Sickle Cell Trait Carriers Research Articles

Could oxygen gradient ektacytometry help to detect sickle cell trait carriers at risk for kidney disorders or exercise-related complications?

The study of Ellsworth etal. (Br J Haematol, 2024) demonstrated the usefulness of oxygen gradient ektacytometry technique to better identify the physiological parameters that could increase the risk of sickling of red blood cells (RBCs) from sickle cell trait (SCT) carriers. Oxygen gradient ektacytometry combined with pH and osmolality modulations could help in identifying SCT carriers at risk for kidney disorders or exercise-related complications. Other factors than the percentages of haemoglobin S are probably involved in the propensity of RBCs from SCT carriers to sickle during deoxygenation. Commentary on: Ellsworth etal. Hypertonicity and/or acidosis induce marked rheological changes under hypoxic conditions in sickle trait red blood cells. Br J Haematol 2024; 205:1565-1569.

Genome-Wide Analysis of Exertional Rhabdomyolysis in Sickle Cell Trait Positive African Americans.

Sickle cell trait (SCT), although generally a benign carrier state of hemoglobin S (HbAS), is a risk factor for exertional rhabdomyolysis (ERM), a rare but potentially fatal consequence of highly intense physical exercise, particularly among active-duty military personnel and high-performance athletes. The association between SCT and ERM is poorly understood. The objective of this study was to elucidate the genetic basis of ERM in an SCT-positive African American cohort. SCT-positive African Americans with a personal history of ERM (cases, n = 30) and without history of ERM (controls, n = 53) were enrolled in this study. Whole-genome sequencing was performed on DNA samples isolated from peripheral white blood cells. Participants' demographic, behavioral, and medical history information was obtained. An additional 131 controls were extracted from SCT-positive subjects of African descent from the 1000 Genomes Project. SCT carriers with ERM were characterized by myotoxicity features, significant muscle involvement dominated by muscle weakness, and severe pain and substantial increase in serum creatine kinase, with a mean value of 50,480 U/L. A distinctive feature of the SCT individuals with ERM was exertional collapse, which was reported in 53.3% of the cases in the study cohort. An important factor for the development of ERM was the duration and frequency of strenuous physical activity in the cases compared to the controls. Whole-genome sequencing identified 79,696 protein-coding variants. Genome-wide association analysis revealed that the p.C477R, rs115958260 variant in the SLC44A3 gene was significantly associated with ERM event in SCT-positive African Americans. The study results suggest that a combination of vigorous exercise and a genetic predisposing factor is involved in ERM.

Sickle cell trait in São Tomé e Príncipe: a population-based prevalence study in women of reproductive age

BackgroundSickle Cell Disorder is Africa’s most prevalent genetic disease. Yet, it remains a neglected condition, with high mortality under-five, and a lack of population-based studies in the region. This is the first of its kind in São Tomé e Príncipe, aiming to estimate the prevalence of sickle cell trait and other haemoglobin variants in women of reproductive age and its associated factors.MethodsWe conducted a cluster survey in 35 neighbourhoods. Haemoglobin was assessed through point-of-care capillary electrophoresis or high-performance liquid chromatography, and sociodemographic data through questionnaires. The weighted prevalence of sickle cell trait (HbAS) and HbC carriers was estimated with a 95% confidence interval (95% CI). We calculated weighted prevalence ratios (95% CI) through robust Poisson regression for its association with age and individual and collective genetic heritage.FindingsThe prevalence of sickle cell trait in women of reproductive age in São Tomé e Príncipe (n = 376) was 13.45% (95% CI: 9.05-19.00). The prevalence of HbC carriers was 8.00% (95% CI: 4.71-12.00). Older age and speaking Forro or Angolar were positively associated with having sickle cell trait.InterpretationThe prevalence of sickle cell trait in São Tomé e Príncipe ranks high in the West African region. The country should follow international guidelines, implementing newborn screening and comprehensive healthcare management.

Perceptions and preferences for genetic testing for sickle cell disease or trait: a qualitative study in Cameroon, Ghana and Tanzania

Sickle cell disease (SCD) is a single gene blood disorder characterised by frequent episodes of pain, chronic anaemic, acute chest syndrome, severe disease complications and lifelong debilitating multi-system organ damage. Genetic testing and screening programs for SCD and the sickle cell trait (SCT) are valuable for early diagnosis and management of children living with SCD, and in the identification of carriers of SCT. People with SCT are for the most part asymptomatic and mainly identified as through genetic testing or when they have a child with SCD. This qualitative study explored perceptions towards genetic testing for SCD and SCT in Cameroon, Ghana, and Tanzania. The results show a general preference for newborn screening for SCD over prenatal and premarital/preconception testing, primarily due to its simpler decision-making process and lower risk for stigmatization. Premarital testing for SCT was perceived to be of low public health value, as couples are unlikely to alter their marriage plans despite being aware of their risk of having a child with SCD. Adolescents were identified as a more suitable population for SCT testing. In the case of prenatal testing, major concerns were centred on cultural, religious, and personal values on pregnancy termination. The study revealed a gender dimension to SCD/SCT testing. Participants mentionned that women bear a heightened burden of decision making in SCD/SCT testing, face a higher risk of rejection by potential in-laws/partners if the carriers of SCT, as well as the possibility of divorce if they have a child with SCD. The study highlights the complex cultural, ethical, religious and social dynamics surrounding genetic testing for SCD and emphasises the need for public education on SCD and the necessity of incorporating genetic and psychosocial counselling into SCD/SCT testing programs.

Comparing Racial Disparities of Cardiovascular Manifestations in Sickle Cell Trait

Introduction Sickle cell trait (SCT) is a genetic condition that affects millions of people globally, particularly those of African and Mediterranean descent. Various mechanisms have been suggested to contribute to cardiovascular pathology in SCT patients, including chronic anemia, arteriopathy, and cardiac remodeling. However, whether SCT carriers, particularly African Americans (AA), are at an increased risk for cardiovascular disease remains controversial. This study aimed to investigate potential differences in cardiovascular outcomes between AA and non-AA SCT carriers. Methods We screened the National Inpatient Sample (NIS) database 2016-2018 for cardiovascular outcomes during hospital admission in African American SCT carriers and compared them to SCT carriers of other races. The primary outcomes were major adverse cardiovascular events, including acute myocardial infarction, cardiac arrest, stroke, acute heart failure, and in-hospital mortality. Secondary outcomes included World Health Organization (WHO) group 5 pulmonary hypertension, acute pulmonary edema, valvular disease, pericarditis, tachyarrhythmia, conduction disorders, acute deep venous thrombosis and/or pulmonary embolism, avascular necrosis, and rhabdomyolysis. Univariate analysis was conducted, with a P value <0.05 considered statistically significant. Results A total of 29,060 SCT admissions were analyzed, with 24,659 attributed to African Americans and the remaining to other races. The study found that majority of the patients admitted were female (86% of African American patients and 84% of patients from other races). The average age of patients was 37 years for African Americans and 40 years for other races. African American patients had higher rates of comorbidities such as hypertension, diabetes, chronic kidney disease, and oral anticoagulant use compared to patients of other races. The study also found that African American SCT patients had a significantly higher risk of acute heart failure (5.7% vs. 3.5%, p<0.01), tachyarrhythmia (4.9% vs. 3.6%, p<0.01), and conduction disorders (1.6% vs. 1.1%, p=0.02) compared to patients of other races. Acute myocardial infarction (1.1% vs. 0.9%), valvular disease (2.7% vs. 2.3%), acute deep vein thrombosis/pulmonary embolism (2.2% vs. 2.0%), and rhabdomyolysis (0.6% vs. 0.5%) occurred at a higher rate in African American patients but did not reach statistical significance. Similarly, in-hospital mortality (0.7% vs 0.9%), cardiac arrest (0.4% vs 0.5%), and pericarditis (0.1% vs 0.2%), although occurring at lower rates in the AA population, did not reach statistical significance. Acute pulmonary edema (0.2% vs 0.2%), pulmonary hypertension (group 5) (0.1% vs 0.1%), stroke (1.1% vs 1.1%) and avascular necrosis (0.1% vs 0.1%) had similar rates in both AA and other races but did not reach statistical significance. Conclusion/Discussion African American patients with sickle cell trait compared to other races had higher rates of acute heart failure, tachyarrhythmias, and other conduction disorders. Aggressive screening for cardiac conditions and management of risk factors including smoking, obesity, high blood pressure, hyperlipidemia, etc., are warranted in this population to improve cardiovascular outcomes. Although the NIS database provides this study with large patient data, this study may be limited by difference in the number of patients in AA and other race cohorts at baseline, coding error, underreporting, misclassification, retrospective nature, and lack of matching. Further studies analyzing the cardiovascular morbidity and mortality in sickle cell trait carriers, including benefit of use of medications for primary/secondary prevention of cardiovascular conditions are warranted.

Sickle Cell Trait As a Risk Factor for Leukemia: A Nationwide Study

INTRODUCTION: Leukemia is a cancer of blood-forming cells. It can arise from cells of lymphoid or myeloid lineage. It can arise from genetic mutations in tumor suppressor genes, proto-oncogenes or both. It affects over two million people worldwide. A combination of genetic factors and extrinsic factors are believed to play a role. Sickle cell disease (SCD), an inherited disorder leading to the formation of abnormal hemoglobin (HbS) and red blood cell sickling, has been shown to increase the risk for leukemia, presumably due to an increased bone marrow turnover rate. We aimed to explore if sickle cell trait (SCT), when people inherit only one of the two sickle cell genes, is associated with an increased risk for leukemia. METHODS: In this case-control study, we evaluated an association between leukemia (and its subtypes) and SCT in a nationwide cohort of hospitalized patients included in the National Inpatient Sample (NIS) 2016-2019 database. The inclusion criteria for cases were patients who had any of the following ICD-10-CM codes for leukemia: C91 (lymphoid leukemia), C92 (myeloid leukemia), C93 (monocytic leukemia), C94 (other leukemia of specified cell type), and C95 (leukemia of unspecified cell type). The exclusion criteria were Down syndrome (Q90), Fanconi anemia (D61.09), ataxia-telangiectasia (G11.3), Bloom syndrome (Q82), myelodysplastic syndrome (D46), lymphoma (C81, 85), and solid malignancies (C00-75) as these diseases and/or their treatments are known to increase the risk for leukemia independently of SCT (ICD-10-CM D57.3). The controls included patients in the NIS database who do not have the ICD-10-CM codes for leukemia and meet the exclusion criteria applied to the cases. For each year, we used a 1:4 propensity score matching routine. Our match variables were sex, the six race categories used by NIS, and 11 age groups. Four perfect matches (controls) were identified for each case (‘any leukemia’ diagnosis). Patient characteristics were compared using Pearson chi-squared test. Odds ratios (ORs) were calculated for ‘any leukemia’ diagnosis, as well as for each subtype of leukemia. Five multivariate logistic regression models were used to examine the relationship between the leukemia subtypes and SCT while controlling for age group, sex, and race. RESULTS: We identified 181,676 cases and 726,704 controls. The mean age of subjects was 59 years. The majority of subjects (56%) were male. A greater proportion of patients with SCT were found among cases (0.12%) compared to controls (0.08%) (p < 0.0001). The OR for ‘any leukemia’ was 1.48 (95% CI 1.27-1.73, p < 0.0001). When the association between SCT and specific subtypes of leukemia was evaluated, it was statistically significant for myeloid and monocytic leukemias, OR 1.74 (95% CI 1.40 - 2.17) and 2.20 (95% CI 1.09 - 4.42) correspondingly. CONCLUSION: Our case-control study revealed statistically significantly higher odds of SCT among patients with any leukemia (and specifically myeloid and monocytic leukemias) as compared to controls which can be postulated to the common myeloid progenitor lineage of erythrocytes. Our results suggest that, similarly to SCD, SCT although a benign condition can increase the risk for leukemia. To better understand this association, future prospective studies are needed for the mapping of individual risk factors and examining the HbS% levels in SCT carriers who go on to develop leukemia.

Sickle Cell Trait Is Associated with Adverse Clinical Outcomes in a Matched Case-Control Study at a Tertiary Care Center

Background: Sickle cell trait (SCT) is a common condition affecting more than 300 million individuals worldwide and 3 million in the United States. Although generally believed to be an asymptomatic condition, there is growing data to suggest potential associations with morbidity, including risk for venous-thromboembolic events and chronic kidney disease. Methods: We conducted this retrospective cohort study using electronic health record data from the University of Colorado Health Data Compass data warehouse. Patients with a coded diagnosis of SCT were analyzed for SCT-related clinical outcomes compared against a 1:1 randomized matched sample of controls without a history of SCT (matched on age, race, sex). Individuals with sickle cell disease, Sickle-cell/Hb-C disease, sickle-thalassemia, other sickle cell disorders, and hemolytic anemias were excluded from both case and control groups. Outcomes included chronic kidney disease (CKD), deep vein thrombosis (DVT), pulmonary embolism (PE), hematuria, rhabdomyolysis, and splenic infarction. Multivariate logistic regression was used to examine the association of each condition based on SCT carrier status, adjusting for age, sex, and race. Results: We included 1447 SCT patients with complete demographic data, along with 1447 matched controls (n = 2894). There were 1019 (70.4%) women and 428 (29.6%) men in each case and control group. A majority (72.7%) were black or African American. The median age of the cohort was 36 years (IQR = 28 - 47). We found significant associations for CKD (OR = 2.95, 95% CI: 2.03 - 4.30), DVT (2.54, 95% CI: 1.42 - 4.54), PE (OR=4.25, 95% CI: 2.43 - 7.45), and hematuria (OR= 2.28, 95% CI: 1.57 - 3.31). (Table) Despite few overall events and wide confidence intervals, association remained significant for rhabdomyolysis (OR=3.32, 95% CI 1.07 - 10.24) and splenic infarction (OR=44.9, 95% CI 6.15 - 328.00). Male sex was strongly associated with splenic infarction (OR = 8.70, 95% CI 4.11 - 18.41) and rhabdomyolysis (OR = 19.14, 95% CI 4.35 - 84.18). Conclusion: In this case-control cohort study we found significantly increased risk for CKD, DVT, PE, hematuria, rhabdomyolysis, and splenic infarction for patients with sickle cell trait with odds ratios similar to those seen in other study cohorts. The significant morbidity associated with this common genotype warrants further research into primary prevention of SCT associated adverse outcomes.

Association of sickle cell trait with adverse pregnancy outcomes in a population-based cohort.

Sickle cell trait (SCT) is common in African descendants. Its association with several adverse pregnancy outcomes (APOs) has been reported but remains inconsistent. The objectives of this study are to test associations of SCT with APOs in non-Hispanic Black women, including (1) validate the associations of SCT with previously reported APOs, (2) test novel associations of SCT with broad spectrum of APOs, and (3) estimate the attributable risk of SCT for implicated APOs. This is a retrospective analysis of a prospectively designed population-based cohort. Women/participants were self-reported non-Hispanic Black women from the UK Biobank (UKB). SCT status was determined based on heterozygous Glu6Val in the HBB gene. Several APOs were studied, including four previously reported SCT-associated APOs (preeclampsia, bacteriuria, pregnancy loss, and preterm delivery), and broad conditions related to pregnancy, childbirth, and the puerperium. APOs were curated by experts' peer review and consensus processes. Associations of SCT with APOs were tested by estimating its relative risk and 95% confidence interval (95% CI), adjusting for number of live births and age at first birth. Attributable risk proportion (ARP) and population attributable risk proportion (PARP) of SCT to APOs were estimated. Among the 4057 self-reported non-Hispanic Black women with pregnancy records in the UKB, 581 (14.32%) were SCT carriers. For four previously reported SCT-associated APOs, two were confirmed at a nominal P < 0.05; relative risk (RR) was 2.39 (95% CI 1.09-5.23) for preeclampsia, and 4.85 (95% CI 1.77-13.27) for bacteriuria. SCT contributed substantially to these two APOs among SCT carriers, with attributable risk proportion estimated at 61.00% and 68.96% for preeclampsia and bacteriuria, respectively. SCT also contributed substantially to these two APOs in the population (self-reported Black UK women), with population attributable risk proportion estimated at 18.30% and 24.14% for preeclampsia and bacteriuria, respectively. In addition, novel associations were found for seven other APOs (nominal P < 0.05). SCT is significantly associated with APOs in this study and contributes substantially to APOs among self-reported Black women in the UK. Confirmation of these findings in independent study populations is required.

Multi-Organ Morphological Findings in a Humanized Murine Model of Sickle Cell Trait.

Sickle cell disease (SCD) is caused by the homozygous beta-globin gene mutation that can lead to ischemic multi-organ damage and consequently reduce life expectancy. On the other hand, sickle cell trait (SCT), the heterozygous beta-globin gene mutation, is still considered a benign condition. Although the mechanisms are not well understood, clinical evidence has recently shown that specific pathological symptoms can also be recognized in SCT carriers. So far, there are still scant data regarding the morphological modifications referable to possible multi-organ damage in the SCT condition. Therefore, after genotypic and hematological characterization, by conventional light microscopy and transmission electron microscopy (TEM), we investigated the presence of tissue alterations in 13 heterozygous Townes mice, one of the best-known animal models that, up to now, was used only for the study of the homozygous condition. We found that endothelial alterations, as among which the thickening of vessel basal lamina, are ubiquitous in the lung, liver, kidney, and spleen of SCT carrier mice. The lung shows the most significant alterations, with a distortion of the general tissue architecture, while the heart is the least affected. Collectively, our findings contribute novel data to the histopathological modifications at microscopic and ultrastructural levels, underlying the heterozygous beta-globin gene mutation, and indicate the translational suitability of the Townes model to characterize the features of multiple organ involvement in the SCT carriers.

Health Equity in Sickle Cell Research and Access to Therapy

Health Equity in Sickle Cell Research and Access to Therapy

National newborn screening for sickle cell disease and communication of carrier status

Portugal is currently implementing a pilot project to screen for sickle cell disease during national newborn screening. This project started in the region of Lisbon and the Tagus valley where there is a higher frequency of African population. Anticipating the expansion of this screening to the rest of the national territory, a question arises: how to deal with cases of identified sickle cell trait carriers?

Adverse Pregnancy Outcomes in Sickle Cell Trait: a Prospective Cohort Study Evaluating Clinical and Haematological Parameters in Postpartum Mothers and Newborns.

Sickle cell trait (SCT) is a congenital condition caused by the inheritance of a single allele of the abnormal haemoglobin beta gene, HbS. Carriers of SCT are generally asymptomatic, and they do not manifest the clinical and haematological abnormalities of sickle cell anaemia (SCA). However, there is evidence that they display some symptoms in stressful situations. Pregnancy is a stressful physiological event, and it is not clear if SCT adversely affects pregnancy outcomes, particularly in those from developing countries where people regularly suffer from nutritional insufficiency. This study aims to investigate pregnancy outcomes in Sudanese women with SCT. Subjects and methods: Pregnant women with (HbAS, n=34) and without (HbAA, n=60) SCT were recruited during their first trimester at El Obeid Hospital, Kordofan, Western Sudan. Following appropriate ethical approval and informed consent from the participants, detailed anthropometric, clinical, haematological, obstetric, and birth outcome data were registered. In addition, blood samples were collected at enrolment and at delivery. At enrolment in the first trimester, the SCT group did not manifest SCA symptoms, and there was no difference in the haematological parameters between the SCT and control groups. However, at delivery, the women with SCT, compared with the control group, had lower levels of hemoglobin (Hb, p=0.000), packed cell volume (PCV, p=0.000), mean corpuscular haemoglobin (MCH, p=0.002) and neutrophil counts (p=0.045) and higher mean corpuscular volume (MCV, p=0.000) and platelet counts (p=0.000). Similarly, at delivery, the babies of SCT women had lower birth weight (p=0.000), lower Hb (p=0.045), PCV (p=0.000), MCH (p=0.000), and higher neutrophil (p=0.004) and platelet counts (p=0.000) than the babies of the healthy control group. Additionally, there were more miscarriages, stillbirths, and admissions to the Special Care Baby Unit (SCBU) in the SCT group. The study revealed that SCT is associated with adverse pregnancy outcomes, including maternal and neonatal anaemia, low birth weight, and increased risk of stillbirth, miscarriage, and admission to SCBU. Therefore, pregnant women with SCT should be given appropriate pre-conceptual advice and multidisciplinary antenatal and postnatal care.

Erythrocyte type 1 equilibrative nucleoside transporter expression in sickle cell disease and sickle cell trait.

Hypoxia-mediated red blood cell (RBC) sickling is central to the pathophysiology of sickle cell disease (SCD). The signalling nucleoside adenosine is thought to play a significant role in this process. This study investigated expression of the erythrocyte type 1 equilibrative nucleoside transporter (ENT1), a key regulator of plasma adenosine, in adult patients with SCD and carriers of sickle cell trait (SCT). Relative quantitative expression analysis of erythrocyte ENT1 was carried out by Western blot and flow cytometry. Patients with SCD with steady state conditions, either with SS or SC genotype, untreated or under hydroxycarbamide (HC) treatment, exhibited a relatively high variability of erythrocyte ENT1, but with levels not significantly different from normal controls. Most strikingly, expression of erythrocyte ENT1 was found to be significantly decreased in patients with SCD undergoing painful vaso-occlusive episode and, unexpectedly, also in healthy SCT carriers. Promoting hypoxia-induced adenosine signalling, the reduced expression of erythrocyte ENT1 might contribute to the pathophysiology of SCD and to the susceptibility of SCT individuals to altitude hypoxia or exercise to exhaustion.

Variability in Notification of Positive Newborn Screening Results for Sickle Cell Trait across States in the US

Background: Newborn screening (NBS) for sickle cell disease has been universal in all 50 states since 2006, with the first state having adopted NBS in 1975. While identification of sickle cell trait (SCT) status is not the primary goal of this screening, SCT is unique among carrier states due to its reproductive and clinical implications. However, because SCT is a byproduct of newborn screening rather than a primary goal, funding availability and notification practices differs widely between states. We performed a survey of newborn screening programs in states and US territories to identify differences in SCT notification practices. Methods: We developed a survey in Qualtrics and delivered it via email to NBS program coordinators in all 50 states, the District of Columbia (DC), and 2 US territories in June 2022. For NBS coordinators who did not complete the survey, a reminder email was sent after 2 weeks followed by a phone call to prompt survey completion. Results: Completed surveys were received from 34 NBS coordinators representing 34 states and 1 US territory (Puerto Rico). All respondents (100%) agreed that knowledge of SCT status is important for reproductive decision-making. Although a majority (62%, n=21/32) agreed that SCT status is a public health concern for their state, only 11 (32%) agreed that ensuring counseling to SCT carriers is the responsibility of state newborn screening programs, as noted in figure 1. Notification procedures: All responding NBS coordinators (100%) provide notification of SCT status to either a pediatrician or parent, with 17 (50%) notifying both the parent and pediatrician, 15 (44%) notifying the pediatrician only, and 2 (6%) notifying the parent only. As depicted in Figure 2, parents are most commonly notified by mail only whereas pediatrician notification varies from mail only to fax only to phone call in addition to written notification. More than one-third (36%) of respondents acknowledged that pediatrician information was missing or inaccurate between 25-50% of the time. Of the 18 NBS programs that notify parents, 6 (33%) provide written/online information about SCT only, 4 (22%) provide resources for local genetic counseling centers only, 6 (33%) provide both written information about SCT and resources for local genetic counseling centers, and 2 (11%) report providing results only. Only two NBS centers note running their own SCT counseling programs. Renotification procedures: No state reported routine renotification of SCT carriers at reproductive age. All states (100%) reported retaining electronic records of SCT status; however, in the majority of states (57%), electronic records are available only after 2000 with the last state adopting electronic records in 2019. NBS electronic records can be accessed directly by pediatricians/primary care doctors in 12/34 (35%) of states; however, no state operates a publicly available database to allow individuals to access their own records. Conclusion: SCT notification procedures vary widely across states in the US. The majority of states rely on pediatricians to counsel parents and individuals about their SCT status. Although knowledge of SCT status is accepted to be an important factor for reproductive-decision making, renotification and/or efficient access of NBS SCT results at reproductive age is not available in most states. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effect of Sickle Cell Trait on Total Hip Arthroplasty in a Matched Cohort.

It is unclear if sickle cell trait (SCT) carrier status conveys an increased risk for poor outcomes following total hip arthroplasty (THA). The purpose of this study is to compare short-term clinical outcomes of THA for patients with SCT vs matched controls. Patient records were queried from the PearlDiver database using International Classification of Diseases, Ninth and Tenth Revision and Current Procedural Terminology codes. Patients with SCT who underwent THA were matched 1:1 with controls across age, gender, Elixhauser Comorbidity Index, obesity, and US region. Thirty-day and 90-day rates of systemic complications and 1-year and 2-year rates of joint complications were compared with logistic regression. In total, 1646 patients were assigned to each cohort. In the 30-day and 90-day postoperative periods, SCT carriers had a higher likelihood of cerebrovascular accident, anemia, acute renal failure, pneumonia, sepsis, deep vein thrombosis, pulmonary embolism, and respiratory failure (all P < .05). SCT carriers exhibited significantly higher risk of periprosthetic joint infection at both 1 (3.5% vs 2.1%; odds ratio [OR] 1.91, 95% confidence interval [CI] 1.22-2.99) and 2 years (3.7% vs 2.6%; OR 1.63, 95% CI 1.07-2.49) postoperatively. Prosthetic loosening was also significantly more likely for SCT carriers within 1 year (1.3% vs 0.3%; OR 4.49, 95% CI 1.75-13.86). Patients with SCT exhibited significantly higher risk for systemic complications, periprosthetic joint infection, and prosthetic loosening after THA. Increased perioperative efforts should be made to prevent hypoxia, acidosis, and dehydration, as these states increase red blood cell sickling, which may reduce complication rates and improve outcomes in patients with SCT.

Sickle Cell Trait and Risk for Common Diseases: Evidence from the UK Biobank

BackgroundSickle cell trait is typically considered benign. Although evidence remains inconsistent, recent studies suggest that it is associated with several common diseases. We systematically assessed associations of sickle cell trait with reported diseases in a large population-based cohort. MethodsStudy subjects were self-reported Blacks from the UK Biobank (UKB), a United Kingdom population-based cohort of subjects aged 40-69 years at recruitment in the United Kingdom. Sickle cell status was based on the International Classification of Diseases, Tenth Revision (ICD-10) or mutations in the HBB gene. Diagnoses of diseases were obtained from ICD-10 and self-reports. Associations of sickle cell trait and diseases were tested using logistic regression, adjusting for age at recruitment, sex, and genetic background (top 10 principal components). ResultsAmong the 8019 Blacks in the UKB, 699 (8.72%) were sickle cell trait carriers; the rate was significantly higher in females (9.74%) than males (7.48%), P = .0005. Sickle cell trait was under-diagnosed; most heterozygous hemoglobin subunit beta (HBB) gene Glu6Val carriers did not have a sickle cell trait ICD-10 record. Compared with non-sickle cell trait, sickle cell trait carriers had significantly increased risk for type 2 diabetes; odds ratio 1.38; 95% confidence interval, 1.12-1.68; P = .002. Sickle cell trait was also significantly associated with increased risk for renal diseases (rhabdomyolysis, end-stage renal disease, chronic kidney disease, renal papillary necrosis) and vascular diseases (hypertension, retinopathy, non-ischemic stroke), P < .05. While most of these diseases are complications/comorbidities of diabetes, their associations with sickle cell trait remained significant after adjusting for diabetes. Association with end-stage renal disease was stronger in subjects without diabetes, odds ratio 6.45; 95% confidence interval, 1.93-19.61; P = .001. ConclusionsSickle cell trait is significantly associated with increased risk for diabetes and diabetes-related complications/comorbidities.

Exercise and the Effects of Hydration on Blood Viscosity in Sickle Cell Trait Carriers: A Critically Appraised Topic

Clinical Question: During bouts of exercises in a hypohydrated state, do patients with sickle cell trait compared with patients without sickle cell trait demonstrate higher blood viscosity? Clinical Bottom Line: There is evidence that there is a difference in hematocrit levels in patients with sickle cell trait and patients without sickle cell trait both pre- and postexercise with suboptimal hydration status. Moreover, the effects on hematocrit levels increase over baseline levels in the recovery stages postexercise in patients with sickle cell trait.

Double Heterozygosity Of Hbs And Hbd Punjab In Two Siblings With Covid-19 Infection: A Case Report

Introduction : HbD Punjab is also known as HbD Los Angeles was first described by Itano in 1951. In HbD point mutation in beta globin chain occurs . HbD associated with HbS in which one gene carries HbD while other gene carries HbS mutation . Infants are at increased risk of life threatening complications like severe anaemia , splenic sequestration , overwhelming septicaemia . Method: Two siblings one 9 year old male and other 4 year old male patients were presented with covid 19 infection in the hospital . Both were known case of sickle cell disease . There blood samples were taken and cbc , retic and HPLC was done . Both were diagnosed as HbSD Heterozygosity by HPLC method .Their mother was a know case of sickle cell trait and father was known case of HbD Punjab trait. RESULT : In above study diagnosis of HbSD in both siblings was confirmed by HPLC. Since both their parents were carriers of sickle cell trait(mother) and HbD trait(father) . HbSD is a heterozygous state beta 121 glutamine residues stabilise the polymer and increases intracellular polymerization of HbS and increase sickling phenomenon . CONCLUSION : HbSD is a rare but very serious disorder with high prevalence in northern part of India . It is a genetically inherited disorder occurs when either of one parent is HbD trait and other one being HbS trait.

Lower Muscle and Blood Lactate Accumulation in Sickle Cell Trait Carriers in Response to Short High-Intensity Exercise.

It remains unclear whether sickle cell trait (SCT) should be considered a risk factor during intense physical activity. By triggering the polymerization-sickling-vaso-occlusion cascade, lactate accumulation-associated acidosis in response to high-intensity exercise is believed to be one of the causes of complications. However, our understanding of lactate metabolism in response to high-intensity exercise in SCT carriers is incomplete. Thirty male SCT carriers (n = 15) and healthy subjects (n = 15) with and without α-thalassemia performed a 2-min high-intensity exercise. Blood and muscle lactate concentrations were measured at exercise completion. Time courses of blood lactate and glucose concentrations were followed during the subsequent recovery. Additional biochemical analyses were performed on biopsies of the vastus lateralis muscle. SCT was associated with lower blood and muscle lactate concentrations in response to the short high-intensity exercise. Compared to controls, the muscle content among SCT carriers of lactate transporter MCT4 and β2-adrenergic receptor were higher and lower, respectively. During recovery, the lactate removal ability was higher in SCT carriers. In the present study, no effect of α-thalassemia was observed. The lower blood and muscle lactate accumulations in SCT carriers may, to some extent, act as protective mechanisms: (i) against exercise-related acidosis and subsequent sickling, that may explain the relatively rare complications observed in exercising SCT carriers; and (ii) against the deleterious effects of intracellular lactate and associated acidosis on muscle function, that might explain the elevated presence of SCT carriers among the best sprinters.

Erythroid Chimerism Measurement As a Predictive Tool of Bone Marrow Transplantation Outcome in Sickle Cell Disease

Allogeneic bone marrow transplantation (BMT) is the only curative treatment available for sickle cell disease (SCD). The effectiveness of the treatment is primarily assessed by the chimerism rate, which is the fraction of cells derived from the donor's hematopoietic stem cells (HSCs) relative to the recipient's cells. New less toxic conditioning agents, described as reduced, nonmyeloablative (as opposed to myeloablative conditioning agents) are now used for BMT with sibling donors. Moreover, most sibling donors are sickle cell trait carriers (heterozygous A/S genotype). In the absence of a test performed on erythroid cells, the rate of chimerism is currently assessed either on different subpopulations of myeloid cells by molecular biology techniques or on hemoglobin measurement by chromatography (HPLC). However, the percentage of myeloid chimerism is rarely representative of the percentage of erythroid chimerism in these patients and HPLC cannot allow analysis at the single cell level.An easy-to-implement method for accurate measurement of fetal hemoglobin (HbF) content in individualized red blood cells (RBCs) has recently been developed (Hebert, et. al, AJH 2020). This method relies on flow cytometry for cell individualization and intracellular labeling of HbF with a fluorescent monoclonal antibody for quantification. Based on the same approach, we propose the use of monoclonal antibodies directed against adult hemoglobins (HbA0 and HbA2) or hemoglobin S (HbS). This strategy allows to discriminate, from a blood sample, the different RBC subpopulations coming from either the recipient or the donor, or from the transfusion associated with this procedure, thus allowing us to precisely determine the rates of erythroid chimerism in patients.As a proof of concept, we show here the evaluation of the percentage of erythroid chimerism during a longitudinal follow-up performed on 3 patients with SCD (P1 - 18 months, P2 - 4 months, and P3 - 4 months). The 3 patients received allogeneic BMT from a sibling A/S donor following nonmyeloablative conditioning consisting of the administration of an anti-CD52 antibody associated with radiotherapy (300 cGy TBI - total-body irradiation). We observed for P1 and P2 donor erythroid chimerism >90% and >95%, 1 and 2 months after BMT, respectively (measured after exclusion of transfused RBCs). These results are in accordance with the presence of most RBCs HbA- and HbS-positive, as determined by flow cytometry. In addition, the analysis of the reticulocyte (retic) subpopulations (CD71-positive cells) of these patients provides precise information on the RBC production of the bone marrow following transplantation. Retic donor chimerism levels were >99% for both P1 and P2, 1 month after BMT procedure. P1 and P2 showed stable donor reticulocyte and donor erythroid chimerism levels during the follow-up. On the contrary, P3 presented a different response with 43%, 41% and 5% donor erythroid chimerism 1, 2 and 3 months after BMT, respectively. Retrospectively, this bad response in P3 would have been predicted by low donor reticulocyte chimerism levels (5%, 6% and 0.5% at 1, 2 and 3 months after BMT, respectively). Our erythroid specific chimerism results were also compared to the assessment of chimerism performed on either total white blood cells (WBCs) or lineage specific subpopulations after sorting. Over 18 months after BMT in P1, the correlation between retic chimerism and total WBCs or T lymphocytes (CD3-positive cells) chimerism were not statistically significant (P = 1 and P = 0.833, respectively - Spearman test) (Figure 1).This new tool to monitor BMT outcome to treat SCD shows great precision and potentially a stronger predictive capability than total WBCs or lineage specific chimerism assessed by molecular biology. Our results highlight the importance of analyzing reticulocyte population to better assess BMT efficacy and predict the outcome a few days after the transplant. Its use could also be considered in the context of the various gene therapy strategies currently under development using modified β-globin gene addition or direct mutation correction through CRISPR/Cas9 and homologous recombination system. [Display omitted] DisclosuresBencheikh: Innovhem: Current Employment. Bartolucci: Innovhem: Current holder of individual stocks in a privately-held company.