Inherited Blood Disorder Research Articles

Natural Course of Albuminuria in Pediatric and Murine Sickle Cell Disease

Sickle cell disease (SCD), an inherited blood disorder, is associated with prevalent chronic kidney disease (CKD), evidenced by persistent albuminuria. It is critical to understand the natural history of albuminuria and albumin to creatinine (ACR) ratio variance to optimally identify, diagnose and treat SCD pediatrics prior to CKD. Thus, we investigated natural course of albuminuria in pediatrics and murine SCD, and identify ACR level predictive of persistent albuminuria.Basic science study: As hyperfiltration occurs at 12 weeks of age in male and 20 weeks of age in female humanized sickle cell (HbSS) mice, we performed metabolic cage studies in 1-week intervals for 4 weeks before (4 weeks old mice, n=21) and after hyperfiltration phase (males: 16 weeks (n=10), females: 20 weeks old (n=8)), and measured albuminuria using GenWay Biotech ELISA kit. Clinical study: We performed a retrospective study of the UAB Pediatric Sickle Cell Kidney Cohort. We identified all participants with HbSS and HbSB0 thalassemia ≥ 5 years of age with ACR measurements performed at a steady-state outpatient clinic visit. We identified the date and age of participants with at least 1 ACR level ≥100mg/g to compare outcomes for albuminuria and to determine the natural course of ACR after an ACR measurement >100mg/g.We observed a significant difference in the trajectory of albuminuria over time prior and post hyperfiltration (p=0.02) in HbSS mice. Young HbSS mice presented with downward trend over time, with average values of albuminuria 47.6±27.2 (week 1), 32.6±20.3 (week 2), 32.0±24.3 (week 3), 31.3±16.1mg/24h (week 4), respectively. After hyperfiltration, older HbSS mice had an upward trend in albuminuria over time (week 1: 49.7±23.6, week 2: 74.5±66.9, week 3: 55.9±82.2, week 4: 73.0±86.4 mg/24h, respectively). Finally, prior to hyperfiltration the average albuminuria over a time of 4 weeks was 35.9±7.8 mg/24h (±21.7%), while following hyperfiltration it was 63.3±12.4 mg/24h (±19.6%). These findings mirror human data in which pediatric patients present with similar degree of natural variability in ACR. We identified 62 patients (17%) with persistent albuminuria, 46 (13%) with intermittent albuminuria, and 247 (70%) with not yet having albuminuria. Out of 107 patients with at least 1 abnormal ACR, 45 had 1 measurement >100mg/g, and 43 of these participants were categorized with persistent albuminuria (50x higher odds ratio than patients with ACR<100mg/g). Assessment of natural history of albuminuria after an initial ACR >100mg/g showed significant variability. Regarding 1-year clinical trial design, the change in ACR showed a decline from 175 to 131 mg/g, accounting for 23% decline in albuminuria without any intervention.The natural course of albuminuria is an important characteristic of renal phenotype in SCD and should be considered while designing and assessing effectiveness of novel therapeutic approaches in preclinical and clinical studies targeting SCD nephropathy. Funded by NIH R25 DK 112731 and NHLBI–R00HL144817 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Outcome of premarital genetic counseling for couples at risk of hemoglobinopathies in Kingdom of Bahrain.

Hemoglobinopathies are the commonest inherited blood disorders and form a serious burden worldwide, affecting communities, patient quality of life and healthcare resources. The Kingdom of Bahrain has issued a law obligating couples to undergo premarital screening to detect those at risk of having children affected with these disorders. The aim of this study was to analyze the marital decisions of couples at risk for hemoglobinopathies and follow up the outcomes. A retrospective study was conducted on couples at risk for hemoglobinopathies identified during the premarital screening program at local health centers in the Kingdom of Bahrain and referred to the genetics department in the Salmaniya Medical Complex for genetic counselling in 2018-2020. A total of 189 couples were found to be at risk for hemoglobinopathies, of whom 159 completed the survey. Of these, 107 (67%) decided to proceed with their marriage and 26 couples achieved pregnancy. Out of 24 at-risk pregnancies with known outcome, 83.3% were spontaneous whereas only 16.7% underwent in-vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD). Eight out of 20 infants born to couples after spontaneous conception were affected. A positive attitude toward IVF with PGD was held by 60% of at-risk couples. Despite undergoing premarital screening and genetic counselling, a large percentage of at-risk couples proceeded with their marriage. Most of them justified their decision due to the availability of advanced methods that aid in the prevention of having an affected child. However, the cost of such intervention was a major barrier for the majority of couples.

Depression, anxiety and burden of care in caregivers of children with β-thalassemia major

β – thalassemia major is a chronic inherited blood disorder requiring lifelong treatment including blood transfusion, putting tremendous burden on caregivers of the affected children. Aims were to measure the burden of care, prevalence and severity of depression and anxiety, and their association with various socio-demographic and illness related factors in caregivers of children with β – thalassemia major. A cross-sectional study was conducted on 100 caregivers of children suffering from β – thalassemia major coming to the Paediatrics department of S.S.G. Hospital, Vadodara. Study tools used were Zarit Burden Interview, General Health Questionnaire-28, Diagnostic and Statistical Manual of mental disorders (fifth edition) diagnostic criteria for depressive disorders and generalised anxiety disorder, Hamilton Depression and Anxiety Rating Scales. Forty seven (47%) caregivers had moderate to severe burden of care. Fifty four (54%) caregivers screened positive for having psychiatric morbidity out of which thirty five (35%) had depressive disorders and fourteen (14%) had generalised anxiety disorder. 24 (68.6%) and 9 (64.3%) had moderate to severe depression and anxiety respectively. Burden of care and depression were significantly associated with lower income and those requiring blood transfusions every 2 weeks or less. Thalassemia has its impact not only on the patients but also on the mental health of their caregivers leading to high levels of depression, anxiety and burden of care in them. They should be routinely screened for depression and anxiety to provide adequate mental health care to these individuals.

Hematologic profiles of Beta thalassemia major patients: An institutional cross-sectional study

Introduction: Thalassemia is inherited blood disorder characterized by decreased hemoglobin with two main types-alpha and beta thalassemia. There are two main varieties of β thalassaemia, β0 thalassaemia, in which no β globin is produced, and β+ thalassaemia, in which some β globin is produced, but less than normal. As the patient is diagnosed, regular blood transfusions and chelating treatment is given lifelong. In this study, we observed the haematological profiles of multi transfused thalassemia major patients with the accompanying complications.Aims and Objectives: To study the clinical features with RBC parameters, serum ferritin levels, chelation therapy and prevalence of blood transfusion related infection in multi transfused beta thalassemia major patients.Materials and Method: In this cross sectional study, total 90 diagnosed thalassemia major patients were taken with their complete history, physical examination and laboratory parameters such as- complete blood counts. All the patients were monitored for serum ferritin levels and chelation therapy along with screening for transfusion transmitted infections over a year. All the data were compiled and appropriate statistical analysis was done.Results: In present study out of 90 patients, 54 patients were males and 36 patients were females. Mean age of 15.26 ± 7.04 years with 68.9% (N=62) of cases required twice monthly transfusion, 30.0% (n=27) cases required once a month transfusion. 25 cases were found to be HCV+ (27.78%), 3 were HIV + (3.3%) and 62 cases were n on-reactive (68.89%). On first post transfusion CBC we found that 30 cases (33.33%) were found to be adequately transfused with levels > 10 gm%, where as in second results 34 cases (37.78%) were found to be adequately transfused with levels >10 gm%. Mean of average yearly average ferritin values in the study duration was found to be 4724 ± 287.65 ng/mL. The chelating agent dose was with mean 1040 mg and standard deviation 476.19.Conclusion: In the present study, it is concluded that haematological parameters like Haematocrit, Red Blood Cell mass, Haemoglobin and Mean Corpuscular volume had large covariances and Serum Ferritin levels was positively correlated with chelation therapy along with increased rate of transfusion transmitted infections in multi transfused thalassemia major patients.

A Comparison of Salivary Properties and Caries Status between Beta-Thalassemia Major Patients and Healthy Patients in Hospital Wanita dan Kanak-Kanak Sabah

Thalassaemia is the most common inherited blood disorder in Malaysia, and the majority of patients are from Sabah. The disease itself poses significant morbidities, and its management is costly. Previous studies showed increased caries prevalence among these patients attributed to possible changes in saliva properties. The objective was to investigate the prevalence of saliva properties and caries among patients with thalassaemia compared to healthy individuals.

Role of Macrophages in Sickle Cell Disease Erythrophagocytosis and Erythropoiesis

Sickle cell disease (SCD) is an inherited blood disorder caused by a β-globin gene point mutation that results in the production of sickle hemoglobin that polymerizes upon deoxygenation, causing the sickling of red blood cells (RBCs). RBC deformation initiates a sequence of events leading to multiple complications, such as hemolytic anemia, vaso-occlusion, chronic inflammation, and tissue damage. Macrophages participate in extravascular hemolysis by removing damaged RBCs, hence preventing the release of free hemoglobin and heme, and triggering inflammation. Upon erythrophagocytosis, macrophages metabolize RBC-derived hemoglobin, activating mechanisms responsible for recycling iron, which is then used for the generation of new RBCs to try to compensate for anemia. In the bone marrow, macrophages can create specialized niches, known as erythroblastic islands (EBIs), which regulate erythropoiesis. Anemia and inflammation present in SCD may trigger mechanisms of stress erythropoiesis, intensifying RBC generation by expanding the number of EBIs in the bone marrow and creating new ones in extramedullary sites. In the current review, we discuss the distinct mechanisms that could induce stress erythropoiesis in SCD, potentially shifting the macrophage phenotype to an inflammatory profile, and changing their supporting role necessary for the proliferation and differentiation of erythroid cells in the disease. The knowledge of the soluble factors, cell surface and intracellular molecules expressed by EBI macrophages that contribute to begin and end the RBC's lifespan, as well as the understanding of their signaling pathways in SCD, may reveal potential targets to control the pathophysiology of the disease.

Gene therapy in sickle cell disease: Attitudes and informational needs of patients and caregivers.

Sickle cell disease (SCD) is an inherited blood disorder that results in serious morbidity and early mortality. Novel therapies for SCD, most notably genetic therapies (GTs) and HLA-mismatched donor hematopoietic cell transplantation, are in clinical trials. While potentially curative, these interventions are some of the most intensive treatments for SCD and are associated with serious and life-altering side effects, which may manifest several years after treatment. Little is known about knowledge, beliefs, and attitudes of individuals with SCD, or their caregivers, toward existing and these emerging therapies. Patients with SCD at least 13 years of age (n=66) and caregivers (n=38) were surveyed about knowledge, attitudes, and beliefs surrounding treatments for SCD. Only 4.8% felt "extremely knowledgeable" about GT for SCD while the majority (63.4%) reported little knowledge. Overall, health literacy was low among respondents. Most respondents had a neutral attitude regarding the safety of GT for SCD, and whether it was a good treatment for the disorder (56.7% and 58.6%, respectively). Only a few respondents endorsed the idea that GT was "unsafe" or "not a good treatment" (5.8% and 4.8%, respectively). There was an association between increasing knowledge about GT and agreement that it is safe (p=.012) and a good treatment for SCD (p=.031). Given that very few patients with SCD feel knowledgeable about GT and a majority have neutral feelings about the safety and utility of this new approach, culturally appropriate patient-centered education is urgently needed as these treatments get regulatory approval and proceed to the clinic.

Hydroxyurea for Children with Sickle Cell Disease in sub-Saharan Africa: A Summary of the Evidence, Opportunities, and Challenges.

Sickle cell disease (SCD) is a common and life-threatening inherited blood disorder that affects more than 300,000 newborns per year. Because of the origins of the sickle gene mutation as a protective mechanism against malaria for those with sickle cell trait, more than 90% of annual SCD births are in sub-Saharan Africa (sSA). Over the past several decades, there have been many important advances in the care of individuals with SCD, including early diagnosis through newborn screening programs (NBS), prophylactic penicillin, the development of vaccines to prevent invasive bacterial infections, and the emergence of hydroxyurea as the primary disease-modifying pharmacologic therapy. These relatively simple and inexpensive interventions have significantly reduced the morbidity and mortality of Sickle cell anemia (SCA) such that individuals with SCD can live longer and more complete lives. Unfortunately, although these interventions are relatively inexpensive and evidence-based, they are only readily available for affected individuals living in high-income settings, representing <5% of the global SCD population. In sSA, where >90% of the global SCD burden exists, SCD still results in early mortality with 50-90% of infants likely dying before reaching 5 years of age. Recently, there are an increasing number of efforts in many African countries to prioritize SCA with pilot NBS programs, improved diagnostics, and expanded SCD education for health care professionals and the general public. It is essential to include access to hydroxyurea as a core component of any SCD care program, but there are still many barriers that prevent the widespread global use of hydroxyurea. Here, we summarize what we know about SCD and hydroxyurea use in Africa and discuss a strategy to respond to what we consider to be a public health imperative to maximize access to and appropriate use of hydroxyurea for all individuals with SCD using innovative dosing and monitoring strategies.

Design, Synthesis, and Evaluation of Allosteric Effectors for Hemoglobin.

ConspectusSickle cell disease (SCD) is an inherited blood disorder caused by a point mutation in hemoglobin (Hb), the protein in the red blood cell (RBC) responsible for the transport of oxygen (O2) throughout the body. The mutation leads to the expression of sickle cell hemoglobin (HbS). Both Hb and HbS exist in equilibrium between oxygenated and deoxygenated forms; however, deoxygenated HbS can polymerize to form long fibers which distort the shape of RBCs into the characteristic sickled shape. The misshapen RBCs can obstruct blood vessels and capillaries, resulting in a vaso-occlusive crisis. Vaso-occulsion deprives tissues and organs of O2 and can cause intense pain which often results in hospitalization. Chronic organ damage is a major cause of reduced life expectancy for SCD patients.Allosteric effectors are molecules which regulate protein function. HbS allosteric effectors can be used to decrease polymerization by stabilizing the oxygenated form of HbS, which leads to an increase in O2 uptake and a decrease in the sickling of RBCs. Allosteric effectors that have been evaluated for the treatment of SCD include vanillin, 5-hydroxymethyl furfural (5-HMF), and voxelotor, which was approved by the U.S. Food and Drug Administration (FDA) for the treatment of SCD in 2019. 5-HMF did not progress to phase III clinical trials since it suffered from rapid metabolic degradation. However, several derivatives of 5-HMF and vanillin have been synthesized and evaluated as potential candidates for SCD treatment. Derivatives of these compounds have shown promise, but their shortcomings, such as high levels of oxidative metabolism, have prevented them from progressing into marketable drugs. Our efforts have produced multiple 5-HMF derivatives which have been evaluated for their potential to treat SCD. Each derivative was evaluated for its ability to increase O2 affinity (i.e., P50, the partial pressure at which hemoglobin is 50% saturated with O2). The synthesized aryl ether derivatives were evaluated, and results suggest that compounds with multiple aromatic aldehydes may have enhanced biological properties. One such derivative, compound 5, which features two furan aldehyde rings, exhibited increased O2 affinity (P50 = 8.82 ± 1.87 mmHg) over that of unmodified Hb (P50 = 13.67 ± 0.22 mmHg). Future studies include obtaining crystal structures of the 5-HMF derivatives complexed with HbS to confirm the protein-allosteric effector interactions.

A Framework for a Health Economic Evaluation Model for Patients with Sickle Cell Disease to Estimate the Value of New Treatments in the United States of America.

Sickle cell disease (SCD) is an inherited blood disorder associated with lifelong morbidity and increased risk of mortality that affects approximately 100,000 individuals in the United States (US), primarily of African-American descent. Due to these complications, individuals with SCD typically incur high healthcare costs. With a number of costly but potentially curative SCD therapies on the horizon, understanding the progression of SCD and economic burden to insurers and patients is vital. The aim is to develop a framework to understand the progression and costs of SCD that could be used to estimate how new treatments can impact the progression and costs of the disease. We detail how we will create a simulation model that represents the natural history of a population and allows for the characterization of the impact of novel therapies on the disease, associated costs, and outcomes in comparison to current management. In this report, we describe a conceptual approach to modeling SCD to determine the relative clinical and economic impact of new gene therapies compared to conventional therapies with a goal of providing a flexible approach that could inform the clinical management of SCD for patients, payers, and policy makers.

No difference in myocardial iron concentration and serum ferritin with deferasirox and deferiprone in pediatric patients with hemoglobinopathies: A systematic review and meta-analysis.

Iron overload is a common complication experienced by transfusion-dependent children with hemoglobin disorders. Chelators such as deferasirox (DFX) and deferiprone (DFP) are effective in overcoming this problem. We conducted this systematic review and meta-analysis to evaluate the effectiveness of DFX compared to DFP in treating iron overload amongst pediatric patients with hemoglobin disorders. PubMed and Cochrane Central were searched from their inception until Dec 21 2021, for randomized clinical trials (RCTs) and observational studies, which assessed the efficacy of DFX compared to DFP in the treatment of inherited hemoglobin disorders. The outcomes of interest included myocardial iron concentration (MRI T2*) at the end of the trial and change in mean serum ferritin (SF) levels at the 6 and 12months mark. Weighted mean differences (WMDs) with their corresponding 95% confidence intervals (CIs) were calculated for continuous outcomes using random effects model. A total of 5 studies comprising 607 children were included. The results of our analysis revealed no significant difference between DFX and DFP in MRI T2* at the end of treatment (WMD: -0.92; 95% CI [-3.35, 1.52]; p=0.46; I2=0). Moreover, there has been no significant difference noted in SF levels at both 6months (WMD: 97.31; 95% CI [-236.16, 430.77]; p=0.57; I2=0) and 12months (WMD: 46.99; 95% CI [-191.42, 285.40]; p=0.70; I2=0) respectively. Our analysis shows no significant difference between the efficacy of DFX and DFP in the management of iron overload in children with inherited blood disorders. Future large-scale clinical trials are required to further validate our results.

Identification of a novel 10.3 kb deletion causing α0-thalassemia by third-generation sequencing: Pedigree analysis and genetic diagnosis

Backgroundα-thalassemia is an inherited blood disorder caused by variants in the α-globin gene cluster. Identification of the pathogenic α-globin gene variants is important for the diagnosis and management of thalassemia. MethodsTwo suspected families from Xiantao, Hubei Province were recruited in this study. The family members underwent hemoglobin testing. Polymerase Chain Reaction based reverse dot blot (PCR-RDB) was employed to identify the known variants. Next-generation sequencing (NGS) and third-generation sequencing (TGS) were performed to screen the potential disease-causing variants, which were validated by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). ResultsHematological analysis suggested that proband A had α-thalassemia traits, and proband B had HbH disease traits. However, only a -α3.7 mutation had been detected by PCR-RDB and NGS in the proband of family B. Subsequent TGS identified a novel 10.3 kb deletion (NC_000016.10:g.172342-182690del) covering the HBA1, HBQ1 and HBA2 genes in the α-globin gene cluster in both family A and B, which was confirmed by Sanger sequencing and MLPA. These results indicated that the novel deletion is likely responsible for α-thalassemia. ConclusionA novel α-thalassemia deletion was identified for the two families by TGS. Our work broadened the molecular spectrum of α-thalassemia, and was beneficial for the diagnosis, genetic counseling and management of α-thalassemia.

‘Only parents can understand the problems and needs of children with thalassaemia’: parental activism for thalassaemia care in Northern India

Evolving knowledge of genetics and improved clinical care have re-shaped life choices for those suffering from chronic, incurable conditions and their families. Yet the realisation of care requires complex navigation to access vital therapies which is often difficult for individuals or their family carers. In the article, we explore the struggles and strategies of parents of children with thalassemia (a genetically inherited blood disorder) in a North Indian city, who have come together to ensure better long-term health of their children. A focus on the ways in which families come together and remain apart in their quest for guaranteed access to life-saving substances such as filtered blood, provides insight into the diversity of bio-social strategies at work. It is not only family relationships and kinship, we suggest, but bio-sociality itself which is reshaped with the advent of new rights-based languages, evolving therapies and state support which hold out new possibilities for young people with thalassemia to live as normal a life-course as possible.

Therapeutic non-compliance among people with beta thalassemia in Côte d'Ivoire

Thalassemias are genetic diseases, an inherited blood disorder which is characterized by a defect in the production of hemoglobin. These diseases result in a decrease in the quantity or size of red cells. There are two types: alpha and beta-thalassemia. The most severe forms are manifested by chronic anemia which can lead to death without proper treatment. Many research works recognize that therapeutic compliance, especially among people with chronic disease, is mandatory for better management of the disease. However, very few studies shed light on the impact of the latter on hemoglobinopathies. This article is a preliminary study which aims to identify the factors observed in patients with beta-thalassemia. Starting from a qualitative approach, nine people were subjected to semi-structured interviews on their experience and perception of the management of beta-thalassemia by the nursing staff. The results obtained made it possible to identify on the one hand three factors of non-compliance which are: the quality of the doctor-patient relationship, the chronicity of the disease and the reliability of care, and the interactions between these factors and the efficient management of their health. Keywords: Beta-thalassemia, therapeutic noncompliance, therapeutic alliance, Côte d'Ivoire.

Third generation sequencing transforms the way of the screening and diagnosis of thalassemia: a mini-review.

Thalassemia is an inherited blood disorder imposing a significant social and economic burden. Comprehensive screening strategies are essential for the prevention and management of this disease. Third-generation sequencing (TGS), a breakthrough technology, has shown great potential for screening and diagnostic applications in various diseases, while its application in thalassemia detection is still in its infancy. This review aims to understand the latest and most widespread uses, advantages of TGS technologies, as well as the challenges and solutions associated with their incorporation into routine screening and diagnosis of thalassemia. Overall, TGS has exhibited higher rates of positive detection and diagnostic accuracy compared to conventional methods and next-generation sequencing technologies, indicating that TGS will be a feasible option for clinical laboratories conducting in-house thalassemia testing. The implementation of TGS technology in thalassemia diagnosis will facilitate the development of effective prevention and management strategies, thereby reducing the burden of this disease on individuals and society.

An observational, prospective, multicenter study on the utilization and effectiveness of elbasvir-grazoprevir treatment association for chronic hepatitis C in France (ZEPHYR study).

The efficacy and safety profiles of elbasvir-grazoprevir (EBR/GZR) has been established in more than 10 clinical trials. However, the characteristics of patients treated in routine clinical practice may differ. The present study was therefore designed to assess the real-life effectiveness of EBR/GZR therapy in the general population and among subgroups with a high hepatitis C virus(HCV) prevalence in France. The Zephyr study was designed as a French, multicentre, prospective, observational study on EBR/GZR use and effectiveness in current practice in chronic hepatitis Cpatients. These results are based on data regardingthe adult patients who received at least one dose of EBR/GZR between December 2017 and June 2019 in 67 French hospitals and clinics. Overall, 478 patients were included. The Full Analysis Setcorresponded to the 467 patients who met all the inclusion criteria and none of the exclusion criteria. Gender was balanced and the mean age was 55.7 ± 13.3 years. The patients were mainly treatment-naive (89.5%) and infected with Genotype 1b (70.4%). Among the 75 patients with HCV Gt1a genotype, 56% had HCV RNA ≥ 800,000 IU/ml. F3-F4 fibrosis stage involved 24.2% of our population. Our subgroups were distributed among 110 migrants (23.6%), 58 (15.3%) using opioid agonist treatment, including people who inject drugs, 30 (6.8%) with chronic kidney disease Stages 3-5, 9 (1.9%) with aninherited blood disorder, and 4 (0.9%) coinfected with HIV. The remaining 269 (58.7%) were included in the general population subgroup. Overall, sustained virologic response 12 weeks after the end of treatment reached 98.0% and remained consistent among genotype, HCV RNA values, fibrosis stage, and the subgroup of interest. The rate of Alcohol Use Disorders Identification Test-Consumption​​​and Life Habit questionnaire completion was high at each visit, with data suggesting alcohol consumption decrease and an improvement in quality of life. Using real-world evidence data on a French population representative of HCV patients, we confirmed the results obtained during EBR/GZR development program.

The Unique Magnetic Signature of Sickle Red Blood Cells: A Comparison Between the Red Blood Cells of Transfused and Non-Transfused Sickle Cell Disease Patients and Healthy Donors.

Sickle cell disease (SCD) is an inherited blood disorder that affects millions of people worldwide, especially in low-resource regions of the world, where a rapid and affordable test to properly diagnose the disease would be highly valued. Magnetophoresis is a technique that could simultaneously analyze, quantify, and potentially separate the patient's sickle red blood cells (RBCs) from healthy RBCs, but the magnetic characteristics of sickle RBCs have yet to be reported. In this work, we present the single cell magnetic characterization of RBCs obtained from SCD patients. Sufficient single cells are analyzed from patient samples undergoing transfusion therapy and not yet having transfusion therapy (TP and NTP, respectively), such that means and distributions of these single RBC mobilities are created in the form of histograms which facilitated comparison to RBCs from healthy donors (HD). The magnetic characterization is obtained using a technique known as Cell Tracking Velocimetry (CTV) that quantitatively characterizes the RBC response to magnetic and gravitational fields. The magnetic properties of RBCs containing oxygenated, deoxygenated hemoglobin (Hb) and methemoglobin (oxyHb-RBCs, deoxyHb-RBCs, and metHb-RBCs) are further determined. The NTP samples reported the highest magnetic character, especially when compared to oxyHb-RBCs from HD, which implies impaired oxygen binding capabilities. Also, the oxygen-Hb equilibrium curves are obtained to estimate the magnetic character of the cells under intermediate oxygen levels. Our results confirm higher magnetic moment of SCD blood (NTP) under intermediate oxygen levels. These data demonstrate the potential feasibility of magnetophoresis to identify, quantify and separate sickle RBCs from healthy RBCs.

The Role of Splenectomy in The Treatment of β-Thalassemia Major Patients: A literature review

Thalassemia is a group of inherited blood disorders due to the reduction or absence of globin chain synthesis which can cause hemolytic anemia. β-thalassemia major is a severe type of thalassemia, in which patients require lifelong transfusions for survival. Extravascular hemolysis on the spleen results in splenomegaly, meanwhile, extramedullary hematopoiesis causing hypersplenism to develop in beta-thalassemia major patients. Hypersplenism, symptomatic splenomegaly, and increased annual need for blood transfusion in thalassemia patients are indicators of splenectomy. However, aside from the benefit of splenectomy which may reduce the need for transfusion in people with thalassemia with the goal of reducing iron overload, it may also be linked to several major negative effects that may outweigh any benefits, such as postoperative infections with high mortality rate and thrombotic events.

Trials in Progress: Two Randomized, Double-Blind, Multicenter, Placebo-Controlled Trials Investigating the Efficacy of Voxelotor on Cerebral Blood Flow and Neurocognitive Function in Patients with Sickle Cell Disease

Background: Sickle cell disease (SCD) is an inherited blood disorder caused by a point mutation in the beta chain of hemoglobin (Hb) that results in the formation of sickle hemoglobin, HbS. Polymerization of HbS under conditions of deoxygenation causes red blood cell sickling that can lead to hemolytic anemia and vascular occlusion with subsequent end-organ damage, infarction, and cognitive dysfunction. In patients with SCD, cerebral blood flow (CBF) is elevated throughout the brain, with silent cerebral infarcts (SCIs) occurring mainly in brain regions with the lowest CBF. SCIs, overt strokes, and cognitive impairment are some of the most common complications of SCD, all of which have a substantial impact on the education, employment, and quality of life of patients with SCD. Cognitive impairment in patients with SCD can also manifest in those without SCI or overt stroke, suggesting a potential role of chronic anemia and cerebral hemodynamics in neurocognitive dysfunction. Despite progress in the development of therapies for SCD, little is known about their effect on cognitive function and cerebral hemodynamics. Voxelotor is a HbS polymerization inhibitor approved in the United States for the treatment of SCD in patients aged ≥4 years and in the United Kingdom, European Union, and the United Arab Emirates for patients aged ≥12 years. Objective: To understand the impact of voxelotor on brain function in patients with SCD, 2 post-approval studies of voxelotor are currently recruiting and are described here. Methods: The Neurocognitive Function study (NCT05228834) is a phase 3b, randomized, double-blind, placebo-controlled, multicenter trial investigating the effect of once-daily oral voxelotor (Figure) on neurocognitive function in children and adolescents with SCD. The Cerebral Hemodynamics study (NCT05228821) is a phase 4, randomized, double-blind, placebo-controlled, multicenter trial investigating the impact of once-daily oral voxelotor (Figure) on CBF in adolescents and adults with SCD. An overview of the study population, study design, and key endpoints for both studies is provided in the Table. Results: The primary objective of the Neurocognitive Function study is to assess the effect of voxelotor compared with placebo on the neurocognitive function in children and adolescents with SCD (aged 8 to <18 years), which will be evaluated by measuring the change from baseline at week 12 in the executive abilities composite score, as assessed by the National Institutes of Health Toolbox Cognition Module. The primary objective of the Cerebral Hemodynamics study is to assess the efficacy of voxelotor compared with placebo on CBF in adolescents and adults (aged 12-30 years) with homozygous hemoglobin S (HbSS) or sickle beta zero thalassemia (HbSβ0), which will be evaluated by assessing the change from baseline in CBF measured by magnetic resonance imaging at week 12. Conclusions: Treatments that improve neurocognitive dysfunction represent an important unmet need in the management of SCD. Results from the Neurocognitive Function study and the Cerebral Hemodynamics study (the latter will enroll adult patients) will provide important information on the impact that inhibition of HbS polymerization may have on cognitive function and cerebral hemodynamics by improving anemia and hemolysis in patients with SCD. Funding: Global Blood Therapeutics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Novel Electronic Consultation for Sickle Cell Disease Inpatient Management

Sickle cell disease (SCD) is an inherited blood disorder that affects 100,000 persons in the US. Despite affecting a small percentage of the US population, health care costs for SCD are approximately 1.7 million for total lifetime cost mostly due to high healthcare utilization. Though outpatient comprehensive SCD centers reduce healthcare costs by decreasing acute visits, there has been little in the literature on optimizing inpatient SCD care and facilitating a successful transition back to outpatient care. Improving the transition between inpatient care and the outpatient provider may also reduce health care expenses. Current inpatient models of care for adults with SCD vary among hospital centers, but are generally a combination of hematology and oncology providers, internists, and/or SCD specialists. Similar to most hospital systems, our internal medicine resident teams and hospitalists provide most of the care for adults with SCD. The hematology consult team is only consulted for a small number of adults with SCD who have severe complications due to limited capacity. Prior to 2020, the discharge planning, transfusion guidance, and pain management for adults with SCD in the hospital was highly variable. To improve continuity of care, we developed a new inpatient model of care using electronic communication (e-consult) notes that encompass the important aspects of management (i.e. individualized care plan, etc.) for every patient admitted with SCD. At the time of admission, the SCD team receives an EMR-alert to initiate the consultation and does not require an order from the inpatient team. This inpatient model of care was also helpful during the COVID-19 pandemic when the hospital experienced a shortage of staff making it more difficult for the hematology consult services to participate in SCD care. We hypothesized that the e-consult service would increase the inpatient medical teams’ satisfaction level with care and improve discharge planning for adults admitted with SCD. Methods: We analyzed 1,282 inpatient visits during January 2019 to July 2021. The e-consult notes, written by a SCD specialist, provided recommendations on the following: electronic medical record review (hospital course, vital signs, and laboratories), outpatient treatment plans, best-practices from the national SCD guidelines, and discharge planning. E-consult notes were written beginning in April 2020. Inpatient provider teams were asked to complete surveys measuring satisfaction of the SCD management before (Jan 2019-Mar 2020) and after (Apr 2020-Jul 2021) the implementation of e-consults. Time to first discharge appointment, length of stay, and hospital readmission were obtained using the electronic medical record. We used ANOVA test to compare mean values between the two time periods. Results: There were a total of 106 providers who participated in the satisfaction survey, but three entries were incomplete. The majority of inpatient provider teams who responded were internal medicine (76%; 80/106). Only 61% (62/103) of the providers were familiar with the e-consult service. Among those familiar with the e-consult service, 79.6% (45/62) of the providers followed the recommendations of the e-consult service. Over 80% of the providers reported that e-consults were valuable to SCD care, promoted good quality of care, and resulted in an overall improvement in the care of SCD. Furthermore, provider satisfaction were significantly improved. The mean number of days between hospital discharge and outpatient follow up were also significantly lower than before the implementation of this service. The length of hospital stay was statistically higher for the post implementation period, however remained under the national average of hospitalizations for SCD. The hospital readmission rate was unchanged. Limitations: We are unable to capture hospital follow up that occurred at another institution due to patients being under another provider's care. Conclusion: Improving inpatient care for people with SCD is important. Due to insufficient SCD staff, new models of inpatient care are needed. The e-consult program initiated at UAB can significantly improve inpatient team satisfaction, inpatient SCD guidance, and facilitate timely discharge with an outpatient SCD provider. E-consult notes can be an acceptable tool to help optimize inpatient care when a formal inpatient SCD service does not exist due to limited SCD staff. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal