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ObjectiveTo estimate the incidence of blood product transfusion, including red blood cells, platelets, and plasma, and characterize pretransfusion hematologic values for infants during their initial hospitalization after birth.Study designRetrospective cohort study using data from 7 geographically diverse US academic and community hospitals that participated in the National Heart Lung and Blood Institute Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) from 2013 to 2016. Pretransfusion hematologic values were evaluated closest to each transfusion and no more than 24 hours beforehand.ResultsData from 60 243 infants were evaluated. The incidence of any transfusion differed by gestational age (P 45 for all gestational age groups examined. The median pretransfusion international normalized ratio for the entire cohort was 1.7 (10th-90th percentile 1.2-2.8).ConclusionsThere is wide variability in pretransfusion hemoglobin, platelet count, and international normalized ratio values for neonatal transfusions. Our findings suggest that a large proportion of neonatal transfusions in the US are administered at thresholds greater than supported by the best-available evidence and highlight an opportunity for improved patient blood management.

Background: Osteonecrosis of the femoral head is a common complication in patients with sickle cell disease, and collapse of the femoral head occurs in 90% of patients within five years after the diagnosis of the osteonecrosis. However, the efficacy of hip core decompression to prevent the progression of osteonecrosis in these patients is still controversial.Methods: In a prospective multicenter study, we evaluated the safety of hip core decompression and compared the results of decompression and physical therapy with those of physical therapy alone for the treatment of osteonecrosis of the femoral head in patients with sickle cell disease. Forty-six patients (forty-six hips) with sickle cell disease and Steinberg Stage-I, II, or III osteonecrosis of the femoral head were randomized to one of two treatment arms: (1) hip core decompression followed by a physical therapy program or (2) a physical therapy program alone. Eight patients withdrew from the study, leaving thirty-eight who participated.Results: Seventeen patients (seventeen hips) underwent decompression combined with physical therapy, and no intraoperative or immediate postoperative complications occurred. Twenty-one patients (twenty-one hips) were treated with physical therapy alone. After a mean of three years, the hip survival rate was 82% in the group treated with decompression and physical therapy and 86% in the group treated with physical therapy alone. According to a modification of the Harris hip score, the mean clinical improvement was 18.1 points for the patients treated with hip core decompression and physical therapy compared with 15.7 points for those treated with physical therapy alone. With the numbers studied, the differences were not significant.Conclusions: In this randomized prospective study, physical therapy alone appeared to be as effective as hip core decompression followed by physical therapy in improving hip function and postponing the need for additional surgical intervention at a mean of three years after treatment. [ABSTRACT FROM AUTHOR]

Objective: To establish the validity and reliability of the Children's Hospital Oakland Hip Evaluation Scale (CHOHES), a modification of the Harris Hip Score, for the evaluation of avascular necrosis (AVN) in sickle cell disease (SCD). Design: Nonrandomized test-retest. Setting: Outpatient clinic. Participants: Forty patients with SCD and 3 healthy controls participated. Twenty-six SCD patients (15 males, 11 females; mean age 25y) had been diagnosed with AVN. This group was compared with 14 SCD patients without AVN and 3 healthy controls (8 males, 9 females; mean age, 16y.) Intervention: On average, subjects were assessed by 2 physical therapists by using the CHOHES on 3 separate outpatient visits within a 2-week period. Main Outcome Measures: A mixed model with random effects was constructed to compare patient scores on the CHOHES with disease severity as estimated by Ficat staging on plain radiographs. Correlations between and within physical therapists using the CHOHES were calculated to assess intra- and interrater reliability. Results: From the random effects model, the CHOHES mean score was 88 for Ficat stage 0, 75 for Ficat stage I or II, and 61 for Ficat stages III or IV (P<.05). Intrarater reliability estimates for the total CHOHES score were very good (r greater than or equal to .87) as were interrater reliability estimates (r greater than or equal to .90) between therapists who measured hips with a wide range of CHOHES scores. Conclusions: the CHOHES appears to be an easy-to-use, valid, and reliable assessment tool and should be considered for use in routing clinical evaluation of SCD patients with AVN. [ABSTRACT FROM AUTHOR]

Objective. Changing patterns of immigration to North America, along with improved treatment, have altered the clinical spectrum of thalassemia, one of the world's most common genetic diseases. The new demography of the disease, with its widely variable phenotypes, has implications for its diagnosis, counseling, and management. Characterization of the new spectrum of this ancient disease, now predominated by minority groups, is essential for optimizing survival.Methods. The National Institutes of Health-sponsored North American Thalassemia Clinical Research Network (TCRN) conducted a cross-sectional study of 721 patients with thalassemia syndromes. A detailed chart review was undertaken to define the relationships between ethnic origins, genotype, and phenotype. These results were compared with 3 previous surveys of similar regions. To determine if the TCRN patient epidemiology is representative of North American patients, 87 additional programs were reviewed, and hemoglobinopathy programs from the 2 largest thalassemia regions, Ontario and California, were analyzed.Results. A total of 721 patients completed analysis in the TCRN study, including 389 (54%) patients with ß-thalassemia major, 105 (15%) patients with ß-thalassemia intermedia, 95 (13%) patients with hemoglobin E-ß-thalassemia, and 132 (18%) patients with alpha-thalassemia. ß-Thalassemia predominated in Eastern North America. Hemoglobin E-ß-thalassemia and alpha-thalassemia were common on the Western continent. Genotype broadly correlated with the clinical phenotype. However, there was marked heterogeneity in clinical phenotype among patients with similar globin mutations. In ß-thalassemia disorders, coinheritance of the alpha-thalassemia trait, triplication of alpha-thalassemia genes, and heterozygosity for the dominant ß-thalassemia allele affected the clinical phenotype. In alpha-thalassemia disorders, structural mutations such as hemoglobin H-Constant Spring resulted in a severe hemoglobin H phenotype. Sixty percent of patients received regular transfusions, and 86% received regular iron-chelation therapy. Increased survival and decreasing birth rates of Mediterranean patients resulted in an aging Greek/Italian population being replaced by a young Asian/Middle Eastern population. Now, Asian patients account for >50% of the thalassemia population. Evidence of increasing survival is reflected in an advancing mean age of white patients with thalassemia major (25 years, up from 11 years in 1974). The results of the non-TCRN thalassemia survey confirm these observations and describe a young multiethnic thalassemia population distributed throughout North America. Newborn-screening results suggest that thalassemia births in North America are increasing and reflect the change in genotype and phenotype observed in the TCRN populations.Conclusions. The epidemiology of thalassemia in North America reflects a heterogeneous group of diseases with new ethnicities, genotypes, and phenotypes. In these communities, physicians will need to provide education, prenatal diagnosis, counseling, and management of this newly diverse group of patients. [ABSTRACT FROM AUTHOR]

Background: Acute chest syndrome (ACS) is the leading cause of mortality, accounting for 25% of all deaths among individuals with sickle cell disease (SCD). There is a lack of evidence-based laboratory and clinical risk stratification guidelines for the diagnosis and management of ACS., Study Design and Methods: To better understand physician practices for the management of ACS in the United States, we created an ACS Working Group including hematology and transfusion medicine physicians from four different SCD treatment centers in the United States. The working group created a physician survey that included physician demographics and ACS diagnostic criteria that they had to rate. The survey also included three case scenarios to assess physician attitudes about the management of ACS. Management options included supportive and preventive strategies in addition to transfusion therapy options., Results: Out of 455 physicians who received the survey, 195 responded (response rate = 43%). The respondents were primarily hematology/oncology physicians. The responses showed wide variability among physicians in how diagnostic criteria for ACS are used and how physicians risk-stratify ACS patients in their practice. The responses also reflected variability in the use of transfusions for ACS., Discussion: Based on our results, we conclude that ACS is diagnosed and managed inconsistently among expert physicians, especially in their transfusion practices due to a lack of consensus on risk stratification criteria. Our data suggest an urgent need for well-designed prospective studies to provide evidence-based guidelines and minimize management variability among physicians who care for individuals with SCD and ACS., (© 2024 The Author(s). Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Intravascular hemolysis results in the release of cell-free hemoglobin and heme in plasma. In sickle cell disease, the fragility of the sickle red blood cell leads to chronic hemolysis, which can contribute to oxidative damage and activation of inflammatory pathways. The scavenger proteins haptoglobin and hemopexin provide pathways to remove hemoglobin and heme, respectively, from the circulation. Heme also intercalates in membranes of blood cells and endothelial cells in the vasculature and associates with other plasma components such as albumin and lipoproteins. Hemopexin has a much higher affinity and can strip heme from the other pools and detoxify plasma from cell-free circulatory heme. However, due to chronic hemolysis, hemopexin is depleted in individuals with sickle cell disease. Thus, cell-free unbound heme is expected to accumulate in plasma. We developed a methodology for the accurate quantification of the fraction of heme, which is pathologically relevant in sickle cell disease, that does not appear to be sequestered to a plasma compartment. Our data show significant variation in the concentration of unbound heme, and rather unexpectedly, the size of the unbound fraction does not correlate to the degree of hemolysis, as measured by the concentration of bound heme. Very high heme concentrations (>150 µM) were obtained in some plasma with unbound concentrations that were several fold lower than in plasma with much lower hemolysis (<50 µM). These findings underscore the long-term effects of chronic hemolysis on the blood components and of the disruption of the essential equilibrium between release of hemoproteins/heme in the circulation and adaptative response of the scavenging/removal mechanisms. Understanding the clinical implications of this loss of response may provide insights into diagnostic and therapeutic targets in patients with sickle cell disease.

Because women with transfusion-dependent thalassemia are seeking pregnancy, ensuring the best outcomes for both mother and baby require concerted and collaborative efforts between the hematologist, obstetrician, cardiologist, hepatologist, and genetic counselor among others. Proactive counseling, early fertility evaluation, optimal management of iron overload and organ function, and application of advances in reproductive technology and prenatal screening are important in ensuring a healthy outcome. Many unanswered questions remain requiring further study, including fertility preservation, non-invasive prenatal diagnosis, chelation therapy during pregnancy, and indications and duration of anticoagulation., Competing Interests: Disclosure FA Sayani: Grant/Research/Clinical Trial Support: Agios Pharmaceuticals, Celgene, Novartis, Imara, Protagonist. EP Vichinsky: Grant/Research/Clinical Trial Support: Agios Pharmaceuticals, Bluebird Bio, Global Blood Therapeutics, Novartis, Novo Nordisk. Consultant/Advisory Boards: BioMarin Pharmaceuticals, Bluebird bio, Chiesi Corp, Forma Therapeutics, Global Blood Therapeutics. All of the relevant financial relationships listed have been mitigated., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Patients with non-transfusion-dependent thalassaemia (NTDT), although they do not require regular blood transfusions for survival, can still accrue a heavy burden of comorbidities. No approved disease-modifying therapies exist for these patients. We aimed to investigate the safety and efficacy of mitapivat (Agios Pharmaceuticals, Cambridge, MA, USA), a pyruvate kinase activator, in adults with non-transfusion-dependent (NTD) α-thalassaemia or NTD β-thalassaemia., Methods: In this open-label, multicentre, phase 2 study, patients were recruited from four academic clinical study sites in Oakland, CA, and Boston, MA, USA; Toronto, ON, Canada; and London, UK. Patients were eligible if they were aged 18 years or older, with NTDT (including β-thalassaemia with or without α-globin gene mutations, haemoglobin E β-thalassaemia, or α-thalassaemia), and a baseline haemoglobin concentration of 10·0 g/dL or lower. During a 24-week core period, mitapivat was administered orally at 50 mg twice daily for the first 6 weeks followed by an escalation to 100 mg twice daily for 18 weeks thereafter. The primary endpoint was haemoglobin response (a ≥1·0 g/dL increase in haemoglobin concentration from baseline at one or more assessments between weeks 4 and 12). Efficacy and safety were assessed in the full analysis set (ie, all patients who received at least one dose of study drug). This study is registered with ClinicalTrials.gov, NCT03692052, and is closed to accrual., Findings: Between Dec 28, 2018, and Feb 6, 2020, 27 patients were screened, of whom 20 were enrolled (15 [75%] with β-thalassaemia and five [25%] with α-thalassaemia) and received mitapivat. The median age of patients was 44 years (IQR 35-56), 15 (75%) of 20 patients were female, five (25%) were male, and ten (50%) identified as Asian. 16 (80% [90% CI 60-93]) of 20 patients had a haemoglobin response (p<0·0001), five (100%) of five with α-thalassaemia and 11 (73%) of 15 with β-thalassaemia. 17 (85%) patients had a treatment-emergent adverse event, and 13 had a treatment-emergent event that was considered to be treatment related. One serious treatment-emergent adverse event occurred (grade 3 renal impairment), which was considered unrelated to study drug, resulting in discontinuation of treatment. The most commonly reported treatment-emergent adverse events were initial insomnia (ten [50%] patients), dizziness (six [30%]), and headache (five [25%]). No patients died during the 24-week core period., Interpretation: These efficacy and safety results support the continued investigation of mitapivat for the treatment of both α-thalassaemia and β-thalassaemia., Funding: Agios Pharmaceuticals., Competing Interests: Declaration of interests KHMK reports consultancy fees from Agios Pharmaceuticals, Alexion, Apellis, bluebird bio, Celgene, Forma, Pfizer, and Novartis; honoraria from Alexion and Novartis; membership on an advisory committee for Agios Pharmaceuticals and Bioverativ/Sanofi/Sangamo; and research funding from Pfizer. DML reports consultancy fees from Agios Pharmaceuticals and membership on the Board of Directors or advisory committee for Agios Pharmaceuticals and Cerus. AL reports research funding from bluebird bio, Celgene, Insight Magnetics, La Jolla Pharmaceutical Company, Novartis, Protagonist Therapeutics, Terumo Corporations, and Forma; consultancy fees from Agios Pharmaceuticals and Chiesi USA; and membership on the Board of Directors or advisory committee for Celgene and Protagonist Therapeutics. HA-S reports consultancy fees from Agios Pharmaceuticals, argenx, Dova/Sobi, Moderna, Novartis, Rigel, and Forma and research funding from Agios Pharmaceuticals, Amgen, and Dova. JB, PAK, BT, ML, and KU are employees and shareholders of Agios Pharmaceuticals. EPV reports consultancy fees and research funding from Agios Pharmaceuticals, bluebird bio, Global Blood Therapeutics, Novartis, and Pfizer., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: L-Glutamine is FDA-approved for sickle cell disease (SCD), yet the mechanism(s)-of-action are poorly understood. We performed a pharmacokinetics (pK) study to determine the metabolic fate of glutamine supplementation on plasma and erythrocyte amino acids in patients with SCD., Design: A pK study was performed where patients with SCD fasting for > 8 h received oral L-glutamine (10 g). Blood was analyzed at baseline, 30/60/90 min/2/3/4/8 hrs. A standardized diet was administered to all participants at 3 established time-points (after 2/5/7hrs). A subset of patients also had pK studies performed without glutamine supplementation to follow normal diurnal fluctuations in amino acids., Setting: Comprehensive SCD Center in Oakland, California RESULTS: Five patients with SCD were included, three of whom performed pK studies both with and without glutamine supplementation. Average age was 50.6 ± 5.6 years, 60% were female, 40% SS, 60% SC. Plasma glutamine levels increased significantly after oral glutamine supplementation, compared to minimal fluctuations with diet. Plasma glutamine concentration peaked within 30-min of ingestion (p = 0.01) before decreasing to a plateau by 2-h that remained higher than baseline by 8 h. Oral glutamine also increased plasma arginine concentration, which peaked by 4-h (p = 0.03) and remained elevated through 8-h. Erythrocyte glutamine levels began to increase by 8-h, while erythrocyte arginine concentration peaked at 4-h., Conclusions: Oral glutamine supplementation acutely improved glutamine and arginine bioavailability in both plasma and erythrocytes. This is the first study to demonstrate that glutamine therapy increases arginine bioavailability and may provide insight into shared mechanisms-of-action between these conditionally-essential amino acids., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The severe forms of thalassemia are the most common inherited anemias managed with regular blood transfusion therapy. Transfusion policies and complications are critical to quality of life and survival, but there is a lack of standardized care., Study Design and Methods: A survey of 58 items was completed in 2016 by 11 centers in California, Washington, Oregon, Nevada, and Arizona providing long-term care for thalassemia. The questionnaire addressed demographic information, transfusion practices and complications, and educational needs., Results: The centers followed 717 patients with β-thalassemia (314, 43.8%) or α-thalassemia (394, 55%). One-third (34.7%) of patients were transfusion-dependent. Indications and goals of transfusion therapy differed between centers. Prestorage leukoreduction was universal, while routine irradiation of units was limited to one site. Red blood cell antigen phenotype was determined before the first transfusion and patients received Rh/Kell-matched units. However, more than half of the transfused patients had received blood at multiple hospitals within or outside the United States. Alloantibodies were seen in 16.9% of transfused group, but management of such patients was variable. Unusual or emerging transfusion-transmitted pathogens were not observed. Multiple educational needs were recognized, with iron overload as the biggest challenge; the approach to iron chelation varied within the group., Conclusion: This study identified many patients not included in earlier surveys limited to major national centers, suggesting that the thalassemia population in the United States is vastly underestimated. Lack of evidence-based guidelines is a barrier to optimal care, which should be addressed through regional consortia of thalassemia centers., (© 2018 AABB.)

Background: Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Oral therapy with pharmaceutical-grade l-glutamine (USAN, glutamine) has been shown to increase the proportion of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes, which probably reduces oxidative stress and could result in fewer episodes of sickle cell-related pain., Methods: In a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial, we tested the efficacy of pharmaceutical-grade l-glutamine (0.3 g per kilogram of body weight per dose) administered twice daily by mouth, as compared with placebo, in reducing the incidence of pain crises among patients with sickle cell anemia or sickle β 0 -thalassemia and a history of two or more pain crises during the previous year. Patients who were receiving hydroxyurea at a dose that had been stable for at least 3 months before screening continued that therapy through the 48-week treatment period., Results: A total of 230 patients (age range, 5 to 58 years; 53.9% female) were randomly assigned, in a 2:1 ratio, to receive l-glutamine (152 patients) or placebo (78 patients). The patients in the l-glutamine group had significantly fewer pain crises than those in the placebo group (P=0.005), with a median of 3.0 in the l-glutamine group and 4.0 in the placebo group. Fewer hospitalizations occurred in the l-glutamine group than in the placebo group (P=0.005), with a median of 2.0 in the l-glutamine group and 3.0 in the placebo group. Two thirds of the patients in both trial groups received concomitant hydroxyurea. Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l-glutamine group than in the placebo group., Conclusions: Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. (Funded by Emmaus Medical; ClinicalTrials.gov number, NCT01179217 .).

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Sickle cell disease (SCD) is a group of inherited disorders caused by mutations in HBB, which encodes haemoglobin subunit β. The incidence is estimated to be between 300,000 and 400,000 neonates globally each year, the majority in sub-Saharan Africa. Haemoglobin molecules that include mutant sickle β-globin subunits can polymerize; erythrocytes that contain mostly haemoglobin polymers assume a sickled form and are prone to haemolysis. Other pathophysiological mechanisms that contribute to the SCD phenotype are vaso-occlusion and activation of the immune system. SCD is characterized by a remarkable phenotypic complexity. Common acute complications are acute pain events, acute chest syndrome and stroke; chronic complications (including chronic kidney disease) can damage all organs. Hydroxycarbamide, blood transfusions and haematopoietic stem cell transplantation can reduce the severity of the disease. Early diagnosis is crucial to improve survival, and universal newborn screening programmes have been implemented in some countries but are challenging in low-income, high-burden settings.

Transfusion-independent patients with thalassemia intermedia (TI) develop fatal iron overload from excessive iron absorption triggered by ineffective erythropoiesis. More information about iron pharmacokinetics and nonheme, dietary iron absorption in such patients is needed to optimize management. To obtain more information, different forms of supplemental nonheme iron sources (ferritin and ferrous sulfate) were compared in 4 TI (hemoglobin <9 g/dL) and 6 control (hemoglobin 12-16 g/dL) patients. Serial serum iron concentrations were measured during the 24 hours following consumption of 1 mg/kg of elemental iron as ferritin or ferrous sulfate. Serum iron concentrations were also measured for one TI patient and one control patient 2 hours after the ingestion of 2 mg/kg of dietary iron in ferritin or ferrous sulfate. Maximum serum iron concentrations were observed 4 hours after the consumption of either dietary iron source. However, the serum iron values were unchanged for either dietary iron source, even at the higher doses of consumed iron. Thus, the bioavailability of dietary iron, either as ferritin or ferrous sulfate, was equivalent in both groups of patients. The pilot data support ferritin as an alternative dietary iron supplement to ferrous sulfate., Abbreviations: CRP C-reactive protein; Hb hemoglobin; IDA iron-deficient anemia; ICP inductively coupled plasma; IE ineffective erythropoiesis; SCD sickle cell disease; sTf transferrin saturation; TI thalassemia intermedia; TIBC total iron binding capacity; TM thalassemia major; Tf transferrin.

Background: Clinical care for children and adults living with sickle cell disease (SCD) is often provided in the emergency department (ED). Population-based surveillance data can be used to describe the ED utilization patterns of this patient population., Procedure: A cohort of pediatric and adult California patients with SCD was identified from multiple data sources, and 10 years (2005-2014) of their treat-and-release ED utilization data were analyzed., Results: Among a cohort of 4,636 patients with SCD, 4,100 (88%) had one or more treat-and-release ED visits. There were 2.1 mean annual visits per person for the cohort (median 0.7; range 0-185). In a single year (2005), 53% had 0 treat-and-release ED visits, 35% had 1-3 visits, 9% had 4-10 visits, and 3% had 11 or more visits; this highest utilization group accounted for 45% of all patients' ED visits. ED utilization in this cohort was highest among young adults and also higher among older adults than pediatric patients., Conclusion: The majority of identified patients in each of the 10 years did not go to the ED, but nearly all had one or more such visits over the full span of time. This study highlights the power and utility of a multisource longitudinal data collection effort for SCD. Further study of the segment of the population with highest ED utilization may highlight areas where changes in healthcare and health policy could improve and extend the lives of patients with SCD., (© 2016 Wiley Periodicals, Inc.)

Invariant NKT (iNKT) cells can be activated to stimulate a broad inflammatory response. In murine models of sickle cell disease (SCD), interruption of iNKT cell activity prevents tissue injury from vaso-occlusion. NKTT120 is an anti-iNKT cell monoclonal antibody that has the potential to rapidly and specifically deplete iNKT cells and, potentially, prevent vaso-occlusion. We conducted an open-label, multi-center, single-ascending-dose study of NKTT120 to determine its pharmacokinetics, pharmacodynamics and safety in steady-state patients with SCD. Doses were escalated in a 3+3 study design over a range from 0.001 mg/kg to 1.0 mg/kg. Twenty-one adults with SCD were administered NKTT120 as part of 7 dose cohorts. Plasma levels of NKTT120 predictably increased with higher doses. Median half-life of NKTT120 was 263 hours. All subjects in the higher dose cohorts (0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg) demonstrated decreased iNKT cells below the lower limit of quantification within 6 hours after infusion, the earliest time point at which they were measured. In those subjects who received the two highest doses of NKTT120 (0.3, 1 mg/kg), iNKT cells were not detectable in the peripheral blood for a range of 2 to 5 months. There were no serious adverse events in the study deemed to be related to NKTT120. In adults with SCD, NKTT120 produced rapid, specific and sustained iNKT cell depletion without any infusional toxicity or attributed serious adverse events. The next step is a trial to determine NKTT120's ability to decrease rate of vaso-occlusive pain episodes., Trial Registration: clinicaltrials.gov NCT01783691., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: The study was funded by NKT Therapeutics Inc. NKT Therapeutics provided support in the form of salaries for RS and RM. JJF and DGN were consultants for NKT Therapeutics. None of this alters our adherence to PLOS ONE policies on sharing data and materials.

Pulmonary hypertension (PH) commonly develops in thalassaemia syndromes, but is poorly characterized. The goal of this study was to provide a comprehensive description of the cardiopulmonary and biological profile of patients with thalassaemia at risk for PH. A case-control study of thalassaemia patients at high versus low PH-risk was performed. A single cross-sectional measurement for variables reflecting cardiopulmonary status and biological pathophysiology were obtained, including Doppler-echocardiography, 6-min-walk-test, Borg Dyspnoea Score, New York Heart Association functional class, cardiac magnetic resonance imaging (MRI), chest-computerized tomography, pulmonary function testing and laboratory analyses targeting mechanisms of coagulation, inflammation, haemolysis, adhesion and the arginine-nitric oxide pathway. Twenty-seven thalassaemia patients were evaluated, 14 with an elevated tricuspid-regurgitant-jet-velocity (TRV) ≥ 2·5 m/s. Patients with increased TRV had a higher frequency of splenectomy, and significantly larger right atrial size, left atrial volume and left septal-wall thickness on echocardiography and/or MRI, with elevated biomarkers of abnormal coagulation, lactate dehydrogenase (LDH) levels and arginase concentration, and lower arginine-bioavailability compared to low-risk patients. Arginase concentration correlated significantly to several echocardiography/MRI parameters of cardiovascular function in addition to global-arginine-bioavailability and biomarkers of haemolytic rate, including LDH, haemoglobin and bilirubin. Thalassaemia patients with a TRV ≥ 2·5 m/s have additional echocardiography and cardiac-MRI parameters suggestive of right and left-sided cardiac dysfunction. In addition, low arginine bioavailability may contribute to cardiopulmonary dysfunction in β-thalassaemia., (© 2015 John Wiley & Sons Ltd.)

Recently, the patient-centered medical home (PCMH) emerged as a viable method to improve delivery of medical care. Due to all the promotion about the effectiveness of the PCMH, patients with sickle cell disease, their families and the community hoped that this could be a possible solution to the problems that arise in the treatment of adult patients with sickle cell disease. Review of the literature and review of the criteria for the establishment of a PCMH show that the PCMH is not an ideal model for patients with sickle cell disease because finding a personal physician, which is the first criteria of a functional PCMH, is a major problem in the process of transitioning the care of patients with sickle cell disease from pediatrics to adult care. Moreover, garnering hospital support to defray the initial costs to establish a PCMH for adults with sickle cell disease is unlikely given the already high costs of care for patients with sickle cell disease. Moreover, recent studies have shown insufficient evidence to determine the presumed beneficial effects of the PCMH, especially in patients with chronic disease.

A high tricuspid regurgitant jet velocity (TRV) signifies a risk for or established pulmonary hypertension (PH), which is a serious complication in thalassemia patients. The underlying pathophysiology in thalassemia subgroups and potential biomarkers for early detection and monitoring are not well defined, in particular as they relate to spleen removal. To better understand some of these unresolved aspects, we examined 76 thalassemia patients (35 non-transfused), 25 splenectomized non-thalassemia patients (15 with hereditary spherocytosis), and 12 healthy controls. An elevated TRV (>2.5 m/s) was found in 25/76 (33 %) of the patients, confined to non-transfused or those with a late start of transfusions, including patients with hemoglobin H-constant spring, a finding not previously described. These non or late-transfused patients (76 % splenectomized) had significantly increased platelet activation (sCD40L), high platelet count, endothelial activation (endothelin-1), and hemolysis (LDH, plasma-free Hb), while hypercoagulable and inflammatory markers were not significantly increased. The same markers were increased in the seven patients with confirmed PH on cardiac catheterization, suggesting their possible role for screening patients at risk for PH. A combination of hemolysis and absence of spleen is necessary for developing a high TRV, as neither chronic hemolysis in the non-splenectomized thalassemia patients nor splenectomy without hemolysis, in the non-thalassemia patients, resulted in an increase in TRV.

Objective: This study was conducted to determine the relationship of frontal lobe cortical thickness and basal ganglia volumes to measures of cognition in adults with sickle cell anemia (SCA)., Methods: Participants included 120 adults with SCA with no history of neurologic dysfunction and 33 healthy controls (HCs). Participants were enrolled at 12 medical center sites, and raters were blinded to diagnostic group. We hypothesized that individuals with SCA would exhibit reductions in frontal lobe cortex thickness and reduced basal ganglia and thalamus volumes compared with HCs and that these structural brain abnormalities would be associated with measures of cognitive functioning (Wechsler Adult Intelligence Scale, 3rd edition)., Results: After adjusting for age, sex, education level, and intracranial volume, participants with SCA exhibited thinner frontal lobe cortex (t = -2.99, p = 0.003) and reduced basal ganglia and thalamus volumes compared with HCs (t = -3.95, p < 0.001). Reduced volume of the basal ganglia and thalamus was significantly associated with lower Performance IQ (model estimate = 3.75, p = 0.004) as well as lower Perceptual Organization (model estimate = 1.44, p = 0.007) and Working Memory scores (model estimate = 1.37, p = 0.015). Frontal lobe cortex thickness was not significantly associated with any cognitive measures., Conclusions: Our findings suggest that basal ganglia and thalamus abnormalities may represent a particularly salient contributor to cognitive dysfunction in adults with SCA.

This study aimed to demonstrate the validity, reliability and responsiveness of a new disease-specific quality of life (QoL) questionnaire for children and adults with thalassaemia major, the Transfusion-dependent QoL questionnaire (TranQol). 106 participants (51 adults and 55 children) were recruited from six North American thalassaemia treatment centres with a mean age of 20·7 years (standard deviation [SD] 9, range 7-51 years). The mean total TranQol score was 71 (SD 17, 32-97) on a scale of 0-100. Patients with co-morbidities had significantly lower scores (63 vs. 75, P = 0·001). TranQol scores showed substantial agreement (P < 0·001) with the Health Utilities Index Mark 3 (all patients, r = 0·65), the Pediatric QoL (children, r = 0·77) and the Short Form (36) physical (adults, r = 0·69) and mental summary scores (r = 0·76). In the subgroup who rated their QoL as better, there was a 4·0 point (SD 9·0) improvement in TranQol scores, from baseline of 67·1-71·1 one week later (P = 0·008). Test-retest reliability was excellent (intra-class correlation coefficient, 0·93). The TranQol was valid, with acceptable correlation for all administered measures and was reliable and responsive to change. The TranQol can be incorporated into future studies of thalassaemia major., (© 2013 John Wiley & Sons Ltd.)

Background: Patients with thalassemia major (Thal) frequently have low plasma zinc, which has been associated with low bone mass., Objective: The objective was to determine the effect of zinc supplementation on bone mass in patients with Thal., Design: Forty-two subjects (21 females aged 10-30 y) with Thal and low bone mass were randomly assigned to receive 25 mg Zn/d or placebo. Bone mineral content (BMC) and areal bone mineral density (aBMD) were assessed by using dual-energy X-ray absorptiometry, and fasting blood was collected for the measurement of plasma zinc at 0, 12, and 18 mo., Results: Thirty-two subjects, 81% of whom were transfusion dependent, completed the study (mean ± SD: 17.1 ± 5.2 y). Plasma zinc was ≤70 μg/dL in 11 subjects at baseline and increased significantly with zinc supplementation (P = 0.014). Use of intention-to-treat analysis and linear models for longitudinal data, adjusted for baseline and pubertal stage, showed that the zinc group had significantly greater increases in whole-body BMC (adjusted mean ± SE: 63 ± 15 g; P = 0.02), and aBMD (0.023 ± 0.006 g/cm(2); P = 0.04) than did the placebo group after 18 mo. Furthermore, adjusted spine and hip aBMD z scores each decreased by 0.3 SDs (both P = 0.04) in the placebo compared with the zinc group over the 18-mo study., Conclusions: In young patients with Thal, zinc supplementation resulted in greater gains in total-body bone mass than did placebo. Zinc was well tolerated and is worthy of investigation in larger trials in Thal patients across a range of ages and disease severity. This trial was registered at clinicaltrials.gov as NCT00459732.

Painful episodes of vaso-occlusion are the leading cause of hospitalizations and emergency department visits in sickle cell disease, and are associated with increased mortality. Low nitric oxide bioavailability contributes to vasculopathy in sickle cell disease. Since arginine is the obligate substrate for nitric oxide production, and an acute deficiency is associated with pain, we hypothesized that arginine may be a beneficial treatment for pain related to sickle cell disease. Thirty-eight children with sickle cell disease hospitalized for 56 episodes of pain were randomized into this double-blinded placebo-controlled trial. Patients received L-arginine (100 mg/kg tid) or placebo for 5 days or until discharge. A significant reduction in total parenteral opioid use by 54% (1.9 ± 2.0 mg/kg versus 4.1 ± 4.1 mg/kg, P=0.02) and lower pain scores at discharge (1.9 ± 2.4 versus 3.9 ± 2.9, P=0.01) were observed in the treatment arm compared to the placebo one. There was no significant difference in hospital length of stay (4.1 ± 01.8 versus 4.8 ± 2.5 days, P=0.34), although a trend favored the arginine arm, and total opioid use was strongly correlated with the duration of the admission (r=0.86, P<0.0001). No drug-related adverse events were observed. Arginine therapy represents a novel intervention for painful vaso-occlusive episodes. A reduction of narcotic use by >50% is remarkable. Arginine is a safe and inexpensive intervention with narcotic-sparing effects that may be a beneficial adjunct to standard therapy for sickle cell-related pain in children. A large multi-center trial is warranted in order to confirm these observations.

Pulmonary hypertension is a common but often overlooked complication associated with thalassemia syndromes. There are limited data on the safety and efficacy of selective pulmonary vasodilators in this at-risk population. We, therefore, designed a 12-week, open-label, phase 1/2, pilot-scale, proof-of-principle trial of sildenafil therapy in 10 patients with β-thalassemia and at increased risk of pulmonary hypertension based on an elevated tricuspid regurgitant jet velocity >2.5 m/s on Doppler-echocardiography. Variables compared at baseline and after 12 weeks of sildenafil treatment included Doppler-echocardiographic parameters, 6-minute walked distance, Borg Dyspnea Score, New York Heart Association functional class, pulmonary function, and laboratory parameters. Treatment with sildenafil resulted in a significant decrease in tricuspid regurgitant jet velocity by 13.3% (3.0±0.7 versus 2.6±0.5 m/s, P=0.04), improved left ventricular end systolic/diastolic volume, and a trend towards a improved New York Heart Association functional class. No significant change in 6-minute walked distance was noted. Sildenafil was well tolerated, although minor expected adverse events were commonly reported. The total dose of sildenafil (mg) was strongly correlated with percent change in nitric oxide metabolite concentration in the plasma (ρ=0.80, P=0.01). There were also significant increases in plasma and erythrocyte arginine concentrations. Our study suggests that sildenafil is safe and may improve pulmonary hemodynamics in patients at risk of pulmonary hypertension; however, it was not demonstrated to improve the distance walked in 6 minutes. Clinical trials are needed to identify the best treatment strategy for pulmonary hypertension in patients with β-thalassemia. (clinicaltrials.gov identifier: NCT00872170).

Background: Established heart failure in thalassaemia major has a poor prognosis and optimal management remains unclear., Methods: 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., Results: 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., Conclusions: 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.

α-Thalassemia mutations affect up to 5% of the world's population. The clinical spectrum ranges from an asymptomatic condition to a fatal in utero disease. Hemoglobin H disease results from mutations of three α-globin genes. Deletional forms result in a relatively mild anemia, whereas nondeletional mutations result in a moderate to severe disease characterized by ineffective erythropoiesis, recurrent transfusions, and growth delay. Hemosiderosis develops secondary to increased iron absorption, as well as transfusion burden. Hemoglobin Bart's hydrops fetalis is usually a fatal in utero disease caused by the absence of α genes. Population screening to identify at-risk couples is essential. Affected pregnancies result in severe fetal and maternal complications. Doppler ultrasonography with intrauterine transfusion therapy may improve the fetal prognosis but creates ethical challenges for the family and health providers.

Hereditary persistence of fetal hemoglobin (HPFH) and δβ-thalassemia (δβ-thal) are heterogeneous disorders caused by deletions within the β-globin gene cluster. When combined with other β-thal mutations or structural hemoglobin (Hb) variants, these deletions give rise to clinical phenotypes ranging from an asymptomatic condition to β-thal major (β-TM). Overlap in hematological parameters and variability in expression of Hbs A2 and F make molecular testing necessary to distinguish clinically relevant deletions. Multiplex ligation-dependent probe amplification (MLPA) was used to screen for β-globin gene cluster deletions in 49 unresolved samples referred for a suspected β-thal anomaly. The 1.39 kb Black β(0), 3.5 kb Thai β(0), 118 kb Filipino β(0), 11.8 kb Black (δβ)(0), 13.4 kb Sicilian (δβ)(0), 35.8 kb Black ((A)γδβ)0, Hb Lepore-Boston-Washington (Hb LBW) and HPFH-2 deletions, and two novel deletions, a 61.7 kb Pakistani β(0) deletion and an ((A)γδβ)(0) deletion, were identified in 15 cases. Detection of both known and unknown deletional Hb disorders provides for appropriate clinical management and genetic counseling.

Therapeutics which reduce the pathology in sickle cell syndromes are needed, particularly noncytotoxic therapeutics. Fetal hemoglobin (HbF, α(2) γ(2) ) is established as a major regulator of disease severity; increased HbF levels correlate with milder clinical courses and improved survival. Accordingly, sodium dimethylbutyrate (HQK-1001), an orally-bioavailable, promoter-targeted fetal globin gene-inducing agent, was evaluated in a randomized, blinded, dose-ranging Phase I/II trial in 24 adult patients with HbSS or S/β thalassemia, to determine safety and tolerability of three escalating dose levels. The study therapeutic was administered once daily for two 6-week cycles, with a two-week interim dose holiday. Twenty-one patients completed the study. Five patients received study drug at 10 or 20 mg/kg doses, seven patients received study drug at 30 mg/kg/dose, and 4 patients received placebo. HQK-1001 was well-tolerated with no unexpected drug-related adverse events; a dose-limiting toxicity was not identified. Plasma drug levels were sustained above targeted levels for 24 hr. Increases in HbF above baseline were observed particularly with 30 mg/kg/day doses; in five of seven treated patients, a mean absolute increase in HbF of 0.2 g/dl and a mean increase in total hemoglobin (Hgb) of 0.83 g/dl above baseline were observed, whereas no increases occurred in placebo-treated controls. These findings of favorable PK profiles, tolerability, early rises in HbF, and total Hgb indicate that trials of longer duration appear warranted to more definitively evaluate the therapeutic potential of HQK-1001 in sickle cell disease., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Patients with thalassemia have low circulating levels of many nutrients, but the contribution of dietary intake has not been assessed., Objective: Our objective was to assess dietary intake in a large contemporary sample of subjects with thalassemia., Design: A prospective, longitudinal cohort study using a validated food frequency questionnaire was conducted., Participants/setting: Two hundred and twenty-one subjects (19.7±11.3 years, 106 were female) were categorized into the following age groups: young children (3 to 7.9 years), older children/adolescents (8 to 18.9 years), and adults (19 years or older); 78.8% had β-thalassemia and 90% were chronically transfused. This study took place at 10 hematology outpatient clinics in the United States and Canada., Main Outcome Measures: We conducted a comparison of intake with US Dietary Reference Intakes and correlated dietary intake of vitamin D with serum 25-OH vitamin D and dietary iron with total body iron stores., Statistical Analyses Performed: Intake was defined as inadequate if it was less than the estimated average requirement. χ(2), Fisher's exact, and Student's t test were used to compare intake between age categories and logistic regression analysis to test the relationship between intake and outcomes, controlling for age, sex, and race., Results: More than 30% of subjects consumed inadequate levels of vitamin A, D, E, K, folate, calcium, and magnesium. The only nutrients for which >90% of subjects consumed adequate amounts were riboflavin, vitamin B-12, and selenium. Dietary inadequacy increased with increasing age group (P<0.01) for vitamins A, C, E, B-6, folate, thiamin, calcium, magnesium, and zinc. More than half of the sample took additional supplements of calcium and vitamin D, although circulating levels of 25-OH vitamin D remained insufficient in 61% of subjects. Dietary iron intake was not related to total body iron stores., Conclusions: Subjects with thalassemia have reduced intake of many key nutrients. These preliminary findings of dietary inadequacy are concerning and support the need for nutritional monitoring to determine which subjects 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., (Copyright © 2012 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Morbidity and mortality in thalassemia are associated with iron burden. Recent advances in organ-specific iron imaging and the availability of oral deferasirox are expected to improve clinical care, but the extent of use of these resources and current chelation practices have not been well described. In the present study, we studied chelation use and the change in iron measurements in 327 subjects with transfusion-dependent thalassemia (mean entry age, 22.1 ± 2.5 years) from 2002-2011, with a mean follow-up of 8.0 years (range, 4.4-9.0 years). The predominant chelator currently used is deferasirox, followed by deferoxamine and then combination therapies. The use of both hepatic and cardiac magnetic resonance imaging increased more than 5-fold (P < .001) during the study period, leading to an 80% increase in the number of subjects undergoing liver iron concentration (LIC) measurements. Overall, LIC significantly improved (median, 10.7 to 5.1 mg/g dry weight, P < .001) with a nonsignificant improvement in cardiac T2* (median, 23.55 to 34.50 ms, P = .23). The percentage of patients with markers of inadequate chelation (ferritin > 2500 ng/mL, LIC > 15 mg/g dry weight, and/or cardiac T2* < 10 ms) also declined from 33% to 26%. In summary, increasing use of magnetic resonance imaging and oral chelation in thalassemia management has likely contributed to improved iron burden.

Three new γ-globin chain mutations were identified in four newborn samples referred to the Hemoglobinopathy Reference Laboratory at the Children's Hospital & Research Center Oakland, Oakland, CA, USA, for diagnostic testing. The variants were characterized by sequencing of amplified γ-globin genes. These three novel variants have been named Hb F-Hayward [(G)γ1(NA1)Gly→Asp, GGT>GAT], Hb F-Chori-I [(A)γ(T)16(A13)Gly→Asp, GGC>GAC] and Hb F-Chori-II [(A)γ(I)29(B11)Gly→Glu, GGA>GAA], respectively. No functional studies could be performed.

An elevated tricuspid regurgitant jet velocity (TRV) is associated with hemolysis and early mortality in sickle cell disease, yet risk factors, clinical parameters, and mortality associated with this biomarker in thalassemia are poorly defined. This report summarizes the prevalence of an elevated TRV in 325 patients screened by Doppler echocardiography in the Thalassemia Clinical Research Network. A documented TRV was reported in 148 of 325 (46%) of patients. Average age was 25.9 years (range, 5-56 years) and 97% were transfusion-dependent. Mean TRV was 2.3 ± 0.4 m/s (range, 0.2-3.5 m/s). An abnormal TRV ≥ 2.5 m/s was identified in 49 of 148 (33%) of patients with a documented TRV, 5% (8/148), with a TRV ≥ 3.0 m/s, suggesting significant PH risk. Older age was strongly associated with a high TRV; however, 16% of children had a TRV ≥ 2.5 m/s. A history of splenectomy, hepatitis C, smoking, or high white blood cell count was associated with TRV elevation. In summary, an elevated TRV is noted in one-third of transfusion-dependent thalassemia patients with a documented value and develops in both children and adults. Age, splenectomy, hepatitis C, and smoking are significant univariate risk factors, with splenectomy surfacing as the dominant risk factor over time. Mortality was low in this cohort. Prospective longitudinal studies are needed. This study is registered at http://www.clinicaltrials.gov as NCT00661804.

The pathophysiology of iron-induced compromised fertility in women with thalassemia major (TM) was evaluated in 26 adult TM females. Low gonadotropin secretion resulted in reduced ovarian antral follicle count and ovarian volume, but levels of anti-müllerian hormone (AMH), a sensitive marker for ovarian reserve independent of gonadotropin effect, were mostly normal. AMH correlated with non-transferrin-bound iron (NTBI), suggesting a role of labile iron in the pathogenesis of decreased reproductive capacity, possibly occurring in parallel to cardiac iron toxicity, as cardiac iron was associated with the presence of amenorrhea and with NTBI levels. AMH emerges as an important biomarker for assessment of reproductive capacity in TM, demonstrating that fertility is preserved in the majority of those younger than 30 to 35 years. AMH can be useful in future studies aiming at improved chelation for fertility preservation, whereas NTBI and labile plasma iron may be valuable for monitoring iron effect on the reproductive system.

Ineffective erythropoiesis, the hallmark of β-thalassemia, is a result of α/non-α globin chain imbalance. One strategy to redress globin-chain imbalance is to induce γ-globin gene (HBG) expression. Repression of HBG in adult erythroid cells involves DNA methylation and other epigenetic changes. Therefore, the cytosine analog decitabine, which can deplete DNA methyltransferase 1 (DNMT1), can potentially activate HBG. In 5 patients with β-thalassemia intermedia, a dose and schedule of decitabine intended to deplete DNMT1 without causing significant cytotoxicity (0.2 mg/kg subcutaneous 2 times per week for 12 weeks) increased total hemoglobin from 7.88 ± 0.88 g/dL to 9.04 ± 0.77 g/dL (P = .004) and absolute fetal hemoglobin from 3.64 ± 1.13 g/dL to 4.29 ± 1.13 g/dL (P = .003). Significant favorable changes also occurred in indices of hemolysis and red blood cell densitometry. Consistent with a noncytotoxic, differentiation altering mechanism of action, the major side effect was an asymptomatic increase in platelet counts without erythrocyte micronucleus or VDJ recombination assay evidence of genotoxicity. This study was registered at www.clinicaltrials.gov as #NCT00661726.

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 years) and local controls (n=34, 15 male, 7 to 30 years). 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 years, 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 years, 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., (Copyright © 2011 Elsevier Inc. All rights reserved.)