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1.  Hemoglobin H-constant spring in North America: an alpha Thalassemia with frequent complications 
American journal of hematology  2009;84(11):759-761.
Hemoglobin H-constant spring (Hb H-CS), the most common nondeletional alpha thalassemia in Asia is increasingly recognized in North America due to shifts in immigration patterns. In California, alpha (α)-thalassemia syndromes are the second most frequent finding among newborns screened for hemoglobinopathies with a two-fold increase compared to a decade earlier [1,2]. Though known to have a more severe anemia than Hb H disease, the other clinical findings of Hb H-CS are not well described. Moreover, beneficial therapies that have become available in the last decade are often not applied to their care. This analysis of 46 patients enrolled in the Thalassemia Clinical Research Network (TCRN) age 13+/− 10 years old, with Hb H-CS revealed moderate anemia (mean 8.7 ± 1.5 g/dl), regular transfusion therapy in 24% of patients, and splenomegaly or prior splenectomy in one-third of them. Serum transferin receptor (sTfr), was elevated; (44.4 ± 18 mcg/ml normal range 2.9–8.3 mcg/ml), reflecting ineffective erythropoiesis, which in turn leads to high iron absorption and increased ferritin levels in younger (median = 187 ng/ml) and older (median = 465 ng/ml) nontransfused patients. These findings along with moderate growth delay and low bone mass were more prevalent in Hb H-CS patients compared to deletional Hb H disease. Our results highlight the required monitoring of the extent of anemia, growth, splenomegaly, iron overload, gallstones, bone density and assessment of need for transfusions and specific treatments for disease complications.
PMCID: PMC4254706  PMID: 19787795
2.  Symptoms of depression and anxiety in patients with thalassemia: Prevalence and correlates in the thalassemia longitudinal cohort 
American journal of hematology  2010;85(10):802-805.
Thalassemia is an inherited blood disorder that requires lifelong adherence to a complicated and burdensome medical regimen which could potentially impact emotional functioning of patients. The importance of understanding and promoting healthy emotional functioning is crucial not only to psychological well-being, but also to physical health as it has been shown to impact adherence to medical regimens [1–4]. The current study aimed to [1] determine the prevalence of depressive and anxiety symptoms in adolescent and adult patients with thalassemia; and [2] explore possible demographic, medical, and psychosocial correlates of these symptoms in 276 patients (14–58 years old, M age = 27.83; 52% female). Overall, most patients did not report experiencing significant symptoms of anxiety and depression (33% of participants indicated experiencing symptoms of anxiety and 11% symptoms of depression). Females and older patients were more likely to experience these symptoms than males and younger patients. Symptoms of anxiety and depression were positively associated with self-report of difficulty with adherence and negatively associated with quality of life. Given these findings, regular screening for anxiety and depression symptoms could help to identify at-risk individuals to provide them with appropriate psychological support with the goal of improving both emotional and physical health.
PMCID: PMC4251654  PMID: 20806230
3.  Renal dysfunction in patients with thalassaemia 
British journal of haematology  2011;153(1):111-117.
Little is known about the effects of thalassaemia on the kidney. Characterization of underlying renal function abnormalities in thalassaemia is timely because the newer iron chelator, deferasirox, can be nephrotoxic. We aimed to determine the prevalence and correlates of renal abnormalities in thalassaemia patients, treated before deferasirox was widely available, using 24-h collections of urine. We calculated creatinine clearance and urine calcium-to-creatinine ratio and measured urinary β2-microglobulin, albumin, and protein. We used multivariate modelling to identify clinical, therapeutic, and laboratory predictors of renal dysfunction. One-third of thalassaemia patients who were not regularly transfused had abnormally high creatinine clearance. Regular transfusions were associated with a decrease in clearance (P = 0·004). Almost one-third of patients with thalassaemia had hypercalciuria, and regular transfusions were associated with an increase in the frequency and degree of hypercalciuria (P < 0·0001). Albuminuria was found in over half of patients, but was not consistently associated with transfusion therapy. In summary, renal hyperfiltration, hypercalciuria, and albuminuria are common in thalassaemia. Higher transfusion intensity is associated with lower creatinine clearance but more frequent hypercalciuria. The transfusion effect needs to be better understood. Awareness of underlying renal dysfunction in thalassaemia can inform decisions now about the use and monitoring of iron chelation.
PMCID: PMC4250090  PMID: 21332704
thalassaemia; kidney; creatinine clearance; hyperfiltration; hypercalciuria; albuminuria; proteinuria; transfusion
4.  Inadequate Dietary Intake in Patients with Thalassemia 
Patients with thalassemia have low circulating levels of many nutrients, but the contribution of dietary intake has not been assessed.
Assess dietary intake in a large contemporary sample of patients with thalassemia.
Prospective, longitudinal cohort study using a validated food frequency questionnaire
221 patients (19.7±11.3 yrs, 106 female) categorized into three age groups: young children (3–7.9 y), older children/adolescents (8–18.9 yr), and adult (≥ 19 yr). 78.8% β-thalassemia; 90% chronically transfused.
10 hematology outpatient clinics in the United States and Canada.
Main outcome measures
Comparison of intake with U.S. Dietary Reference Intakes, and correlation with serum 25-OH vitamin D and total body iron stores.
Statistical Analyses Performed
Intake was defined as inadequate if less than the estimated average requirement (EAR). Chi-square, Fisher’s exact and Student’s t-test were utilized to compare intake between age categories and logistic regression analysis to test the relationship between intake and outcomes, controlling for age, gender and race.
Over 30% of patients consumed inadequate levels of vitamin A, D, E, K, folate, calcium, and magnesium. The only nutrients for which >90% of patients consumed adequate amounts were riboflavin, vitamin B12 and selenium. Dietary inadequacy increased with increasing age group (p<0.01) for vitamins A, C, E, B6, folate, thiamin, calcium, magnesium and zinc. Over half the sample took additional supplements of calcium and vitamin D, although circulating levels of 25-OH vitamin D remained insufficient in 61% of patients. Dietary iron intake was not related to total body iron stores.
Patients with thalassemia have reduced intake of many key nutrients. These preliminary findings of dietary inadequacy is concerning and supports the need for nutritional monitoring to determine which patients are at greatest risk for nutritional deficiency. Future research should focus on the effect of dietary quality and nutritional status on health outcomes in thalassemia.
PMCID: PMC3419338  PMID: 22551675
Thalassemia; dietary intake; iron; vitamin D
6.  Management of transfusional iron overload – differential properties and efficacy of iron chelating agents 
Journal of blood medicine  2011;2:135-149.
Regular red cell transfusion therapy ameliorates disease-related morbidity and can be lifesaving in patients with various hematological disorders. Transfusion therapy, however, causes progressive iron loading, which, if untreated, results in endocrinopathies, cardiac arrhythmias and congestive heart failure, hepatic fibrosis, and premature death. Iron chelation therapy is used to prevent iron loading, remove excess accumulated iron, detoxify iron, and reverse some of the iron-related complications. Three chelators have undergone extensive testing to date: deferoxamine, deferasirox, and deferiprone (although the latter drug is not currently licensed for use in North America where it is available only through compassionate use programs and research protocols). These chelators differ in their modes of administration, pharmacokinetics, efficacy with regard to organ-specific iron removal, and adverse-effect profiles. These differential properties influence acceptability, tolerability and adherence to therapy, and, ultimately, the effectiveness of treatment. Chelation therapy, therefore, must be individualized, taking into account patient preferences, toxicities, ongoing transfusional iron intake, and the degree of cardiac and hepatic iron loading.
PMCID: PMC3262345  PMID: 22287873
transfusion; iron; chelation; magnetic resonance imaging
7.  Transcranial Doppler Screening and Prophylactic Transfusion Program Is Effective in Preventing Overt Stroke in Children With Sickle Cell Disease 
The Journal of pediatrics  2010;157(3):479-484.
To assess the impact of our transcranial doppler ultrasonography (TCD) program on the incidence of first stroke and the rate of transfusion for stroke prevention in children with sickle cell disease.
Study design
In this single-institution, retrospective study, we compared the incidence of stroke and of transfusion for stroke prevention in 475 patients followed in the 8-year period prior to instituting TCD screening to the rate in 530 children in the 8-year period afterwards.
The incidence of overt stroke in the pre-TCD period was 0.67 per 100 patient-years, compared with 0.06 per 100 patient-years in the post-TCD period (p<0.0001). Of the two strokes in the post-TCD period, one occurred in a child too young for the screening protocol and one in a child with high velocities solely in the anterior cerebral arteries. The rate of transfusion therapy for stroke prevention increased from 0.67 per 100 patient-years to 1.12 per 100 patient-years since instituting our program (p=0.008).
Our program has been successful in reducing the rate of first overt stroke, but with increased use of transfusion. Additional modifications to screening might further reduce the risk of first stroke, and studies of alternative treatments may be beneficial.
PMCID: PMC2931594  PMID: 20434165
Sickle cell disease; stroke; Transcranial Doppler ultrasonography; blood transfusion; pediatric hematology
8.  Silent Infarcts in Young Children with Sickle Cell Disease 
British journal of haematology  2009;146(3):300-305.
Silent infarcts have been reported most commonly in school-aged children with homozygous sickle cell disease (SCD-SS) and are associated with neurocognitive deficits. However, the prevalence of silent infarcts in younger children with SCD-SS is not well defined. In this retrospective study, brain magnetic resonance imaging and angiography (MRI/A) studies performed before six years of age in a cohort of children with SCD-SS were analyzed and the prevalence of abnormalities was calculated. Clinical and laboratory parameters were compared between the groups with and without silent infarcts. Sixty-eight of 96 children in the cohort had brain MRI/A performed prior to age 6 years. Of the 65 who were neurologically asymptomatic, 18 (27.7%, 95% confidence interval 17.3 – 40.2%) had silent infarcts (mean age 3.7 ± 1.1 years, range 1.3 – 5.9 years). Factors associated with silent infarcts included cerebral vessel stensosis by magnetic resonance angiography, lower rates of vaso-occlusive pain and acute chest syndrome, and lower hemoglobin levels. The prevalence of silent infarcts in young children with SCD-SS is similar to that of older children and anemia and severe vasculopathy may be risk factors.
PMCID: PMC2793684  PMID: 19500105
sickle cell disease; sickle cell radiology; stroke; pediatric hematology; silent infarct
9.  Headache in Children with Sickle Cell Disease 
The Journal of pediatrics  2007;151(1):67-72.e1.
To compare the prevalence of frequent headache in children with sickle cell disease (SCD) to that of black control subjects and to assess factors associated with headache in SCD.
Study design
In this cross-sectional study, a headache questionnaire was administered to subjects with SCD and black control subjects. Subjects answered supplementary questions about SCD complications. Clinical and radiographic information were abstracted from medical charts for subjects with SCD.
Children (n = 241) with SCD and 141 control subjects were studied; 32.4% (95% CI 26.5%-38.7%) of subjects with SCD reported having headaches at least weekly, similar to control subjects at 27% (95% CI 19.8%-35.1%, P = NS); however, in children <13 years, headache was more common in subjects with SCD than in control subjects (24% vs 9.7%, P = .013). The prevalence of headache was similar among the different SCD genotypes. Factors associated with frequent headaches in subjects with SCD included older age, frequent vaso-occlusive pain episodes, symptoms of obstructive sleep apnea, and cerebral vessel stenosis detected by magnetic resonance angiography.
The prevalence of headaches in children with SCD is similar to the general population; however, younger children with SCD report headaches more frequently than control subjects. The cause of headache is likely multifactorial, and SCD-specific factors may contribute.
PMCID: PMC2538680  PMID: 17586193
10.  Acute Silent Cerebral Ischemic Events in Children with Sickle Cell Anemia 
JAMA neurology  2013;70(1):58-65.
Irregular, sporadic episodes of ischemic brain injury are known to occur in sickle cell anemia (SCA), resulting in overt stroke and silent cerebral infarction. Ongoing ischemia in other organs is common in SCA but has never been documented in the brain.
To test the hypothesis that acute silent cerebral ischemic events (ASCIEs) are frequent and potentially transient.
Cross-sectional and cohort study of children with SCA screened by magnetic resonance imaging (MRI) of the brain for a randomized clinical trial.
Clinical trial setting in tertiary care centers.
Asymptomatic children with SCA without known stroke, neurologic injury, or epilepsy not receiving treatment with transfusions or hydroxyurea.
Main Outcome Measure
Incidence of ASCIEs calculated using single diffusion-weighted MRI scans (acute ischemic events that occurred within 10 days of the MRI).
Acute silent cerebral ischemic events were detected on 1.3% of MRIs (10 of 771) in 652 children (mean age, 10.0 years), with an incidence of 47.3 events per 100 patient-years (95% CI, 22.7–87.2). Two of 10 children with ASCIEs had follow-up MRIs of the brain; only 1 had silent cerebral infarction in the same location as the previously detected ASCIE.
Children with SCA experience ongoing (chronic, intermittent) cerebral ischemia, sometimes reversible, far more frequently than previously recognized. The brain in SCA is at constant threat of ischemia.
PMCID: PMC3677221  PMID: 23108767
11.  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
Pediatric blood & cancer  2010;56(5):777-782.
Children with sickle cell disease and abnormal transcranial Doppler (TCD) ultrasonography have a high risk of stroke, but this risk is greatly reduced when chronic transfusion therapy is administered. The change in TCD velocities during chronic transfusion therapy and rate and frequency of normalization of TCD findings have not been studied extensively.
Using data from children with sickle cell disease enrolled as potential subjects in the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) trial, we characterized the change in TCD velocities on transfusion therapy and identified predictors of developing a normal TCD.
Among 88 children with serial TCD data after starting transfusions for abnormal TCD 46 (52%) converted to normal TCD after a mean of 4.3 months (median 3.0; range 0.85-14.3 months) of transfusions. TCD studies remained abnormal in 19/88 (21.6%) after a mean of 2.4 years of transfusion. The median TCD velocity was lowered by 38 cm/s within three months of initiating transfusions, followed by a more gradual decline then stabilization of velocities, although with significant individual variation. Factors associated with conversion to normal TCD included lower initial TCD velocity, younger age, and higher pre-transfusion hemoglobin level during transfusion therapy.
Younger children with higher pre-transfusion hemoglobin levels and lower abnormal TCD velocities are most likely to have rapid normalization of TCD on transfusions. Long-term follow-up of children with persistently abnormal exams or worsening velocities on transfusion is needed to determine if these children are at higher risk of stroke.
PMCID: PMC3368333  PMID: 21370410
sickle cell disease; transcranial Doppler ultrasonography; red blood cell transfusions
13.  Characterization of Low Bone Mass in Young Patients with Thalassemia by DXA, pQCT and Markers of Bone Turnover 
Bone  2011;48(6):1305-1312.
Previous reports using dual x-ray absorptiometry (DXA) suggest that up to 70% of adults with thalassemia major (Thal) have low bone mass. However, few studies have controlled for body size and pubertal delay, variables known to affect bone mass in this population. In this study, bone mineral content and areal density (BMC, aBMD) of the spine and whole body were assessed by DXA, and volumetric BMD and cortical geometries of the distal tibia by peripheral quantitative computed tomography (pQCT) in subjects with Thal (n=25, 11 male, 10 to 30 yrs) and local controls (n=34, 15 male, 7 to 30 yrs). Z-scores for bone outcomes were calculated from reference data from a large sample of healthy children and young adults. Fasting blood and urine were collected, pubertal status determined by self-assessment and dietary intake and physical activity assessed by written questionnaires. Subjects with Thal were similar in age, but had lower height, weight and lean mass index Z-scores (all p<0.001) compared to controls. DXA aBMD was significantly lower in Thal compared to controls at all sites. Adult Thal subjects (>18 yrs, n=11) had lower tibial trabecular vBMD (p=0.03), cortical area, cortical BMC, cortical thickness, periosteal circumference and section modulus Z-scores (all p<0.01) compared to controls. Cortical area, cortical BMC, cortical thickness, and periosteal circumference Z-scores (p=0.02) were significantly lower in young Thal (≤18 yrs, n=14) compared to controls. In separate multivariate models, tibial cortical area, BMC, and thickness and spine aBMD and whole body BMC Z-scores remained lower in Thal compared to controls after adjustment for gender, lean mass and/or growth deficits (all p<0.01). Tanner stage was not predictive in these models. Osteocalcin, a marker of bone formation, was significantly reduced in Thal compared to controls after adjusting for age, puberty and whole body BMC (p=0.029). In summary, we have found evidence of skeletal deficits that cannot be dismissed as an artifact of small bone size or delayed maturity alone. Given that reduced bone density and strength are associated with increased risk of fracture, therapies focused on increasing bone formation and bone size in younger patients are worthy of further evaluation.
PMCID: PMC3095710  PMID: 21443975
14.  Sickle cell disease and TCD imaging: inter-hemispheric differences in blood flow Doppler parameters 
To establish reference values of inter-hemispheric differences and ratios of blood flow Doppler parameters in the terminal internal carotid artery (tICA), middle (MCA) and anterior (ACA) cerebral arteries in children with sickle cell anemia.
Subjects and Methods
Fifty seven out of 74 recruited children (mean age 7.8±3.4 years, 3-14 years), who were free of neurological deficits and intracranial narrowings detectable by magnetic resonance angiography (MRA) and had flow velocities below 170 cm/s by conventional transcranial Doppler ultrasound underwent transcranial color-coded duplex ultrasonography. Reference limits of flow parameters corrected and uncorrected for the angle of insonation were estimated using tolerance intervals, within which are included with probability of 0.90 all possible data values from 95% of a population.
Reference limits for left-to-right differences in cm/s in the mean angle-corrected and uncorrected flow velocities were: −56 to 53 and −72 to 75 for MCA; −49 to 57 and −81 to 91 for ACA and −55 to 64 and −73 to 78 for tICA, respectively. Respective reference limits for left-to-right velocity ratios were: 0.31 to 1.84 and 0.38 to 1.75 for MCA; 0.48 to 2.99 and 0.46 to 2.89 for ACA, and 0.61 to 2.56 and 0.56 to 2.23 for tICA.
The study provides reference limits of inter-hemispheric differences and ratios of blood flow Doppler parameters that may be helpful in identification of intracranial arterial narrowings in children with sickle cell disease undergoing ultrasound screening for stroke prevention.
PMCID: PMC3079337  PMID: 21088242
sickle cell disease; transcranial Doppler; sonography; blood flow; stroke
15.  Education and Employment Status of Children and Adults with Thalassemia in North America 
Pediatric blood & cancer  2010;55(4):678-683.
Advances in the management of thalassemia have resulted in increased life expectancy and new challenges. We conducted the first survey of education and employment status of people with thalassemia in North America.
A total of 633 patients (349 adults and 284 school age children) enrolled in the Thalassemia Clinical Research Network (TCRN) registry in Canada and the US were included in the data analysis. Predictors considered for analysis were age, gender, race/ethnicity, site of treatment (Canada vs. United States), transfusion and chelation status, serum ferritin, and clinical complications.
Seventy percent of adults were employed of which 67 percent reported working full-time. Sixty percent had a college degree and 14% had achieved some post college education. Eighty-two percent of school age children were at expected grade level. In a multivariate analysis for adults, Whites (OR=2.76, 95% CI: 1.50-5.06) were more likely to be employed compared to Asians. Higher education in adults was associated with older age (OR=1.67, 95% CI: 1.29-2.15), female gender (OR=2.08, 95% CI: 1.32-3.23) and absence of lung disease (OR=14.3, 95% CI: 2.04-100). Younger children (OR=5.7 for 10 year increments, 95% CI: 2.0 – 16.7) and Canadian patients (OR=5.6, 95% CI: 1.5-20) were more likely to be at the expected education level. Neither transfusion nor chelation was associated with lower employment or educational achievement.
Individuals with thalassemia in North America can achieve higher education; however, full-time employment remains a problem. Transfusion and chelation do not affect employment or education status of this patient population.
PMCID: PMC2932798  PMID: 20535817
Employment; Education; Thalassemia
16.  Bone Disease in Thalassemia: A Frequent and Still Unresolved Problem 
Adults with β thalassemia major frequently have low BMD, fractures, and bone pain. The purpose of this study was to determine the prevalence of low BMD, fractures, and bone pain in all thalassemia syndromes in childhood, adolescence, and adulthood, associations of BMD with fractures and bone pain, and etiology of bone disease in thalassemia. Patients of all thalassemia syndromes in the Thalassemia Clinical Research Network, ≥6 yr of age, with no preexisting medical condition affecting bone mass or requiring steroids, participated. We measured spine and femur BMD and whole body BMC by DXA and assessed vertebral abnormalities by morphometric X-ray absorptiometry (MXA). Medical history by interview and review of medical records, physical examinations, and blood and urine collections were performed. Three hundred sixty-one subjects, 49% male, with a mean age of 23.2 yr (range, 6.1–75 yr), were studied. Spine and femur BMD Z-scores < −2 occurred in 46% and 25% of participants, respectively. Greater age, lower weight, hypogonadism, and increased bone turnover were strong independent predictors of low bone mass regardless of thalassemia syndrome. Peak bone mass was suboptimal. Thirty-six percent of patients had a history of fractures, and 34% reported bone pain. BMD was negatively associated with fractures but not with bone pain. Nine percent of participants had uniformly decreased height of several vertebrae by MXA, which was associated with the use of iron chelator deferoxamine before 6 yr of age. In patients with thalassemia, low BMD and fractures occur frequently and independently of the particular syndrome. Peak bone mass is suboptimal. Low BMD is associated with hypogonadism, increased bone turnover, and an increased risk for fractures.
PMCID: PMC3276604  PMID: 18505376
DXA; BMD; fractures; vertebral morphometry; thalassemia

Results 1-16 (16)