Sickle Cell Trait Research Articles

COVID-19 in Adults with Sickle Cell Disease

Introduction Sickle cell disease (SCD) is the most common inherited hemoglobinopathy and is estimated to affect more than 100,000 Americans. The unique constellation of SCD manifestations complicates both the diagnosis and management of COVID-19, particularly related to anticoagulation and transfusion practices. A previous literature review of COVID-19 outcome and SCD noted the need for studies evaluating genotype and SCD-modifying therapies (Hoogenboom et al. 2022). We report on the outcomes for all hospitalized inpatients with SARS-CoV-2 and SCD at institutions using the Cerner Real World Database (RWDB). Methods The Cerner RWD is a large, cloud-based deidentified database that includes electronic health records (EHR) data from >100 United States health systems (Ehwerhemuepha et al. 2022). We obtained approval to access these data with an exempt status from IRB to conduct a retrospective study including patients records from February 27, 2020 to August 14, 2022. Those with sickle cell trait were excluded. Descriptive statistics were performed. Results: The final dataset included 1547 adult patients, 609 of whom were hospitalized, 25 of whom received invasive ventilation, and 51 of whom died. Hospitalized patients were more likely to be male, have Medicaid or Medicare, and have Hgb SS or Hgb SC genotype than the 938 ambulatory patients (Table 1). Of the hospitalized patients, the 51 who died and the 25 who received invasive ventilation were, older, and as expected, had longer length of stays. Labs and treatments for hospitalized patients are summarized in Tables 2 & 3. We were not able to find evidence of exchange transfusion; however, 14% of hospitalized patients received red blood cell transfusion. Those who were under invasive ventilation were more likely to have higher C-reactive protein (CRP), creatinine (CRT), erythrocyte sedimentation rate (ESR), and procalcitonin as well as lower white blood cell counts on initial labs. Hemoglobin, hematocrit, and ferritin levels were similar. A majority of patients under invasive ventilation received dexamethasone and heparin while as many as 24% of all hospitalized patients received dexamethasone and 57% received heparin or enoxaparin. Only 199 (33%) hospitalized patients received hydroxyurea while admitted and few patients who received invasive ventilation were transfused (<44%). Discussion This study describes one of the largest populations of patients with SCD and COVID-19 in the United States. Demographics of the overall cohort were consistent with known characteristics. More patients with Hgb SS or Hgb SC were hospitalized than expected. Although steroids are used with caution in patients with SCD, almost a quarter of hospitalized patients were treated with dexamethasone. The small number of hospitalized patients receiving hydroxyurea while admitted is surprising, although it is not known how this compares to ambulatory patients with COVID-19. The small number of patients being transfused is also concerning. One of the notable limitations is that the dataset draws only from institutions using Cerner EHR, a 26% market share. Additionally, there is likely significant variability between institutions' treatment protocols, particularly in the early months of the pandemic. Finally, we were not able to compare these patients to a control population, an area which offers opportunity for future investigation. TABLE 1- Demographics- hospitalized vs. ambulatory patients TABLE 2- Hospitalized patients- all vs. mechanically ventilated vs. deaths TABLE 3- Treatments- Invasively ventilated vs. all hospitalized patients

Impact of Acute Exercise Challenge on Airway Dynamics in Children and Young Adults with Sickle Cell Anemia

Background Sickle cell anemia (SCA) complications such as frequent pain, chronic anemia, and acute and chronic organ damage lead to reduced physical functioning and cardiopulmonary fitness in affected individuals. Limited data support the safety of maximal cardiopulmonary exercise testing (CPET) in SCA, yet the safety of submaximal, longer-duration exercise at moderate to high intensity in SCA is unclear. The Sickle Cell Pro-Inflammatory Response to Interval Testing Study (SPRINTS) was a multicenter, prospective study that evaluated the impact of longer, submaximal exercise, which mimics the physical activity patterns of children better than CPET, on the acute inflammatory response and airway dynamics in children and young adults with SCA. In this analysis, we defined the effect of moderate to vigorous exercise on forced expiratory volume in 1 second (FEV1) and acute bronchoconstriction. We hypothesized the risk of exercise-induced bronchoconstriction (EIB) in children with SCA is greater than in controls. Methods SPRINTS was approved by the Lurie Children's central Institutional Review Board. Subjects 10-21 years old with hemoglobin (Hb) SS or S/β0 thalassemia and race-matched controls without SCA or sickle cell trait were enrolled across 4 institutions. Subjects were excluded for 1) inability to perform exercise, 2) receiving chronic transfusions, 3) history of exercise-related arrhythmia/syncope, 4) physician-diagnosed asthma, 5) history of EIB, or 6) history of cardiac disease precluding exercise testing. Participants performed maximal CPET on a cycle ergometer using a standardized Godfrey protocol. At least 2 weeks later, participants performed a controlled intensity interval test (CIIT) consisting of 8 bouts of constant workload cycling randomized to either 50% (moderate intensity) or 70% (vigorous intensity) of peak workload achieved during CPET. Exercise bouts were 2 min each with 1-min rest intervals between bouts. Spirometry was performed pre/post (5, 10, 15, and 30 min) CPET and CIIT. EIB was defined as a drop in FEV1 ≥10% from baseline to the lowest FEV1 recorded. Bivariable comparisons were performed, and logistic regression models analyzed the association between EIB and covariables (age, sex, SCA status, max workload, exercise intensity (CIIT only), baseline FEV1 % predicted, FEV1/FVC % predicted) using IBM ® SPSS ® Statistics. Results Available data from 64 subjects (48% F, 73% on hydroxyurea, mean 13.8±2.8 years) and 40 controls (45% F, mean 15.4±2.9 years) were analyzed. Baseline Hb (8.5±1.2 vs. 13±1.4 g/dL, p < 0.001) and maximal workload achieved during CPET (85±26 vs. 135±45 watts, p < 0.001) were lower in subjects vs. controls. The percentage of participants who completed CIIT did not differ between subjects and controls, and no respiratory-related adverse events, including need for bronchodilator therapy, occurred. At baseline, FEV1 and FEV1 % predicted and other parameters (FVC and FVC % predicted, MMEF and MMEF % predicted) were significantly lower in subjects vs. controls (Table 1). However, there was no between-group difference in baseline FEV1/FVC % predicted. Post-exercise, the percentage of participants who met criteria for EIB did not differ between subjects and controls after CPET (21 vs. 26%, p = 0.537) or CIIT (32 vs. 17%, p = 0.126). There was also no significant between-group difference in the greatest drop in FEV1 from baseline to any post-exercise timepoint (mean value or as % of baseline) after CPET or CIIT. In logistic regression models, SCA status, age, sex, maximal workload during CPET, exercise intensity (CIIT only), baseline FEV1 % predicted and FEV1/FVC % predicted were not associated with EIB after CPET or CIIT (Table 2). Conclusion Compared to controls, children and young adults with SCA and no history of asthma or EIB had lower baseline values on all spirometry parameters except FEV1/FVC % predicted. EIB was not more common in subjects with SCA vs. controls after maximal CPET or a submaximal exercise challenge of longer duration at moderate or vigorous intensity. No independent factors were associated with development of EIB after acute exercise. Despite concerns that undiagnosed lower airways disease in children with SCA is common, our results suggest the risk of EIB in SCA is low and underscore the safety of moderate to vigorous exercise toward developing evidence-based exercise guidelines in non-asthmatic children and young adults with SCA.

Hypertonicity and/or Acidosis Induce Marked Rheological Changes Under Hypoxic Conditions in Sickle Trait Red Blood Cells

Hemoglobin S (HbS) is an abnormal hemoglobin resulting from a single nucleotide substitution in the beta-globin gene. Individuals who are heterozygous for the HbS genotype are regarded as carriers of sickle cell anemia (SCA; HbSS) and are said to have sickle cell trait (SCT; HbAS). Recent data have established SCT as a risk factor for venous thromboembolism (VTE), chronic kidney disease (CKD), and end-stage renal disease (ESRD) (Naik RP, 2018). These complications have a relative risk of approximately 1.5 - 2.0 compared to race- and age-matched controls, but the mechanisms that account for these complications are not well understood. To study potential mechanisms for renal disease, we evaluated red blood cell (RBC) deformability from SCT donors under conditions designed to mimic the hypertonic, acidemic, and hypoxemic environment of the inner renal medulla. RBC deformability was measured using the Laser Optical Rotational Red Cell Analyzer (LORRCA; RR Mechatronics, The Netherlands). In SCA, LORRCA has been used to monitor RBC rigidity at baseline and under progressive hypoxia by calculating the Elongation Index (EI; the longitudinal dimension of the RBC along the axis of applied shear stress divided by transverse dimension of the cell along the same axis). The OxygenScan function measures EI during a cycle of continuously decreasing pO2 from about 150 mmHg (ambient air) to near 20 mm Hg, before reversing in a re-oxygenation phase. In SS RBCs, EI decreases from a stable baseline as RBCs start to sickle; this ‘point of sickling (PoS)‘ is defined as the pO2 at which there is a >5% decrease in EI. Similarly, the Osmoscan function can record the RBC EI at ambient oxygenation while osmolality of the blood progressively increases from approximately 100 to 600 mOsm. First, OxygenScan profiles were performed utilizing modified LORRCA buffers to evaluate four separate conditions: isotonic + neutral pH, isotonic + pH 6.9, 460 mOsm + neutral pH, and 460 mOsm + pH 6.9. Buffers were modified by the addition of sodium chloride, hydrochloric acid, or both. HbS percentage (HbS%) and RBC indices were recorded for each subject. HbS% and RBC indices were compared to PoS for all samples and conditions. EI from AS and AA samples were compared at physiologic serum osmolality (290 mOsm) and at 460 mOsm. AA samples demonstrated no measurable PoS under any condition. Some (11/21) AS samples demonstrated sickling under hypoxia alone, with mean PoS of 32.26 mmHg. Mean PoS for AS samples in isotonic buffer + pH 6.9 was 40.73 mmHg, but with sickling detected in all samples. Mean PoS in hypertonic buffer (460 mOsm) significantly increased to 60.68 mmHg, with notable inter-individual heterogeneity (Fig. 1). Mean PoS in hypertonic buffer + pH 6.9 was 79.04 mmHg, with less inter-sample heterogeneity. In exploratory experiments, we have observed similar changes in the Townes AS murine model of SCT (not shown). PoS was compared to HbS% in the human samples under all conditions. A positive correlation was observed between HbS% and PoS in isotonic buffer at pH 6.9 (r=0.566, p=0.012). PoS was also compared to RBC indices, with a trend towards a positive correlation with mean corpuscular hemoglobin concentration (MCHC) under hypertonic + neutral pH conditions ( p=0.11). Next, utilizing the Osmoscan function, no difference in EI at physiologic osmolality (290 mOsm) was observed between AA (n= 7) vs. AS (n= 8). However, at 460 mOsm, EI trended lower in AS RBCs ( p=0.12) (Fig. 2). Given the presence of severe tissue hypoxia (as low as 10 mmHg), hypertonicity (as high as 1,200 mOsm), and acidemia (as low as pH 5.5) in the inner renal medulla, these data provide an explanation for RBC-mediated occlusion of the vasa recta that is known to occur in the kidneys of subjects with SCT. We demonstrate that extracellular hypertonicity contributes significantly to SCT RBC sickling in the presence of hypoxemia, and that there is significant inter-individual susceptibility to sickling under these harsh biophysical conditions that is only partially explained by HbS%.

A Miniaturized, Rapid Technique for Measuring Red Blood Cell-Mediated Microcapillary Occlusion in HbAS, HbSC, and HbSS Sickle Cell Disease Genotypes

Introduction Sickle cell disease (SCD) is caused by a genetic mutation that produces sickle hemoglobin (HbS). HbS polymerizes upon deoxygenation, causing red blood cells (RBCs) to become sickle-shaped and poorly deformable. Stiff sickle RBCs contribute to microvascular occlusion and organ damage. Previous studies have developed microfluidic devices for assessing RBC-mediated occlusion under hypoxia, but the complexity of the setup and data acquisition limits their adoption. A rapid, easy-to-use, point-of-care assay for assessing RBC-mediated occlusion could increase throughput and aid in determining outcomes of novel therapies, including gene therapies, for SCD. Here, we induced RBC sickling using a chemical method in a simplified workflow to study hypoxic RBC-mediated microcapillary occlusion for healthy (HbAA), sickle cell trait (HbAS), hemoglobin SC disease (HbSC), and homozygous SCD (HbSS) RBCs. Additionally, a custom miniaturized impedance analyzer (MIA) was developed to provide a rapid and fully electronic measurement of occlusion within 10 minutes of sample perfusion. Methods Microfluidic devices were fabricated using standard photolithography and polydimethylsiloxane (PDMS) micro-molding protocols. Glass slides were coated with gold electrodes by sputter deposition and bound to the PDMS microfluidic devices using oxygen plasma. The microfluidic devices comprised six microcapillary arrays of widths 12, 10, 8, 6, 4, and 3 μm, with each array coupled with a pair of gold electrodes [3]. The MIA included an ADALM2000 software-defined instrument module, a custom-designed front-end interface board, and a Raspberry Pi single-board computing module. The ADALM2000 was used to generate and acquire a 10-kHz measurement signal, while the front-end interface board handled signal amplification and multiplexed signal routing through the microcapillary arrays. A custom graphical user interface on the Raspberry Pi allowed users to set experimental parameters and monitor data in real time. Venous blood samples were collected in EDTA tubes from participants with HbAS (n=9), HbSC (n=9), HbSS (n=13), and HbAA (n=6) under an IRB-approved protocol. To induce hypoxia, washed RBCs were suspended at 20% hematocrit in a 1.5% (w/v) sodium metabisulphite in 1× PBS buffer and incubated for 3 minutes at room temperature. For normoxia, RBCs from the same donors were suspended at 20% hematocrit in PBS and incubated with the same conditions. Samples were then perfused through the microfluidic device at a constant inlet pressure. After 10 minutes of perfusion, the change in electrical impedance across each array was used to calculate an occlusion index (OI), representing the percent occlusion of the capillary network. Results Normoxic OI for HbSS and HbSC was significantly higher than HbAA but there were no statistical differences in HbAA vs. HbAS and HbSC vs. HbSS (Figure 1A). HbAS, HbSC, and HbSS RBCs had significantly higher occlusion under hypoxia than in normoxia (Figure 1A, 1.46 ± 1.67% vs. 8.43 ± 2.78%, P = 0.004 for HbAS, 4.56 ± 2.77% vs. 27.1 ± 17.0%, P = 0.004 for HbSC, and 8.01 ± 6.26% vs. 58.3 ± 26.2%, P = 0.0002 for HbSS). Occlusion of HbAA RBCs remained low in both normoxia and hypoxia (2.70 ± 0.643% vs. 4.72 ± 0.953%, P = 0.0625). Hypoxic OI was significantly different between HbAA vs. HbAS (P = 0.017), HbAS vs. HbSC (P = 0.004), and HbSC vs. HbSS (P = 0.007). Hypoxic OI in HbSC and HbSS was associated with elevated markers of RBC hemolysis - absolute reticulocyte count (ARC, P = 0.0061) and lactate dehydrogenase (LDH, P < 0.0001, Figure 1B). Conclusion In normoxia, HbSC had comparable OI to HbSS likely due to HbC induced efflux of potassium ions and water resulting in cellular dehydration and poor RBC deformability. The hypoxic assay, however, unmasked the greater severity of HbSS. Further, elevated hypoxic OI in HbAS may be linked to higher risk of organ damage in this genotype. Chemically-induced hypoxia combined with electrical impedance-based measurement of RBC-mediated microcapillary occlusion offers a new technique for rapidly assessing RBC health and function in a low-oxygen environment. This approach eliminates the need for expensive, high-resolution microscopes and complex gas-exchange chambers. This may serve as a new standard for assessing the clinical efficacy of new treatments that improve RBC deformability and identifying at-risk patients in otherwise mild SCD genotypes.

Sickle cell allele HBB-rs334(T) is associated with decreased risk of childhood Burkitt lymphoma in East Africa.

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that significantly contributes to childhood cancer burden in sub-Saharan Africa. Plasmodium falciparum, which causes malaria, is geographically associated with BL, but the evidence remains insufficient for causal inference. Inference could be strengthened by demonstrating that mendelian genes known to protect against malaria-such as the sickle cell trait variant, HBB-rs334(T)-also protect against BL. We investigated this hypothesis among 800 BL cases and 3845 controls in four East African countries using genome-scan data to detect polymorphisms in 22 genes known to affect malaria risk. We fit generalized linear mixed models to estimate odds ratios (OR) and 95% confidence intervals (95% CI), controlling for age, sex, country, and ancestry. The ORs of the loci with BL and P. falciparum infection among controls were correlated (Spearman's ρ = 0.37, p = .039). HBB-rs334(T) was associated with lower P. falciparum infection risk among controls (OR = 0.752, 95% CI 0.628-0.9; p = .00189) and BL risk (OR = 0.687, 95% CI 0.533-0.885; p = .0037). ABO-rs8176703(T) was associated with decreased risk of BL (OR = 0.591, 95% CI 0.379-0.992; p = .00271), but not of P. falciparum infection. Our results increase support for the etiological correlation between P. falciparum and BL risk.

Case report: The Circle Game

The authors present a rare case of a family in which both the mother, and four decades later the son, committed second-degree murder while suffering from major mental illnesses. The mother had successfully used a mental disorder defence and it was likely that the son who had raised the defence would have qualified also. The mother has a history of adverse childhood experiences. The son had also experienced various severe childhood adversities, though there were no functional impairments, personality dysfunction, suicidality or violent crimes until the onset of treatment-resistant schizoaffective disorder around age 18. His earlier comorbidities included sport-related traumatic brain injuries, sickle cell trait, severe burns, and tardive dyskinesia. His comorbidities around the material time included occasional cannabis use and dementia pugilistica. While awaiting court ruling on criminal responsibility, additional stressors triggered significant deterioration of his schizoaffective disorder and the court found him unfit to stand trial. During rehabilitation, he was severely injured by another accused, which subsequently led to his demise. This case is the first report of intergenerational mental disorder defence and involved almost every facet of criminal forensic psychiatry, which highlights the need for further research on the association between intergenerational ACEs and intergenerational risk for criminal behaviour from a comprehensive and longitudinal perspective.

Catastrophic Sports Injuries: Causation and Prevention.

➤ Catastrophic injuries in U.S. high school and college athletes are rare but devastating injuries.➤ Catastrophic sports injuries are classified as either traumatic, caused by direct contact during sports participation, or nontraumatic, associated with exertion while participating in a sport.➤ Football is associated with the greatest number of traumatic and nontraumatic catastrophic injuries for male athletes, whereas cheerleading has the highest number of traumatic catastrophic injuries and basketball has the highest number of nontraumatic catastrophic injuries for female athletes.➤ The incidence of traumatic catastrophic injuries for all sports has declined over the past 40 years, due to effective rule changes, especially in football, pole-vaulting, cheerleading, ice hockey, and rugby. Further research is necessary to reduce the incidence of structural brain injury in contact sports such as football.➤ The incidence of nontraumatic catastrophic injuries has increased over the last 40 years and requires additional research and preventive measures. Avoiding overexertion during training, confirming sickle cell trait status in high school athletes during the preparticipation physical examination, and developing cost-effective screening tools for cardiac abnormalities are critical next steps.

Sickle Cell Trait and Mortality Risk: California Newborn Screening Longitudinal Follow up of Births 1991-2013

Sickle cell trait (SCT) represents a significant global public health issue with approximately three million carriers in United States and over 300 million worldwide. Yet, the mortality risk of sickle cell trait is unknown. Early anecdotal research on SCT led to social bias and stigmatization of individuals with the trait, which unfortunately hindered the conduct of well-designed morbidity and mortality studies in this population. This resulted in SCT being perceived as a benign asymptomatic condition that protects against malaria and its importance confined to the genetic risk for sickle cell disease. As research in SCT gradually increased, it became evident that SCT is indeed a risk factor for several complications including exertional related rhabdomyolysis, chronic kidney disease, venous thromboembolism, and other morbidities. SCT red cells in abnormal physiologic conditions sickle and can cause morbidity and mortality. Additionally, SCT could potentially influence the severity of various illnesses. Individuals with SCT commonly experience hyposthenuria and are at risk for dehydration which could further exacerbate the severity of many medical problems. It is essential to determine if SCT is a risk factor for overall mortality. This study is the first population-level investigation of all-cause mortality risk for individuals with SCT. This longitudinal analysis included all live births with SCT identified by the California newborn screening (NBS) program between 1991 and 2013. For each newborn with SCT, three matched controls with hemoglobin AA were randomly selected from the NBS cohort. Controls were matched to SCT cases on year of birth, sex, race/ethnicity, and city of birth. SCT records with incomplete data for the matched variables or those with fewer than three matching controls were excluded from the analysis. SCT cases and controls were linked to all deaths within the state of California for the years 1991-2013 using statewide death data files. Cox proportional hazard ratios and 95% confidence intervals were calculated to compare mortality between individuals with SCT and controls with hemoglobin AA, including stratified by age (<1, 1-4, 5-14, 15-22). The study identified 94,240 live births with SCT (Table 1), which represents 96% of all SCT live births identified by the California NBS program in 1991-2013, and 282,720 matched controls. Between 1991 to 2013, there were 693 (0.74%) SCT deaths and 1,910 (0.68%) control deaths. Those with SCT had an increased mortality hazard rate compared to those with hemoglobin AA (11% higher, p=0.015). When stratified by age, mortality hazard rates in the age strata 1-4 years (44% higher, p= .0009) and 5-14 years (48% higher, p=.0047) were higher than those with hemoglobin AA (Table 2). These age strata describe periods of follow up time, and an individual may appear in more than one stratum. Mortality hazard ratios calculated for each age stratum are conditional to individuals surviving to the starting age of that stratum. This analysis of mortality risk for a cohort of over 94,000 infants identified with SCT is the first of its kind and adds important information to the assessment of health risk for the condition. This is the first study that reports a higher risk of mortality for children and young adults with SCT compared to those with hemoglobin AA. These findings highlight the need for comprehensive research, including confirming the study results in other longitudinal sickle cell trait population-level studies and investigation into underlying causes of death, to inform clinical management and counseling for individuals with SCT.

Risk and Protective Factors for COVID-19 Infection Among Pregnant Women with Sickle Cell Trait

BACKGROUND: Pregnant women and individuals with sickle cell trait (SCT) and underlying comorbidities are more vulnerable to severe illness from the coronavirus disease of 2019 (COVID-19) compared to nonpregnant women and those without SCT (PMID: 35916859, 34129519). However, the impact of the pandemic and factors affecting susceptibility to COVID-19 among pregnant women with SCT is unknown. This study aims to examine various factors that can alter the likelihood of COVID-19 among pregnant women with SCT, including vaccination against COVID-19 and influenza and the presence of underlying comorbidities such as cardiac disease, diabetes, obesity, renal disease, and stroke. In addition, the study aims to provide insights into the fetal outcomes among pregnant women with SCT who have contracted COVID-19. METHODS: A total of 295 individuals with the diagnosis of SCT who had encounters at three large hospitals in Michigan from January 1, 2022, to December 31, 2022, were screened in this retrospective study. 151 women with SCT met the inclusion criteria and are within the reproductive age group between 15-49 years old. Demographics, underlying comorbidities, fetal outcomes, and other clinical information were collected by electronic medical records review. COVID-19 and influenza vaccination were verified from the immunization records registry in Michigan. Multivariable regression analysis was used to analyze the protective or risk factors associated with COVID-19 infection. Statistical analyses were performed using the SPSS version 29 statistical software, and a p-value of <0.05 was considered statistically significant. RESULTS: Data was collected from 151 women with SCT, with 34% being pregnant and 66% being non-pregnant. Approximately 85% of the participants were Black, and their mean age was 32 years. 35% contracted COVID-19 among pregnant women, while 31% among non-pregnant women (p>0.05). In a multivariable regression analysis, the study found that pregnant women with SCT who received COVID-19 vaccine were 90% less likely to have a COVID-19 infection (OR=0.102 with 95%CI: 0.011-0.950) and 9 times more likely to have a COVID-19 infection if they had a history of pulmonary conditions such as asthma, chronic obstructive pulmonary disease, or obstructive sleep apnea (OR=9.375 with 95% CI: 1.090-80.627). There were no other protective or risk factors that showed a significant statistical association with COVID-19 infection among pregnant women, including influenza vaccination, obesity, underlying cardiac history, diabetes mellitus, renal disorder, stroke, or transient ischemic attack (p>0.05). Most pregnant women with SCT who contracted COVID-19 in the study had mild-moderate disease, except for one patient who developed severe disease in the third trimester, warranting premature delivery of an infant via emergency cesarean section. 72% did not have fetal complications, except for 3 newborns who were delivered preterm (<37 weeks) and 2 with low birth weight (<2500 grams). While 2 newborns initially had a low Apgar score (APGAR<7) at 1 minute, their condition eventually improved after 5 minutes. Overall, all newborns delivered to COVID-19-infected women with SCT had a good 5-minute Apgar score. CONCLUSION: The study further emphasizes the importance of encouraging COVID-19 vaccination among individuals with SCT, particularly pregnant, reproductive age group women and those with underlying comorbidities. Pregnant women with SCT and underlying comorbidities should be carefully monitored to prevent severe disease, as they may be more vulnerable to COVID-19 infection. Further studies with larger sample sizes are recommended to investigate factors associated with severe COVID-19 infection among these populations.

A Retrospective Analysis of COVID-19 Coagulopathy in Hospitalized and Intensive Care Patients with Sickle Cell Disease

Purpose/Objective: The implications of COVID-19 induced hypercoagulability in patients with sickle cell disease (SCD) remain largely unknown. Both COVID-19 and SCD have independent pathophysiological mechanisms which impact each aspect of Virchow's triad to induce a hypercoagulable state (Saxena and Muthu., 2023), however the joint impact of COVID-19-SCD on venous thromboembolism (VTE) remains understudied. As such, our primary objective involved investigating the incidence of VTE events in SCD patients with COVID-19. Our secondary objective involved assessing parameters of COVID-19 infection severity in SCD patients. Methods: We conducted a retrospective cross-sectional study at New York City Health and Hospitals, Kings County involving SCD, sickle cell trait (SCT) and the general population of COVID-19 patients (non-sickle). Data was collected from the onset of the pandemic on March 1, 2020 to December 31, 2021 for hospitalized and intensive care patients. We collected information on incidence of VTE, type of VTE (deep vein thrombosis or pulmonary embolism), age, sex, comorbidities, VTE prophylaxis, D-dimer, ferritin, LDH, BMI, sickle cell phenotype, transfusion requirements, COVID-19 management, SCD management, and outcomes. Data was analyzed on GraphPad PRISM, using one-way ANOVA and odds ratios. A p-value of <0.05 was considered statistically significant. Results: The study included three patient cohorts, consisting of 24 SCT, 26 SCD and 675 non-sickle patients (non-SS) to study incidence of VTE. Additional information regarding infection parameters was obtained on 146 non-sickle patients, and all SCT and SCD patients. We found that there was no significant difference between VTE risk in the SCD and non-sickle patients (OR=0.3736, 95% CI 0.0223 to 6.2675) or SCT and SCD patients (OR=0.2956, 95% CI 0.0115 to 7.6121). There was no significant difference in mortality (OR=0.4909, 95% CI 0.0606 to 3.9736) or intensive care requirements (OR=0.4137, 95% CI 0.1171 to 1.4608) between SCD and non-SS patients (Table 1). We also investigated markers of infection and hypercoagulability and found that there was no significant difference between D-dimer or LDH levels between the three cohorts, however ferritin was significantly increased in the SCD group compared to the non-sickle cohort (Figure 1, p=0.0123). Conclusions/Implications: Current ASH guidelines recommend use of prophylactic dose anticoagulation for critically ill COVID-19 patients and therapeutic dose anticoagulation for acute, but not critically ill patients (Cuker et. al., 2022). There are currently no formal recommendations regarding VTE prevention for hospitalized SCD patients with COVID-19. Our data supports prior reports on VTE in SCD (Singh et. al., 2022) which note that SCD patients with COVID-19 do not have an increased risk of VTE compared with uninfected SCD patients. Similarly, our data suggests that there is no statistical difference in VTE incidence in SCD-COVID-19 patients compared to the general population affected by COVID-19. Given no differences in VTE incidence, we recommend that anticoagulation parameters for the general population of hospitalized and intensive care patients be applied to SCD patients.

The Quality of Life of Sickle Cell Disease Patients in Saudi Arabia 2023

The quality of life of sickle cell disease patients in Saudi Arabia 2023. Sickle cell disease (SCD) is a genetic blood disorder that affects millions of people around the world. It is caused by a mutation in the hemoglobin gene that results in the production of abnormal hemoglobin, which is the protein responsible for carrying oxygen in the blood. SCD is relatively common in Saudi Arabia, with a prevalence of around 2.3%, while the carrier state for SCD, sickle cell trait (SCT), is estimated to be 3.1%. The southern region of the country has the highest prevalence of both SCD and SCT, followed by the eastern region, with lower rates in the central and northern regions. The high prevalence of SCD and SCT in Saudi Arabia poses significant challenges to the healthcare system, with individuals experiencing complications such as pain crises, infections, and stroke, leading to increased hospitalizations and costly treatments. The government has taken steps to address this issue through newborn screening programs and comprehensive care provision, but further efforts are required to ensure equitable access to healthcare for all affected individuals. The disease can have a significant impact on the quality of life of patients due to its chronic nature, pain, and complications. In this study, we aimed to comprehensively investigate various aspects of SCD patients' experiences in Saudi Arabia. We explored the experiences of SCD patients, focusing on their encounters with pain, hospitalizations, and interactions with healthcare providers, the impact of SCD on the social lives and relationships of patients and the educational and support needs of both SCD patients and their families By addressing these research objectives, we gain a comprehensive understanding of the challenges and needs of SCD patients in Saudi Arabia, ultimately contributing to the development of more patient-centered and effective care strategies. Data Collection methods, instruments used, measurements: Patients were recruited through treating doctors during routine consultations utilizing an online based comprehensive survey. Result: The recruitment period for this study was from March 1, 2023, to the end of June of the same year. A total of 75 patients participated in the survey. However, only 50 responses were included in the analysis due to missing or conflicting data found in the excluded answers. The median age of the surveyed patients was 28 years, indicating an improvement in the care provided compared to previous published articles. Among the participants, 66.7% were males, and all the responses came from individuals affected by the disease. The majority of the patients (83.3%) resided in the southern region of the kingdom, followed by (16.7%) from the eastern region. Regarding patient support, all included participants stated that their support came solely from their families, as they declined any support from other patients, religious groups, or healthcare professionals. The main sources of support were the parents, followed by life partners and siblings. Although the patients expressed satisfaction with their family support, (50%) were unsure if support from outside the family was necessary. Regarding pain status, 50% of the patients reported experiencing pain more than three times in the last six months. Medical attention was sought in 50% of these cases, and 33.3% of the attacks required admission. In managing their crises, all patients used opioid-based analgesics. However, only (66.7%) used hydration in addition to home remedies, hot compressions, and local treatments, while (16.7%) used non-opioid-based medications. Despite experiencing emotional distress due to the disease symptoms, anxiety, and feelings of being dismissed, none of the patients sought emotional support from certified professional personnel. The disease had a notable impact on the professional lives of the patients, with 50% being unemployed, and others considering quitting their jobs, refusing promotions, or needing job assistance. The treatment goals from the patients' perspective were to reduce disease complications, improve their quality of life, and decrease pain crises and hospital admissions. Unfortunately, less than 49% of the patients achieved these treatment goals with the provided medications.

Are We Diagnosing and Managing Diabetes in Patients with Sickle Cell Disorders Accurately?

Introduction: Patients with hemolytic anemias, especially those resulting from severe sickle cell disorders (SCD), may experience increased red blood cell (RBC) turnover, influencing hemoglobin (Hb) glycation rates. The American Diabetes Association (ADA) recommends measuring plasma glucose levels for diabetes mellitus (DM) diagnosis. However, to monitor glycemic control, fructosamine provides a valuable measure of glycated serum protein byproduct, independent of RBC lifespan. It is important to note that G6PD can aggravate anemia and its co-existence with SCDs is reported to vary between 7%-35.83% depending on genotype, ethnicity and location. Despite National Glycohemoglobin Standardization Program's (NSGP) reporting that most chemistry analyzers exhibit no assay interference, Lacy et al. showed that HbA1C systematically underestimated past glycemia in black patients with sickle cell trait. It is hypothesized that numerous SCD patients with DM receive diagnosis and management based on HbA1C. This study seeks to evaluate the management patterns and the correlation between Hb and HbA1C in the context of a hemoglobinopathy, aiming to enhance patient care standards. Methods: We identified 61 adult sickle cell disorder patients who also had a diagnosis of type 2 DM or prediabetes between January 2019 and May 2023. Patients with acute blood loss events (with or without transfusions), iron deficiency, hyperbilirubinemia, liver or renal disease, HIV infection on antiretroviral therapy, and those receiving Vit A/C supplementation were excluded from the study, as these conditions are known to impact the HbA1C levels. HbA1C testing at our institution was formerly done using Siemens Dimension Vista 500/1500 analyzer until it was switched to Abbott Alinity-c in October 2022. According to NGSP, there are no reports of assay interference in patients with Sickle Cell Disease (SCD) for either of these chemistry analyzers. Descriptive statistics were utilized to report data as means and percentages. Pearson correlation coefficient was used to assess the relationship between Hb and HbA1C values. Results: Mean age of the study participants was 52.59 years (SD 15.56) with a female predominance (53/61, 86.89%). All patients were of African American descent. The study included 49/61 (80.33%) patients with sickle cell trait, 3/61 (4.92%) with HbSC, 2/61 (3.28%) with HbSS, and 1/61 (1.64%) with HbS β+thal genotype. None of the patients had documented evidence of G6PD testing. Initially, all 61 patients had been diagnosed with DM or prediabetes via HbA1C. Only 3/61 (4.92%) patients had a fructosamine test documented in chart. The mean and median HbA1c values were 7.57% and 6.70% respectively (SD 2.07%). Among the participants, 53/61 (86.89%) patients were actively undergoing treatment for DM or prediabetes. There was a negative correlation (r = -0.142) between average Hb (at diagnosis) and HbA1C (at diagnosis) values (p = 0.286) (Figure 1). Conclusions: None of the patients in our study had evidence of G6PD testing. All patients with SCD and DM or prediabetes were initially diagnosed and managed using HbA1C. Only 3/61 patients had documentation of a fructosamine test. In the context of SCD, there was a poor correlation between Hb and HbA1C. The HbA1C test can either overpredict or underpredict DM in SCD patients due to assay interference (Siemens DCA Vantage analyzer is known to overpredict and is commonly used for point-of-care testing in an office setting) or hemoglobinopathy, respectively. Marked discrepancies between plasma glucose levels and measured HbA1C should prompt alternate diagnostic testing. It is recommended to use fasting blood glucose or oral glucose tolerance test to diagnose DM and prediabetes in patients with SCD. The reported cost difference between these tests is not significant. Fructosamine levels remain unaffected by hemoglobinopathies and can thus be used to monitor DM in patients with SCD.

Incidence of Maternal and Perinatal Morbidity in Sickle Cell Disease and Sickle Cell Trait Patients during Pregnancy

Background: Sickle cell disease (SCD) patients have a higher risk of maternal and neonatal morbidity during pregnancy than the general population. Pregnancy in SCD is associated with increased metabolic demands, a hypercoagulable state, endothelial dysfunction, severe anemia, and increased vaso-occlusive episodes. We designed a study to retrospectively review the clinical outcomes of pregnant patients with SCD and SCD trait to examine the incidence of maternal and perinatal morbidity and mortality. We hypothesized that SCD patients should have a higher morbidity during pregnancy and SCD trait patients should not have higher morbidity. Methods: We conducted a retrospective cohort study and reviewed 29,822 patient encounters. Pregnant patients with the SCD genotype - Hb SS, Hb S beta 0 thalassemia, Hb S beta + thalassemia and Hb SC disease, and sickle cell trait (SCD trait) - Hb AS were included. Maternal clinical outcome variables for the entire pregnancy duration were vaso-occlusive crisis (VOC), deep vein thrombosis (DVT), pulmonary embolism (PE), infections - sepsis, septic shock, asymptomatic bacteriuria, acute pyelonephritis, and urinary tract infection (UTI), cerebrovascular accident (CVA), myocardial infarction (MI) and transient ischemic attack (TIA). Clinical outcome variables for pregnancy complications were preeclampsia, gestational diabetes mellitus (GDM), and C-section rate. Clinical outcome variables for neonatal complications included preterm birth and low birth weight. ICD 9 and ICD 10 codes were used to search for the pregnancy, SCD, sickle cell trait, maternal and neonatal outcomes. Data was collected from the Health Facts Database, which contains de-identified information from electronic medical records (EMR) of hospitals in which Cerner© has a data use agreement. The categorical clinical outcome variables were analyzed using Chi-square test. Results: There were 29,822 patient encounters reviewed. Patients with SCD had higher percentages for C-section rates, CVA, preeclampsia, sepsis, septic shock, and VOC compared to those with SCD trait. C-section rates were higher in SCD patients with 76.43% versus 13.76% in SCD trait patients. CVA was higher in SCD patients with 73.78% versus 0% in SCD trait patients. Preeclampsia was higher in SCD patients with 75.92% in SCD patients versus 5.43% in SCD trait patients. Sepsis and septic shock were higher in SCD patients with 73.75% in SCD patients versus 0% in SCD trait patients. VOC was evident in SCD patients with 0.06% versus 0% in SCD trait patients. Patients with SCD trait had higher percentages for asymptomatic bacteriuria, GDM, low birth weight, preterm birth, and UTI compared to patients with SCD. Asymptomatic bacteriuria was higher in SCD trait patients with 0.25% versus 0.08 in SCD patients. GDM was higher in SCD trait patients with 3.09% versus 0% in SCD patients. Low birth weight was higher in SCD trait patients with 0.61% versus 0.17% in SCD patients. Preterm birth was higher in SCD trait patients with 0.78% versus 0.44% in SCD patients. UTI was noted in SCD trait patients with 0.02% versus 0% in SCD patients. There were no findings for DVT, PE, acute pyelonephritis, MI, and TIA in both SCD and SCD trait patients. Conclusion: Pregnant patients with SCD were more likely to have C-sections, CVA, preeclampsia, sepsis, septic shock, and VOC. Pregnant patients with SCD trait were more likely to have asymptomatic bacteriuria, GDM, low birth weight, preterm birth, and UTI. Our findings indicate that prevention and management of CVA, preeclampsia, sepsis, and septic shock is important for pregnant patients with SCD to prevent adverse maternal and neonatal outcomes. The higher rate of C-sections may have been to reduce the severity of maternal and perinatal morbidity in SCD patients. Our study has significant limitations - retrospective nature and use of ICD9 and ICD10 codes for clinical outcome variables. Certain clinical outcome variables, such as CVA, sepsis or septic shock, may have been overestimated as these diagnoses may have been recorded prior to the start of pregnancy in the EMR. Nevertheless, SCD patients have higher maternal and perinatal morbidity that needs to be addressed.

Low-Cost Automated Microscopy and Morphology-Based Machine Learning Classification of Sickle Cell Disease and Beta-Thalassemia in Nepal and Canada

INTRODUCTION Sickle cell disease (SCD) is the most common inherited blood disorder, and is associated with a high mortality rate for children in low-resource settings, where the disease burden is high. Early screening and treatment options reduce morbidity and mortality. In addition to screening for SCD, screening for asymptomatic, heterozygous conditions, such as sickle cell trait (SCT) and β-thalassemia trait, is required for effective SCD and thalassemia screening programs. However, rural and remote communities lack accurate low-cost screening techniques. The goal of this study is to augment a common low-cost screening test, the sickling test, using automated microscopy and machine learning to classify individuals with SCD (HbS/β-thalassemia and HbSS), trait conditions (HbAS and HbA/β-thalassemia), and those without common beta-globin disorders (HbAA) for implementation in Nepal. As HbC mutation is not encountered in Nepal, screening for HbSC or HbAC was not included. Additionally, we aim to evaluate the feasibility of 5 low-cost techniques to supplement/replace the local gold standard test (Hb HPLC), which is inaccessible in rural/remote settings. METHODS In this study (ClinicalTrials.gov Identifier: NCT05506358), blood samples were collected and tested at respective clinical sites in Nepal (Mount Sagarmatha Polyclinic and Diagnostic Center, Nepalgunj) and Canada (St. Paul's Hospital and BC Children's Hospital, Vancouver). Participants (138 total: 111 Nepal; 27 Canada) between ages 2 to 74 whose diagnoses were previously established by Hb HPLC were recruited. Five low-cost tests (our augmented sickling test, HbS solubility test, HemoTypeSC, Sickle SCAN, Gazelle Hb variant test) and Hb HPLC were performed on all participants (30 HbAA; 23 HbA/β-thalassemia; 45 HbAS; 11 HbS/β-thalassemia; 29 HbSS). Informed consent was provided by the participants or parents, according to protocols approved by institutional/national research ethics boards. For the sickling test, a sealed wet preparation of blood mixed with 2% sodium metabisulphite was imaged with a robotic microscope (Octopi) with automated scanning/focusing. The images of blood cells were segmented using Cellpose 2.0, allowing for morphological characterization of cells and morphology based classification, with an 80:20 participant-wise split of training and testing data. RESULTS Using high-throughput imaging, more than 300,000 de-identified images of blood films were collected, resulting in more than 1.5 trillion segmented cells. The de-identified images and processed data will be released in an open-access data repository. The frequency distribution of 11 different morphological parameters were used for machine learning based classification, resulting in testing sensitivity and specificity of 82.9% and 82.4%, respectively. The confusion matrix (Figure 1) shows that sensitivity of detecting SCD cases (HbS/β-thalassemia and HbSS) was 98.6%, and most misclassifications were between trait and normal conditions. Comparing the different low-cost techniques (Table 1), the Gazelle Hb variant test had the highest sensitivity and specificity (97.0% and 99.3%), but is more than twice as expensive than the augmented sickling test, while lateral flow assays (HemoTypeSC and SickleSCAN) had lower sensitivity (74-75%) than the augmented sickling test, due to their inability to detect β-thalassemia trait. CONCLUSIONS The sickling test, which is traditionally unable to distinguish between SCT and SCD, was augmented to detect SCD and trait conditions (including β-thalassemia) with an overall sensitivity of 82.4% (98.6% sensitivity for SCD detection). The preliminary results indicate that image-based classification can be a promising low-cost and automated screening tool for low-resource settings, reducing the need for highly-trained personnel for device operation and disease detection. Furthermore, the open-access image dataset can be used to improve classification in the future, as segmentation/classification algorithms improve over time.

Addressing Reproductive Education Among Young Adults with Sickle Cell Disease (SCD): Sickle Cell Reproductive Outreach and Education (ROE) Project

Background: As children with sickle cell disease (SCD) survive into adulthood, it is important to address emerging reproductive health concerns. This population faces unique fertility challenges, including balancing the desire for biological parenthood, risk of pregnancy-associated complications, unintended pregnancy, and fertility concerns with the use of SCD modifying therapies (DMTs) (Smith-Whitley, Blood, 2014, Pecker, Br J Haematol, 2021) . Recent research identified knowledge gaps that impact reproductive care for adults with SCD (Carrithers, Frontiers, 2023). To overcome these gaps, we need to evaluate the baseline knowledge of young adults with SCD regarding reproduction to understand the complex implications of reproductive decision-making. This study was done to gauge young adults' knowledge of reproduction, understanding of fertility, and current reproductive behaviors in order to develop educational material to support young adults' with SCD reproductive decisions. Methods: This IRB-approved, cross-sectional study included young adults living with SCD (ages 18-35) from University of Alabama-Birmingham's Lifespan Comprehensive SCD Center. Patients were recruited during routine clinic visits to complete an electronic 33-question survey to evaluate reproductive health topics adapted from the Sisters Informing Sisters About AIDS (SISTA) questionnaire (CDC, 2008), including demographics (age separated into younger age (18-25) and older age (26-35), sexual health behaviors (contraception, sexually transmitted infection (STI) prevention), family planning, patient advocacy, and attitudes towards reproductive education. Responses were recorded as “Yes, No, Don't Know”, unless questions specifically asked for participants to choose an option. Attitudes toward reproductive education were graded on 5-point Likert scale (1= strongly disagree to 5=strongly agree). Data analysis includes averages to evaluate subgroup comparisons and independent student's t-test to compare subgroups with statistical significance set at p<0.05. Results: We enrolled 47 participants (55% women and 51% were of older age). In this cohort, 87% completed high school and 60% were sexually active. Among those who were sexually active, 86% had previously undergone STI testing and 36% had prior history of STI (22% men vs. 77% women, 22% younger age vs. 77% older age, p<0.05). Thirty-eight percent identified personal or partner contraceptive use. Regarding children, 19% had birthed/fathered a child(ren) (55% men vs. 45% women, 22% younger age vs. 77% older age, p>0.005) among whom 11% knew their child had SCD, 55% knew their child had sickle cell trait (SCT), and 33% did not know if their child had SCD/SCT. Only 26% were aware of contraceptive options for people with SCD (17% men vs. 83% women, p<0.05). Importantly, 89% recognized high risk sexual activity as a risk factor for STIs but no one in the cohort recognized the risk of infertility due to STIs. When asking about their partners, 32% knew if their partner had SCD/SCT (20% men vs. 80% women, p<0.05). Notably, 79% desired biologic children. Among those who desired children, 41% felt that their SCD changed their decision to have children and 26% were previously told they could not have children due to SCD (12% men vs. 88% women, 25% younger age vs. 75% older age, p<0.05). Notably, 57% were interested in conceiving if pregnancy was planned (41% men vs. 59% women, 37% younger age vs. 63% older age, p<0.05). When asked if patients wanted to discuss their reproductive health, 87% wanted to discuss this with their hematologist but only 51% would discuss this with PCPs. Conclusion: In this study, we identified evaluated 4 tenets of reproductive health knowledge: contraceptive use, STI prevention, family planning, and patient advocacy. We identified gaps in knowledge in these areas that can be addressed to improve reproductive education in young adults with SCD. Young adults with SCD in our cohort have low contraceptive use and were often not aware of contraceptive options for people with SCD or their partner's SCD/SCT status. Our cohort also reported a significant history of STI but was unaware of the associated increasing risk for infertility. Importantly. young adults are especially interested in discussing reproductive health with their hematologists, which provides an opportunity to improve reproductive education within this unique population.

Donor Hemoglobin Genotype Does Not Impact Outcomes Following Matched Related Donor Hematopoietic Cell Transplantation for Sickle Cell Disease: A STAR Study

Sickle cell disease (SCD) is an inherited hemoglobin (Hb) disorder which leads to significant morbidity and early mortality. Hematopoietic cell transplantation (HCT) is the only curative treatment with long-term outcome data, demonstrating excellent symptom-free survival particularly when a matched related donor (MRD) is available. Most MRD have sickle cell trait (Hb AS), but trait donor HCT is considered acceptable by the FDA and without negative impact. Further, initial gene addition and editing approaches for SCD have resulted in a trait-like status with benefit. Sickle trait, however, is associated with complications such as papillary necrosis, bacteriuria, splenic infarction, and exercise-induced death. The primary aim of this study was to compare long-term outcomes following MRD HCT for SCD based on donor Hb genotype, to objectively describe any impact on outcomes. Retrospective data was available for this analysis on 182 SCD patients ≥1 year post MRD HCT at 10 participating Sickle Transplant Advocacy and Research (STAR) Alliance centers. Summary statistics were presented as mean (standard deviation) for continuous variables and count (%) for categorical variables. Comparisons were made between Hb AA and Hb AS donor groups using both parametric and non-parametric tests for continuous variables and Chi-square test/exact test for categorical variables, with p-value <0.05 set as significant. Amongst 182 patients undergoing MRD HCT, 67% (n=122) had a Hb AS donor ( Table). In the overall cohort, median age at HCT was 8.7 (4.8) years and most patients had HbSS (n=174; 96%) with a severe clinical phenotype (n=97; 54%). HCT was performed using bone marrow (n=166; 92%) with myeloablative conditioning (n=156; 86%) in the majority. Patients with a severe disease phenotype and Hb AS donor were significantly more likely to have recurrent vaso-occlusive pain crises as an indication for HCT (p=0.033), otherwise there were no differences in baseline patient or HCT characteristics between cohorts. With mean post-HCT follow up of 4.5 (3.9) and 5.1 (4.1) years in Hb AA and Hb AS donor cohorts (p=0.145), no significant differences were seen in recipient outcomes including time to neutrophil and platelet engraftment, number of or time to last platelet transfusion, myeloid or unsorted % donor chimerism, number with acute (day 100) or chronic GVHD (1 year), or time to discontinue immunosuppression (data not shown). Disease recurrence and need for 2 nd HCT were rare in both cohorts (AA: 2 [3%] and 2 [3%]; AS: 3 [3%] and 4 [3%]; p=0.665 and 1.0, respectively). Two (3%) and 5 (4%) patients died in the AA and AS cohorts, respectively (p=1.0). Aside from a statistically (but not clinically) significant difference in Hb at day 30 (p=0.044), no difference was seen in longitudinal Hb or markers of hemolysis (LDH and ARC; Figure). No significant difference was seen in median number of RBC units transfused (AA: 4.0 [2.0-6.0]; AS: 3.0 [2.0-6.0]; p=0.454) or days to last transfusion (AA: 23.0 [14.0-77.0]; AS: 22.0 [13.0-75.0]; p=0.86). SCD complications were rare post-HCT, with no difference seen between cohorts in number (%) with VOC (AA: 1 [2%; had 2 separate VOC events]; AS: 3 [3%]; p=1.0), ACS (none reported), chronic pain (AA: 0 [0%]; AS: 1 [<1%]; p=1.0), or other SCD-related complications (AA: 2 [3%]; AS: 9 [7%; had 11 separate other events]; p=0.456). Stroke occurred in a significantly higher proportion with an AA versus AS donor (5 [8%] and 2 [2%], respectively; p=0.04). No significant differences were seen in longitudinal (1 and 2 years and at last follow up) post-HCT cardiac (EF, SF, TRJ velocity), pulmonary (FEV1, FVC, DLCO), or renal (GFR) function between cohorts (data not shown). Our results indicate that in MRD HCT for SCD, AS and AA donors yield comparable long-term outcomes. In this retrospective and registry-based study design, detailed analyses did not show differences between the two cohorts at baseline or at any timepoint post-HCT. While there were some outcome differences between the cohorts, they were either not clinically significant or did not have a scientific rationale, and thus were likely due to chance alone (denoted by bolding in Table). Given the young age of our cohort at HCT and thus a smaller proportion with SCD-related organ dysfunction, our results may not be applicable to an older cohort with significant organ dysfunction which will require a separate analysis.

Implementation of a Newborn Screening for Sickle Cell Disease, at the Hospital Materno Infantil Dr Manuel Pedro Azancot De Menezes, Angola

Sickle Cell Disease (SCD) is a hereditary disease, and a worldwide public health problem, with a higher incidence in sub-Saharan Africa, where the prevalence is very high (about 80%). SCD prevalence can reach 3,3 % in Angola, while carriers of the sickle cell trait account for more than 25% of the population. The early identification of patients and their follow-up in consultation are an added value for the reduction of morbidity and mortality of children with SCD. The implementation of early infant screening and follow-up programs for children with SCD showed excellent results in increasing the survival of these children. With this project we intend to implement a Newborn screening in Hospital Materno Infantil Dr Manuel Pedro Azancot de Menezes, a referral of the main maternity in Angola, located in Luanda, the country capital, that could be replicated in other hospitals, giving training to the health professionals, and to the laboratory technicians, in order to diagnose the SCD patients. The objective of this project is to establish a neonatal screening for SCD at a main Hospital in Angola, contributing to reduce the under 5 mortality, and to support for pediatric follow-up consultations of children diagnosed with SCD. Specific aims include: record the data and medical history of babies diagnosed with SCD up to 5 years of age at regular appointments; estimate the prevalence of SCD in the municipality of Camama, Luanda; and to evaluate the costs of neonatal screening and early interventions in Angola, by supporting a registry of SCD. The newborn screening has started in June 2023, with the training of the team at the hospital, and with the creation of all documents and forms needed. The project received ethical approval in June 2023. The study includes every child born in the maternity ward of the Hospital, and also every child that take vaccinations there (in this way we can include newborns delivered at home), that the legal guardians authorize the collection of blood sample by prick heel for screening for SCD. The samples of filter paper duly identified with the sample number and date of collection are being sent to Lisbon (Portugal), for hemoglobin electrophoresis by isoelectric focusing (IEF) carried out in the Migele equipment (acquired with the support of Perkin Elmer, and the ARISE project) (Figure 1). All SS samples are being genotyped for the HbS mutation by PCR-RFLP. Since the start of the newborn screening (June 28 th) we have collected 1000 samples in 4 weeks and have started the IEF analysis with MIGELE (Perkin Elmer). The preliminary results (221 samples, 177 AA, 41 AS and 3 SS) showed a 1.4% prevalence of SS, and 19.5% of AS, confirmed by PCR-RFLP (in all AS and SS). The frequencies were in Hardy-Weinberg equilibrium. Moreover, we are searching for other possible hemoglobinopathies. More results will be presented. All children diagnosed as SS (SCD) are being contacted by the Hospital Materno Infantil Dr Manuel Pedro Azancot de Menezes, Angola, to be followed in consultation. Newborn screening and early interventions for SCD should be a health priority and implemented at national level. It is our plan to catalyze progress toward this aim by demonstrating the high prevalence of neonatal SCD in the Luanda Hospital and demonstrate the feasibility of this screening in reducing under 5 mortalities. The present project has the support of ARISE project “African Research and Innovative initiative for Sickle cell Education: Improving Research Capacity for Service Improvement” project (GA 824021 - ARISE - H2020-MSCA-RISE-2018) by supporting the secondments of Angolan Laboratory technicians in Lisbon (Portugal) to perform the IEF and genetic analysis and be trained. Until now 5 Angolan secondees, and 3 Nigerian secondees have been trained in Lisbon. Perkin Elmer (Revvity) is giving llogistical support by kindly support the low-cost acquisition, installation and training in MIGELE equipment for IEF, and being always available to technical support. Figure 1 - Flow diagram of the methodology followed in the present study.

Hemolytic anemia in a two-year-old child: A case of multiple red blood cell abnormalities

The discovery of hemolytic anemia requires a meticulous investigation to determine its etiology. Among patients of African origin, it is not uncommon to find multiple constitutional red blood cell abnormalities, which can complicate diagnosis. We herein describe the case of a two-year-old child presenting with acute hemolytic anemia. A G6PD deficiency, hereditary spherocytosis, and a sickle cell trait A/S were simultaneously identified, all within the context of a primary infection with Parvovirus B19. This virus commonly triggers acute anemia in children exhibiting constitutional red blood cell abnormalities and need to be considered in such cases.

Renal Cortical Necrosis in Sickle Cell Trait

Renal Cortical Necrosis in Sickle Cell Trait

Factors affecting haemoglobin dynamics in African children with acute uncomplicated Plasmodium falciparum malaria treated with single low-dose primaquine or placebo

BackgroundSingle 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.MethodsThis 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.ResultsOne 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).ConclusionsIn 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 registrationThe trial is registered at ISRCTN 11594437.