Assessing cardiac and liver iron overload in chronically transfused patients with sickle cell disease

Transfusional iron overload represents a substantial challenge in the management of patients with sickle cell disease (SCD) who receive chronic or episodic red blood cell transfusions. Iron‐induced cardiomyopathy is a leading cause of death in other chronically transfused populations but rarely seen in SCD. Study objectives were to: (i) examine the extent of myocardial and hepatic siderosis using magnetic resonance imaging (MRI) in chronically transfused SCD patients, and (ii) evaluate the relationship between long‐term (over the 5 years prior to enrolment) mean serum ferritin (MSF), spot‐ferritin values and liver iron content (LIC) measured using MRI and liver biopsy. Thirty‐two SCD patients (median age 15 years) with transfusional iron overload were recruited from two U.S. institutions. Long‐term MSF and spot‐ferritin values significantly correlated with LIC by MRI‐R2* (r = 0·77, P < 0·001; r = 0·82, P < 0·001, respectively). LIC by MRI‐R2* had strong positive correlation with LIC by liver biopsy (r = 0·98, P < 0·001) but modest inverse correlation with cardiac MRI‐T2* (r = ?0·41, P = 0·02). Moderate to severe transfusional iron overload in SCD was not associated with aberrations in other measures of cardiac function based on echocardiogram or serum biomarkers. Our results suggest that SCD patients receiving chronic transfusions may not demonstrate significant cardiac iron loading irrespective of ferritin trends, LIC and erythropoiesis suppression.     

Deferasirox for iron chelation in multitransfused children with sickle cell disease; long‐term experience in the East London clinical haemoglobinopathy network

Deferasirox (DFX) has been licensed for iron chelation in patients with sickle cell disease (SCD), but there is limited data on its long‐term efficacy and safety in children. This retrospective study included 62 regularly transfused children managed in the East London and Essex Clinical Haemoglobinopathy Network (mean age 9.2 ± 3.2 yr). Efficacy measurements consisted of monthly serum ferritin (SF) and annual R2 MRI‐estimated liver iron concentration (LIC), and safety markers included serum creatinine and alanine aminotransferase (ALT). The mean duration of DFX treatment was 2.5 ± 1.4 yr, and mean dose at 36 months was 25 mg/kg/d. Mean SF at initiation of treatment was 2542 ± 952 ng/mL and increased to 4691 ± 2255 ng/mL at 36 months (P = 0.05). Mean LIC on first scan was 10.3 mg/g dry weight and did not decrease significantly on follow‐up scans. There was a significant correlation between relative change in LIC and in SF (R² = 0.66, P < 0.001). Reversible transaminitis episodes, probably due to drug‐induced hepatitis, were noted in 53% of patients. Responses to an adherence and acceptability questionnaire indicated that more than 50% of children had difficulties in taking DFX, commonly because of unpleasant taste. Our results show that more than 50% of children with SCD have inadequate control of iron overload with DFX. It is not clear whether this is because of frequent dose interruptions, poor tolerability and adherence, or poor efficacy of the drug. We recommend further studies to confirm these findings and to optimise iron chelation in this population.     

Transcranial Doppler velocity among Jamaican children with sickle cell anaemia: determining the significance of haematological values and nutrition

This study investigated the association of nutritional and haematological variables with maximum time‐averaged mean velocity (TAMV) measured by transcranial Doppler (TCD) velocity and the agreement of classification between two protocols. TCD categories included: normal (<170 cm/s), conditional (170–199 cm/s) and abnormal (≥200 cm/s) based on TAMV in distal internal carotid artery (dICA), middle cerebral artery (MCA), internal carotid bifurcation, anterior and posterior cerebral arteries. Of 358 children with sickle cell anaemia (SCA) examined, the mean age (±standard deviation) was 7·4 ± 2·7 years; 13·1% and 6·7% had conditional and abnormal velocities, respectively. Children with abnormal TCD velocities had higher prevalence of prior stroke (P = 0·006). Increased TAMV was associated with younger age (P = 0·001), lower weight (P = 0·001), height (P = 0·007) and oxygen saturation (P = 0·005). There was no association of TAMV with height‐age or body mass index (BMI) z‐scores. Adjusting for gender, BMI z‐score, age, previous stroke and oxygen saturation, mean corpuscular volume (P = 0·005) and reticulocyte count (P = 0·013) were positively associated with TAMV, while haemoglobin concentration (P = 0·009) was negatively associated. There was good agreement [99%; weighted Kappa 0·98 (95% confidence interval 0·89–1), P = 0·0001] in TCD classification using data from five vessels versus two vessels (dICA and MCA). Haematological variables, rather than nutritional status, may be useful markers that identify high‐risk children with SCA.     

Liver iron concentration measurements by MRI in chronically transfused children with sickle cell anemia: baseline results from the TWiTCH trial

Noninvasive, quantitative, and accurate assessment of liver iron concentration (LIC) by MRI is useful for patients receiving transfusions, but R2 and R2* MRI techniques have not been systematically compared in sickle cell anemia (SCA). We report baseline LIC results from the TWiTCH trial, which compares hydroxyurea with blood transfusion treatment for primary stroke prophylaxis assessed by transcranial Doppler sonography in pediatric SCA patients. Liver R2 was collected and processed using a FDA‐approved commercial process (FerriScan^®), while liver R2* quality control and processing were performed by a Core Laboratory blinded to clinical site and patient data. Baseline LIC studies using both MRI techniques were available for 120 participants. LIC_R2* and LIC_R2 results were highly correlated (r² = 0.93). A proportional bias of LIC(R2*)/LIC(R2), decreasing with average LIC, was observed. Systematic differences between LIC_R2* and LIC_R2 were also observed by MRI manufacturer. Importantly, LIC_R2* and LIC_R2 estimates had broad 95% limits of agreement with respect to each other. We recommend LIC_R2 and LIC_R2* not be used interchangeably in SCA patients to follow individual patient trends in iron burden.Am. J. Hematol. 90:806–810, 2015. © 2015 Wiley Periodicals, Inc.     

Increased prevalence of potential right‐to‐left shunting in children with sickle cell anaemia and stroke

‘Paradoxical’ embolization via intracardiac or intrapulmonary right‐to‐left shunts (RLS ) is an established cause of stroke. Hypercoagulable states and increased right heart pressure, which both occur in sickle cell anaemia (SCA ), predispose to paradoxical embolization. We hypothesized that children with SCA and overt stroke (SCA  + stroke) have an increased prevalence of potential RLS . We performed contrasted transthoracic echocardiograms on 147 children (aged 2–19 years) with SCA  + stroke) mean age 12·7 ± 4·8 years, 54·4% male) and a control group without SCA or stroke (n  = 123; mean age 12·1 ± 4·9 years, 53·3% male). RLS was defined as any potential RLS detected by any method, including intrapulmonary shunting. Echocardiograms were masked and adjudicated centrally. The prevalence of potential RLS was significantly higher in the SCA +stroke group than controls (45·6% vs. 23·6%, P  < 0·001). The odds ratio for potential RLS in the SCA  + stroke group was 2·7 (95% confidence interval: 1·6–4·6) vs controls. In post hoc analyses, the SCA  + stroke group had a higher prevalence of intrapulmonary (23·8% vs. 5·7%, P  < 0·001) but not intracardiac shunting (21·8% vs. 18·7%, P  = 0·533). SCA patients with potential RLS were more likely to report headache at stroke onset than those without. Intrapulmonary and intracardiac shunting may be an overlooked, independent and potentially modifiable risk factor for stroke in SCA .     

Absence of cardiac siderosis by MRI T2* despite transfusion burden,hepatic and serum iron overload in Lebanese patients with sickle cell disease

Background: The use of magnetic resonance imaging (MRI) to detect organ‐specific iron overload is becoming increasingly common. Although hepatic iron overload has been recognized in patients with sickle cell disease (SCD), cardiac iron deposition has only been examined in a few reports. Methods: This was a cross‐sectional study of 23 patients with SCD. Patient charts were reviewed and data collected for drug use, total lifetime transfusions (TLT), transfusion rate (TR), status of the spleen, and comorbid illnesses or infections. Blood samples were obtained for assessment of hemoglobin, serum ferritin, non‐transferrin‐bound iron (NTBI), and liver enzyme levels. Doppler echocardiography was performed to detect pulmonary hypertension (PHT) and assess left ventricular ejection fraction. Cardiac iron levels were measured by MRI T2*. Direct determination of liver iron concentration (LIC) was performed using R2 MRI. In this study, cardiac T2* >20 ms was considered normal. Results: The mean age was 24.4 ± 9.7 yr, with a male to female ratio of 15:8. A total of 9 (49.9%) patients were splenectomized. The mean TR was 14.1 ± 13.2 Units/yr, and the mean hemoglobin level was 9.0 g/dL. PHT was detected in 6 (27.3%) patients, but none had evidence of heart failure. The mean serum ferritin, LIC, and NTBI levels were 997.7 ng/mL, 4.6 mg Fe/g dw, and 1.1 ± 2.2, respectively. TR was a much better predictor of iron burden (LIC, ferritin, NTBI) than TLT. In fact, TR less than 10 Units/yr did not produce significant iron overload reflecting spontaneous losses as high as 0.11 mg/kg/d. None of the patients had evidence of cardiac iron overload (mean cardiac T2* = 37.3 ± 6.2 ms; range: 21.9–46.8 ms). There was also no statistically significant correlation between cardiac T2* values and any of the study variables. Conclusion: Our study demonstrates that TR is a stronger predictor of iron overload than TLT. It also confirms cardiac sparing in patients with SCD, even in subjects with significant transfusion burden, systemic and hepatic iron overload.     

Outcome of overt stroke in sickle cell anaemia,a single institution's experience

Stroke is a traumatic complication in sickle cell anaemia (SCA) that is associated with significant morbidity and a risk of recurrent overt stroke of 2·2–6·4 events per 100 patient‐years. A retrospective study was performed on all paediatric SCA patients diagnosed with a history of overt stroke between 1997 and 2010. A total of 31 children with SCA had new onset overt stroke. The mean age of the active patients (n = 27) was 17·9 years (range 6·8–27·6 years) with a total period of observation of 305 patient‐years. Twenty‐two of 27 (81%) were receiving long term red blood cell transfusions and 16 (59%) were taking the anti‐platelet agent, aspirin, since diagnosis of the stroke. Two of 27 (7%) patients had a second overt stroke with an overall risk of recurrent stroke of 0·66/100 patient‐years (one stroke was ischaemic and the other haemorrhagic). In patients taking aspirin with 180 patient‐years of follow up, the recurrence rate of haemorrhagic stroke was 0·58/100 patient‐years. We have an excellent outcome for overt stroke in paediatric SCA patients with a low rate of recurrent stroke. Further studies are needed to determine the risk‐benefit ratio of aspirin therapy in the prevention of recurrent stroke in paediatric SCA.     

Bacteraemia in sickle cell anaemia is associated with low haemoglobin: a report of 890 admissions to a tertiary hospital in Tanzania

Bacteraemia is a leading cause of morbidity in sickle cell anaemia (SCA), but information from studies in Africa is limited. We evaluated 890 admissions from 648 SCA patients at a tertiary hospital in Tanzania. Bacteraemia was present in 43 admissions (4·8%); isolates included Staphylococcus aureus (12/43; 28%), non‐Typhi Salmonella (9/43; 21%), Streptococcus pneumoniae (3/43; 7%) and Salmonella Typhi (2/43; 5%). Compared to SCA patients without bacteraemia, SCA patients with bacteraemia had significantly lower haemoglobin [71 g/l vs. 62 g/l, odds ratio 0·72 (95% confidence interval 0·56–0·91), P < 0·01]. Further exploration is needed of the relationship between anaemia and bacterial infections in SCA in Africa.     

Improvement of medical care in a cohort of newborns with sickle‐cell disease in North Paris: impact of national guidelines

We conducted a retrospective study on newborns with sickle‐cell disease (SCD), born 1995–2009, followed in a multicentre hospital‐based network. We assessed patient outcomes, medical care and compliance with the national guidelines published in December 2005. Data from 1033 patients (742 SS/Sβ°‐thalassaemia) with 6776 patient‐years of follow‐up were analysed (mean age 7·1 ± 3·9 years). SCD‐related deaths (n = 13) occurred only in SS‐genotype patients at a median age of 23·1 months, mainly due to acute anaemia (n = 5, including 2 acute splenic sequestrations) and infection (n = 3). Treatment non‐compliance was associated with a 10‐fold higher risk of SCD‐related death (P = 0·01). Therapeutic intensification was provided for all stroke patients (n = 12), almost all patients with abnormal transcranial Doppler (TCD) (n = 76) or with >1 acute chest syndrome/lifetime (n = 64) and/or ≥3 severe vaso‐occlusive crises/year (n = 100). Only 2/3 of patients with baseline haemoglobin <70 g/l received intensification, mainly for other severity criteria. Overall, hydroxycarbamide was under‐prescribed, given to 2/3 of severe vaso‐occlusive patients and 1/3 of severely anaemic patients. Nevertheless, introduction of the on‐line guidelines was concomitant with an improvement in medical care in the 2006–2009 cohort with a trend towards increased survival at 5 years, from 98·3% to 99·2%, significantly increased TCD coverage (P = 0·004) and earlier initiation of intensification of therapy (P ≤ 0·01).     

Pulmonary dysfunction in thalassaemia major: is there any relationship with body iron stores?

Although pulmonary function abnormalities in thalassaemia major (TM ) were described in 1980, the pathogenetic mechanism is not clear and data are contradictory, probably because of study heterogeneity and the multifactorial nature of the pathogenesis. We retrospectively analysed 73 adult TM patients to evaluate the prevalence of pulmonary dysfunction in adult TM and investigate relationships with iron load. All patients underwent body plethysmography and carbon monoxide diffusion (DLCO ) was assessed in 63, in addition to blood tests, echocardiogram and T2* myocardial and liver magnetic resonance imaging. Restrictive lung disease was present in 26 (35·6%) patients. Serum ferritin levels were higher in patients with restrictive pattern (1526 μg/l vs. 975 μg/l, P  = 0·05). Restrictive lung disease did not correlate with cardiac or liver iron overload. However, considering only patients with serum ferritin >2500 μg/l, those with restrictive pattern also had heart (T2* 14·28 ± 9·99 ms vs. 31·59 ± 7·43 ms) and liver iron overload (LIC 16·02 ± 8·44 mg vs. 5·02 ± 2·69 mg Fe/g dry weight) compared to those without restrictive pattern. Twenty‐five patients (39·7%) had decreased DLCO . No correlation was observed with iron parameters. In our data restrictive pattern was predominant; we observed a relationship with serum ferritin levels suggesting that iron, particularly its chronic effect, could play a role in the pathogenesis of pulmonary disease.     

Interim assessment of liver damage in patients with sickle cell disease using new non‐invasive techniques

We explored transient elastography (TE ) and enhanced liver fibrosis (ELF ^™) score with standard markers of liver function to assess liver damage in 193 well patients with sickle cell disease (SCD ). Patients with HbSS or HbSβ⁰ thalassaemia (sickle cell anaemia, SCA ; N  = 134), had significantly higher TE results and ELF scores than those with HbSC (N  = 49) disease (TE , 6·8 vs. 5·3, P  < 0·0001 and ELF , 9·2 vs. 8·6 P  < 0·0001). In SCA patients, TE and ELF correlated significantly with age and all serum liver function tests (LFT s). Additionally, (weak) positive correlation was found with lactate dehydrogenase (TE : r  = 0·24, P  = 0·004; ELF : r  = 0·26 P  = 0·002), and (weak) negative correlation with haemoglobin (TE : r  = −0·25, P  = 0·002; ELF : r  = −0·25 P  = 0·004). In HbSC patients, correlations were weaker or not significant between TE or ELF , and serum LFT s. All markers of iron loading correlated with TE values when corrected for sickle genotype (serum ferritin, β = 0·25, P  < 0·0001, total blood transfusion units, β = 0·25, P  < 0·0001 and LIC β = 0·32, P  = 0·046). The exploratory study suggests that, while TE could have a role, the utility of ELF score in monitoring liver damage in SCD , needs further longitudinal studies.     

Haemoglobinuria is associated with chronic kidney disease and its progression in patients with sickle cell anaemia

To evaluate the association between haemoglobinuria and chronic kidney disease (CKD) in sickle cell anaemia (SCA), we analysed 356 adult haemoglobin SS or Sβ^o thalassaemia patients from the University of Illinois at Chicago (UIC) and 439 from the multi‐centre Walk‐Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk‐PHaSST) cohort. CKD was classified according to National Kidney Foundation Kidney Disease Outcomes Quality Initiatives guidelines. Haemoglobinuria, defined as positive haem on urine dipstick with absent red blood cells on microscopy, was confirmed by enzyme‐linked immunosorbent assay in a subset of patients. The prevalence of CKD was 58% in the UIC cohort and 54% in the Walk‐PHaSST cohort, and haemoglobinuria was observed in 36% and 20% of the patients, respectively. Pathway analysis in both cohorts indicated an independent association of lactate dehydrogenase with haemoglobinuria and, in turn, independent associations of haemoglobinuria and age with CKD (P < 0·0001). After a median of 32 months of follow‐up in the UIC cohort, haemoglobinuria was associated with progression of CKD [halving of estimated glomerular filtration rate or requirement for dialysis; Hazard ratio (HR) 13·9, 95% confidence interval (CI) 1·7–113·2, P = 0·0012] and increasing albuminuria (HR 3·1, 95% CI: 1·3–7·7; logrank P = 0·0035). In conclusion haemoglobinuria is common in SCA and is associated with CKD, consistent with a role for intravascular haemolysis in the pathogenesis of renal dysfunction in SCA.     

Liver complications of haemoglobin H disease in adults

Haemoglobin H (HbH) disease is a type of non‐transfusion‐dependent thalassaemia. This cross‐sectional study aimed at determining the prevalence and severity of liver iron overload and liver fibrosis in patients with HbH disease. Risk factors for advanced liver fibrosis were also identified. A total of 80 patients were evaluated [median (range) age 53 (24–79) years, male 34%, non‐deletional HbH disease 24%]. Patients underwent ‘observed’ T2‐weighted magnetic resonance imaging examination for liver iron concentration (LIC) quantification, and transient elastography for liver stiffness measurement (LSM) and fibrosis staging. In all, 25 patients (31%) had moderate‐to‐severe liver iron overload (LIC ≥7 mg/g dry weight). The median LIC was higher in non‐deletional than in deletional HbH disease (7·8 vs. 2.9 mg/g dry weight, P = 0·002). In all, 16 patients (20%) had advanced liver fibrosis (LSM >7.9 kPa) and seven (9%) out of them had probable cirrhosis (LSM >11.9 kPa). LSM positively correlated with age (R = 0·24, P = 0·03), serum ferritin (R = 0·36, P = 0·001) and LIC (R = 0·28, P = 0·01). In multivariable regression, age ≥65 years [odds ratio (OR) 4·97, 95% confidence interval (CI) 1·52–17·50; P = 0·047] and moderate‐to‐severe liver iron overload (OR 3·47, 95% CI 1·01–12·14; P = 0·01) were independently associated with advanced liver fibrosis. The findings suggest that regular screening for liver complications should be considered in the management of HbH disease.     

The acute phase inflammatory response to maximal exercise testing in children and young adults with sickle cell anaemia

Although individuals with sickle cell anaemia (SCA) have elevated baseline inflammation and endothelial activation, the acute phase response to maximal exercise has not been evaluated among children with SCA. We measured the acute phase response to maximal exercise testing for soluble vascular cell adhesion molecule (sVCAM) as well as interleukin 6 (IL6), total white blood cell (WBC) count, C‐reactive protein (CRP) and D‐dimer in a cohort of children with SCA and matched controls at baseline, immediately after, and 30, 60 and 120 min following exercise. Despite higher baseline levels of all biomarkers except CRP, the acute phase response from baseline to immediately after exercise was significantly greater in subjects versus controls for CRP (2·1 vs. 0·2 mg/l, P = 0·02) and D‐dimer (160 vs. 10 μg/l, P < 0·01) only. Similar between‐group trends were observed over time for all biomarkers, including sVCAM, IL6, total WBC, CRP and D‐dimer. Lower fitness, defined by peak oxygen consumption (VO₂), was independently associated with greater acute phase responses to exercise for sVCAM. Our results suggest maximal exercise may not be associated with any greater escalation of endothelial activation or inflammation in SCA and provide preliminary biomarker evidence for the safety of brief, high‐intensity physical exertion in children with SCA.     

The effects of hydroxycarbamide on the plasma proteome of children with sickle cell anaemia

We investigated changes in the plasma proteome of children with sickle cell anaemia (SCA) associated with hydroxycarbamide (HC) use, to further characterize the actions of HC. Fifty-one children with SCA consented to take part in this study. Eighteen were taking HC at a median dose of 22 mg/kg, and 33 were not on HC. Plasma was analysed using an unbiased proteomic approach and a panel of 92 neurological biomarkers. HC was associated with increased haemoglobin (Hb) (89·8 vs. 81·4 g/l, P = 0·007) and HbF (6·7 vs. 15·3%, P < 0·001). Seventeen proteins were decreased on HC compared to controls by a factor of <0·77, and six proteins showed >1·3 increased concentration. HC use was associated with reduced haemolysis (lower α, β, δ globin chains, haptoglobin-related protein, complement C9; higher haemopexin), reduced inflammation (lower α-1-acid glycoprotein, CD5 antigen-like protein, ceruloplasmin, factor XII, immunoglobulins, cysteine-rich secretory protein 3, vitamin D-binding protein) and decreased activation of coagulation (lower factor XII, carboxypeptidase B2, platelet basic protein). There was a significant correlation between the increase in HbF% on HC and haemopexin levels (r = 0·603, P = 0·023). This study demonstrated three ways in which HC may be beneficial in SCA, and identified novel proteins that may be useful to monitor therapeutic response.     

Cerebral and skeletal muscle tissue oxygenation during exercise challenge in children and young adults with sickle cell anaemia

We used near-infrared spectroscopy to examine tissue oxygenation (StO₂₎ during exercise in 17 children and young adults with sickle cell anaemia (SCA) and 13 controls. Patients had lower cerebral StO₂ at all exercise stages and demonstrated significantly greater decreases in cerebral StO₂ later during exercise. Quadriceps StO₂ increased similarly in patients and controls during early exercise, but decreases from baseline were greater in patients during later exercise. At similar workloads, patients demonstrated lower cerebral StO₂ (69·2 ± 6·6 vs. 79·5 ± 5·3%, P < 0·001) and trended towards lower quadriceps StO₂ (67·7 ± 9·0 vs. 73·2 ± 7·9%, P = 0·09) Further studies of tissue oxygenation during exercise in SCA are warranted.     

Simvastatin reduces vaso‐occlusive pain in sickle cell anaemia: a pilot efficacy trial

Sickle cell anaemia (SCA ) is a progressive vascular disease characterized by episodic vaso‐occlusive pain. Despite the broad impact of inflammation on acute and chronic clinical manifestations of SCA , no directed anti‐inflammatory therapies currently exist. Statins are cholesterol‐lowering agents shown to confer protection from vascular injury by suppressing inflammation. We previously documented a reduction in soluble biomarkers of inflammation in patients with sickle cell disease treated with simvastatin. To determine the potential clinical efficacy of simvastatin, we treated 19 SCA patients with single daily dose simvastatin for 3 months and assessed changes from baseline in the frequency and intensity of diary‐reported pain and levels of circulating nitric oxide metabolites (NO x), high sensitivity C‐reactive protein (hs‐CRP ), vascular cell adhesion molecule 1 (VCAM ‐1), intercellular adhesion molecule 1 (ICAM ‐1), ICAM ‐3, E‐selectin, and vascular endothelial growth factor (VEGF ). Treatment with simvastatin resulted in a significant reduction in the frequency of pain (P  =  0·0003), oral analgesic use (P  =  0·003) and circulating hs‐CRP (P  =  0·003), soluble (s)E‐selectin (P  =  0·01), sICAM ‐1 (P  =  0·02), sICAM ‐3 (P  =  0·02) and sVEGF (P  =  0·01). Simvastatin had no effect on pain intensity or levels of NO x, sP ‐selectin and sVCAM ‐1. The observed reductions in pain rate and markers of inflammation were greatest in subjects receiving hydroxycarbamide (HC ), suggesting a synergistic effect of simvastatin. These results provide preliminary clinical data to support a larger trial of simvastatin in SCA.     

Hydroxycarbamide treatment and brain MRI/MRA findings in children with sickle cell anaemia

Silent cerebral infarction (SCI) is the most common neurological abnormality among children with sickle cell anaemia (SCA). The effect of hydroxycarbamide (also termed hydroxyurea) on the development and progression of SCI is unclear. We evaluated brain magnetic resonance imaging/angiography (MRI/MRA) in children with SCA receiving long‐term hydroxycarbamide therapy. Fifty participants (median 9·4 years, range 1·1–17·3) enrolled in the Hydroxyurea Study of Long‐Term Effects (HUSTLE; NCT00305175) underwent brain MRI/MRA and laboratory evaluations before hydroxycarbamide initiation and after 3 and 6 years of treatment to maximum tolerated dose. SCI and vascular stenosis were evaluated. At baseline, 3 and 6 years, SCI were present in 19/50 (38%), 20/49 (41%), and 7/17 (41%), respectively. At 3 years, one child developed a SCI lesion, and another progressed (single lesion to multiple). Lower haemoglobin (Hb) (80 g/l vs. 86 g/l, P = 0·049), fetal Hb (5·0% vs. 10·4%, P < 0·001) and oxygen saturation (97% vs. 98%, P = 0·027) before hydroxycarbamide initiation were associated with SCI. No patients had vascular stenosis identified on MRA, transient ischaemic attack or stroke. Our data indicate that children receiving hydroxycarbamide over a 3‐ to 6‐year period have a low rate of new or worsening cerebrovascular disease. Further studies are needed to confirm that hydroxycarbamide can prevent the onset and progression of SCI.     

Magnetic resonance angiography-defined intracranial vasculopathy is associated with silent cerebral infarcts and glucose-6-phosphate dehydrogenase mutation in children with sickle cell anaemia

Silent cerebral infarct (SCI) is the most commonly recognized cause of neurological injury in sickle cell anaemia (SCA). We tested the hypothesis that magnetic resonance angiography (MRA)-defined vasculopathy is associated with SCI. Furthermore, we examined genetic variations in glucose-6-phosphate dehydrogenase (G6PD) and HBA (α-globin) genes to determine their association with intracranial vasculopathy in children with SCA. Magnetic resonance imaging (MRI) of the brain and MRA of the cerebral vasculature were available in 516 paediatric patients with SCA, enrolled in the Silent Infarct Transfusion (SIT) Trial. All patients were screened for G6PD mutations and HBA deletions. SCI were present in 41·5% (214 of 516) of SIT Trial children. The frequency of intracranial vasculopathy with and without SCI was 15·9% and 6·3%, respectively (P < 0·001). Using a multivariable logistic regression model, only the presence of a SCI was associated with increased odds of vasculopathy (P = 0·0007, odds ratio (OR) 2·84; 95% Confidence Interval (CI) = 1·55–5·21). Among male children with SCA, G6PD status was associated with vasculopathy (P = 0·04, OR 2·78; 95% CI = 1·04–7·42), while no significant association was noted for HBA deletions. Intracranial vasculopathy was observed in a minority of children with SCA, and when present, was associated with G6PD status in males and SCI.     

MRI guided iron assessment and oral chelator use improve iron status in thalassemia major patients

Oral iron chelators and magnetic resonance imaging (MRI) assessment of heart and liver iron burden have become widely available since the mid 2000s, allowing for improved patient compliance with chelation and noninvasive monitoring of iron levels for titration of therapy. We evaluated the impact of these changes in our center for patients with thalassemia major and transfusional iron overload. This single center, retrospective observational study covered the period from 2005 through 2012. Liver iron content (LIC) was estimated both by a T2* method and by R2 (Ferriscan^®) technique. Cardiac iron was assessed as cT2*. Forty‐two patients (55% male) with transfused thalassemia and at least two MRIs were included (median age at first MRI, 17.5 y). Over a mean follow‐up period of 5.2 ± 1.9 y, 190 MRIs were performed (median 4.5 per patient). Comparing baseline to last MRI, 63% of patients remained within target ranges for cT2* and LIC, and 13% improved from high values to the target range. Both the median LIC and cT2* (cR2* = 1000/cT2*) status improved over time: LIC 7.3 to 4.5 mg/g dry weight, P = 0.0004; cR2* 33.4 to 28.3 Hz, P = 0.01. Individual responses varied widely. Two patients died of heart failure during the study period. Annual MRI iron assessments and availability of oral chelators both facilitate changes in chelation dose and strategies to optimize care. Am. J. Hematol. 89:684–688, 2014. © 2014 Wiley Periodicals, Inc.