Protection from sickle cell retinopathy is associated with elevated HbF levels and hydroxycarbamide use in children

Elevated foetal haemoglobin (HbF) levels are protective against some manifestations of sickle cell anaemia but the impact on retinopathy is unknown. We report on 123 children with HbSS, 10·6% of whom developed retinopathy. Independent of hydroxycarbamide, children with a HbF <15% had 7·1‐fold (95% confidence interval, 1·5–33·6) higher odds of developing retinopathy. In children treated with hydroxycarbamide, those with retinopathy had lower HbF levels compared to children without retinopathy (9% vs. 16%; P = 0·005). We report a protective benefit of elevated HbF regarding retinopathy, and our data suggests induction of HbF with hydroxycarbamide may prevent retinopathy in children.     

Daytime steady-state haemoglobin desaturation is a risk factor for overt stroke in children with sickle cell anaemia

Haemoglobin (Hb) desaturation could increase the risk of stroke in sickle cell anaemia (SS) by perturbing endothelial function and limiting oxygen delivery to the brain. We performed a nested case-control study of the Dallas Newborn Cohort to determine whether daytime steady-state Hb desaturation was associated with overt stroke in children with SS. Cases had SS and overt ischaemic strokes. Controls had comparable genotypes but no overt stroke. Cases had lower prestroke steady-state pulse oximetry values (SpO(2)) than controls, and cases' SpO(2) fell even lower as the time to impending stroke decreased. The odds ratio for stroke was 1.32 for each 1% decrease in SpO(2). In conclusion, steady-state Hb desaturation is a risk factor for overt ischaemic stroke in children with SS. Decline in SpO(2) over time further increases this risk. Hb desaturation is easily measured, potentially modifiable, and could be used to identify children with SS at increased risk of stroke.     

Low educational level of head of household,as a proxy for poverty,is associated with severe anaemia among children with sickle cell disease living in a low-resource setting: evidence from the SPRING trial

Severe anaemia, defined as haemoglobin level < 6·0 g/dl, is an independent risk factor for death in individuals with sickle cell disease living in resource-limited settings. We conducted a cross-sectional study of 941 children with sickle cell anaemia, who had been defined as phenotype HbSS or HbSβ⁰ thalassaemia, aged five to 12 years, and were screened for enrollment into a large primary stroke prevention trial in Nigeria (SPRING; NCT02560935). The main aim of the study was to determine the prevalence and risk factors for severe anaemia. We found severe anaemia to be present in 3·9% (37 of 941) of the SPRING study participants. Severe anaemia was significantly associated with the lower educational level of the head of the household (P = 0·003), as a proxy for poverty, and a greater number of children per room in the household (P = 0·004). Body mass index was not associated with severe anaemia. The etiology of severe anaemia in children living with sickle cell anaemia in Nigeria is likely to be multifactorial with an interplay between an individual's disease severity and other socio-economic factors related to poverty.     

Effect of myeloablative bone marrow transplantation on growth in children with sickle cell anaemia: results of the multicenter study of haematopoietic cell transplantation for sickle cell anaemia

Although haematopoietic cell transplantation (HCT) is curative for sickle cell anaemia (SCA), concerns about its short- and long-term toxicities limit its application. A potential toxicity is an adverse effect on growth. To identify an HCT growth effect, serial height and weight measurements from 53 children and adolescents with SCA after receiving a transplant were compared to historical controls. Hierarchical Linear Models for longitudinal data were used for analysis. In general growth was not impaired by HCT for SCA in young children; however, diminished growth may occur if HCT is carried out near or during the adolescent growth spurt.     

Association of G6PD202A,376G with lower haemoglobin concentration but not increased haemolysis in patients with sickle cell anaemia

The genetic bases of the highly variable degrees of anaemia and haemolysis in persons with Hb SS are not fully known, but several studies have indicated that G6PD deficiency is not a factor. The G6PD^202A and G6PD^376G alleles and α‐thalassaemia were determined by molecular genetic testing in 261 children and adolescents with Hb SS in a multicentre study. G6PD^202A,376G (G6PD A?) was defined as hemizygosity for both alleles in males and homozygosity in females. Among the participants 41% were receiving hydroxycarbamide. The prevalence of G6PD^202A,376G was 13·6% in males and 3·3% in females with an overall prevalence of 8·7%. G6PD^202A,376G was associated with a 10 g/l decrease in haemoglobin concentration (P = 0·008) but not with increased haemolysis as measured by lactate dehydrogenase, bilirubin, aspartate‐aminotransferase, reticulocyte count or a haemolytic component derived from these markers (P > 0·09). Similar results were found within a sub‐group of children who were not receiving hydroxycarbamide. By comparison, single and double α‐globin deletions were associated with progressively higher haemoglobin concentrations (P = 0·005 for trend), progressively lower values for haemolytic component (P = 0·007), and increased severe pain episodes (P < 0·001). In conclusion, G6PD^202A,376G may be associated with lower haemoglobin concentration in sickle cell anaemia by a mechanism other than increased haemolysis.     

Knowledge insufficient: the management of haemoglobin SC disease

Although haemoglobin SC (HbSC) accounts for 30% of sickle cell disease (SCD) in the United States and United Kingdom, evidence‐based guidelines for genotype specific management are lacking. The unique pathology of HbSC disease is complex, characterized by erythrocyte dehydration, intracellular sickling and increased blood viscosity. The evaluation and treatment of patients with HbSC is largely inferred from studies of SCD consisting mostly of haemoglobin SS (HbSS) patients. These studies are underpowered to allow definitive conclusions about HbSC. We review the pathophysiology of HbSC disease, including known and potential differences between HbSS and HbSC, and highlight knowledge gaps in HbSC disease management. Clinical and translational research is needed to develop targeted treatments and to validate management recommendations for efficacy, safety and impact on quality of life for people with HbSC.     

An exploratory study of physiological correlates of neurodevelopmental delay in infants with sickle cell anaemia

This study aimed to investigate whether infants with sickle cell anaemia (SCA) are at risk of neurodevelopmental delay, and whether any delay is associated with SCA pathology. Twenty-eight infants (14 SCA; 14 age- and ethnic-similar controls) were assessed longitudinally with the Bayley Infant Neurodevelopmental Screener (BINS) at 3, 9 and 12 months. Transcranial Doppler (TCD) and pulse oximetry (SpO2) measures were recorded longitudinally in SCA infants, and a subgroup of controls. Haemoglobin values were obtained from SCA infants. At each age, SCA infants obtained BINS scores indicative of greater risk of neurodevelopmental delay compared with controls. The number of moderate-high BINS risk scores increased significantly between 3 and 9 months. At 9 months BINS raw scores correlated negatively with TCD velocity and positively with haemoglobin. This exploratory study suggests that SCA infants may be at greater risk of neurodevelopmental delay than previously considered, and may provide the impetus for further research into the very early precursors of cognitive impairment.     

Splenic regrowth in sickle cell anaemia following hypertransfusion

We describe five adult patients with sickle cell anaemia (SS) who developed clinical, radiological and histological evidence of splenic regrowth while receiving regular blood transfusions. Five patients, all homozygous SS, range 23–34 years, were commenced on hypertransfusion therapy. Three patients were transfused because of severe recurrent vaso-occlusive crises, one for chronic sickle lung and one in an attempt to prevent deterioration of renal function. The mean duration of hypertransfusion prior to documentation of splenic regrowth was 52 months (range 12–97 months). Two patients developed significant hypersplenism. One patient had clinically-apparent splenomegaly and four patients had splenomegaly documented on ultrasound. Splenic regrowth in hypertransfused adults with sickle cell anaemia is not infrequent and may have important clinical implications.     

Genetic determinants of haemolysis in sickle cell anaemia

Haemolytic anaemia is variable among patients with sickle cell anaemia and can be estimated by reticulocyte count, lactate dehydrogenase, aspartate aminotransferase and bilirubin levels. Using principal component analysis of these measurements we computed a haemolytic score that we used as a subphenotype in a genome‐wide association study. We identified in one cohort and replicated in two additional cohorts the association of a single nucleotide polymorphism in NPRL3 (rs7203560; chr16p13·3) (P = 6·04 × 10⁻⁰⁷). This association was validated by targeted genotyping in a fourth independent cohort. The HBA1/HBA2 regulatory elements, hypersensitive sites (HS)‐33, HS‐40 and HS‐48 are located in introns of NPRL3. Rs7203560 was in perfect linkage disequilibrium (LD) with rs9926112 (r² = 1) and in strong LD with rs7197554 (r² = 0·75) and rs13336641 (r² = 0·77); the latter is located between HS‐33 and HS‐40 sites and next to a CTCF binding site. The minor allele for rs7203560 was associated with the −∝^3·7thalassaemia gene deletion. When adjusting for HbF and ∝ thalassaemia, the association of NPRL3 with the haemolytic score was significant (P = 0·00375) and remained significant when examining only cases without gene deletion∝ thalassaemia (P = 0·02463). Perhaps by independently down‐regulating expression of the HBA1/HBA2 genes, variants of the HBA1/HBA2 gene regulatory loci, tagged by rs7203560, reduce haemolysis in sickle cell anaemia.     

Sickle cell β-thalassaemia compared with sickle cell anaemia in Algeria

Clinical, haematological and biochemical features in 42 subjects with S-beta thalassaemia (31 subjects with S-beta° thalassaemia and 11 subjects with S-beta⁺ thalassaemia); and in 42 with homozygous sickle cell disease were compared. Persistent splenomegaly was more common and painful crises less common in the S-beta thalassaemia group. Total Hb was higher and reticulocyte count lower in S-beta⁺ thalassaemia than in S-beta° thalassaemia or SS disease. Microcytosis was marked in the S-beta thalassaemia group while the MCV was normal in sickle cell anaemia. Hb F was significantly higher in the S-beta° thalassaemia group, without any influence on the severity of the disease. Many features suggest that sickle cell thalassaemia is more severe in Algeria than in Negro subjects and similar to the disease in Italian patients.     

P-wave dispersion: relationship to left ventricular function in sickle cell anaemia

Background

The prognostic implications of P-wave dispersion in patients with a variety of cardiac disease conditions are increasingly being recognised. The relationship between P-wave dispersion and left ventricular function in sickle cell anaemia is unknown.

Objective

This study was aimed at evaluating the relationship between P-wave dispersion and left ventricular function in adult Nigerian sickle cell anaemia patients.

Methods

Between February and August 2007, a total of 62 sickle cell anaemia patients (aged 18–44 years; mean 28.27 ± 5.58) enrolled in the study. These were drawn from patients attending the adult sickle cell clinic of the University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu. An equal number of age- and gender-matched normal subjects served as controls. All the participants were evaluated with electrocardiography and echocardiography. P-wave dispersion was defined as the difference between the maximum and minimum P-wave duration measured in a 12-lead electrocardiogram.

Results

P-wave duration and P-wave dispersion were significantly higher in patients than in controls. Significant correlation was demonstrated between P-wave dispersion and age in the patients (r = 0.387; p = 0.031). A comparison of subsets of sickle cell anaemia patients and controls with comparable haematocrit values (30–35%) showed significantly higher P-wave duration and P-wave dispersion in the patients than in the controls. The P-wave duration in patients and controls, respectively, was 111.10 ± 14.53 ms and 89.14 ± 16.45 ms (t = 3.141; p = 0.006). P-wave dispersion was 64.44 ± 15.86 ms in the patients and 36.43 ± 10.35 ms in the controls (t = 2.752; p = 0.013). Significant negative correlation was found between P-wave dispersion and left ventricular transmitral E/A ratio (r = –0.289; p = 0.023).

Conclusion

These findings suggest that P-wave dispersion could be useful in the evaluation of sickle cell patients with left ventricular diastolic dysfunction. Further prospective studies are recommended to evaluate its prognostic implication on the long-term disease outcome in sickle cell disease patients.     

Red cell deformability in oral contraceptive pill users with sickle cell anaemia

The use of the combined oral contraceptive pill (COCP) in women with sickle cell anaemia (SCA) is controversial, as contraceptive steroids are thought to adversely affect erythrocyte deformability. This observational study was performed to investigate whether hormonal contraception influenced erythrocyte deformability in women with SCA. 30 women with SCA using various contraceptive modalities: COCP (n = 10); progestogen only (PO) contraception (n = 10) and non-hormonal contraception (n = 10) were recruited. Erythrocyte deformability was assessed using the clogging rate (CR) and red cell transit time (RCTT). There was no statistical difference in the mean CR and RCTT between the three groups of women (one-way ANOVA). Current contraceptive steroids do not appear to impair red cell deformability in women with SCA.     

Subcortical and cerebellar volumetric deficits in paediatric sickle cell anaemia

Sickle cell anaemia (SCA) is associated with silent cerebral infarction (SCI), affecting white and cortical grey matter, but there are few data on subcortical volumes. We analysed retrospective magnetic resonance imaging (MRI) data in 26 SCA patients and 20 controls, comparing mean subcortical volumes between three groups: controls, SCA with SCI (n = 13) and SCA without visible abnormality (n = 13). Specific volumetric differences were found in the hippocampus, amygdala, pallidum, caudate, putamen, thalamus, and cerebellum. This is the first study to demonstrate subcortical volume change in SCA, with the most severe volumetric deficits occurring in children with SCI seen on MRI.     

Plasma and erythrocyte lipids in sickle cell anaemia

Summary. The content and composition of plasma and erythrocyte lipids from individuals having sickle cell anaemia has been determined. The plasma contains a significantly reduced content of both cholesterol and phospholipid while the ratio of cholesteryl ester to total cholesterol, the distribution of phospholipids classes, triglyceride concentration and the fatty acid content were similar to normal values. However, the free glycerol content of the plasma was eight-fold higher than normal. Erythrocyte lipids contain an elevated level of cholesterol and control levels of phospholipid content, phospholipid distribution and fatty acid content. The plasma was separated by ultracentrifugation into VLDL (density <1.006), LDL (1.006< d <1.063) and HDL (1.063< d< 1.21). Significant decreases in cholesterol and phospholipid were observed in LDL and HDL.     

Defining stroke risk in children with sickle cell anaemia

Sickle cell anaemia (SCA) is the most common cause of childhood stroke, occurring with the highest frequency before the age of 6 years. Despite the relative frequency of stroke in SCA, few predictors of risk exist. Anaemia, leucocytosis, hypertension, silent infarction, and history of acute chest syndrome are well-documented risk factors for ischaemic stroke in SCA. Recent data suggest that other environmental and genetic factors, many unrelated to SCA, influence the development of cerebrovascular disease. Non-invasive assessment of individual stroke risk using transcranial Doppler ultrasonography has provided a means of selecting and prophylactically treating SCA children at highest risk. With the ultimate goal of preventing stroke, the information gained from the studies reviewed here may lead to improved prediction of stroke so that clinical trials to assess risk-based therapy may be carried out on selected children with SCA.