Prevalence of sickle cell disease, hemoglobin S, and hemoglobin C among Haitian newborns

Seth Rotz; Genevieve Arty; Roberto Dall'Amico; Lucia De Zen; Francesco Zanolli; Prasad Bodas

doi:10.1002/ajh.23510

Alloimmunization Does Not Modify the Clinical Profile of Sickle Cell Disease Patients from Salvador-Brazil

Blood ◽

10.1182/blood.v112.11.4799.4799 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4799-4799

Author(s):

Angela Zanette ◽

Karla O. Mota ◽

Marilda Souza Goncalves ◽

Laise Vilasboas Schettini ◽

Lais Magalhaes Aguiar ◽

...

Keyword(s):

Sickle Cell Disease ◽

Clinical Outcomes ◽

Sickle Cell ◽

Laboratory Data ◽

Clinical Profile ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Hemoglobin S ◽

Hemoglobin C ◽

Significant Difference

Abstract Introduction: The hemoglobinopathies are the most common monogenic disorders known. A mutation in the gene for β globin gave origin to hemoglobin S, an abnormal hemoglobin originated in Africa. Sickle cell disease (SCD) is characterized by the presence of hemoglobin S, which results in vasoocclusion episodes and hemolytic anemia throughout patients life. Vascular occlusion leads to acute events and progressive disabling organ damage. Sickle cell anemia is the homozygous state SS, while hemoglobinopathy SC is a doubly heterozygous state, where hemoglobin S occurs in combination with hemoglobin C. Brazil has a prominent African ancestry and SCD is highly prevalent in some regions of the country. In Bahia State, for example, neonatal screening data have shown that, from every 650 children born alive, one has SCD, mostly homozygous SS. Among other therapeutic measures, packed red blood cells (RBC) play a prominent role in SCD management. In situations such as acute chest syndrome (ACS), primary and secondary prevention of stroke, splenic or hepatic sequestration crisis, severe anemia, complicated pregnancy, isquemic organ damages and others, the transfusions may save lives. Although RBC may contribute to reduce morbidity and improve quality of life in SCD patients, there still are risks. Among other risk categories, alloimmunization may result from transfusions and occurs in 5 % to 50 % of SCD patients. It is still not known whether allosensibilization significantly affects the clinical outcomes in SCD. Objecive: The purpose of this study was to compare the clinical profile of multitransfused adult SCD patients who developed alloantibodies (ALO) to patients with the same disease, coming from the same population who did not become alloimmunized (non-ALO). Methods: This is a cross sectional study where medical records of SCD patients, referred to a reference center of Salvador, the capital of Bahia State, Brazil, were reviewed. Only SCD patients 18 years of age or older were included. They had received at least 3 RBC transfusions from 2004 to 2007, or had any alloantibody identified during this period. Patient characteristics, clinical findings, number of transfusions, frequency and specificity of alloantibodies, laboratory data, and the main clinical outcomes were reviewed. Results: a hundred and eight patients were included: 105 SS and 3 SC. The pre-transfusional RBC matching was done to ABH, D,C,c,E,e and Kell antigens. 56 patients developed alloantibodies (53 SS and 3 SC). Anti-E, anti-K, and anti-C were the most prevalent alloantibodies identified (39,3 %, 21,4 % and 16,1 %, respectively). Among the variables addressed in this study, age (higher in non-ALO, .041) and antiglobulin test positivity, more prevalente in ALO (.0001), depicted statistically significant difference. A few patients developed immune hemolysis, controlled successfully with corticosteroids. Alloimmunization was more prevalent among women, although no statistically significant difference was reached between ALO and non-ALO Other variables such as number of transfusions, hematological profile, biochemical data and complications such as stroke, leg ulcers, osteonecrosis, renal disease, abnormal cardiac features, and pulmonary hypertension did not show significant difference between both groups. Conclusion: his study shows that, although alloimmunization is a potential dangerous consequence of RBC transfusions, it did not modify the clinical profile of SCD alloimmunized patients. The concomitance of allosensibilization and autoantibodies in SCD leads to additional difficulties in the RBC matching for transfusion and may exacerbate hemolysis. In order to address autoimmunity in SCD, prospective studies with larger samples are needed.

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Use of an automated pyrosequencing technique for confirmation of Sickle Cell Disease

10.1101/610063 ◽

2019 ◽

Author(s):

CC Martino ◽

CS Alencar ◽

P Loureiro ◽

AB Carneiro-Proietti ◽

CA Máximo ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

High Performance ◽

Large Scale ◽

Clinical Care ◽

Beta Thalassemia ◽

Cell Disease ◽

Hemoglobin S ◽

Hemoglobin C ◽

Confirmatory Assay

ABSTRACTBackgroundThe diagnosis of sickle cell disease (SCD) is made by hemoglobin assays such as high-performance liquid chromatography (HPLC), isoelectric focusing and cellulose acetate or citrate agar electrophoresis. These assays are easy to perform and used in large-scale newborn screening in many countries. These tests however may not easily differentiate Sβ0 thalassemia from SS or identify other hemoglobin variants, and in this case, hemoglobin (HBB) gene sequencing may be necessary.ObjectivesTo develop a high throughput DNA based confirmatory assay for SCD and to detect mutations in the HBB gene.MethodsWe developed an automated pyrosequencing technique (PyS) based on QIAGEN technology (Hilden, Germany) to detect homozygous or heterozygous hemoglobin S mutations as well as hemoglobin C mutations. The technique was tested on 2,748 samples from patients enrolled in a multi-center SCD cohort in Brazil. Patients were previously tested using HPLC to diagnose SCD as part of routine clinical care. Any subjects with discrepant results between HPLC and PyS or with heterozygous hemoglobin S detected had Sanger sequencing of the HBB gene.ResultsWe identified 168 samples with discrepant results between HPLC and PyS and 100 with concordant HPLC and PyS= heterozygous S, which would suggest Sβ-thalassemia or other hemoglobin S variants. The PyS assay correctly identified 1906 (98.7%) of the 1930 HbSS and 628 (98.7%) of the 636 HbSC samples. Of the 179 remaining samples, PyS correctly indicated S heterozygosis in 165 (92.2%). Of the 165 heterozygous S samples confirmed by Sanger as consistent with Sβ thalassemia genotype, 84 samples were classified as Sβ0 thalassemia and 81 as Sβ+ thalassemia. The most frequent beta thalassemia mutations of Sβ0 and Sβ+ were HBB: c.118C>T (Gln40Stop) and HBB c.92 + 6T> C, respectively.DiscussionThe PyS proved to be satisfactory for large-scale confirmatory testing of hemoglobin mutation. Moreover, with this study we were able to describe the most common β+ and β0 mutations in SCD patients with Sβ-thalassemia in a large multi-institutional SCD cohort in Brazil.

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Is Skeletal Muscle Dysfunction a Limiting Factor of Exercise Functional Capacity in Patients with Sickle Cell Disease?

Journal of Clinical Medicine ◽

10.3390/jcm10112250 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2250

Author(s):

Etienne Gouraud ◽

Philippe Connes ◽

Alexandra Gauthier-Vasserot ◽

Camille Faes ◽

Salima Merazga ◽

...

Keyword(s):

Skeletal Muscle ◽

Sickle Cell Disease ◽

Muscle Fatigue ◽

Sickle Cell ◽

Functional Capacity ◽

Muscle Dysfunction ◽

Electromyographic Activity ◽

Cell Disease ◽

Step Frequency ◽

Hemoglobin C

Patients with sickle cell disease (SCD) have reduced functional capacity due to anemia and cardio–respiratory abnormalities. Recent studies also suggest the presence of muscle dysfunction. However, the interaction between exercise capacity and muscle function is currently unknown in SCD. The aim of this study was to explore how muscle dysfunction may explain the reduced functional capacity. Nineteen African healthy subjects (AA), and 24 sickle cell anemia (SS) and 18 sickle cell hemoglobin C (SC) patients were recruited. Maximal isometric torque (Tmax) was measured before and after a self-paced 6-min walk test (6-MWT). Electromyographic activity of the Vastus Lateralis was recorded. The 6-MWT distance was reduced in SS (p < 0.05) and SC (p < 0.01) patients compared to AA subjects. However, Tmax and root mean square value were not modified by the 6-MWT, showing no skeletal muscle fatigue in all groups. In a multiple linear regression model, genotype, step frequency and hematocrit were independent predictors of the 6-MWT distance in SCD patients. Our results suggest that the 6-MWT performance might be primarily explained by anemia and the self-paced step frequency in SCD patients attempting to limit metabolic cost and fatigue, which could explain the absence of muscle fatigue.

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Lead Neuropathy and Sickle Cell Disease

PEDIATRICS ◽

10.1542/peds.54.4.438 ◽

1974 ◽

Vol 54 (4) ◽

pp. 438-441

Author(s):

Gerald Erenberg ◽

Steven S. Rinsler ◽

Bernard G. Fish

Keyword(s):

Case Report ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Lead Poisoning ◽

Cell Disease ◽

Hemoglobin S ◽

Increased Risk ◽

Rare Manifestation ◽

Poisoning In Children

Four cases of lead neuropathy in children with hemoglobin S-S or S-C disease are reported. Neuropathy is a rare manifestation of lead poisoning in children, and only ten other cases have been well documented in the pediatric literature. The last previous case report of lead neuropathy was also in a child with hemoglobin S-S disease. The neuropathy seen in the children with sickle cell disease was clinically similar to that seen in the previously reported cases in nonsicklers, but differed in both groups from that usually seen in adult cases. It is, therefore, postulated that children with sickle cell disease have an increased risk of developing neuropathy with exposure to lead. The exact mechanism for this association remains unknown, but in children with sickle cell disease presenting with symptoms or signs of peripheral weakness, the possibility of lead poisoning must be considered.

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Sickle Retinopathy in a Person with Hemoglobin S/New York Disease

Case Reports in Genetics ◽

10.1155/2012/136582 ◽

2012 ◽

Vol 2012 ◽

pp. 1-3 ◽

Cited By ~ 1

Author(s):

Donovan Calder ◽

Maryse Etienne-Julan ◽

Marc Romana ◽

Naomi Watkins ◽

Jennifer M. Knight-Madden

Keyword(s):

New York ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Sickle Cell Trait ◽

Laboratory Diagnosis ◽

Compound Heterozygote ◽

Cell Disease ◽

Hemoglobin S

A patient who presented with sickle retinopathy and hemoglobin electrophoresis results compatible with sickle cell trait was found, on further investigation, to be a compound heterozygote with hemoglobin S and hemoglobin New York disease. This recently reported form of sickle cell disease was not previously known to cause retinopathy and surprisingly was observed in a non-Asian individual. The ophthalmological findings, the laboratory diagnosis, and possible pathophysiology of this disorder are discussed. Persons diagnosed with sickle cell trait who present with symptoms of sickle cell disease may benefit from specific screening for this variant.

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Newborn Screening for Sickle Cell Disease: Effect on Mortality

PEDIATRICS ◽

10.1542/peds.81.6.749 ◽

1988 ◽

Vol 81 (6) ◽

pp. 749-755

Author(s):

Elliott Vichinsky ◽

Deborah Hurst ◽

Ann Earles ◽

Klara Kleman ◽

Bertram Lubin

Keyword(s):

Sickle Cell Disease ◽

Mortality Rate ◽

Newborn Screening ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Comprehensive Treatment ◽

Cell Disease ◽

Hemoglobin S ◽

Screening Programs ◽

Overall Mortality

Newborn screening for sickle cell disease has been recommended as a method of decreasing patient mortality. However, its effectiveness in accomplishing this has not been reliably measured. To help determine the effectiveness, 10 years of experience in newborn screening have been summarized. The effects of early patient enrollment in a comprehensive treatment program on long-term morbidity and mortality are reported. From 1975 to 1985, 84,663 newborns were screened regardless of race or ethnic background. Bart's hemoglobin was present in 5%, hemoglobin AS in 2.6%, and hemoglobin AC in 0.75%. Excluding Bart's, approximately 3.6% of all newborns were carriers for hemoglobinopathy. Sickle cell disease occurred in 1:951 births (58 hemoglobin SS, 25 hemoglobin FSC, three hemoglobin S-β+-thalassemia, and three hemoglobin S-β°-thalassemia). In addition, one in every 4,233 newborns had a clinically significant thalassemia syndrome (eight hemoglobin FE, ten hemoglobin F only, two hemoglobin H). Compared with other newborn screening programs in California, (congenital hypothyroidism, 1:3,849; phenylketonuria 1:22,474, galactosemia 1:74,103), hemoglobinopathies are the most prevalent congenital disease. Eighty-one newborns with sickle cell disease were followed for 7.2 years. Patients experienced 513 hospitalizations, including 13 episodes of sepsis with or without meningitis and ten acute sequestration crises. The overall mortality rate for patients with sickle cell anemia diagnosed in the newborn period was 1.8%. In comparison, the clinical course of 64 patients with sickle cell anemia diagnosed after 3 months of age and followed for an average of 9.4 years was analyzed. Five of these patients died. In two of these, sickle cell anemia was diagnosed at the time of the death. Overall mortality rate in this group was 8%. In summary, the data indicate that newborn screening, when coupled with extensive follow-up and education, will significantly decrease patient mortality.

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Sickle cell trait and the risk of venous thromboembolism among blacks

Blood ◽

10.1182/blood-2006-11-057604 ◽

2007 ◽

Vol 110 (3) ◽

pp. 908-912 ◽

Cited By ~ 142

Author(s):

Harland Austin ◽

Nigel S. Key ◽

Jane M. Benson ◽

Cathy Lally ◽

Nicole F. Dowling ◽

...

Keyword(s):

Venous Thromboembolism ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Odds Ratio ◽

Sickle Cell Trait ◽

Coagulation System ◽

Cell Disease ◽

Hemoglobin C ◽

Increased Risk ◽

S Allele

Abstract People with sickle cell disease have a chronically activated coagulation system and display hemostatic perturbations, but it is unknown whether they experience an increased risk of venous thromboembolism. We conducted a case–control study of venous thromboembolism that included 515 hospitalized black patients and 555 black controls obtained from medical clinics. All subjects were assayed for hemoglobin S and hemoglobin C genotypes. The prevalence of the S allele was 0.070 and 0.032 for case patients and controls, respectively (P < .001). The odds that a patient had sickle cell trait were approximately twice that of a control, indicating that the risk of venous thromboembolism is increased approximately 2-fold among blacks with sickle cell trait compared with those with the wild-type genotype (odds ratio = 1.8 with 95% confidence interval, 1.2-2.9). The odds ratio for pulmonary embolism and sickle cell trait was higher, 3.9 (2.2-6.9). The prevalence of sickle cell disease was also increased among case patients compared with controls. We conclude that sickle cell trait is a risk factor for venous thromboembolism and that the proportion of venous thromboembolism among blacks attributable to the mutation is approximately 7%.

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Variation in fetal hemoglobin parameters and predicted hemoglobin S polymerization in sickle cell children in the first two years of life: Parisian Prospective Study on Sickle Cell Disease

Blood ◽

10.1182/blood.v84.9.3182.3182 ◽

1994 ◽

Vol 84 (9) ◽

pp. 3182-3188 ◽

Cited By ~ 37

Author(s):

M Maier-Redelsperger ◽

CT Noguchi ◽

M de Montalembert ◽

GP Rodgers ◽

AN Schechter ◽

...

Keyword(s):

Sickle Cell Disease ◽

Oxygen Saturation ◽

Cell Population ◽

Sickle Cell ◽

Clinical Manifestations ◽

Fetal Hemoglobin ◽

Cell Disease ◽

Normal Children ◽

Hemoglobin S ◽

F Cells

Abstract Intracellular hemoglobin S (HbS) polymerization is most likely to be the primary determinant of the clinical and biologic manifestations of sickle cell disease (SCD). Fetal hemoglobin (HbF) does not enter the HbS polymer and its intracellular expression in sickle erythrocytes inhibits polymerization. HbF levels, high at birth but decreasing thereafter, protect the newborn from the clinical manifestations of this hemoglobinopathy. We have measured the sequential changes in HbF, F reticulocytes, and F cells in the first 2 years of life in 25 children with SCD and compared the results with those obtained in 30 normal children (AA). We have also calculated HbF per F cell (F/F cell), the preferential survival of F cells versus non-F cells, as measured by the ratio F cells versus F reticulocytes (FC/FR) and polymer tendency at 40% and 70% oxygen saturation. HbF levels decreased from about 80.4% +/- 4.0% at birth to 9.2% +/- 2.9% at 24 months. During this time, we observed a regular decrease of the F reticulocytes and the F cells. The kinetics of the decline of F/F cell was comparable with the decline of HbF, rapid from birth (mean, 27.0 +/- 3.6 pg) to 12 months of age (mean, 8.5 +/- 1.5 pg) and then slower from 12 to 24 months of age (mean, 6.2 +/- 1.0 pg) in the SCD children. In the AA children, the decrease in HbF, due to changes in both numbers of F cells and F/F cell, was more precipitous, reaching steady-state levels by 10 months of age. Calculated values for mean polymer tendency in the F-cell population showed that polymerization should begin to occur at 40% oxygen saturation at about 3 months and increase progressively with age, whereas polymerization at 70% oxygen saturation would not occur until about 24 months. These values correspond to HbF levels of 50.8% +/- 10.8% and 9.2% +/- 2.9%, respectively, and F/F cell levels of 15.6 +/- 4.5 pg and 6.2 +/- 1.0 pg, respectively. In the non--F-cell population, polymerization was expected at birth at both oxygen saturation values. Three individuals had significantly greater predicted polymerization tendency than the remainder of the group because of early decreases in HbF. These individuals in particular, the remainder of the cohort, as well as other recruited newborns, will be studied prospectively to ascertain the relationship among hematologic parameters, which determine polymerization tendency and the various clinical manifestations of SCD.

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Elevated Cerebral Blood Oxygen Extraction in Non-Transfused Sickle Cell Disease Patients

Blood ◽

10.1182/blood.v124.21.1387.1387 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1387-1387

Author(s):

Adam M Bush ◽

Matthew Borzage ◽

Soyoung Choi ◽

Thomas Coates ◽

John C Wood

Keyword(s):

Sickle Cell Disease ◽

Metabolic Rate ◽

Sickle Cell ◽

Oxygen Extraction Fraction ◽

Oxygen Extraction ◽

Cell Disease ◽

T2 Relaxation ◽

Hemoglobin S ◽

Cerebral Metabolic Rate ◽

Extraction Fraction

Abstract Introduction Chronic Transfusion Therapy (CTT) has been successful in decreasing stroke frequency in patients with sickle cell disease (SCD). Despite this, indication for CTT is largely based on empirical evidence and the mechanisms by which CTT protects the brain remain unclear. CTT improves oxygen carrying capacity and lowers hemoglobin S%, but the corresponding impact on cerebral blood flow(CBF), cerebral metabolic rate (CMRO2), and oxygen extraction fraction (OEF) is unknown. Understanding the impact of these competing influences in non-transfused (NT) and chronically transfused (CT) SCD patients will inform stroke prevention. Thus, we measured CBF, CMRO2, and OEF, in NT and CT patients with SCD using magnetic resonance imaging (MRI). Methods All patients were recruited with informed consent or assent and this study was approved by the CHLA IRB. Fourteen (6 NT, 8 CT) patients with SCD and 12 healthy ethnicity matched controls (CTL) were studied. Exclusion criteria included pregnancy, previous stroke, acute chest or pain crisis hospitalization within one month. Complete blood count and hemoglobin electrophoresis were performed. Arterial oxygen saturation (SaO2) was measured via peripheral pulse oximetery. CaO2 was calculated as the product of hemoglobin, SaO2 and the oxygen density of hemoglobin (1.36 ml/g). Phase contrast imaging of the carotid and vertebral arteries was used to measure global CBF. T2 Relaxation Under Spin Tagging (TRUST) was used to measured T2 relaxation of blood within the sagittal sinus. T2 relaxation was converted to SvO2 via previously validated calibration curves. OEF represented the difference of SaO2 andSvO2 divided bySaO2. CMRO2 was calculated as the product of CBF and OEF. High resolution, 3D, T1 weighted images were used for brain volume calculation using BrainSuiteñ software. Results Table 1 summarizes the results. Hemoglobin and oxygen content were well matched between transfused and non transfused SCD patients. Cerebral metabolic rate was also nearly identical in the two groups. However, CT patients exhibited 25% higher CBF than NT SCD patients, allowing them to have a normal oxygen extraction fraction ~30%. In contrast, OEF in NT SCD patients was abnormally high (37.8%), suggesting a decreased extraction reserve. Total oxygenation index (TOI) by NIRS also trended lower in NT SCD patients, consistent with the greater oxygen extraction and lower cerebral venous saturations observed. Abstract 1387. TableCTL (reference)NTCTp value (NT vs CT)Hemoglobin (g/dl)13.5 ± 1.229.7 ± 1.259.7 ± 1.05nsCaO2 (umol O2/ml)9.85 ± .996.84 ± 1.176.95 ±.71nsCMRO2 (umol O2/100g/min)193.1 ± 44.9239.7 ± 35.3238.6 ± 38.3nsCBF (ml/100g/min)70.0 ± 12.8101.5 ± 16.6127.1 ± 23.5< 0.05OEF (%)30.0 ± 7.137.8. ± 3.0629.7 ± 7.53< 0.05NIRS TOI56.0 ± 4.0948.5 ± 4.2153.5 ± 8.760.076SvO2 (%)65.6 ± 6.856.2 ± 5.267.1 ± 6.7< 0.05 Discussion: Chronically transfused SCD patients achieve normal brain oxygenation metrics (SvO2, OEF, and NIRS) but require very high CBF to achieve this balance (lowering flow reserve). In contrast, NT SCD patients have smaller increases in CBF but require greater oxygen extraction to meet cerebrovascular demands (lowering extraction reserve). Hemoglobin S mediate changes in oxygen dissociation, blood viscosity, red cell deformability and microvascular damage potentially mediate these differences but their interplay is complicated and requires further study. Disclosures Coates: novartis: Consultancy, Honoraria, Speakers Bureau; shire: Consultancy, Honoraria; apo pharma: Consultancy, Honoraria; acceleron: Consultancy, Honoraria.

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