One hundred years of sickle cell disease

The first formal report of sickle cell disease occurred 100 years ago. This review traces the early historical reports, the evolution of understanding of the genetics, the molecular and chemical basis of sickle haemoglobin, and the advances made over the last 30-40 years in improving the management. Newborn screening and close follow-up, especially early in life, has significantly improved survival but these advances require resources and sophisticated infrastructure. In sub-Saharan Africa over 250 000 births annually suggest that these advances are unlikely to be implemented within the foreseeable future. Prevention of the disease where possible, could reduce the numbers of new patients allowing better facilities for the care of others. As the disease results from the inheritance of abnormal haemoglobin genes from both parents, it is eminently preventable. The unanswered question, whether genotype detection and counselling will influence reproductive decisions, is currently being addressed by a project in central Jamaica.     

Saving lives through early diagnosis: the promise and role of point of care testing for sickle cell disease

Sickle cell disease (SCD) is a devastating and under-recognised global child health issue affecting over 300,000 infants annually, with the highest prevalence in India and sub-Saharan Africa. Most affected infants born in low- and middle-income countries (LMIC) lack access to SCD testing and die from complications in the first years of life without a formal diagnosis. The majority of deaths are preventable with early diagnosis and provision of inexpensive interventions. Despite global recognition of the urgent need, expansion of SCD newborn screening (NBS) programmes beyond the pilot stage has been obstructed by a dependence on an expensive and logistically challenging centralised laboratory testing model. Recently, several point-of-care tests (POCT) for SCD have been developed with promising field validation studies. Here, we summarise the state of POCT for SCD, review barriers and unanswered questions, and discuss optimal strategies for utilising POCT to address the growing global burden of SCD. There is an urgent need to prospectively evaluate the ability of POCT to reduce the morbidity and high early mortality of SCD. To impact a sustainable reduction to this end, it is essential to link a diagnosis with comprehensive SCD care, including wide and affordable access to affordable hydroxycarbamide therapy.     

Cardiac manifestations in sickle cell disease varies with patient genotype

Cardiac involvement is well characterized in sickle cell anaemia (SCA) but cardiac features associated with Haemoglobin SC (HbSC) disease are mostly unknown. We compared 60 patients with HbSC disease (median age 31 years, 25 men) to 60 SCA patients and 60 controls matched for age and gender. Left ventricular ejection fraction (LVEF), left ventricle (LV) mass index (LVMi), cardiac index and peak tricuspid regurgitation velocity (TRV) were measured using echocardiography. LV filling pressures were assessed using the ratio of early diastolic transmitral velocity to tissue velocity (E/e’ ratio). The LVMi was higher in both genotypes compared to controls. However, whereas LV hypertrophy was observed only in 3(5%) HbSC patients, this condition was diagnosed in 27(45%) SCA patients (P < 0·0001). While cardiac index and TRV were similar in HbSC compared to controls, SCA patients exhibited elevated cardiac output and TRV. LVEF was similar in the 3 groups. However, both genotypes had a higher E/e’ ratio compared to controls. Cardiac involvement in SCA was related to anaemia and haemolysis, while LV diastolic dysfunction and TRV in HbSC disease patients were related to arterial hypertension and overweight comorbidities. In summary, cardiac involvement and its determinants are different in HbSC disease and SCA. Patient's genotype should be considered with regard to the echocardiographic indications and findings.     

Enhanced IgG immune response to COVID-19 vaccination in patients with sickle cell disease

Patients with sickle cell disease (SCD) are considered to be immunocompromised, yet data on the antibody response to SARS-CoV-2 vaccination in SCD is limited. We investigated anti-SARS-CoV-2 IgG titres and overall neutralizing activity in 201 adults with SCD and demographically matched non-SCD controls. Unexpectedly, patients with SCD generate a more robust and durable COVID-19 vaccine IgG response compared to matched controls, though the neutralizing activity remained similar across both cohorts. These findings suggest that patients with SCD achieve a similar antibody response following COVID-19 vaccination compared to the general population, with implications for optimal vaccination strategies for patients with SCD.     

Microparticles as biomarkers of osteonecrosis of the hip in sickle cell disease

Osteonecrosis of the femoral head (ONFH) is a common complication of sickle cell disease (SCD). To examine the association between microparticles and ONFH in SCD, we compared plasma microparticle levels in 20 patients with and without ONFH. Microparticles were quantified using nanoparticle tracking analysis and found to be 2·3‐fold higher in patients with ONFH compared to patients without ONFH, and 2·5‐fold higher than in healthy controls. These results suggest that microparticles may be a clinically useful biomarker of ONFH in SCD. Further investigations are needed to determine the functional relevance of microparticles in the pathogenesis of ONFH in SCD.     

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.     

Current developmental screening practices in young children with sickle cell disease

Despite recent developmental screening guidelines, rates of neurodevelopmental disorders (NDDs) remain lower than expected in children with sickle cell disease (SCD). A retrospective chart review identified 276 eligible patients; 214 charts were available for developmental screening and 207 charts for autism-specific screening. Developmental surveillance/screening was conducted in 70% of charts and autism-specific screening in 19% of charts. Validated tools were used in 32% of developmental screenings and 92% of autism-specific screenings. Many children (57%) were screened outside recommended ages. In conclusion, children with SCD are not regularly receiving appropriate developmental screening and surveillance by their healthcare providers.     

Haemoglobin F modulation in childhood sickle cell disease

While supportive care remains the best option for most well children with sickle cell disease (SCD), increasing awareness of early signs of chronic organ damage in childhood has focused attention on therapy which modulates the natural history of the disease. Since cure by stem cell transplantation is only feasible for a minority and gene therapy remains developmental, pharmacological modification by Haemoglobin F (HbF)-inducers, is the most widely used approach in SCD. Currently, the only HbF modulator with a clear place in the management of childhood SCD is hydroxycarbamide for which the main indications are frequent painful crises and recurrent acute chest syndrome. In the majority of SCD children treated with hydroxycarbamide there is clear evidence of clinical benefit and the drug is well tolerated. The main disadvantages are the need for frequent monitoring and uncertainity about long-term risks of carcinogenicity and impaired fertility, although these risks appear to be very low. The role of hydroxycarbamide in sickle-associated central nervous system disease remains to be established. Decitabine and butyrate derivatives show some promise although robust data in children with SCD are lacking. A number of other drugs are currently under investigation for their effects on HbF production including thalidomide and lenolidamide.     

Association between hydroxycarbamide exposure and neurocognitive function in adolescents with sickle cell disease

Patients with sickle cell disease (SCD) are at increased risk for neurocognitive impairments. While disease-modifying treatment, such as hydroxycarbamide (hydroxyurea), may decrease this risk, it has not been systematically investigated in children with SCD. We screened neurocognitive functioning in 103 adolescents with SCD (16–17 years, 50% female) and compared outcomes between patients with a history of exposure to hydroxycarbamide (n = 12 HbSC/HbSβ⁺ thalassaemia; n = 52 HbSS/HbSβ⁰ thalassaemia) and those never treated with hydroxycarbamide (n = 31 HbSC/HbSβ⁺ thalassaemia; n = 8 HbSS/HbSβ⁰ thalassaemia). Demographic distributions were similar between the groups. After adjusting for socioeconomic status, the hydroxycarbamide group had significantly higher scores on nonverbal IQ (HbSC/HbSβ thalassaemia: P = 0·036, effect size [d] = 0·65), reaction speed (HbSS/HbSβ⁰ thalassaemia: P = 0·002, d = 1·70), sustained attention (HbSS/HbSβ⁰ thalassaemia: P = 0·014, d = 1·30), working memory (HbSC/HbSβ⁺ thalassaemia: P = 0·034, d = 0·71) and verbal memory (HbSC/HbSβ⁺ thalassaemia: P = 0·038, d = 0·84) when compared to those who did not receive hydroxycarbamide. In patients with HbSS/HbSβ⁰ thalassaemia, longer treatment duration with hydroxycarbamide was associated with better verbal memory (P = 0·009) and reading (P = 0·002). Markers of hydroxycarbamide effect, including higher fetal haemoglobin (HbF), higher mean corpuscular volume (MCV) and lower white blood cell count (WBC), were associated with better verbal fluency (HbF: P = 0·014, MCV: P = 0·006, WBC: P = 0·047) and reading (MCV: P = 0·021, WBC: P = 0·037). Cognitive impairment may be mitigated by exposure to hydroxycarbamide in adolescents with SCD.     

Seizures in the Jamaica cohort study of sickle cell disease

Although there is some evidence that epilepsy is more common in Sickle Cell Disease (SCD), we sought to establish the incidence rates, risk factors for and specific types of seizures in a SCD cohort followed from birth, and how seizure occurrence affects morbidity and mortality . We examined all records of persons in the Jamaica cohort Study of Sickle Cell Disease (JSSCD) clinically identified as having experienced a seizure during their lifetime. At first presentation, seizures were classified as Febrile Convulsion, Acute Symptomatic Seizure or Single Unprovoked Seizure. The seizure classification was revised to include Epilepsy if seizures recurred. Thirty‐eight persons in the JSSCD (N = 543) were identified with seizures. The 5‐year cumulative incidence of febrile convulsions was 2·2%. The incidence rate of epilepsy (all genotypes) was 100/100 000 person‐years, 139/100 000 for the SS genotype. Despite limited availability of diagnostic investigations, clinical seizures were associated with increased all‐cause mortality. Male gender (Odds Ratio [OR]: 4·0[95% confidence interval [CI]; 1·03–20·0]) and dactylitis in childhood (OR: 17·4 [95% CI; 4·82–62·85]) were associated with increased risk of developing epilepsy. Epilepsy in persons with SCD is 2–3 times more common than in non‐sickle populations and is associated with increased all‐cause mortality in all sickle cell genotypes.     

Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease

Background

Sickle cell disease is characterized by a hypercoagulable state as a result of multiple factors, including chronic hemolysis and circulating cell-derived microparticles. There is still no consensus on the cellular origin of such microparticles and the exact mechanism by which they may enhance coagulation activation in sickle cell disease.

Design and Methods

In the present study, we analyzed the origin of circulating microparticles and their procoagulant phenotype during painful crises and steady state in 25 consecutive patients with sickle cell disease.

Results

The majority of microparticles originated from platelets (GPIIIa,CD61) and erythrocytes (glycophorin A,CD235), and their numbers did not differ significantly between crisis and steady state. Erythrocyte-derived microparticles strongly correlated with plasma levels of markers of hemolysis, i.e. hemoglobin (r=−0.58, p<0.001) and lactate dehydrogenase (r=0.59, p<0.001), von Willebrand factor as a marker of platelet/endothelial activation (r=0.44, p<0.001), and D-dimer and prothrombin fragment F1+2 (r=0.52, p<0.001 and r=0.59, p<0.001, respectively) as markers of fibrinolysis and coagulation activation. Thrombin generation depended on the total number of microparticles (r=0.63, p<0.001). Anti-human factor XI inhibited thrombin generation by about 50% (p<0.001), whereas anti-human factor VII was ineffective (p>0.05). The extent of factor XI inhibition was associated with erythrocyte-derived microparticles (r=0.50, p=0.023).

Conclusions

We conclude that the procoagulant state in sickle cell disease is partially explained by the factor XI-dependent procoagulant properties of circulating erythrocyte-derived microparticles.     

Wheezing and asthma are independent risk factors for increased sickle cell disease morbidity

To assess the associations between a doctor diagnosis of asthma and wheezing (independent of a diagnosis of asthma) with sickle cell disease (SCD) morbidity, we conducted a retrospective review of Emergency Department (ED) visits to the Mount Sinai Medical Center for SCD between 1 January 2007 and 1 January 2011. Outcomes were ED visits for pain and acute chest syndrome. The cohort included 262 individuals, median age 23·8 years, (range: 6 months to 67·5 years). At least one episode of wheezing recorded on a physical examination was present in 18·7% (49 of 262). Asthma and wheezing did not overlap completely, 53·1% of patients with wheezing did not carry a diagnosis of asthma. Wheezing was associated with a 118% increase in ED visits for pain (95% confidence interval [CI]: 56–205%) and a 158% increase in ED visits for acute chest syndrome (95% CI: 11–498%). A diagnosis of asthma was associated with a 44% increase in ED utilization for pain (95% CI: 2–104%) and no increase in ED utilization for acute chest syndrome (rate ratio 1·00, 95%CI 0·41–2·47). In conclusion, asthma and wheezing are independent risk factors for increased painful episodes in individuals with SCD. Only wheezing was associated with more acute chest syndrome.     

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.     

Clinical and genetic factors are associated with kidney complications in African children with sickle cell anaemia

Clinical and genetic factors have been reported as influencing the development of sickle cell nephropathy (SCN). However, such data remain limited in the paediatric population. In this cross-sectional study, we enrolled 361 sickle cell disease children from the Democratic Republic of Congo. Participants were genotyped for the beta (β)-globin gene, apolipoprotein L1 (APOL1) risk variants, and haem oxygenase-1 (HMOX1) GT-dinucleotide repeats. As markers of kidney damage, albuminuria, hyperfiltration and decreased estimated glomerular filtration with creatinine (eGFRcr) were measured. An association of independent clinical and genetic factors with these markers of kidney damage were assessed via regression analysis. Genetic sequencing confirmed sickle cell anaemia in 326 participants. Albuminuria, hyperfiltration and decreased eGFRcr were present in 65 (20%), 52 (16%) and 18 (5·5%) patients, respectively. Regression analysis revealed frequent blood transfusions, indirect bilirubin and male gender as clinical predictors of SCN. APOL1 high-risk genotype (G1/G1, G2/G2 and G1/G2) was significantly associated with albuminuria (P = 0·04) and hyperfiltration (P = 0·001). HMOX1 GT-dinucleotide long repeats were significantly associated with lower eGFRcr. The study revealed a high burden of kidney damage among Congolese children and provided evidence of the possible role of APOL1 and HMOX1 in making children more susceptible to kidney complications.     

Acute phase reactants and severity of homozygous sickle cell disease

Abstract. Serum concentrations of seven acute-phase reactants: albumin, transferrin (Tf), alpha-1-antitrypsin (AIAT), caeruloplasmin (Cp), α2-macroglobulin (α2-MG), haptoglobin (hp) and C-reactive protein (CRP) were determined in 73 subjects with varying severities of homozygous sickle cell (HbSS) disease. Fifty healthy subjects of comparable sex, age and socio-economic class distributions as the HbSS subjects served as controls. Albumin and α2-MG were comparable in all the subject groups. Tf and hp levels were significantly reduced in the HbSS groups relative to the control group. Conversely, AIAT, CRP and CP were significantly elevated. However only Tf and CRP manifested significant correlations with any of the indices of disease severity employed. Transferrin and CRP are suggested as plasma proteins worthy of further evaluation as indicators of severity in homozygous sickle cell disease.