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Objectives Voxelotor can increase hemoglobin levels in patients living with sickle cell disease (SCD). A clinician who is monitoring voxelotor response may want to know whole-blood voxelotor concentration, but this cannot be measured in most clinical settings. However, voxelotor has been demonstrated to cause "peak splitting" in common methods of hemoglobin measurement such as capillary zone electrophoresis (CZE) and high-performance liquid chromatography (HPLC). We hypothesized that we could use the size of the peak split to estimate the whole-blood concentration. Methods Blood from people with SCD was dosed with known concentrations of voxelotor, and multiparameter regression was used to derive the relationship of voxelotor concentration to the degree of peak splitting observed. To validate these equations, 21 patients started on voxelotor at 1500 mg/d had blood samples drawn at days 0, 14, 30, and 60. Samples were sent out for gold standard voxelotor concentration testing. The derived equations were then used to calculate voxelotor concentration. Results Calculated concentrations correlated strongly with measured concentrations for both CZE (R 2 = 0.83, P <.001) and HPLC (R 2 = 0.76, P <.001). Voxelotor concentration also had a significant effect on increases in hemoglobin (R 2 = 0.40, P <.001). Conclusions Thus, peak splitting CZE and HPLC can be used to estimate voxelotor concentration. [ABSTRACT FROM AUTHOR]

Summary: The degree of anaemia in sickle cell disease (SCD) is a well‐known contributor to morbidity and mortality. We aimed to explore the factors affecting haemoglobin (Hb) level in African SCD patients, considering haemolysis biomarkers (LDH and bilirubin level, and reticulocyte count), leucocyte and platelet counts and socio‐demographic characteristics (gender, age group, country of residence and BMI). The research was part of the CADRE multinational cohort and involved 3699 SCD patients living in Mali, Senegal, Ivory Coast, Democratic Republic of Congo, Gabon and Cameroon: 2936 SS/Sβ0, 587 SC and 176 Sβ + patients with median Hb level of 8, 11.3 and 11.2 g/dL respectively (p < 0.001). In multivariate analysis conducted in 1394 SS/Sβ0 patients, living in Cameroon, female gender, lower BMI, higher haemolysis markers (especially LDH) and higher leucocyte and platelet counts were independently associated with lower Hb level (all p < 0.05). In 497 SC and 156 Sβ + patients, female gender (p < 0.001), lower BMI (p < 0.05) and higher platelet counts (p < 0.001) were independently associated with lower Hb level. Anaemia in African SCD patients is not only associated with haemolysis but also with the country of residence, lower BMI and leucocyte or platelet counts which might reflect inflammation related to infectious burden in the region. [ABSTRACT FROM AUTHOR]

Summary: Sickle cell disease (SCD) includes a group of heterogenous disorders that result in significant morbidities. HbSS is the most common type of SCD and HbSC is the second most common type of SCD. The prevalence of HbSC disease in the United States and United Kingdom is ~1 in 7174 births and 1 in 6174 births respectively. Despite its frequency, however, HbSC disease has been insufficiently studied and was historically categorized as a more 'mild' form of SCD. We conducted this study of HbSC disease as part of the NHLBI funded Sickle Cell Disease Implementation Consortium (SCDIC). The SCDIC registry included 2282 individuals with SCD, ages 15–45 years of whom 502 (22%) had HbSC disease. Compared with people with sickle cell anaemia (SCA), the study found that people with HbSC disease had a higher frequency of splenomegaly (n (%) = 169 (33.7) vs. 392 (22.1)) and retinopathy (n (%) = 116 (23.1) vs. 189 (10.6)). A Many people with HbSC also had avascular necrosis (n (%) = 112 (22.3)), pulmonary embolism (n (%) = 43 (8.6)) and acute chest syndrome (n (%) = 228 (45.4)) demonstrating significant disease severity. HbSC disease is more clinically severe than was previously recognized and deserves additional evaluation and targeted treatments. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD)-associated chronic hemolysis promotes oxidative stress, inflammation, and thrombosis leading to organ damage, including liver damage. Hemoglobin scavenger receptor CD163 plays a protective role in SCD by scavenging both hemoglobin-haptoglobin complexes and cell-free hemoglobin. A limited number of studies in the past have shown a positive correlation of CD163 expression with poor disease outcomes in patients with SCD. However, the role and regulation of CD163 in SCD-related hepatobiliary injury have not been fully elucidated yet. Here we show that chronic liver injury in SCD patients is associated with elevated levels of hepatic membrane-bound CD163. Hemolysis and increase in hepatic heme, hemoglobin, and iron levels elevate CD163 expression in the SCD mouse liver. Mechanistically we show that heme oxygenase-1 (HO-1) positively regulates membrane-bound CD163 expression independent of nuclear factor erythroid 2-related factor 2 (NRF2) signaling in SCD liver. We further demonstrate that the interaction between CD163 and HO-1 is not dependent on CD163-hemoglobin binding. These findings indicate that CD163 is a potential biomarker of SCD-associated hepatobiliary injury. Understanding the role of HO-1 in membrane-bound CD163 regulation may help identify novel therapeutic targets for hemolysis-induced chronic liver injury. [ABSTRACT FROM AUTHOR]

Hemoglobin diseases like sickle cell disease (SCD) and β-thalassemia (BT) present fertility challenges for affected patients. SCD and BT result from abnormal hemoglobin production or structure and pose numerous health concerns. Despite medical advancements improving the quality of life or even providing cures, SCD and BT pose unique fertility concerns for women. Young women with these disorders already contend with reduced ovarian reserve and a narrower fertile window, a situation that is compounded by the gonadotoxic effects of treatments like medications, transfusions, stem cell transplants, and gene therapy. While crucial for disease control, these interventions may lead to reproductive health issues, increasing infertility and early menopause risks. Ovarian tissue cryopreservation (OTC) offers potential for future motherhood to women with hemoglobin disorders facing infertility related to curative treatments. OTC involves surgically removing, preparing, and freezing ovarian tissue containing primordial follicles capable of producing mature oocytes, offering advantages over oocyte cryopreservation alone. However, the application of OTC for patients with hemoglobin disorders presents unique challenges, including special health risks, financial barriers, and access to care. This comprehensive literature review delves into the current state of ovarian tissue cryopreservation for fertility preservation in patients with hemoglobin disorders. Empowering patients with informed reproductive choices in the context of their hemoglobin disorders stands as the ultimate goal. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is a severe monogenic hereditary hemoglobinopathy that is characterized by repeated clinical and biological manifestations able to generate stress erythopoiesis. A clonal hematopoiesis involving mainly variants of TP53, DNMT3A, ASXL1, and/or TET2 may be more prevalent in patients with SCD, suggesting that mutations in these genes may lead to an increased risk of leukemia. An increased prevalence of leukemia in patients with SCD has been confirmed by an increasing number of acute myeloid leukemia cases with myelodysplastic features reported in this patient population even in the absence of disease-modifying treatments. This leads to the hypothesis of a mechanism involving multifactorial causes through the pathophysiologic manifestations of SCD, in which cells are undergoing constant hematopoietic hyperplasia, inducing genomic damage and somatic mutations. [ABSTRACT FROM AUTHOR]

Iron deficiency anaemia (IDA) is unusual in sickle cell disease (SCD). However, excessive urinary iron loss and mucosal/submucosal infarcts may result in poor absorption of iron in SCD. During the first decade of the disease, environmental factors and poor nutrition may also affect iron metabolism and contribute to iron deficiency in SCD. The present study assessed iron status and haematological profile of young children with SCD using serum Iron, Ferritin and Total Iron Binding Capacity (TIBC) to establish early diagnosis of IDA.Results showed that out of 6276 newborns screened, 33(0.52%) were detected to have SCD. Amongst 33,14(14.28%) children were suspected to have IDA. Iron studies revealed 42.4% of coexistent IDA with low serum Iron among 3 children, whereas high normal or raised TIBC was seen in 14 children. The findings emphasize that raised TIBC with normal serum iron may indicate early onset of IDA in the early decade of SCD, highlighting the need of timely initiation of iron therapy to prevent further severe events. [ABSTRACT FROM AUTHOR]

Three sickle cell disease (SCD) treatment strategies, stabilizing oxygenated hemoglobin (oxyHb), lowering 2,3‐BPG, and inducing fetal hemoglobin (HbF) expression aim to prevent red blood cell (RBC) sickling by reducing tense‐state sickle hemoglobin that contributes to polymer formation. Induction of 30% HbF is seen as the gold standard because 30% endogenous expression is associated with a lack of symptoms. However, the level of intervention required to achieve equivalent polymerization protection by the other strategies is uncertain, and there is little understanding of how these approaches could work in combination. We sought to develop an oxygen saturation model that could assess polymerization protection of all three approaches alone or in combination by extending the Monod‐Wymann‐Changeux model to include additional mechanisms. Applying the model to monotherapies suggests 51% sickle hemoglobin (HbS) occupancy with an oxyHb stabilizer or lowering RBC 2,3 BPG concentrations to 1.8 mM would produce comparable polymerization protection as 30% HbF. The model predictions are consistent with observed clinical response to the oxyHb stabilizer voxelotor and the 2,3‐BPG reducer etavopivat. The model also suggests combination therapy will have added benefit in the case of dose limitations, as is the case for voxelotor, which the model predicts could be combined with 20% HbF or 2,3‐BPG reduction to 3.75 mM to reach equivalent protection as 30% HbF. The proposed model represents a unified framework that is useful in supporting decisions in preclinical and early clinical development and capable of evolving with clinical experience to gain new and increasingly confident insights into treatment strategies for SCD. [ABSTRACT FROM AUTHOR]

Objective: To assess nationally endorsed claims-based quality measures in pediatric sickle cell anemia (SCA). Methods: Using data from the Sickle Cell Data Collection programs in California and Georgia from 2010 to 2019, we evaluated 2 quality measures in individuals with hemoglobin S/S or S/β-zero thalassemia: (1) the proportion of patients aged 3 months to 5 years who were dispensed antibiotic prophylaxis for at least 300 days within each measurement year and (2) the proportion of patients aged 2 to 15 years who received at least 1 transcranial Doppler ultrasound (TCD) within each measurement year. We then evaluated differences by year and tested whether performance on quality measures differed according to demographic and clinical factors. Results: Only 22.2% of those in California and 15.5% in Georgia met or exceeded the quality measure for antibiotic prophylaxis, with increased odds associated with rural residence in Georgia (odds ratio 1.61; 95% confidence interval 1.21-2.14) compared with urban residence and a trend toward increased odds associated with a pediatric hematologist prescriber (odds ratio 1.28; 95% confidence interval 0.97, 1.69) compared with a general pediatrician. Approximately one-half of the sample received an annual assessment of stroke risk using TCD (47.4% in California and 52.7% in Georgia), with increased odds each additional year in both states and among younger children. Conclusions: The rates of receipt of recommended antibiotic prophylaxis and annual TCD were low in this sample of children with SCA. These evidence-based quality measures can be tracked over time to help identify policies and practices that maximize survival in SCA. [ABSTRACT FROM AUTHOR]

SCD is a hereditary disorder caused by genetic mutation in the beta-globin gene, resulting in abnormal hemoglobin, HbS that forms sickle-shaped erythrocytes under hypoxia. Patients with SCD have endocrine disorders and it was described that 7% of these patients have clinical hypothyroidism. Recent studies have shown that mature erythrocytes possess TSH receptors. Thus, we aimed to assess the effects of TSH on SCD erythrocytes. The experiments were conducted using different concentrations of TSH (1, 2, 3, and 5 mIU/L). In HbS polymerization assay, erythrocytes were exposed to TSH in hypoxia to induce polymerization, and measurements were taken for 30 minutes. The deformability assay was made using Sephacryl-S 500 columns to separate deformable from nondeformable cells. Static adhesion test utilized thrombospondin to assess erythrocyte adhesion in the presence of TSH. TSH at all contractions were able to reduce polymerization of HbS and increase deformability. The static adhesion of erythrocytes at the lowest concentrations of 1 and 2 mIU/L were increased, but at higher contractions of 3 and 5 mIU/L, static adhesion was not modulated. The results suggest that TSH has potential involvement in the pathophysiology of sickle cell disease by inhibiting HbS polymerization, positively modulating deformability and impacting static adhesion to thrombospondin. [ABSTRACT FROM AUTHOR]

Background: Red blood cell exchange is often used prophylactically in patients with sickle cell disease, with the goal to maintain hemoglobin S (HbS) below a target threshold level. We reviewed whether the daily "rate of rise" (RoR) in HbS that occurs between procedures can be used for patient management. For some patients not achieving their HbS goals despite efficient exchanges, the post‐procedure hematocrit (Hct) target is increased to potentially suppress HbS production. This case series explores the utility of this approach, other clinical uses of the daily RoR in HbS, and the factors that influence it. Study Design and Methods: A total of 660 procedures from 24 patients undergoing prophylactic RBC depletion/exchange procedures were included. Laboratory values and clinical parameters were collected and used to calculate the daily RoR in HbS. Factors such as Hct or medications that might influence the RoR in HbS were evaluated. Results: The RoR in HbS varied widely between patients but remained relatively stable within individuals. Surprisingly, this value was not significantly influenced by changes in post‐procedure Hct or concurrent hydroxyurea use. A patient's average RoR in HbS effectively predicted the pre‐procedure HbS at the following visit (R2 = 0.65). Discussion: The RoR in HbS is a relatively consistent parameter for individual patients that is unaffected by medication use or procedural Hct targets and may be useful in determining intervals between procedures. [ABSTRACT FROM AUTHOR]

Summary: We report a large series of 40 patients presenting EPAS1‐mutated paraganglioma (PGL) in whom we investigated a cause underlying chronic hypoxia. Four patients suffered from hypoxaemic heart disease. In patients with available haemoglobin electrophoresis results, 59% presented with a haemoglobin disorder, including six with sickle cell disease, five with sickle cell trait and two with heterozygous haemoglobin C disease. Histological and transcriptomic characterization of EPAS1 tumours revealed increased angiogenesis and high similarities with pseudohypoxic PGLs caused by VHL gene mutations. Sickle haemoglobinopathy carriers could thus be at increased risk for developing EPAS1‐PGLs, which should be taken into account in their management and surveillance. [ABSTRACT FROM AUTHOR]

Summary: We evaluated the impact of peer reviews in driving improvement in healthcare quality for people with haemoglobinopathy in the United Kingdom. We analysed compliance to four Quality Standards (QS)‐based peer reviews from 2010 to 2020 to evaluate its impact in driving healthcare quality. Seventeen paediatric and 29 adult haemoglobinopathy centres were reviewed in 2010/11 and 2012/13 respectively; 33 paediatric and 33 adult centres were reviewed in 2014/16, and 32 paediatric and 32 adult centres were reviewed in 2018/2020. Compliance with QS and participant feedback were analysed to assess the impact of peer review programmes to drive improvement in quality of care. We noted that haemoglobinopathy centres significantly improved their compliance to QS between the first two review programmes, but not in the final review programme. In comparison to other disease‐group reviews, the haemoglobinopathy departments were less able to address critical peer review recommendations in their own institutions. The peer review programme was unable to drive sustained improvement in healthcare quality, underscoring the need for sustained development and support for haemoglobinopathy services in the National Health Service. Further work is needed to understand why disparities exist among peer review‐driven improvement initiatives within different disease groups. [ABSTRACT FROM AUTHOR]

Background: Sickle cell disease in pregnancy is associated with high maternal and fetal mortality. However, studies reporting pregnancy, fetal, and neonatal outcomes in women with sickle cell disease are extremely limited. Objectives: The objectives of the study are to determine whether women with sickle cell disease have a greater risk of adverse pregnancy, fetal, and neonatal outcomes than women without sickle cell disease and identify the predictors of adverse pregnancy, fetal, and neonatal outcomes in women with sickle cell disease. Design: A retrospective pair-matched case-control study was conducted to compare 171 pregnant women with sickle cell disease to 171 pregnant women without sickle cell disease in Muscat, Sultanate of Oman. Methods: All pregnant Omani women with sickle cell disease who delivered between January 2015 and August 2021 at Sultan Qaboos University Hospital and Royal Hospital, who were either primipara or multipara and who had a gestational age of 24–42 weeks, were included as patients, whereas women who had no sickle cell disease or any comorbidity during pregnancy, who delivered within the same timeframe and at the same hospitals, were recruited as controls. The data were retrieved from electronic medical records and delivery registry books between January 2015 and August 2021. Results: Women with sickle cell disease who had severe anemia had increased odds of (χ2 = 58.56, p < 0.001) having adverse pregnancy outcomes. Women with sickle cell disease had 21.97% higher odds of delivering a baby with intrauterine growth retardation (χ2 = 17.80, unadjusted odds ratio = 2.91–166.13, p < 0.001). Newborns born to women with sickle cell disease had 3.93% greater odds of being admitted to the neonatal intensive care unit (χ2 = 16.80, unadjusted odds ratio = 1.97–7.84, p < 0.001). In addition, the children born to women with sickle cell disease had 10.90% higher odds of being born with low birth weight (χ2 = 56.92, unadjusted odds ratio = 5.36–22.16, p < 0.001). Hemoglobin level (odds ratio = 0.17, p < 0.001, 95% confidence interval = 0.10–3.0), past medical history (odds ratio = 7.95, p < 0.001, 95% confidence interval = 2.39–26.43), past surgical history (odds ratio = 17.69, p < 0.001, 95% confidence interval = 3.41–91.76), and preterm delivery (odds ratio = 9.48, p = 0.005, 95% confidence interval = 1.95–46.23) were identified as predictors of adverse pregnancy, fetal, and neonatal outcomes in women with sickle cell disease. Conclusion: As pregnant women with sickle cell disease are at increased risk for pregnancy, fetal, and neonatal adverse outcomes; improved antenatal surveillance and management may improve the outcomes. [ABSTRACT FROM AUTHOR]

Rationale: Sickle cell disease, a debilitating genetic disorder affecting numerous newborns globally, has historically received limited attention in pharmaceutical research. However, recent years have witnessed a notable shift, with the Food and Drug Administration approving three innovative disease‐modifying medications. Voxelotor, also known as GBT440, is a promising compound that effectively prevents sickling, providing a safe approach to alleviate chronic hemolytic anemia in sickle cell disease. It is a novel, orally bioavailable small molecule that inhibits hemoglobin S polymerization by enhancing oxygen affinity to hemoglobin. The investigation demonstrated that voxelotor led to an unintended elevation of hemoglobin levels in healthy individuals by increasing serum erythropoietin levels. Methods: Voxelotor and its metabolites in an in vitro setting utilizing equine liver microsomes were discussed. Plausible structures of the identified metabolites were inferred through the application of liquid chromatography in conjunction with high‐resolution mass spectrometry. Results: Under the experimental conditions, a total of 31 metabolites were detected, including 16 phase I metabolites, two phase II metabolites, and 13 conjugates of phase I metabolites. The principal phase I metabolites were generated through processes such as hydroxylation, reduction, and dissociation. The presence of glucuronide and sulfate conjugates of the parent drug were also observed, along with hydroxylated, reduced, and dissociated analogs. Conclusions: The data acquired will accelerate the identification of voxelotor and related compounds, aiding in the detection of their illicit use in competitive sports. It is crucial to emphasize that the metabolites detailed in this manuscript were identified through in vitro experiments and their detection in an in vivo study may not be guaranteed. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) affects millions worldwide, yet there are few therapeutic options. To develop effective treatments, preclinical models that recapitulate human physiology and SCD pathophysiology are needed. SCD arises from a single Glu-to-Val substitution at position 6 in the β subunit of hemoglobin (Hb), promoting Hb polymerization and subsequent disease. Sheep share important physiological and developmental characteristics with humans, including the same developmental pattern of fetal to adult Hb switching. Herein, we investigated whether introducing the SCD mutation into the sheep β-globin locus would recapitulate SCD's complex pathophysiology by generating high quality SWISS-MODEL sheep Hb structures and performing MD simulations of normal/sickle human (huHbA/huHbS) and sheep (shHbB/shHbS) Hb, establishing how accurately shHbS mimics huHbS behavior. shHbS, like huHbS, remained stable with low RMSD, while huHbA and shHbB had higher and fluctuating RMSD. shHbB and shHbS also behaved identically to huHbA and huHbS with respect to β2-Glu6 and β1-Asp73 (β1-Asn72 in sheep) solvent interactions. These data demonstrate that introducing the single SCD-causing Glu-to-Val substitution into sheep β-globin causes alterations consistent with the Hb polymerization that drives RBC sickling, supporting the development of a SCD sheep model to pave the way for alternative cures for this debilitating, globally impactful disease. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is the most common genetic disorder, affecting millions of people worldwide. Aromatic aldehydes, which increase the oxygen affinity of human hemoglobin to prevent polymerization of sickle hemoglobin and inhibit red blood cell (RBC) sickling, have been the subject of keen interest for the development of effective treatment against SCD. However, the aldehyde functional group metabolic instability has severly hampered their development, except for voxelotor, which was approved in 2019 for SCD treatment. To improve the metabolic stability of aromatic aldehydes, we designed and synthesized novel molecules by incorporating Michael acceptor reactive centers into the previously clinically studied aromatic aldehyde, 5‐hydroxymethylfurfural (5‐HMF). Eight such derivatives, referred to as MMA compounds were synthesized and studied for their functional and biological activities. Unlike 5‐HMF, which forms Schiff‐base interaction with αVal1 nitrogen of hemoglobin, the MMA compounds covalently interacted with βCys93, as evidenced by reverse‐phase HPLC and disulfide exchange reaction, explaining their RBC sickling inhibitory activities, which at 2 mM and 5 mM, range from 0% to 21% and 9% to 64%, respectively. Additionally, the MMA compounds showed a second mechanism of sickling inhibition (12%–41% and 13%–62% at 2 mM and 5 mM, respectively) by directly destabilizing the sickle hemoglobin polymer. In vitro studies demonstrated sustained pharmacologic activities of the compounds compared to 5‐HMF. These findings hold promise for advancing SCD therapeutics. [ABSTRACT FROM AUTHOR]

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Highlights: The following are some of the highlights of our study: The SpHb concentration was found to be higher than the lab Hb concentrations, with a positive correlation. SpHb measurement sensitivity and precision were lower than expected. Non-invasive SpHb measurement can play a role in excluding anemia in outpatient clinics. The PI values among the SCD patients were lower than the patients with a normal hemoglobin structure. SpHb measurement requires technological improvements to overcome the low PI observed in SCD patients. Patients with sickle cell disease (SCD) require repeated blood sampling for hemoglobin (Hb) concentration measurements. The primary aim of this study was to compare non-invasive spectrophotometric hemoglobin (SpHb, g/dL) measurements to those taken via an automated hematology analyzer (Hb, g/dL) in patients with SCD visiting outpatient clinics and to investigate the correlations and agreements between both measurement techniques. Secondarily, we aimed to identify the SpHb cut-off concentration for the diagnosis of anemia and to monitor the effects of the pleth variability index (PVI, %) and perfusion index (PI) on SpHb measurements. The results gained from the examination of one hundred and fifty-eight patients indicated that the SpHb measurements overestimated the lab Hb concentrations, with a mean (SpHb-Hb) bias of 0.82 g/dL (SD 1.29). The SpHb measurements were positively correlated with the Hb measurements (Kendall's tau correlation (τ), n = 158, τ = 0.68, p < 0.001), with an intra-class correlation (ICC) of 0.67 and a 95% CI from 0.57 to 0.74 (p = 0.000). The SpHb cut-off concentration to diagnose anemia was 11.4 and 11.7 g/dL for males and females, respectively. SpHb sensitivity was low for males and females at 64.4% and 57.1%; however, the specificity was higher at 90.9% and 75%, with positive predictive values (PPVs) of 95.6 and 85.7, respectively. No correlation existed between SpHb measurements and the PVI (%) in contrast with a moderate correlation with the PI (r = 0.049, p = 0.54, and r = 0.36, p < 0.001, respectively). The mean PI was low at 2.52 ± 1.7. In conclusion, the SpHb measurements were consistently higher than the lab Hb concentrations, with a positive correlation. The sensitivity and precision of the SpHb measurements were lower than expected. However, the SpHb specificity and its positive predictive values (PPVs) indicated that it is less likely for a patient with a positive SpHb test result for anemia to be non-anemic. These results will allow SpHb measurement to play a role in excluding the presence of anemia. In light of the low PI values determined, the SpHb measurements were challenging to take and, thus, require further technological improvements. [ABSTRACT FROM AUTHOR]

This manuscript describes a novel approach for treating patients with long‐term sequelae from hemoglobin Evans (Hb Evans). After instituting conservative therapies for approximately 2 years, our patient's symptoms continually worsened. Therefore, we performed red blood cell exchange (RBCx) to reduce his Hb Evans percentage and his co‐existing elevation of methemoglobin. Our assumptions of clinical benefit were based on our collective experience performing RBCx for patients with sickle cell disease. After the first exchange, pre‐ and post‐laboratory results supported our approach and the patient experienced marked improvement in his clinical signs and symptoms. This report provides preliminary proof of principle for the use of RBCx to treat Hb Evans and other non‐Hb S hemoglobinopathies. [ABSTRACT FROM AUTHOR]

Background: Sickle cell disease (SCD) patients with a history of stroke are encouraged to receive chronic red blood cell exchange (RBCx) for stroke prevention. The American Society of Hematology guideline published in 2020 recommends an HbS target of <30%. However, this approach necessitates more frequent RBCx and more RBC units. UT Southwestern has devised a chronic exchange protocol that elevates the HbS target to <50% in patients with a low risk of stroke. Study Design: This retrospective chart review study reviewed the medical records of patients receiving chronic RBCx with a target of HbS <50% over the past 10‐year period to assess the safety of maintaining higher HbS targets in SCD patients with a low risk of cerebrovascular accidents (CVA). Results: Among 49 SCD patients in the chronic RBCx program for secondary stroke prevention, 33 patients were maintained on an HbS target of <50% (average measured: 35.4%) for the duration of RBCx program enrollment (median 93.0 months, 95% CI, 83‐99). Stroke or transient ischemic attack (TIA) clearly attributable to changing target HbS had not been identified among the 33 study subjects. Seven patients experienced conversion between the HbS targets of <50% and <30% HbS target. Significant reductions were observed in the frequency of RBCx and usage of blood volume in four of them. Conclusion: The findings suggest that liberalizing the HbS target could confer clinical flexibility without increasing the risk of CVA in a selective population. Further studies to fully evaluate the potential benefits of this approach are indicated. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Sickle cell anemia (SCA) is a hematological condition that involves the synthesis of sickle‑shaped, hemoglobin with a short lifespan. This study employed three‑dimensional (3D) scanning to pinpoint the most common arch form in a sample of Iraqi adults with SCA. MATERIALS AND METHODS: A cross‑sectional study included maxillary and mandibular casts of 50 patients (25 male and 25 female) with SCA and 50 participants in a control group (25 male and 25 female). The facio‑axial (FA) point was digitized on each tooth’s labial or buccal surface using SolidWorks® 2020 software. The dimensions of the arch were calculated using two proportional measures and four linear measurements. The dental arch form was determined using 3M templates, and the arches were categorized as square, ovoid, or tapered to establish the most‑common arch form. Chi‑square was used to compare arch form distribution, and an independent t‑test was used to calculate the difference between the control group and the SCA group. RESULTS: The tapered arch was the predominant form in SCA males and females for the maxilla and the mandible. The molar vertical distance (upper and lower) was significantly higher in males in the SCA group than in males in the control group. There was no significant difference between females in the SCA group and females in the control group. CONCLUSION: Most patients with SCA had tapered arches. Sagittal jaw dimensions in males with SCA were more affected by marrow hyperplasia. There was little if any to no effect on females with SCA. [ABSTRACT FROM AUTHOR]

Background: Single low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in patients with glucose-6-phopshate dehydrogenase (G6PD) deficiency. We, therefore, examined the independent effects of several factors on haemoglobin (Hb) dynamics in falciparum-infected children with a particular interest in SLDPQ and G6PD status. Methods: This randomised, double-blind, placebo-controlled, safety trial was conducted in Congolese and Ugandan children aged 6 months–11 years with acute uncomplicated P. falciparum and day (D) 0 Hbs ≥ 6 g/dL who were treated with age-dosed SLDPQ/placebo and weight-dosed artemether lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPP). Genotyping defined G6PD (G6PD c.202T allele), haemoglobin S (HbS), and α-thalassaemia status. Multivariable linear and logistic regression assessed factor independence for continuous Hb parameters and Hb recovery (D42 Hb > D0 Hb), respectively. Results: One thousand one hundred thirty-seven children, whose median age was 5 years, were randomised to receive: AL + SLDPQ (n = 286), AL + placebo (286), DHAPP + SLDPQ (283), and DHAPP + placebo (282). By G6PD status, 284 were G6PD deficient (239 hemizygous males, 45 homozygous females), 119 were heterozygous females, 418 and 299 were normal males and females, respectively, and 17 were of unknown status. The mean D0 Hb was 10.6 (SD 1.6) g/dL and was lower in younger children with longer illnesses, lower mid-upper arm circumferences, splenomegaly, and α-thalassaemia trait, who were either G6PDd or heterozygous females. The initial fractional fall in Hb was greater in younger children with higher D0 Hbs and D0 parasitaemias and longer illnesses but less in sickle cell trait. Older G6PDd children with lower starting Hbs and greater factional falls were more likely to achieve Hb recovery, whilst lower D42 Hb concentrations were associated with younger G6PD normal children with lower fractional falls, sickle cell disease, α-thalassaemia silent carrier and trait, and late treatment failures. Ten blood transfusions were given in the first week (5 SLDPQ, 5 placebo). Conclusions: In these falciparum-infected African children, posttreatment Hb changes were unaffected by SLDPQ, and G6PDd patients had favourable posttreatment Hb changes and a higher probability of Hb recovery. These reassuring findings support SLDPQ deployment without G6PD screening in Africa. Trial registration: The trial is registered at ISRCTN 11594437. [ABSTRACT FROM AUTHOR]

Introduction: Coronavirus disease 2019 (COVID‐19) is associated with poor outcomes in sickle cell disease (SCD) patients. However, there is a paucity of data comparing hemoglobin (Hb) genotypes in SCD and infection outcomes. Methods: The National Inpatient Sample was used to identify the record of hospitalizations with COVID‐19 and SCD in 2020 using the International Classification of Disease, Tenth Revision codes. Study outcomes (invasive mechanical ventilation, extracorporeal membrane oxygenation, shock, vasopressor use, measures of resource utilization, and in‐hospital mortality) were compared between hemoglobin SS, SC, and S‐beta thalassemia (Sβ). Results: Of the 102 975 COVID‐19 hospitalizations with SCD, 87.26% had HbSS, 7.16% had HbSC, and 5.58% had HbSβ. Younger patients were more likely to have HbSS, while older patients were likely to have HbSC and HbSβ. HbSS was more frequent with Blacks, while HbSβ was more prevalent with Whites and Hispanics. Though measures of resource utilization were higher in HbSS, there was no significant difference in in‐hospital outcomes between the three genotypes. Conclusion: There is no difference in COVID‐19 outcomes among Hb genotypes in SCD. Further studies are needed to explore the reasons for this observation. [ABSTRACT FROM AUTHOR]

Adult patients with sickle cell disease usually have atrophied spleens due to autosplenectomy, and only rarely have complications related to the spleen, such as splenic sequestration and infarctions. However, some sickle cell haplotypes/genotypes are associated with persistent spleen until adulthood and thus are at risk of splenic complications. In this case report, upon or shortly after arrival at high altitude, three patients with sickle cell anemia were presented with acute splenic sequestration and splenic infarction. This major complication can be the presenting feature of an otherwise benign course of sickle cell anemia. A national travel recommendation is merited to advise patients with sickle cell anemia before traveling to high altitudes, especially those with Arab-Indian haplotype. [ABSTRACT FROM AUTHOR]

Executive function and processing speed difficulties are observed in children living with sickle cell anemia (SCA). The influence of processing speed on executive function is not well understood. We recruited 59 children living with SCA and 24 matched controls aged 8–18 years between 2010 and 2016 from clinics in the UK. Children completed tests in processing speed and cognitive flexibility, subdomains of executive function. MRI scans were conducted within one year of testing; oxygen saturation was obtained on the day of testing. Hemoglobin levels were obtained from medical records. Caregivers completed the executive function questionnaire. Hierarchical linear regressions found that hemoglobin, oxygen saturation, age, infarct status, and processing speed were not independent predictors for any model. However, for all cognitive flexibility tests, there was a significant interaction between infarct status and processing speed; children without silent cerebral infarction (SCI) with faster processing speed had better cognitive flexibility. Our findings indicate that, when interpreting executive function difficulties, it is important to account for the relationship between SCI status and processing speed. More research is needed to elucidate the mechanisms, but clinically, including executive function testing as part of clinic visits by embedding psychologists within the healthcare team would appear to be a critical step. [ABSTRACT FROM AUTHOR]

Background: Patients with sickle cell disease (SCD) frequently undergo prophylactic red blood cell (RBC) exchange transfusion and simple transfusion (RCE/T) to prevent complications of disease, such as stroke. These treatment procedures are performed with a target hemoglobin S (HbS) of ≤30%, or a goal of maintaining an HbS level of <30% immediately prior to the next transfusion. However, there is a lack of evidence‐based instructions for how to perform RCE/T in a way that will result in an HbS value <30% between treatments. Principal objective: To determine whether targets for post‐treatment HbS (post‐HbS) or post‐treatment HCT (post‐HCT) can help to maintain an HbS <30% or <40% between treatments. Materials and methods: We performed a retrospective study of patients with SCD treated with RCE/T at Montefiore Medical Center from June 2014 to June 2016. The analysis included patients of all ages, and data including 3 documented parameters for each RCE/T event: post‐HbS, post‐HCT, and follow‐up HbS (F/u‐HbS), which is the pre‐treatment HbS prior to the next RCE/T. Generalized linear mixed model was used for estimating the association between post‐HbS or post‐HCT levels and F/u‐HbS <30%. Results: Based on our results, targeting post‐HbS ≤10% was associated with higher odds of having events of F/u‐HbS <30% between monthly treatments. Targeting post‐HbS ≤15% was associated with higher odds of events of F/u‐HbS < 40%. As compared to post‐HCT ≤30%, a post‐HCT >30%‐36% did not contribute to more F/u‐HbS <30% or HbS <40% events. Conclusions: For patients with SCD undergoing regular RCE/T for stroke prevention, a post‐HbS ≤10% can be used as a goal to help maintain an HbS <30% for 1 month, and a post‐HbS ≤15% allowed patients to maintain HbS <40%. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is a life-threatening condition. Given the nature of the disease and associated complications with high mortality and morbidity rates, it is imperative that patients are diagnosed in early infancy, are established with specialists and general pediatric care immediately, and receive continuity in care. A percentage of patients diagnosed with SCD fall within a vulnerable, at-risk population. This population may face greater social barriers that lead to missed or late diagnosis and therefore delayed management, significantly increasing the risk of morbidity and mortality. Screening tools such as state newborn screens help to identify the diagnosis early. However, patients in vulnerable, at-risk populations who are not established in the health care system may not receive timely communication about their illness and necessary next steps for care. We present a case of a 12-month-old female who is an example of one of the many patients who despite having undergone newborn screening, fell through the cracks due to social barriers including housing instability, food insecurity, and lack of access to transportation. This paper emphasizes the need for and provides a real example of the benefit of access to longitudinal primary care for vulnerable patients. We also demonstrate the role of primary care in clearing the care gaps and coordinating services quickly to ultimately prevent life-threatening complications specifically for children with previously undiagnosed chronic illnesses. [ABSTRACT FROM AUTHOR]

BACKGROUND: Lipid alterations have been described in sickle cell anemia (SCA), but their association with the disease severity is not fully understood and their correlation with the nutritional status of this population has not been widely studied. OBJECTIVES: This study aimed to assess the lipid profile and its relation with the nutritional status, including anthropometric characteristics and daily macronutrient intake, and with the severity biomarkers in adults with SCA in a steady state. DESIGN: Cross-sectional study METHODS: This was an analytical cross-sectional study with 55 adults with SCA and 60 members of the control group. Sociodemographic, anthropometric, nutritional, and laboratory data were collected between March 2019 and June 2020. Mann–Whitney test was used to compare groups and Spearman's correlation coefficient was used to test the relation between variables. RESULTS: The SCA group presented higher calorie, protein, and carbohydrate intake, lower levels of high-density lipoprotein-cholesterol (HDL-c), and a higher triglyceride (TG)/HDL-c ratio than the control. HDL-c showed a positive correlation with hemoglobin and hematocrit (HcT) and a negative correlation with indirect bilirubin and lactate dehydrogenase (LDH). The TG/HDL-c ratio was positively linked with reticulocyte count, LDH, and leukocyte count and negatively linked with Hb. CONCLUSIONS: The study findings showed hypocholesterolemia in SCA and its independent correlation with macronutrient intake. The links of HDL-c and TG/HDL-c ratio with hemolysis indices indicate that they are easily accessible, low-cost markers capable of predicting SCA severity. [ABSTRACT FROM AUTHOR]

Background: Among individuals with sickle cell disease (SCD), decreased hemoglobin is associated with lower oxygen saturation (SpO2) and increased risk of stroke, both of which are associated with lower intelligence quotient (IQ) scores. Thus, increasing hemoglobin and SpO2 in individuals with SCD may increase IQ and educational attainment. Methods: A cohort simulation model was built to determine academic performance and educational attainment based on cognitive function (measured by IQ) of a pediatric SCD cohort randomly assigned to treatment and control groups. The model contained two key stages: childhood (<10 years) and adolescence (≥10 years). In stage 1, increased hemoglobin and increased SpO2 (assigned to the treatment group) were determinants of higher IQ, prevention of IQ deterioration over time. Increased hemoglobin was also a determinant of decreased stroke risk. In stage 2, improvement in adolescent IQ as a result of treatment was a determinant of academic performance. Results: In a simulated cohort of 2000 children and adolescents with SCD (52.5% female, 50% treated), stroke incidence was predicted to be 44.4% lower among the treated group than the untreated group (4.5% versus 8.1%, respectively). The average IQ among the treated group was estimated to be 91.1 compared with 82.9 in the untreated group (a 9.9% difference; P<0.001). Finally, high school (≥12 years of education) completion rates were estimated to be 64.7% higher among the treated group: 76.1% of the treated group was projected to complete high school compared with 46.2% of the untreated group. Conclusions: Our model predicts that an average improvement in hemoglobin of 1.1 g/dL (11 g/L) among individuals with SCD may be associated with improved neurocognition and educational outcomes. These improvements may also generate benefits not captured by our model, including improved quality of life, employment, and income. [ABSTRACT FROM AUTHOR]

Background and Purpose: Sickle cell disease (SCD) is an inherited hemoglobin disease affecting the red cells and causing hemolytic anemia. It is a very common, endemic disease in Sudan, particularly in the central and western areas of Sudan. Sickle cell anemia (SCA) is when the patient has beta-globin gene variant (Hb S variant). In this study, we screened the co-inheritance of hemoglobin O-Arab mutation among Sudanese sickle cell disease patients.Study Population and Methods: This cross-sectional study was conducted in the Sudan-Khartoum state from November 2016 to December 2021. Blood samples were collected from a random sample of the known sickle cell disease patients of Kordofan-central Sudan origin. Study-appropriate blood samples were subjected to complete blood count (CBC), hemoglobin capillary electrophoresis (CE) and molecular laboratory investigations. Initial laboratory investigations were done in Sudan, where the DNA sequencing technique was carried out at the Egyptian National Research Center (NRC)-Cairo-Egypt.Results: The final study's main results revealed the presence of HB O-Arab genetic mutations among Sudanese Sickle cell disease patients, which estimated to be (5%) co-inherited mutations among our study population (Hb-O Arab; (HBB):c.364G>A (p.Glu122Lys)).Conclusion: The frequency of Hb-O Arab gene mutations was determined among Sudanese sickle cell disease patients, and the results have shown a (5%) frequency of Hb-O Arab mutation. The study result is the first molecular confirmation of co-inherited Hb-O Arab/sickle cell disease clinical condition in Sudan. The results raise the importance of extended studies of other sickle variant conditions. [ABSTRACT FROM AUTHOR]

Historically understudied and regarded as a mild type of sickle cell disease, HbSC can be associated with significant, progressive complications. Prospective studies are urgently needed to address treatment gaps for HbSC disease. Commentary on: Nelson et al. The clinical spectrum of HbSC sickle cell disease‐not a benign condition. Br J Haematol 2024;205:653‐663. [ABSTRACT FROM AUTHOR]

Accurate laboratory screening for sickle cell disease and other haemoglobin disorders is expanding worldwide. Two new reports describe different methods and strategies for screening in Mali and Denmark, respectively, and their encouraging results suggest that countries should tailor their screening programmes according to local needs, resources and opportunities. Commentary on: Guindo et al. Potential for a large‐scale newborn screening strategy for sickle cell disease in Mali: a comparative diagnostic performance study of two rapid diagnostic tests (SickleScan® and HemotypeSC®) on cord blood. Br J Haematol 2024;204:337–345 and Gravholt et al. The Danish national haemoglobinopathy screening programme: report from 16 years of screening in a low‐prevalence, non‐endemic region. Br J Haematol 2024;204:329–336. [ABSTRACT FROM AUTHOR]

Summary: The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of deoxygenated haemoglobin S (HbS), leading to red blood cell (RBC) sickling, decreased RBC deformability, microvascular obstruction, haemolysis, anaemia and downstream clinical complications. Pharmacological increase in the concentration of oxygenated HbS in RBCs has been shown to be a novel approach to inhibit HbS polymerization and reduce RBC sickling and haemolysis. We report that GBT021601, a small molecule that increases HbS‐oxygen affinity, inhibits HbS polymerization and prevents RBC sickling in blood from patients with SCD. Moreover, in a murine model of SCD (SS mice), GBT021601 reduces RBC sickling, improves RBC deformability, prolongs RBC half‐life and restores haemoglobin levels to the normal range, while improving oxygen delivery and increasing tolerance to severe hypoxia. Notably, oral dosing of GBT021601 in animals results in higher levels of Hb occupancy than voxelotor and suggests the feasibility of once‐daily dosing in humans. In summary, GBT021601 improves RBC health and normalizes haemoglobin in SS mice, suggesting that it may be useful for the treatment of SCD. These data are being used as a foundation for clinical research and development of GBT021601. [ABSTRACT FROM AUTHOR]

Hypoxia is encountered frequently in the ICU as a result of a wide range of pathologic characteristics. The oxygen-hemoglobin dissociation curve describes hemoglobin's affinity for a given P o 2 and factors affecting uptake and offload. Research in manipulating this relationship between hemoglobin and oxygen is sparing. Voxelotor is a hemoglobin oxygen-affinity modulator that is approved by the US Food and Drug Association for use in the management of sickle cell disease. We present two patients without sickle cell disease who underwent treatment with this novel agent to assist with chronic hypoxia and weaning of mechanical support. [ABSTRACT FROM AUTHOR]

Sickle cell disease and ß-thalassaemia can be ameliorated or perhaps even 'cured' if most erythrocytes can be induced to contain high levels of foetal haemoglobin. While this is not yet possible using foetal haemoglobin-inducing drugs, it might be feasible with cell-based gene therapy. After mobilization of autologous haematopoietic stem and progenitor cells, these cells are engineered with vectors that lead to the derepression of foetal haemoglobin genes or add a globin gene that mimics the effects of foetal haemoglobin. Auto-transplantation after myeloablative conditioning is associated with levels of foetal haemoglobin or an antisickling haemoglobin of about 40% of total haemoglobin. In nearly every patient symptoms of sickle cell disease disappear; patients with ß-thalassaemia rarely require blood transfusions. In both groups of patients anaemia is absent or minimal. Optimistically, treated patients appear functionally 'cured'. These are very early days of gene therapy. Less than 200 patients have been followed, usually for no more than 5 years. It is highly likely that improved methods that are being intensively studied will simplify gene therapy leading to its wider applicability for individuals with these very common monogenic diseases. [ABSTRACT FROM AUTHOR]

Sickle cell disease is a monogenic hemoglobinopathy that results in the abnormal production of hemoglobin S, which yields the characteristic sickleshaped red blood cells. Sickle cell vaso-occlusive crisis is a painful complication of sickle cell disease caused by red blood cell entrapment within the microcirculation. The resulting tissue ischemia triggers a secondary inflammatory process involved in the pathogenesis of varying inflammatory skin conditions. Chronic leg ulcers are the most common skin presentation in sickle cell disease. A 58-year-old woman with sickle cell disease presented with systemic edematous plaques with the most notable involvement of her bilateral legs, which exhibited reticulated purpuric patches with central pallor. We report a case highlighting an unusual presentation of livedo racemosa as the presenting sign in a patient with sickle cell disease in vaso-occlusive crisis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Homocysteinemia is regarded as potential predictor for vaso-occlusive phenomenon often observed in sickle cell hemoglobinopathy. The objective was to determine the relationship of these genotypes with homocysteinemia and the predictive coefficient of these polymorphisms on the vascular-related crisis in the presence of sickle cell gene. MATERIALS AND METHODS: The case-control study comprised 89 children diagnosed with sickle disease with features of vascular crisis, 160 children without crisis and 252 apparently healthy children as the control group. The genotypes were assayed for C677T and A1298C variants and their association and predictor effect for homocysteinemia of different grades were analyzed. Sequential multiple regression model was used to assess the predictive effect. RESULTS: Homocysteine levels were significantly higher in the crisis group (P < 0.001). When compared to the wild genotype the variants depicted significantly raised homocysteine levels (P < 0.001). The prevalence of C677T was 29.9% and that for A1298 was 66.3% in the study population. The odds for crisis was 2.3 times for crisis in TT677 and 1.34 times in CC1298 variants. The genotypes revealed a significant association with different grades of homocysteinemia (P < 0.001). Plasma homocysteine depicted significant negative correlation with weight, height, body mass index and hemoglobin levels. None of the TT variants reported normal homocysteine values. Shift toward the variant form showed an increase of homocysteine levels by 7.3 units and 6.9 units for C677T and A1298C single-nucleotide polymorphisms respectively. CONCLUSION: Co-presence of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms could be important predictor for homocysteinemia and thus contribute toward vascular crisis in sickle cell patients. [ABSTRACT FROM AUTHOR]

Objective: To describe the development and implementation of a population-based screening programme for sickle cell disease (SCD) implemented in 12 SCD-endemic and tribal-dominated primary/community health centres (PHCs/CHCs) across six districts of India. Setting: India reports a huge burden of SCD, especially among indigenous (tribal) communities. However, there is no state-led SCD programme in many places, and systematic screening is absent. This situation necessitates developing a model of population screening. Methods: This programme was meant to screen all people and was carried out in three tiers. The first tier was a symptomatic survey carried out by community health workers. Regular health workers then screened those referred by sickle cell solubility test at sub-health centres as the second tier. The third tier was confirmation by haemoglobin electrophoresis at PHCs/CHCs. Communities were mobilised and prepared to accept the screening. Capacity building of health facilities was ensured through training and supply of equipment and material. Results: Initial observation based on six months' data revealed that out of the 110,754 tribal population of 12 PHCs/CHCs, 8418 (7.6%) were identified in the symptomatic survey. Subsequently, 9416 people, including the above 8418, underwent the solubility test, and 2607 (27.7%) were found to be positive. Of these, 1978 (78.9%) underwent electrophoresis. About 64.2% were found to be positive for sickle haemoglobin (233 (18.4%) SCD and 1036 (81.6%) SCD trait). Conclusions: The study demonstrates the feasibility of establishing a population-based screening programme in the primary health care system. It is easy to implement in tribal habitations as part of the proposed national SCD/haemoglobinopathies programme. [ABSTRACT FROM AUTHOR]

Objective: Mechanisms underlying the oral outcomes in sickle cell anemia (HbSS) have been less explored. This study aimed to investigate the association of morbimortality indicators and hydroxyurea use with adaptive pulp and jaw bone trabecular changes in HbSS. Methods: This cross‐sectional study included 123 individuals with HbSS. The exposures were the morbimortality indicators of HbSS (number of vaso‐occlusive crises, organ damage, hemoglobin level, and leukocyte count) and the use of hydroxyurea for HbSS treatment. The outcomes were adaptive pulp and jaw bone trabecular changes confirmed by radiographic examination. Associations were estimated by Poisson regression in crude and adjusted analyses for sex, skin color, socioeconomic class, and age. Results: The vaso‐occlusive crises (mean ratio (MR) = 3.5, p = 0.045), lower hemoglobin (MR = 2.4, p = 0.037), and higher leukocyte count (MR = 2.17, p = 0.036) were risk factors, while the use of hydroxyurea was inversely associated with adaptive pulp changes (MR = 0.23, p = 0.024). The vaso‐occlusive crises were associated with jaw bone trabecular changes (MR = 1.33, p = 0.02). Conclusion: Adaptive pulp changes may be a potential clinical marker of chronic vasculopathy in HbSS. The use of hydroxyurea may reduce the frequency of adaptive pulp changes. [ABSTRACT FROM AUTHOR]

Background: Intracellular hemoglobin polymerization has been supposed to be the major determinant for the elevated rigidity/stiffness of sickle erythrocytes from sickle cell anemia (SCA) patients. However, the contribution of the cell envelope remains unclear. Results: In this study, using atomic force microscopy (AFM), we compared the normal and sickled erythrocyte surfaces for stiffness and topography. AFM detected that sickle cells had a rougher surface and were stiffer than normal erythrocytes and that sickle cell ghosts had a rougher surface (for both outer and inner surfaces) and were thicker than normal ghosts, the latter implying a higher membrane-associated hemoglobin content/layer in the sickle cell envelope. Compared to healthy subjects, the SCA patients had lower plasma lipoprotein levels. AFM further revealed that a mild concentration of methyl-β-cyclodextrin (MβCD, a putative cholesterol-depleting reagent) could induce an increase in roughness of erythrocytes/ghosts and a decrease in thickness of ghosts for both normal and sickle cells, implying that MβCD can alter the cell envelope from outside (cholesterol in the plasma membrane) to inside (membrane-associated hemoglobin). More importantly, MβCD also caused a more significant decrease in stiffness of sickle cells than that of normal erythrocytes. Conclusions: The data reveal that besides the cytosolic hemoglobin fibers, the cell envelope containing the membrane-associated hemoglobin also is involved in the biomechanical properties (e.g., stiffness and shape maintenance) of sickle erythrocytes. [ABSTRACT FROM AUTHOR]

Hemoglobin is a biomarker of interest for the diagnosis and prognosis of various diseases such as anemia, sickle cell disease, and thalassemia. In this paper, we present a disposable device that has the potential of being used in a setting for accurately quantifying hemoglobin levels in whole blood based on colorimetric analysis using a smartphone camera. Our biosensor employs a disposable microfluidic chip which is made using medical-grade tapes and filter paper on a glass slide in conjunction with a custom-made PolyDimethylSiloaxane (PDMS) micropump for enhancing capillary flow. Once the blood flows through the device, the glass slide is imaged using a smartphone equipped with a custom 3D printed attachment. The attachment has a Light Emitting Diode (LED) that functions as an independent light source to reduce the noise caused by background illumination and external light sources. We then use the RGB values obtained from the image to quantify the hemoglobin levels. We demonstrated the capability of our device for quantifying hemoglobin in Bovine Hemoglobin Powder, Frozen Beef Blood, and human blood. We present a logarithmic model that specifies the relationship between the Red channel of the RGB values and Hemoglobin concentration. [ABSTRACT FROM AUTHOR]

Objective: To report the diagnostic challenges of newborn screening for abnormal haemoglobins. Setting: Cord blood samples from 13 hospitals in southwest Jamaica taken in 2008–2019. Methods: Blood spots, collected from the umbilical cord, were analysed by high pressure liquid chromatography (HPLC) to reveal phenotypes for HbSS and HbCC, but genotype confirmation may require parental studies or gene sequencing. Such cases that were successfully traced were analysed in this follow-up study. Results: HPLC screening of 121,306 samples detected HbAS in 11,846 (9.8%), HbAC in 4508 (3.7%) and other electrophoretic abnormalities in 1090 babies. Among 101 previously unconfirmed cases, 34/90 (38%) with HPLC evidence of a HbSS phenotype had other genotypes, and 7/11 (64%) with a HbCC phenotype had other genotypes. Syndromes from the interaction of β thalassaemia occurred in 112 babies (85 with HbS, 27 with HbC) and of genes for hereditary persistence of fetal haemoglobin (HPFH) in 18 (12 with HbS, 6 with HbC). Variants other than HbS and HbC occurred in 270 babies, 16 in combination with either HbS or HbC, and 254 as traits. Most variants are benign even when inherited with HbS, although HbO Arab, HbD Punjab, or Hb Lepore Washington, which occurred in 6 cases, may cause sickle cell disease. Conclusions: Genes for β thalassaemia and HPFH are common in western Jamaica and when associated with HbS may present diagnostic challenges in newborns, as HbF and HbA2 have not reached diagnostic levels. Family and DNA studies may be necessary for genotype confirmation. [ABSTRACT FROM AUTHOR]

The burden of Sickle cell anaemia (SCA) is huge in Sub Sahara Africa as it affects 1–2% of the population. HbSS impacts negatively on the quality of life of the sufferers. The clinical manifestations start between 3 and 5 months of life as a result of reduction in foetal hemoglobin. This study describes the clinical and laboratory characteristics of HbSS patients at presentation in steady state, vaso-occlusive and hemolytic crises states. This was a cross sectional, analytical study. Ninety HbSS participants were divided into three groups; steady state, hemolytic and vaso-occlusive crises with 30 individuals in each group. The survey contained sections on bio-data and past medical history obtained from the patients' notes and results of laboratory tests. Data were analysed using SPSS version 23.0. Results were considered statistically significant if p < 0.05. Ninety participants were analysed in this study. The mean age of the participants was 29.4 ± 8.9 years. Only one-third of the participants were diagnosed within the first year of age. Forty-seven (52.2%) participants have steady state haematocrit in the range of 21–25%. All the participants experienced bone pain in a year, about 25% of these participants had more than three episodes of pain per year. There was a statistically significant difference in the mean values of PCV (p <.001), WBC (p <.001), platelet (p =.008), ANC (p <.001), ALC (p <.001), AMC (p <.001), reticulocyte count and ISC % among the different categories. This study established the fact that only a minority of the SCD patients are diagnosed in the first year of life and vaso-occlusive crisis is the most frequent reason for hospital presentation. We therefore recommend the institutionalisation by government policy, neonatal screening programme in Nigeria. The study highlight delay in early diagnosis of SCA due to unavailability of neonatal diagnosis program in our setting. Bone pain remains the major cause of presentation for SCA and most patients presented after a day of onset of pain to the hospital. [ABSTRACT FROM AUTHOR]

Under hemolytic conditions, hemoglobin and subsequently heme are rapidly released, leading to the toxic effects characterizing diseases such as β-thalassemia and sickle cell disease. Herein, we provide evidence that human hemoglobin can bind heme in a transient fashion via surface-exposed sequence motifs. Following the synthesis of potential heme-binding motifs (HBMs) as peptides, their heme-binding capacity was investigated by UV–vis spectroscopy and ranked according to their binding affinity. Heme binding to human hemoglobin was subsequently studied by UV–vis and surface plasmon resonance (SPR) spectroscopy, revealing a heme-binding affinity in the sub- to micromolar range and a stoichiometry that clearly exceeds a 1:1 ratio. In silico molecular docking and simulation studies confirmed heme binding to the respective motifs in the β-chain of hemoglobin. Finally, the peroxidase-like activity of hemoglobin and the hemoglobin-heme complex was monitored, which indicated a much higher activity (>1800%) than other heme-peptide/protein complexes reported so far. The present study provides novel insights into the nature of intact hemoglobin concerning its transient interaction with heme, which suggests for the first time potential heme-scavenging properties of the protein at concomitant disassembly and, consequently, a potentiation of hemolysis and related processes. [ABSTRACT FROM AUTHOR]

Background: Sickle cell disease is the most common genetic hematologic disorder especially in Sub-Saharan Africa. Newborn screening (NBS) for sickle cell disease is a tool for early disease detection and treatment. Objective: To report the outcome of newborn screening for sickle cell disease at Abakaliki, Ebonyi state. Setting: Alex Ekwueme Federal University Teaching Hospital (AEFUTHA), Ebonyi State. Design: Retrospective study. Methods: A two- year period data on sociodemographic characteristics, haemoglobin phenotype of 1,165 babies and parents were obtained from the laboratory register. Main Outcome measures: Prevalence of haemoglobin (Hb) phenotypes in newborns, couples’ Hb phenotype compatibility. Statistical analysis: Data were summarized using proportion, mean, median and standard deviation. Chi-square and Fisher’s exact tests were used where appropriate. Results: A total of 1,165 newborns were screened for hemoglobin phenotype consisting of 589 (50.4%) males and 572 (47.1%) females. Majority, 856 (73.9%) had haemoglobin (Hb) phenotype AA, 283 (24.4%) had AS, 12 (1.0%) and 6 (0.5%) had SS and AD; respectively while SC and AC were (0.1%) each. Nine (0.9%) of the parents who reported a compatible Hb phenotype had newborns with SS. There was a significant difference in Hb phenotype of the newborns of parents with compatible and those with incompatible Hb phenotypes (p <0.001). Conclusions: The prevalence of SCD (HbSS 1.0% and HbSC 0.1%) is 1.1% among newborns in Ebonyi state. There is a high level of Hb phenotype incompatibility between couples in the state. Public awareness, premarital education and screening of couples are needed. [ABSTRACT FROM AUTHOR]

Aim: Children with sickle cell disease (SCD) have historically weighed less than their healthy peers. More recently, a retrospective chart review from six institutions in New England reported nearly one-quarter of children and adolescents with SCD had raised body mass index (BMI). This study aimed to examine rates of children with SCD with raised BMI in Mississippi compared to state and national norms and assess the correlation between haemoglobin and BMI.Methods: A retrospective chart review of paediatric patients with SCD at the University of Mississippi Medical Center (UMMC) was conducted using data from the most recent clinic visit. Mississippi and national weight status estimates for youth 10-17 years were obtained from the 2016-2017 National Survey of Children's Health.Results: For youth 10-17 years with SCD (n = 345), 21.4.% of children with SS/Sβ° and 36.1% with SC/Sβ+ had raised BMI compared to Mississippi and national rates, 39.2 and 31%, respectively. The prevalence of children with raised BMI with SC/Sβ+ did not differ from state and national rates, while children with SS/Sβ° were half as likely as their Mississippi peers to have raised BMI. Haemoglobin levels were different among children with SCD who had low BMI (8.80 g/dL), average BMI (9.2 g/dL) and raised BMI (10.5 g/dL) (P < 0.001).Conclusions: Children with SCD evaluated at UMMC have similar rates of raised BMI compared to state and national norms. Children with raised BMI have higher mean haemoglobin levels compared to children with SCD with low or average BMI.Implications and Contribution: Historically, patients with SCD have been underweight and normal weight. Our paediatric and adolescent patients with SCD now have prevalence rates of raised BMI that approach state and national rates. Further work must be done to determine whether this reflects healthier children with SCD or raises concerns about life-style-related comorbidities. [ABSTRACT FROM AUTHOR]

Hemoglobin S is caused by a nucleotide change in HBB gene (HBB:c.20A>T, p.Glu6Val), is presented in diverse forms: simple carriers (HbSA), homozygotes (HbSS) also known as sickle cell anemia, and compound heterozygotes with other β-hemoglobinopathies. It is worldwide distributed, in Mexico, is frequently observed in the southern states Guerrero, Oaxaca and Chiapas. Elevated fetal hemoglobin (HbF) is associated with mild phenotype; single-nucleotide variants (SNVs) in modifier genes, such as BCL11A, HBG2, HBBP1 pseudogene and HBS1L-MYB intergenic region, upregulate HbF synthesis. The aim of this study was to identify HbF regulating genetic variants in HbSS and HbSA Mexican subjects. We studied 39 individuals (HbSS = 24, 61%, HbSA = 15, 39%) from Chiapas (67%) and Guerrero (33%), peripheral blood was collected in ethylenediamine tetraacetic acid (EDTA) for molecular and hematological studies, DNA was isolated by salting-out technic and genotyping was performed through allelic discrimination by real time polymerase chain reaction (RT-PCR) using Taqman® probes for 15 SNV (in BCL11A: rs6706648, rs7557939, rs4671393, rs11886868, rs766432, rs7599488, rs1427407; HBS1L-MYB: rs28384513, rs7776054, rs9399137, rs4895441, rs9402686, rs1320963; HBG2: rs7482144; and HBBP1: rs10128556). The obtained data were analyzed using IMB SPSS v.22.0 software. All minor alleles were observed in frequencies over 0.05, the most frequent was rs9402686 (0.82), while the less frequent was rs101028556 (0.08). In HbSS group, the mean fetal hemoglobin was 11.9 ± 5.9% and was significantly elevated in BCL11A rs11886868 wildtype homozygotes and in carriers of HBS1L-MYB intergenic region rs7776054 (p = 0.04 and p = 0.03, respectively). In conclusion, in HbSS Mexican patients, two SNVs were observed related to increased HbF; BCL11A rs11886868 and HBS1L-MYB rs7776054. [ABSTRACT FROM AUTHOR]

BACKGROUND: Sickle cell disease and its variants result from an abnormal hemoglobin, hemoglobin S (HbS), caused by a single point mutation in the Beta-Globin gene. Hypoxia causes polymerization and distortion of Hb S containing red blood cells resulting in sickle crisis and hemolytic anemia. Common diagnostic methods include high-performance liquid chromatography (HPLC) and hemoglobin electrophoresis. The purpose of this research is to determine the frequency of sickle cell hemoglobin in HPLC samples and its geographical distribution in Pakistan. MATERIALS AND METHODS: Data was collected from the samples received from 1st February 2020 to 31st January 2021. Proforma included demography, complete blood count parameters, and variants of sickle cell disease which were extracted from hospital records. Analysis was done using the SPSS (version 26). RESULTS: Out of 14,740 samples, 295 (2%) revealed HbS. These patients had a mean age of 14.2 years. The male-to-female ratio was 1.5:1. The samples were received from Baluchistan (43%), followed by Sindh (32.1%), Khyber Pakhtunkhwa (16%), and Punjab (8.9%). Mean hemoglobin was 8.6 ± 2.6 g/dl, lowest and highest were 2.4 g/dl and 16.9 g/dl, respectively. Sickle cell trait was found in 21.3% of the patients, homozygous HbSS in 27.7%, sickle beta thalassemia in 30.8%, 4.4% were compound heterozygotes for Hb S and Hb D, whereas 15.5% were posttransfusion samples. CONCLUSION: Our analysis showed that the highest frequency was of sickle beta thalassemia and other variants being low. This study also proved it to be more prevalent in Baluchistan with relatively high male preponderance. [ABSTRACT FROM AUTHOR]