chelation (89%), with lower “concern” about treatment (48%, 39%, 19% respectively). Concern about oral chelation was significantly lower than that of DFO (p<0.001). Self-reported adherence to chelation was not associated with views about necessity or concerns, but negatively correlated with perceived sensitivity to DFO (Sensitive Soma scale; r=−0.23, p=0.01) and side effects of oral chelation (r=−0.14, p=0.04). High ferritin iron levels, potentially indicating lower adherence, were found in 41% of patients reporting low necessity of oral chelation compared to 24% reporting high necessity (p=0.048). Concerns about treatment were associated with lower quality of life and more symptoms of anxiety and depression.
Despite their requirement for multimodal therapy, thalassemia patients have positive views about medicine, more so than in other disease populations. Patients may benefit from education about the tolerability of chelation and strategies to effectively cope with side effects, both of which might be beneficial in lowering body iron burden. identifier
PMCID: PMC3545841  PMID: 23216870
Thalassemia; Necessity; Concerns; Chelation; Adherence
2.  Comparative Efficacy and Safety of Deferoxamine, Deferiprone and Deferasirox on Severe Thalassemia: A Meta-Analysis of 16 Randomized Controlled Trials 
PLoS ONE  2013;8(12):e82662.
A meta-analysis was conducted to investigate the efficacy and safety of three main iron chelators, namely, deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX) for thalassemia major (TM) patients.
Randomized controlled trials comparing mono-therapy DFO, DFP, DFX and combined DFP with DFO therapy in TM patients from January 1990 to December 2012 were searched and selected. Two independent authors assessed data from extracted randomized trials for efficacy and safety in the measurements of serum ferritin (SF), live iron concentration (LIC), myocardial iron content (MIC), left ventricular ejection fraction (LVEF) and adverse events (AEs).
Sixteen studies were selected. In the comparison of DFP versus DFO treatment groups, a significant difference was revealed on MIC and LVEF (P=0.01 and P=0.007, respectively) but not on SF or LIC level (P=0.65 and P=0.37, respectively). In comparing combined therapy (DFP plus DFO) versus DFO, a significant difference was shown on MIC and LVEF measurements (P<0.00001 and P=0.003, respectively), but not on SF or LIC levels (P=0.93 and P=0.62, respectively). Moreover, the combined DFP with DFO treatment had significantly higher risk than DFO treatment (RR 1.46 with 95%CI 1.04 to 2.04). When comparing DFX with DFO, a significant difference was shown on the SF level (P=0.003), and there was no difference between DFX and DFO in safety evaluation (RR 1.53 with 95%CI 0.31 to 7.49).
Findings indicated that the most effective and safe iron chelators remains to be proven, and further large-scale, long-term studies are needed.
PMCID: PMC3871701  PMID: 24376563
3.  Major Causes of Hospital Admission in Beta Thalassemia Major Patients in Southern Iran 
Iranian Journal of Pediatrics  2011;21(4):509-513.
Beta thalassemia major is a prevalent hereditary disease in Mediterranean region especially Iran. Early blood transfusion is necessary for most of the patients and frequent transfusion can cause various medical problems for the patients. The aim of this study was to find major causes of hospital admission in beta thalassemia major patients to reach the accurate preventive and therapeutic plans for these patients.
Four hundred twenty six patients were admitted to the Nemazee Hospital (the main University referral Hospital Center affiliated to Shiraz University of Medical Sciences in Fars Province, southern Iran) during 3 years period (January 2007 to January 2010). A questionnaire was filled containing age, gender, hemoglobin level, frequency of blood transfusions, deferoxamine injection, cause of hospital admission and hospital course.
The mean age of patients was 11.28 years. The mean serum ferritin level was 1820±749 µg/lit. Two hundred fifty five (59.75%) patients were male and 171 (40.25%) patients were female. The top five most prevalent causes of hospital admission were splenectomy (21.8%), infections (19.9%), congestive heart failure (19.0%), diabetes mellitus (13.4%), and Liver biopsy (11.5%). (P=0.0002)
Results of this study revealed that infections and complications due to iron overload are major causes of hospital admission in beta thalassemia major patients.
PMCID: PMC3446139  PMID: 23056840
Beta Thalassemia major; Hospitalization; Complication; Iran
4.  Renal functions in pediatric patients with beta-thalassemia major: relation to chelation therapy: original prospective study 
In β-thalassemia, profound anemia and severe hemosiderosis cause functional and physiological abnormalities in various organ systems. In recent years, there have been few published studies mainly in adult demonstrating renal involvement in β-thalassemia. This prospective study was aimed to investigate renal involvement in pediatric patients with transfusion dependant beta-thalassemia major (TD-βTM), using both conventional and early markers of glomerular and tubular dysfunctions, and to correlate findings to oxidative stress and iron chelation therapy.
Sixty-nine TD-βTM patients (aged 1-16 years) and 15 healthy controls (aged 3-14 years) were enrolled in this study. Based on receiving chelation therapy (deferoxamine, DFO), patients were divided into two groups: group [I] with chelation (n = 34) and group [II] without chelation (n = 35). Levels of creatinine (Cr), calcium (Ca), inorganic phosphorus (PO4), uric acid (UA) and albumin were measured by spectrophotometer. Serum (S) levels of cystatin-C (SCysC) and total antioxidant capacity (STAC) and urinary (U) levels of β2-microglobulin (Uβ2MG) were measured by immunosorbent assay (ELISA). Urinary N-acetyl-beta-D-glucosaminidase (UNAG) activity and malondialdehyde (UMDA) were measured by chemical methods. Estimated glomerular filtration rate (eGFR) was determined from serum creatinine.
In patient with and without chelation, glomerular [elevated SCysC, SCr, Ualbumin/Cr and diminished eGFR]; and tubular dysfunctions [elevated SUA, SPO4, UNAG/Cr, Uβ2MG/Cr] and oxidative stress marker disturbances [diminished STAC and elevated UMDA/Cr] were reported than controls. In patients with chelation, SCysC was significantly higher while, STAC was significantly lower than those without chelation. In all patients, SCysC showed significant positive correlation with SCr and negative correlation with eGFR; STAC showed significant positive correlation with eGFR and negative correlation with SCysC, SCr, UNAG/Cr; UMDA/Cr showed significant positive correlation with Ualbumin/Cr, Uβ2MG/Cr, UNAG/Cr.
Our data confirm high frequency of glomerular and tubular dysfunctions in TD-βTM pediatric patients which could be attributed to oxidative stress and DFO therapy.
PMCID: PMC2894023  PMID: 20500848
5.  Cardiac and hepatic iron and ejection fraction in thalassemia major: Multicentre prospective comparison of combined Deferiprone and Deferoxamine therapy against Deferiprone or Deferoxamine Monotherapy 
Due to the limited data available in literature, the aim of this multi-centre study was to prospectively compare in thalassemia major (TM) patients the efficacy of combined deferiprone (DFP) and deferoxamine (DFO) regimen versus either DFP and DFO in monotherapy by cardiovascular magnetic resonance (CMR) over a follow up of 18 months.
Among the first 1135 TM patients in the MIOT (Myocardial Iron Overload in Thalassemia) network, we evaluated those who had received either combined regimen (DFO + DFP, N=51) or DFP (N=39) and DFO (N=74) monotherapies between the two CMR scans. Iron overload was measured by T2* multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images.
The percentage of patients that maintained a normal global heart T2* value was comparable between DFP+DFO versus both monotherapy groups. Among the patients with myocardial iron overload at baseline, the changes in the global heart T2* and in biventricular function were not significantly different in DFP+DFO compared with the DFP group. The improvement in the global heart T2* was significantly higher in the DFP+DFO than the DFO group, without a difference in biventricular function. Among the patients with hepatic iron at baseline, the decrease in liver iron concentration values was significantly higher with combination therapy than with either monotherapy group.
In TM patients at the dosages used in the real world, the combined DFP+DFO regimen was more effective in removing cardiac iron than DFO, and was superior in clearing hepatic iron than either DFO or DFP monotherapy. Combined therapy did not show an additional effect on heart function over DFP.
PMCID: PMC3599638  PMID: 23324167
Thalassemia; Chelation therapy; Cardiovascular magnetic resonance
6.  Longitudinal Study on Liver Functions in Patients with Thalassemia Major before and after Deferasirox (DFX) Therapy 
By performing regular blood transfusion and iron chelation therapy, most patients with beta thalassemia major (BTM) now survive beyond the third decade of life. Liver disease is becoming an important cause of morbidity and mortality in these patients. Chronic hepatitis and/or severe iron overload are both important causes of liver pathology. Iron chelation with desferrioxamine (DFO) reduces excessive body iron, but its efficacy is limited by poor compliance and dose related toxicity. The recent use of Deferasirox ( DFX ), an oral single dose therapy, has improved the compliance to chelation.
To study the long-term liver functions in BMT patients, seronegative for liver infections before versus after DFX treatment in relation to ferritin level.
Only BTM patients with hepatitis negative screening (checked every year) and on treatment with DFO for at least five years and with DFX for four years were enrolled. Liver function tests including serum bilirubin, alanine transferase (ALT), aspartate transferase (AST), albumin, insulin-like growth factor – I (IGF-I) and serum ferritin concentrations were followed every six months in 40 patients with BTM.
DFX treatment (20 mg/kg/day) significantly decreased serum ferritin level in patients with BTM; this was associated with a significant decrease in serum ALT, AST, ALP and increase in IGF-I concentrations. Albumin concentrations did not change after DFX treatment. ALT and AST levels were correlated significantly with serum ferritin concentrations ( r = 0.45 and 0.33 respectively, p < 0.05). IGF-I concentrations were correlated significantly with serum ALT (r= 0.26, p = 0.05) but not with AST, ALP, bilirubin or albumin levels.
The negative correlation between serum ferritin concentrations and ALT suggests that the impairment of hepatic function negatively affect IGF-I synthesis in these patients due to iron toxicity, even in the absence of hepatitis.
Some impairment of liver function can occur in hepatitis negative thalassemic patients with iron overload. The use of DFX was associated with mild but significant reduction of ALT, AST and ALP and increase in IGF-I levels. The negative correlation between IGF-I and ALT concentrations suggest that preventing hepatic dysfunction may improve the growth potential in these patients.
PMCID: PMC4010606  PMID: 24803998
7.  Objectives and Methods of Iron Chelation Therapy 
Recent developments in the understanding of the molecular control of iron homeostasis provided novel insights into the mechanisms responsible for normal iron balance. However in chronic anemias associated with iron overload, such mechanisms are no longer sufficient to offer protection from iron toxicity, and iron chelating therapy is the only method available for preventing early death caused mainly by myocardial and hepatic damage. Today, long-term deferoxamine (DFO) therapy is an integral part of the management of thalassemia and other transfusion-dependent anemias, with a major impact on well-being and survival. However, the high cost and rigorous requirements of DFO therapy, and the significant toxicity of deferiprone underline the need for the continued development of new and improved orally effective iron chelators. Within recent years more than one thousand candidate compounds have been screened in animal models. The most outstanding of these compounds include deferiprone (L1); pyridoxal isonicotinoyl hydrazone (PIH) and; bishydroxy- phenyl thiazole. Deferiprone has been used extensively as a substitute for DFO in clinical trials involving hundreds of patients. However, L1 treatment alone fails to achieve a negative iron balance in a substantial proportion of subjects. Deferiprone is less effective than DFO and its potential hepatotoxicity is an issue of current controversy. A new orally effective iron chelator should not necessarily be regarded as one displacing the presently accepted and highly effective parenteral drug DFO. Rather, it could be employed to extend the scope of iron chelating strategies in a manner analogous with the combined use of medications in the management of other conditions such as hypertension or diabetes. Coadministration or alternating use of DFO and a suitable oral chelator may allow a decrease in dosage of both drugs and improve compliance by decreasing the demand on tedious parenteral drug administration. Combined use of DFO and L1 has already been shown to result in successful depletion of iron stores in patients previously failing to respond to single drug therapy, and to lead to improved compliance with treatment. It may also result in a “shuttle effect” between weak intracellular chelators and powerful extracellular chelators or exploit the entero-hepatic cycle to promote fecal iron excretion. All of these innovative ways of chelator usage are now awaiting evaluation in experimental models and in the clinical setting.
PMCID: PMC2267048  PMID: 18365050
8.  Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone 
Established heart failure in thalassaemia major has a poor prognosis and optimal management remains unclear.
A 1 year prospective study comparing deferoxamine (DFO) monotherapy or when combined with deferiprone (DFP) for patients with left ventricular ejection fraction (LVEF) <56% was conducted by the Thalassemia Clinical Research Network (TCRN). All patients received DFO at 50–60 mg/kg 12–24 hr/day sc or iv 7 times weekly, combined with either DFP 75 at mg/kg/day (combination arm) or placebo (DFO monotherapy arm). The primary endpoint was the change in LVEF by CMR.
Improvement in LVEF was significant in both study arms at 6 and 12 months (p = 0.04), normalizing ventricular function in 9/16 evaluable patients. With combination therapy, the LVEF increased from 49.9% to 55.2% (+5.3% p = 0.04; n = 10) at 6 months and to 58.3% at 12 months (+8.4% p = 0.04; n = 7). With DFO monotherapy, the LVEF increased from 52.8% to 55.7% (+2.9% p = 0.04; n = 6) at 6 months and to 56.9% at 12 months (+4.1% p = 0.04; n = 4). The LVEF trend did not reach statistical difference between study arms (p = 0.89). In 2 patients on DFO monotherapy during the study and in 1 patient on combined therapy during follow up, heart failure deteriorated fatally. The study was originally powered for 86 participants to determine a 5% difference in LVEF improvement between treatments. The study was prematurely terminated due to slow recruitment and with the achieved sample size of 20 patients there was 80% power to detect an 8.6% difference in EF, which was not demonstrated. Myocardial T2* improved in both arms (combination +1.9 ± 1.6 ms p = 0.04; and DFO monotherapy +1.9 ± 1.4 ms p = 0.04), but with no significant difference between treatments (p = 0.65). Liver iron (p = 0.03) and ferritin (p < 0.001) both decreased significantly in only the combination group.
Both treatments significantly improved LVEF and myocardial T2*. Although this is the largest and only randomized study in patients with LV decompensation, further prospective evaluation is needed to identify optimal chelation management in these high-risk patients.
PMCID: PMC3669105  PMID: 23688265
Thalassemia; Heart failure; Deferoxamine; Deferiprone; Combination
9.  Iron Chelation Therapy in Thalassemia Syndromes 
Transfusional hemosiderosis is a frequent complication in patients with transfusion dependent chronic diseases such as thalassemias and severe type of sickle cell diseases. As there are no physiological mechanisms to excrete the iron contained in transfused red cells (1 unit of blood contains approximately 200 mg of iron) the excess of iron is stored in various organs. Cardiomyopathy is the most severe complication covering more than 70% of the causes of death of thalassemic patients. Although the current reference standard iron chelator deferoxamine (DFO) has been used clinically for over four decades, its effectiveness is limited by a demanding therapeutic regimen that leads to poor compliance. Despite poor compliance, because of the inconvenience of subcutaneous infusion, DFO improved considerably the survival and quality of life of patients with thalassemia. Deferiprone since 1998 and Deferasirox since 2005 were licensed for clinical use. The oral chelators have a better compliance because of oral use, a comparable efficacy to DFO in iron excretion and probably a better penetration to myocardial cells. Considerable increase in iron excretion was documented with combination therapy of DFO and Deferiprone. The proper use of the three chelators will improve the prevention and treatment of iron overload, it will reduce complications, and improve survival and quality of life of transfused patients.
PMCID: PMC3033168  PMID: 21415999
10.  The Frequency of Adrenal Insufficiency in Adolescents and Young Adults with Thalassemia Major versus Thalassemia Intermedia in Iran 
Endocrine dysfunction is not uncommon complication in patients with transfusion-dependent thalassemia and is thought to occur as a consequence of excessive iron overload. The primary objective of this study is to determine the frequency of adrenal insufficiency in patients with thalassemia major and thalassemia intermediate.
This cross-sectional study was done at the Shiraz University of Medical Sciences, Shiraz, Southern Iran, in 2013. One hundred and ninety patients were divided into two groups; thalassemia major(TM) and thalassemia intermediate (TI) groups. We measured 8 AM serum cortisol, ACTH and ferritin concentrations in all patients.
The mean age of the TM and TI group were 22.5±5.7 and 23.8±6 years, respectively. 90 patients (47.4%) were splenectomized, 34 (36.2%) with TM and 56 (58.2%) with TI (p :<0.001). The median and interquartile range of serum ferritin levels were 2184±3700 ng/ml and 437±443ng/ml in TM and TI respectively (p< 0.001). Three patients with TM (1.6%) had low basal cortisol and ACTH levels. However, their cortisol response to ACTH stimulation was normal.
Low basal concentrations of cortisol and ACTH occurred in 1.6% of our adolescents young adult patients with TM suggesting a central defect in cortisol secretion at the basal state. However, cortisol response to standard – dose ACTH was normal in all patients with TM and TI.
PMCID: PMC4283918  PMID: 25574364
In iron overload conditions, plasma contains non-transferrin bound iron species, collectively referred to as plasma NTBI. These include iron-citrate species, some of which are protein bound. Because NTBI is taken into tissues susceptible to iron loading, its removal by chelation is desirable but only partial using standard deferoxamine (DFO) therapy. Speciation plots suggest that, at clinically achievable concentrations, deferiprone (DFP) will shuttle iron onto DFO to form feroxamine (FO), but whether NTBI chelation is enhanced to therapeutically relevant rates is unknown. As FO is highly stable, kinetic measurements of FO formation by HPLC or by stopped-flow spectrometry is achievable. In serum from thalassemia major patients, supplemented with 10µM DFO, FO formation paralleled NTBI removal but never exceeded 50% of potentially available NTBI: approximately one third of NTBI was chelated rapidly but only 15% of the remainder at 20h. Addition of DFP increased the magnitude of the slower component, with increments in FO formation equivalent to complete NTBI removal by 8h. This shuttling effect was absent in serum from healthy control subjects, indicating no transferrin iron removal. Studies with iron-citrate solutions also showed biphasic chelation by DFO, the slow component being accelerated by the addition of DFP, with optimal enhancement at 30µM. Physiological concentrations of albumin also enhanced DFO chelation from iron citrate, and co-addition of DFP further accelerated this effect. We conclude that at clinically relevant concentrations, DFP enhances plasma NTBI chelation with DFO by rapidly accessing and shuttling NTBI fractions that are otherwise only slowly available to DFO.
PMCID: PMC2927975  PMID: 20627190
12.  Bone density in transfusion dependent thalassemia patients in Urmia, Iran 
Patients with thalassemia major and intermedia are susceptible to osteopenia and osteoporosis. The mechanism of osteoporosis in these patients is multifactorial. Transfusion related iron overload in endocrine organs leads to impaired growth hormone secretion, diabetes mellitus, hypothyroidism, hypoparathyroidism, lack of sex steroids and vitamin D deficiency that contribute to impairment in achieving an adequate bone mass .The aim of this study was assessment of frequency of bone loss in patients with thalassemia major and intermedia in Urmia City of West Azerbaijan, Iran
Materials and Methods
In this cross sectional descriptive study,10 patients (lower than 18 y/o)with transfusion dependent thalassemia attending to Motahari and Emam Khomeini hospitals in Urmia city of Iran were enrolled and scanned for Bone Mineral Density (BMD) starting at around 10 years old.
Tenatients (6 male and 4 female) with transfusion dependent thalassemia (β-thalassemia major and intermedia) aged 13to 17 years in Urmia city of Iran were enrolled. Mean age of patients was 15.1±.37year old. Among them, 8 patients (80%)had low BMD and2 of them (20%) had normal BMD in lumbar spine. Only 30% of patients had low BMD in the neck of femur.
We should perform annual BMD in patients with thalassemia major and intermedia and hemoglobin H disease in age of higher than 8 year old and treat low BMD with administration of bisphosphonate, calcium and vitamin D supplements. Medical consultation with a rheumatologist and /or an endocrinologist should be performed in these patients. Changing lifestyle with mild daily exercise, adequate calcium containing foods, avoiding heavy activities, stop smoking, iron chelation therapy in adequate dosage, early diagnosis and treatment of endocrine insufficiency and regular blood transfusions can help to achieve an optimal bone density in these patients.
PMCID: PMC4083203  PMID: 25002928
Thalassemia; Bone mineral density; Osteoporosis; Bone Loss
13.  Beta-thalassemia 
Beta-thalassemias are a group of hereditary blood disorders characterized by anomalies in the synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. The total annual incidence of symptomatic individuals is estimated at 1 in 100,000 throughout the world and 1 in 10,000 people in the European Union. Three main forms have been described: thalassemia major, thalassemia intermedia and thalassemia minor. Individuals with thalassemia major usually present within the first two years of life with severe anemia, requiring regular red blood cell (RBC) transfusions. Findings in untreated or poorly transfused individuals with thalassemia major, as seen in some developing countries, are growth retardation, pallor, jaundice, poor musculature, hepatosplenomegaly, leg ulcers, development of masses from extramedullary hematopoiesis, and skeletal changes that result from expansion of the bone marrow. Regular transfusion therapy leads to iron overload-related complications including endocrine complication (growth retardation, failure of sexual maturation, diabetes mellitus, and insufficiency of the parathyroid, thyroid, pituitary, and less commonly, adrenal glands), dilated myocardiopathy, liver fibrosis and cirrhosis). Patients with thalassemia intermedia present later in life with moderate anemia and do not require regular transfusions. Main clinical features in these patients are hypertrophy of erythroid marrow with medullary and extramedullary hematopoiesis and its complications (osteoporosis, masses of erythropoietic tissue that primarily affect the spleen, liver, lymph nodes, chest and spine, and bone deformities and typical facial changes), gallstones, painful leg ulcers and increased predisposition to thrombosis. Thalassemia minor is clinically asymptomatic but some subjects may have moderate anemia. Beta-thalassemias are caused by point mutations or, more rarely, deletions in the beta globin gene on chromosome 11, leading to reduced (beta+) or absent (beta0) synthesis of the beta chains of hemoglobin (Hb). Transmission is autosomal recessive; however, dominant mutations have also been reported. Diagnosis of thalassemia is based on hematologic and molecular genetic testing. Differential diagnosis is usually straightforward but may include genetic sideroblastic anemias, congenital dyserythropoietic anemias, and other conditions with high levels of HbF (such as juvenile myelomonocytic leukemia and aplastic anemia). Genetic counseling is recommended and prenatal diagnosis may be offered. Treatment of thalassemia major includes regular RBC transfusions, iron chelation and management of secondary complications of iron overload. In some circumstances, spleen removal may be required. Bone marrow transplantation remains the only definitive cure currently available. Individuals with thalassemia intermedia may require splenectomy, folic acid supplementation, treatment of extramedullary erythropoietic masses and leg ulcers, prevention and therapy of thromboembolic events. Prognosis for individuals with beta-thalassemia has improved substantially in the last 20 years following recent medical advances in transfusion, iron chelation and bone marrow transplantation therapy. However, cardiac disease remains the main cause of death in patients with iron overload.
PMCID: PMC2893117  PMID: 20492708
14.  Hydroxyurea Treatment in Transfusion-Dependent β-Thalassemia Patients 
β-Thalassemia is an inherited hemoglobin disorder caused by defective synthesis of ß-globin chains. Hemoglobin (Hb) F induction is a possible therapeutic approach which can partially compensate for α and non-α globin chains imbalance.
We aimed to investigate the efficacy and safety of Hydroxyurea (HU) in diminishing transfusion requirements of patients with β-thalassemia major in Southern Iran.
Patients and Methods:
In this single-arm clinical trial, all transfusion-dependent β-thalassemia patients older than two years old (n = 97) who had inclusion criteria of the study and had been registered for at least six months in Dastgheib thalassemia outpatient clinic (a referral center affiliated to Shiraz University of Medical Sciences) were evaluated from October 2010 to December 2011. The patients were treated with HU with a mean dose of 10.5 mg/kg for a mean duration of 8 months (range 3-14 months). Transfusion needs and Hb levels were compared before and after HU treatment.
The mean volume of blood transfusion decreased significantly following HU treatment (0.71 mL/kg/day vs. 0.43 mL/kg/day, P < 0.001). Two-thirds of the patients showed good and partial response. No serious adverse reaction was observed except persistent neutropenia in two patients.
Hydroxyurea can be safely used in some transfusion-dependent β-thalassemia patients to decrease their transfusion needs.
PMCID: PMC4102988  PMID: 25068055
Hydroxyurea; Blood Transfusion; β-Thalassemia
15.  Combined Chelation Therapy with Deferasirox and Deferoxamine in Thalassemia 
Iron overload is the primary cause of mortality and morbidity in thalassemia major despite advances in chelation therapy. We performed a pilot clinical trial to evaluate the safety and efficacy of combined therapy with deferasirox (DFX, 20-30 mg/kg daily) and deferoxamine (DFO, 35-50 mg/kg on 3-7 days/week) in 22 patients with persistent iron overload or organ damage. In the 18 subjects completing 12 months of therapy, median liver iron concentration decreased by 31% from 17.4 mg/g (range 3.9-38.2 mg/g) to 12.0 mg/g (range 0.96-26.7 mg/g, P<0.001). Median ferritin decreased by 24% from 2,465 ng/mL (range 1,110-10,700 ng/mL) to 1,875 ng/mL (range 421-5,800 ng/mL, p=0.002). All 6 subjects with elevated myocardial iron showed improvement in MRI T2* (p=0.031). The mean ± S.E. plasma non-transferrin-bound iron (NTBI) declined from 3.10 ± 0.25 μM to 2.15 ± 0.29 μM (p=0.028). The administration of DFX during infusion of DFO further lowered NTBI (-0.28 ±0.08 μM, p=0.004) and labile plasma iron (LPI, -0.03 ± 0.01 μM, p=0.006). The simultaneous administration of DFO and DFX rapidly reduced systemic and myocardial iron, and provided an excellent control of the toxic labile plasma iron species without an increase in toxicity.
PMCID: PMC3592978  PMID: 23151373
Thalassemia Major; Iron overload; Deferoxamine; Deferasirox
16.  Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies. 
Journal of Clinical Investigation  1993;91(5):1979-1986.
This study investigates the pathophysiology of mucormycosis caused by Rhizopus, which has been reported in 46 dialysis patients, while treated with deferoxamine (DFO). This drug aggravates mucormycosis, which we experimentally induced in guinea pigs and which lead to a shortened animal survival (P < or = 0.01). The drug's effect on Rhizopus is not mediated through the polymorphonuclear cells. Fe.DFO, the iron chelate of DFO, abolishes the fungistatic effect of serum on Rhizopus and increases the in vitro growth of the fungus (P < or = 0.0001). This effect is present at Fe.DFO concentrations > or = 0.01 microM, at which fungal uptake of radioiron from 55Fe.DFO is observed. A 1,000-fold higher concentration of iron citrate is required to achieve a similar rate of radioiron uptake and of in vitro growth stimulation as observed with Fe.DFO. These in vitro effects of Fe.DFO (1 microM) in serum on radioiron uptake and on growth stimulation are more striking for Rhizopus than for Aspergillus fumigatus and are practically absent for Candida albicans. For these three fungal species, the rates of radioiron uptake from 55Fe.DFO and of growth stimulation in the presence of Fe.DFO in serum are directly related (r = 0.886). These results underscore the major role of Fe.DFO in the pathogenesis of DFO-related mucormycosis. Pharmacokinetic changes in uremia lead to a prolonged accumulation of Fe.DFO after DFO administration, which helps explain the increased sensitivity of dialysis patients to DFO-related mucormycosis.
PMCID: PMC288195  PMID: 8486769
17.  Screening of Five Common Beta Thalassemia Mutations in the Pakistani Population 
Thalassemia is one of the most common autosomal single-gene disorder worldwide. The highest prevalence of the disease is in the “thalassemia belt” which includes the Mediterranean region, parts of the Middle East, the Indian subcontinent, the southern parts of the Far East, Pakistan and South-East Asia. This study aimed to detect the common molecular abnormalities of the beta thalassemia syndrome in Pakistan.
The study was conducted at the Institute of Hematology, Baqai Medical University, Karachi, Pakistan from August 2004 to November 2007. Blood samples of patients with beta thalassemia major (n = 400) were collected from hospital transfusion centres and diagnostic laboratories in different districts of Karachi representing five major ethnic groups including Punjabi, Pathan, Sindhi, Baluchi and Urdu speaking. All the samples were analysed for five common mutations by using the polymerase chain reaction technique ARMS (amplification of refractory mutation system).
The data revealed five common mutations including IVS 1–5(G→C), Fr 41/42(-CTTT), Fr 8/9 (+G), IVS 1–1 and Del 619. These accounted for 90% of the total beta thalassemia genes in Pakistan. The IVS 1–5(G→C) was found to be the most common beta thalassemia gene in the Pakistani population with a frequency of 44.4% present in all major ethnic groups.
The results of this study will be helpful in the establishment of a large scale prenatal diagnosis programme in Pakistan.
PMCID: PMC3074786  PMID: 21509314
Beta thalassemia; Mutations; Pakistani population; Prenatal diagnosis
18.  Frequency of Cholelithiasis in Patients With Beta-Thalassemia Intermedia With and Without Hydroxyurea 
Recent studies regarding the effect of hydroxyurea (HU) in thalassemia have revealed favorable effects on the reduction of ineffective erythropoiesis.
The aim of the current study was to evaluate whether or not HU can have an effect on the gallstone formation rate in patients with beta-thalassemia intermedia (BTI).
Patients and Methods:
In this case control cross-sectional study, from a total of 250 transfusion-independent BTI patients, 51 patients who were taking HU, participated in the study. Patients were registered in the Thalassemia clinic of Shiraz University of Medical Sciences, Shiraz, which is a referral center located in southern Iran, during 2011-2012. Mean dose of HU consumption in the case group was 10 ± 2.5 mg/kg/day (range of 8-15 mg/kg/day), with a mean duration of consumption of 7.5 ± 3.8 years (range 1-14 years). In addition, 41 age- and sex-matched BTI patients who did not use HU were randomly selected as a control group. All patients underwent abdominal ultrasound by a radiologist for evaluation of gallstones.
Mean age of the participants was 21.4 ± 6.5 years (10-40 years). There was no statistically significant difference regarding the frequency of cholelithiasis between the two groups of patients (P = 0.822). Our study showed significantly lower hemoglobin levels and a higher percentage of nucleated red blood cells in the HU group compared with the control group (P = 0.001 and P = 0.005, respectively).
It seems that taking HU for long periods can reduce hemolysis and bone marrow suppression, and that decreases the rate of cholelithiasis. We believe that if these patients had not been treated with HU, we would probably have observed a significantly higher frequency of cholelithiasis, due to more hemolysis compared with patients not taking HU. Further studies with larger sample sizes are suggested.
PMCID: PMC4166105  PMID: 25237586
Beta Thalassemia Intermedia; Cholelithiasis; Hydroxyurea
19.  Safety and Tolerability of Deferoxamine Mesylate in Patients with Acute Intracerebral Hemorrhage 
Background and Purpose
Treatment with the iron chelator, deferoxamine mesylate (DFO), improves neurological recovery in animal models of Intracerebral hemorrhage (ICH). We aimed to evaluate the feasibility, safety, and tolerability of varying dose-tiers of DFO in patients with spontaneous ICH, and to determine the Maximum Tolerated Dose (MTD) to be adopted in future efficacy studies.
A multicenter, phase-I, dose-finding study using the Continual Reassessment Method. DFO was administered by an intravenous infusion for 3 consecutive days, starting within 18 hours of ICH onset. Subjects underwent repeated clinical assessments through 90 days, and CT neuroimaging pre- and post-drug administration.
Twenty subjects were enrolled into 5 dose tiers, starting with 7 mg/kg/day and ending with 62 mg/kg/day as the MTD. Median age was 68 years (range: 50–90); 60% were men; and median GCS and NIHSS scores on admission were 15 (5–15) and 9 (0–39), respectively. ICH location was lobar in 40%, deep in 50%, and brainstem in 10%; intraventricular hemorrhage was present in 15%. DFO was discontinued due to adverse events in 2 subjects (10%). Six subjects (30%) experienced 12 serious adverse events (SAEs), none were drug-related. DFO infusions were associated with mild blood pressure lowering effects. Fifty percent of patients had mRS ≤2 and 39% had mRS 4–6 on day-90; 15% died.
Consecutive daily infusions of DFO after ICH are feasible, well-tolerated, and not associated with excessive SAEs or mortality. Our findings lay the groundwork for future studies to evaluate the efficacy of DFO in ICH.
PMCID: PMC3202043  PMID: 21868742
Deferoxamine Mesylate; Iron; ICH
20.  Spectrum of Beta Globin Gene Mutations in Egyptian Children with β-Thalassemia 
The molecular defects resulting in a β-thalassemia phenotype, in the Egyptian population, show a clear heterogenic mutations pattern. PCR-based techniques, including direct DNA sequencing are effective on the molecular detection and characterization of these mutations. The molecular characterization of β-thalassemia is necessary for carrier screening, genetic counseling, and to offer prenatal diagnosis.
The aim of the work
was to evaluate the different β-globin gene mutations in two hundred β-thalassemic Egyptian children.
Subjects and Methods
This study was carried out on two hundred β-thalassemic Egyptian children covering most Egyptian Governorates including 158 (79%) children with thalassemia major (TM) and 42 (21%) children with thalassemia intermedia(TI). All patients were subjected to meticulous history taking, clinical examination, complete blood count, hemoglobin electrophoresis, serum ferritin and direct fluorescent DNA sequencing of the β-globin gene to detect the frequency of different mutations.
The most common mutations among patients were IVS I-110(G>A) 48%, IVS I-6(T>C) 40%, IVS I-1(G>A) 24%, IVS I-5(G>C)10%, IVS II-848 (C>A) 9%, IVS II-745(C>G) 8%, IVS II-1(G>A) 7%, codon “Cd”39(C> T) 4%, −87(C>G) 3% and the rare mutations were: Cd37 (G>A), Cd8 (−AA), Cd29(−G), Cd5 (−CT), Cd6(−A), Cd8/9(+G), Cd 106/107(+G), Cd27(C>T), IVS II-16(G> C), Cd 28 (−C), Cap+1(A>C), −88(C>A), all of these rare mutations were present in 1%. There was a considerable variation in phenotypic severity among patients resulting from the interaction of different β∘ and β+mutations. Furthermore, no genotype-phenotype association was found both among the cases with thalassemia major and the cases with thalassemia intermedia.
Direct DNA sequencing provides insights for the frequency of different mutations in patients with β-thalassemia including rare and/or unknown ones. The most common mutations in Egyptian children with beta thalassemia were IVS I-110(G>A) 48%, IVS I-6(T>C) 40%, IVS I-1(G>A)24%, IVS I-5(G>C)10%, IVS II-848 (C>A) 9%, IVS II-745(C>G) 8%, IVS II-1(G>A) 7%.
PMCID: PMC4235483  PMID: 25408857
21.  Assessment Hepatomegaly and liver Enzymes in 100 Patients with beta Thalassemia Major in Mashhad, Iran 
Frequent blood transfusion in patients with beta thalassemia major can lead to iron overload especially in liver. Chronic iron overload could cause cirrhosis of the liver. Transfusion- transmitted hepatitis B and C also could develop cirrhosis in individuals.
Materials and Methods
The present cross- sectional descriptive study is to assess hepatomegaly and liver enzymes in 100 patients with beta thalassemia major, ages between 2-18 years old. The study was carried out retrospectively. One hundred medical records have chosen from 400 samples of thalassemia major patients, who are under a regular care of the department of sarvar clinic.
Out of these patients, 55% were male and 45% female. The mean age of thalassemia patients was 10.8± 4.4 years. The mean and S. D of hemoglobin, ferritin, deferoxamine dosage was 8.5 ± 1.5g/dl , 2183 ± 1528 ng , 30 ± 11.16 mg/kg, respectively. Forty six percent of them had hepatomegaly. The mean and S. D of AST and ALT were 95± 70 IU/L and 70 ±35U/L respectively. Splenectomy was performed on 44% of patient.
Hepatomegaly is one of the most common findings in the thalassemic patient that induced with hemosiderosis and hepatitis.
PMCID: PMC3915436  PMID: 24575259
Epidemiology; Hepatomegaly; Liver; beta-Thalassemia
22.  Conservative management of Beta-thalassemia major cases in the sub-division level hospital of rural West Bengal, India 
The ideal management of thalassemia involves a multidisciplinary therapeutic team approach and should be preferably done at a comprehensive thalassemia care center with all sorts of specialists and the backup of a well-equipped blood bank. However, in developing country like ours, these facilities are not available in rural set up. So, a situation where conservative therapy with regular blood transfusion is the only choice left to innumerable thalassemic children.
To evaluate the existing conservative management protocol of Beta-thalassemia major patients in the setup of a subdivision level Government Hospital of rural West Bengal, India.
Materials and Methods:
The study was performed between December 2009 and December 2011. Beta-thalassemia major patients, registered in blood bank for moderate transfusion regimen, were taken in study. All the patients were screened for Transfusion Transmittable Infections at the time of registration and thereafter periodically every six months. Iron chelation therapy was given simultaneously with transfusion at a dose of 20 to 40 mg/kg/day for six days. The patients were advised to follow up with chelation therapy at home by daily infusion with a goal of maintaining serum ferritin level below 1000 ng/ml. Over this long period of study, the patients were periodically evaluated for complications.
The average blood requirement (ml/kg/year) in 1-5 years, 6-10 years, and 11-15 years were 110, 150, and 180, respectively. Incidence of Hepatitis C Virus infection in 1-5 years and 6-10 years were 1.75% and 2.08%, respectively. It is well seen that serum ferritin level increase with ascending age as does the blood consumption.
Conservative management may be the best alternative and at times the only hope for patients in developing country like ours. However, in order to decrease the disease load, steps need to be taken to introduce preventive measures.
PMCID: PMC3633258  PMID: 23633844
Beta-thalassemia major; blood transfusion; conservative management; iron chelation; prevention program
23.  Zinc and Copper Status in Children with Beta-Thalassemia Major  
Iranian Journal of Pediatrics  2010;20(3):297-302.
There are some reports in which a condition of zinc deficiency and its associated outcomes with a change in concentration of serum copper among the thalassemic patients has been highlighted. The aim of this prospective study was to determine the serum zinc and copper levels in children with beta-thalassemia major.
In this cross sectional study all children under 12 years affected by beta thalassemia major (40 patients) were evaluated for serum zinc and copper levels in Qazvin thalassemia center (Qazvin, Iran) in 2007. Serum measurements for zinc and copper were performed by atomic absorption spectrophotometer.
The mean concentrations of serum zinc and copper levels were 67.35±20.38 and 152.42±24.17 µg/dl respectively. Twenty-six (65%) of thalassemic patients had zinc concentration under 70 µg/dl (hypozincemia). None of the thalassemic children had copper deficiency. No significant correlation between serum zinc level with age, weight, height, body mass index, duration of blood transfusion, desferrioxamine dose and ferritin level was observed in thalassemic patients (P=0.3).
This study revealed that hypozincemia is common in thalassemic patients, but in contrast, there is no copper deficiency. Further evaluation in this regard is recommended.
PMCID: PMC3446035  PMID: 23056720
Beta-thalassemia; Zinc; Copper; Children
24.  Prophylactic neuroprotection against stroke: low-dose, prolonged treatment with deferoxamine or deferasirox establishes prolonged neuroprotection independent of HIF-1 function 
Prophylactic neuroprotection against stroke could reduce stroke burden in thousands of patients at high risk of stroke, including those with recent transient ischemic attacks (TIAs). Prolyl hydroxylase inhibitors (PHIs), such as deferoxamine (DFO), reduce stroke volume when administered at high doses in the peristroke period, which is largely mediated by the hypoxia-inducible transcription factor (HIF-1). Yet, in vitro experiments suggest that PHIs may also induce neuroprotection independent of HIF-1. In this study, we examine chronic, prophylactic, low-dose treatment with DFO, or another iron chelator deferasirox (DFR), to determine whether they are neuroprotective with this paradigm and mediate their effects through a HIF-1-dependent mechanism. In fact, prophylactic administration of low-dose DFO or DFR significantly reduces stroke volume. Surprisingly, DFO remained neuroprotective in mice haploinsufficient for HIF-1 (HIF-1+/−) and transgenic mice with conditional loss of HIF-1 function in neurons and astrocytes. Similarly, DFR was neuroprotective in HIF-1+/− mice. Neither DFO nor DFR induced expression of HIF-1 targets. Thus, low-dose chronic administration of DFO or DFR induced a prolonged neuroprotective state independent of HIF-1 function. As DFR is an orally administered and well-tolerated medication in clinical use, it has promise for prophylaxis against stroke in patients at high risk of stroke.
PMCID: PMC3130314  PMID: 21245873
HIF-1; hypoxia; ischemia; stroke
25.  Quality of Life in Patients with Thalassemia Major and Intermedia in Kerman-Iran (I.R.) 
Thalassemia is the most common hemoglobin disorder in the world and thalassemia major and intermedia stand among the most severe forms. Due to recent improvements in treatment, patients with thalassemia have longer life expectancies; hence it is of utmost importance to pay careful attention to their quality of life together with life expectancy. This study was conducted to assess the quality of life in patients with thalassemia and also to compare it between thalassemia major and intermedia. In this cross-sectional study, patients who referred for blood transfusion or follow-up visits were evaluated for their quality of life (QOL). Short Form-36 questionnaire was applied to evaluate QOL. In this study, 308 patients with a mean age of 22.95±4.82 years were evaluated. The scores of QOL were regarded as moderate in eight domains under evaluation; the least score was given to General Health (53.05±16.96) whereas the highest score was given to Physical Functioning (67.95±22.68). The QOL in the patients with thalassemia major was better than those with thalassemia intermedia regarding Physical Functioning and Role Limitation Emotional domains. Compared to injecting chelators, patients who received oral chelators showed to have a better QOL considering Social Functioning and Mental Health domain. The patients under study didn’t have a satisfying QOL ; the QOL of patients with thalassemia major was better than that of patients with thalassemia intermedia in only 2 domains of sf-36(Physical Functioning & Role limitation-Emotional). It is then essential that experts pay proper attention to improve QOL among patients.
PMCID: PMC3499998  PMID: 23170187

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