Pathophysiology Of Sickle Cell Disease Research Articles

Malnutrition in sickle cell anemia: Prevalence, impact, and interventions: A Review.

Sickle Cell Anemia (SCA) is a hereditary hemoglobinopathy characterized by chronic hemolytic anemia, vaso-occlusive events, and a wide range of clinical complications. Malnutrition, often an underexplored aspect of this complex condition, plays a critical role in disease management and overall patient well-being. This publication provides a comprehensive review of the prevalence, impact, and interventions related to malnutrition in individuals with SCA. A thorough literature review reveals the multifaceted challenges faced by SCA patients in maintaining adequate nutrition. The pathophysiology of SCA, involving chronic inflammation, oxidative stress, and hypermetabolism, contributes to increased nutritional requirements and altered dietary patterns. Factors such as reduced appetite, nutrient malabsorption, dietary restrictions, and socioeconomic disparities further exacerbate the risk of malnutrition. Malnutrition is a prevalent issue among individuals with SCA, affecting patients of different age groups and disease severities. Nutritional deficiencies, including vitamins, minerals, and essential nutrients, are common in this population. The impact of malnutrition on disease outcomes is significant, with associations between nutrient status and complications such as pain crises, infections, and impaired quality of life. This paper also reviews nutritional interventions aimed at addressing malnutrition in SCA patients. While dietary counseling, supplementation, and personalized nutrition plans have shown promise in improving nutritional status, challenges such as patient adherence and access to healthcare must be addressed to optimize their effectiveness.

Eosinophilic dialogues: A molecular exploration of sickle cell anemia severity

Sickle cell anemia (SCA) is a genetically inherited hemoglobinopathy characterized by the abnormal morphology of red blood cells, resulting in vaso-occlusive events and diverse clinical complications. Recent investigations have unveiled a novel dimension in understanding SCA severity through the lens of eosinophilic dialogues. This review article synthesizes current knowledge on the molecular intricacies of eosinophils in the context of SCA, exploring their biology, molecular markers, and interactions with other cellular components. Eosinophil-mediated inflammation and oxidative stress are dissected to elucidate their impact on the disease course. Furthermore, the review evaluates potential therapeutic interventions and outlines future directions in this burgeoning field. The term “Eosinophilic Dialogues” encapsulates the multifaceted molecular exchanges that influence SCA severity, presenting a promising avenue for targeted interventions and improved clinical outcomes. This review serves as a comprehensive resource for researchers, clinicians, and healthcare practitioners engaged in unraveling the complex pathophysiology of SCA and exploring novel therapeutic avenues.

Managing gastrointestinal challenges: Diarrhea in sickle cell anemia.

Sickle cell anemia (SCA), a hereditary hemoglobinopathy, is characterized by the presence of abnormal hemoglobin and has long been associated with a wide range of complications. While much attention has been given to the condition hematological aspects, gastrointestinal complications, particularly diarrhea, have been relatively understudied and often overlooked. This publication delves into the management of gastrointestinal challenges, with a focus on diarrhea, in individuals living with SCA. The pathophysiology of SCA is intrinsically linked to gastrointestinal complications, and diarrhea is a common manifestation of this condition. This abstract publication outlines the key elements discussed in the full-length work, which includes the clinical presentation of diarrhea in these patients, the diagnostic tools used to evaluate the condition, and various management strategies to alleviate symptoms and enhance the overall quality of life for affected individuals. The paper emphasizes the importance of patient education, offering healthcare professionals valuable insights into how to inform and support patients in managing their conditions effectively. It also highlights the need for continued research to further our understanding of gastrointestinal challenges in SCA and to identify potential areas for future therapeutic interventions. Ultimately, the comprehensive management of diarrhea in individuals with SCA is vital for their overall well-being. This publication serves as a valuable resource for healthcare providers, researchers, and caregivers in addressing the gastrointestinal challenges that accompany SCA, ultimately working toward a better quality of life for those affected by this condition.

TSH Receptor Reduces Hemoglobin S Polymerization and Increases Deformability and Adhesion of Sickle Erythrocytes.

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

Bidirectional Relationship Between Sickle Cell Disease and Food Insecurity: Scoping Review.

In the United States, sickle cell disease (SCD)-the homozygous inheritance of a point mutation within the beta-globin chain of hemoglobin-affects between 80,000 and 100,000 people. Adequate nutrition can influence the pathophysiology of SCD, and individuals with SCD who are undernourished are more likely to have impaired immune function and disease exacerbation. Undernourishment is often caused by food insecurity (FI), which is defined as "a household-level economic and social condition of limited or uncertain access to adequate food" by the USDA. FI disproportionately affects African Americans, a population disproportionately affected by SCD in the United States. We performed a scoping review to better understand the relationship between FI and SCD severity. A comprehensive search for peer-reviewed research articles and meeting abstracts was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Selected studies were reviewed for descriptive analysis by three independent reviewers. In total, 72 studies were identified, 62 were excluded for meeting inclusion criteria. The remaining 10 studies, 5 of which were meeting abstracts, were reviewed. Although limited evidence is available, the results of this scoping review suggest a bidirectional relationship between SCD and FI. Seven key themes were identified to help elucidate this relationship: 1) prevalence of FI among individuals with SCD, 2) child versus caregiver experiences of FI, 3) psychosocial factors, 4) food assistance benefits, 5) dietary intake, 6) external spending, 7) healthcare utilization. Findings from this scoping review suggest how SCD and FI work in tandem to exacerbate each other. Furthermore, the findings illustrate current gaps in the literature and opportunities for actions to address FI among individuals living with SCD.

DEPRESSIVE DISORDER AND SICKLE CELL DISEASE: A state of art

The connection between sickle cell disease and depression, although crucial, remains an inadequately explored field, calling for further investigation. This notably concerning health scenario demands more specialized attention from professionals in the field. The present study aims to meticulously analyze the relationship between sickle cell disease and depression, delving into the state of the art on this subject, incorporating sources such as articles, books, dissertations, and theses. Individuals with sickle cell disease show a propensity for elevated levels of depression compared to the general population. Additionally, it has been observed that patients with sickle cell disease and depression experience an intensification of pain compared to their counterparts without depression, suggesting an intrinsic correlation between pain and both conditions. The in-depth analysis of the pathophysiology of both sickle cell disease and depression played a fundamental role in understanding this interconnection. It is concluded that the quality of life for these individuals is compromised, not only in terms of pathophysiological aspects but also in the realms of mental health, highlighting a significant increase in morbidity associated with the presence of depression. In this context, seeking medical assistance proves crucial to mitigate the impacts on the mental health of individuals with sickle cell disease, emphasizing the need for a holistic and integrated approach to substantially improve their quality of life.

Constitutive hypercoagulability in pediatric sickle cell disease patients with hemoglobin SS genotype

BackgroundConstitutive inflammation and hemostatic activation have been identified as key contributors to the pathophysiology of sickle cell disease (SCD), leading to clinical consequences such as vaso-occlusive crises and stroke. Patients with hemoglobin SS (HbSS) and hemoglobin SC (HbSC) genotypes are reported to have different symptoms, as do patients in steady-state and crisis situations. Differences among these groups remain unclear in pediatric patients. ObjectivesTo compare hemostatic activity in HbSS and HbSC pediatric patients during steady state, in crisis, and in clinical follow-up and compare HbSS and HbSC patients with normal healthy children. MethodsWhole-blood coagulation assay thromboelastography (TEG) was used to assess hemostatic activity. In parallel, flow cytometry was used to assess procoagulant surface expression of platelets and red blood cells. ResultsTEG results indicated no significant differences in clotting onset (R time), clot maximum amplitude, or maximum rate of thrombus generation among steady-state, crisis, and follow-up subgroups of HbSS and HbSC patients. TEG parameters did not differ significantly between HbSC patients and healthy children, while HbSS patients showed significantly shorter R time and greater maximum amplitude and maximum rate of thrombus generation, all indicative of a constitutive hypercoagulable state. Flow cytometry results did not detect increased platelet integrin αIIbβ3 activation or red blood cell procoagulant surface expression in SCD patients compared with unaffected children. ConclusionOur results indicate that pediatric SCD patients with the HbSS genotype have constitutively activated hemostasis relative to HbSC patients and healthy children. It remains to be determined how treatments that improve clinical outcomes in SCD patients affect this constitutively hypercoagulable state.

Soluble guanylate cyclase stimulators and activators: new horizons in the treatment of priapism associated with sickle cell disease.

Priapism, defined as a prolonged and often painful penile erection occurring without sexual stimulation or desire, is a common complication in sickle cell disease (SCD), affecting up to 48% of male patients. This condition presents significant clinical challenges and can lead to erectile dysfunction if not properly managed. Current pharmacological treatments for SCD-related priapism are primarily reactive rather than preventative, highlighting a gap in effective medical intervention strategies. A critical factor in developing priapism is the reduced basal bioavailability of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) in erectile tissues. New prevention strategies should ideally target the underlying pathophysiology of the disease. Compounds that stimulate and activate soluble guanylate cyclase (sGC) emerge as potential therapeutic candidates since these compounds have the property of inducing cGMP production by sGC. This review explores the potential of sGC stimulators and activators in treating priapism associated with SCD. We discuss the advantages of these agents in the face of the challenging pathophysiology of SCD. Additionally, the review underscores the impact of intravascular hemolysis and oxidative stress on priapism pathophysiology in SCD, areas in which sGC stimulators and activators may also have beneficial therapeutic effects.

Red Blood Cells as Therapeutic Target to Treat Sickle Cell Disease.

Significance: Sickle cell disease (SCD) is the most common inherited diathesis affecting mostly underserved populations globally. SCD is characterized by chronic pain and fatigue, severe acute painful crises requiring hospitalization and opioids, strokes, multiorgan damage, and a shortened life span. Symptoms may appear shortly after birth, and, in less developed countries, most children with SCD die before attaining age 5. Hematopoietic stem cell transplant and gene therapy offer a curative therapeutic approach, but, due to many challenges, are limited in their availability and effectiveness for a majority of persons with SCD. A critical unmet need is to develop safe and effective novel targeted therapies. A wide array of drugs currently undergoing clinical investigation hold promise for an expanded pharmacological armamentarium against SCD. Recent Advances: Hydroxyurea, the most widely used intervention for SCD management, has improved the survival in the Western world and more recently, voxelotor (R-state-stabilizer), l-glutamine, and crizanlizumab (anti-P-selectin antibody) have been approved by the Food and Drug Administration (FDA) for use in SCD. The recent FDA approval emphasizes the need to revisit the advances in understanding the core pathophysiology of SCD to accelerate novel evidence-based strategies to treat SCD. The biomechanical breakdown of erythrocytesis, the core pathophysiology of SCD, is associated with intrinsic factors, including the composition of hemoglobin, membrane integrity, cellular volume, hydration, andoxidative stress. Critical Issues and Future Directions: In this context, this review focuses on advances in emerging nongenetic interventions directed toward the therapeutic targets intrinsic to sickle red blood cells (RBCs), which can prevent impaired rheology of RBCs to impede disease progression and reduce the sequelae of comorbidities, including pain, vasculopathy, and organ damage. In addition, given the intricate pathophysiology of the disease, it is unlikely that a single pharmacotherapeutic intervention will comprehensively ameliorate the multifaceted complications associated with SCD. However, the availability of multiple drug options affords the opportunity for individualized therapeutic regimens tailored to specific SCD-related complications. Furthermore, it opens avenues for combination drug therapy, capitalizing on distinct mechanisms of action and profiles of adverse effects.

Evaluating sheep hemoglobins with MD simulations as an animal model for sickle cell disease

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

Oxidative Stress and Redox Signaling in the Pathophysiology of Sickle Cell Disease: A Review

Sickle Cell Disease (SCD) is a hereditary hemoglobinopathy characterized by the aberrant hemoglobin S, resulting in the formation of sickle-shaped red blood cells and a cascade of clinical complications. While the molecular aspects of SCD are well-elucidated, recent investigations underscore the critical influence of oxidative stress and redox signaling in the disease’s pathophysiology. This comprehensive review synthesizes current knowledge on the interplay between oxidative stress, redox signaling, and SCD, providing insights into potential therapeutic targets. Discussions encompass the generation of reactive oxygen species (ROS), antioxidant defense mechanisms, and the activation of redox-sensitive signaling pathways. The consequences of oxidative stress, such as vaso-occlusion, inflammation, and endothelial dysfunction, are examined in detail. Furthermore, the review evaluates existing antioxidant therapies, explores potential strategies targeting redox signaling pathways, and discusses emerging therapeutic targets. By elucidating the intricate relationship between oxidative stress and SCD, this review aims to advance our understanding of the disease’s complexity and pave the way for innovative therapeutic interventions, offering renewed hope for enhanced patient care and management.

Unraveling the Molecular Complexity of Eosinophil Dynamics in Sickle Cell Anemia: An Overview of the Literature

Sickle Cell Anemia (SCA) is a genetic disorder characterized by abnormal hemoglobin, leading to distorted red blood cells and a myriad of clinical complications. Recent research has highlighted the role of eosinophils in the pathophysiology of SCA, emphasizing the need to explore their dynamics from a molecular perspective. This review synthesizes current knowledge on seven key aspects of eosinophil involvement in SCA, shedding light on the intricate molecular mechanisms driving their activation, recruitment, and impact on disease progression. We delve into the molecular crosstalk between eosinophils and cytokine signaling, their contribution to endothelial dysfunction, and their role in oxidative stress. Furthermore, the review examines the molecular basis of eosinophil-induced vaso-occlusive crises and the formation of eosinophil extracellular traps. Lastly, we discuss the therapeutic implications of understanding eosinophil dynamics in SCA and propose future research directions. This comprehensive exploration aims to enhance our understanding of the molecular intricacies underlying eosinophil involvement in SCA, paving the way for targeted therapeutic interventions to alleviate the burden of this debilitating disease.

Hemolysis in Pregnancy: Considerations for Sickle Cell Anemia Patients

Hemolysis in pregnancy represents a complex and multifaceted challenge, particularly for individuals grappling with sickle cell anemia. This review delves into the intricate interplay between the physiological changes induced by pregnancy and the underlying pathophysiology of sickle cell anemia. It provides a comprehensive examination of the clinical implications, management strategies, and recent research advances pertaining to hemolysis in pregnant women with sickle cell anemia. The physiological adaptations inherent in pregnancy, including alterations in the cardiovascular and hematologic systems, create a dynamic environment that may exacerbate hemolysis in individuals with sickle cell anemia. This review elucidates the intricacies of these changes, establishing a foundation for understanding the heightened risks and challenges faced by pregnant women with this inherited blood disorder. Effective management strategies are crucial for optimizing outcomes in pregnant women with sickle cell anemia experiencing hemolysis. This review provides an in-depth analysis of various approaches, including the role of hydroxyurea therapy, blood transfusions, and meticulous monitoring of maternal and fetal parameters. By evaluating the potential benefits and risks of each strategy, clinicians are equipped with valuable insights to tailor interventions to individual patient needs. In conclusion, this comprehensive review offers a synthesized perspective on the considerations surrounding hemolysis in pregnancy for individuals with sickle cell anemia. Bridging the realms of physiology, clinical practice, and research, it provides a valuable resource for healthcare professionals, researchers, and policymakers seeking to enhance the care and outcomes of pregnant women grappling with sickle cell anemia and heightened hemolytic challenges.

Comprehensive Insights into Eosinophil Interactions in Sickle Cell Anemia Severity

Sickle Cell Anemia (SCA) is a prevalent inherited blood disorder characterized by abnormal hemoglobin leading to erythrocyte deformation and consequential vaso-occlusive events. While the primary focus has traditionally centered on the role of red blood cells in SCA pathophysiology, recent investigations have unveiled the intricate involvement of eosinophils in modulating disease severity. Eosinophils, classically recognized for their role in parasitic infections and allergic responses, have emerged as significant contributors to the inflammatory milieu and vascular dysfunction observed in SCA. This paper aims to provide an extensive understanding of the multifaceted interactions between eosinophils and the pathogenesis of sickle cell anemia, emphasizing their impact on disease severity. Insights into eosinophil biology, including their cytokine release profile, granule protein activity, and endothelial interactions, underscore their dual role in both propagating and modulating inflammation in the context of SCA. The complex interplay between eosinophils and the inflammatory microenvironment in SCA dictates disease severity, warranting a deeper understanding of these interactions for the development of targeted therapeutic strategies. In conclusion, this comprehensive review consolidates current knowledge regarding eosinophil involvement in sickle cell anemia severity, emphasizing the necessity for further investigations into specific eosinophilic mechanisms. A deeper comprehension of eosinophilic contributions to SCA pathophysiology presents a pathway toward novel therapeutic modalities, ultimately enhancing the management and prognosis of individuals afflicted with this challenging hematologic disorder.

Clinical Implications of Neutrophil-to-Lymphocyte Ratio in Sickle Cell Disease

Sickle Cell Disease (SCD) is a hereditary hemoglobinopathy characterized by chronic hemolytic anemia and vaso-occlusive events. In recent years, the Neutrophil-to-Lymphocyte Ratio (NLR) has emerged as a potential biomarker with prognostic and diagnostic significance in various medical conditions. This review explores the clinical implications of NLR in the context of SCD, shedding light on its role as a valuable indicator of inflammation, disease severity, and treatment response. The inflammatory state is a key contributor to the pathophysiology of SCD, influencing disease progression and complications. NLR, calculated from routine complete blood counts, reflects the balance between the immune response’s cellular components and has been implicated in assessing the inflammatory status in various diseases. In the context of SCD, elevated NLR has been associated with increased vaso-occlusive events, suggesting its potential utility as a predictive marker for disease complications. In conclusion, this perspective review consolidates current knowledge on the clinical implications of NLR in Sickle Cell Disease. It highlights the potential of NLR as a readily available and cost-effective biomarker for assessing inflammation, predicting disease severity, and monitoring treatment response in individuals with SCD. As the understanding of the immunological aspects of SCD continues to evolve, NLR stands out as a promising parameter that may contribute to a more comprehensive approach to managing this complex hematologic disorder.

Clearance of VWF by hepatic macrophages is critical for the protective effect of ADAMTS13 in sickle cell anemia mice

AbstractAlthough it is caused by a single-nucleotide mutation in the β-globin gene, sickle cell anemia (SCA) is a systemic disease with complex, incompletely elucidated pathologies. The mononuclear phagocyte system plays critical roles in SCA pathophysiology. However, how heterogeneous populations of hepatic macrophages contribute to SCA remains unclear. Using a combination of single-cell RNA sequencing and spatial transcriptomics via multiplexed error-robust fluorescence in situ hybridization, we identified distinct macrophage populations with diversified origins and biological functions in SCA mouse liver. We previously found that administering the von Willebrand factor (VWF)–cleaving protease ADAMTS13 alleviated vaso-occlusive episode in mice with SCA. Here, we discovered that the ADAMTS13-cleaved VWF was cleared from the circulation by a Clec4f+Marcohigh macrophage subset in a desialylation-dependent manner in the liver. In addition, sickle erythrocytes were phagocytized predominantly by Clec4f+Marcohigh macrophages. Depletion of macrophages not only abolished the protective effect of ADAMTS13 but exacerbated vaso-occlusive episode in mice with SCA. Furthermore, promoting macrophage-mediated VWF clearance reduced vaso-occlusion in SCA mice. Our study demonstrates that hepatic macrophages are important in the pathogenesis of SCA, and efficient clearance of VWF by hepatic macrophages is critical for the protective effect of ADAMTS13 in SCA mice.

NOS3, ET1, TGF-β1, and THBS1 polymorphisms modulating clinical complications in sickle cell disease patients

Clinical manifestations are highly variable in sickle cell disease (SCD) and polymorphisms (SNP) may modify vascular homeostasis. Because of this, we investigated of SNP of NOS3, ET1, TGF-β1 and THBS1 genes in vascular complications of SCD. High risk of hospitalization was found for genotypes NOS3TC/CC (rs2070744 - RR: 1.94) and THBS1AG/GG (rs1478604 - RR: 1.59) while low risk to NOS3GT/TT (rs1799983 - RR: 0.53). Hydroxyurea treatment was more frequent in the genotypes NOS3TC/CC (rs2070744 - RR: 1.83), ET1GT/TT (rs5370 - RR: 2.67) and ET1TG/GG (rs1800541 - RR: 1.43). Alleles ET1TG/GG (rs1800541) showed correlation for abdominal, arm and leg pain, bone disorders, cholelithiasis and vaso-occlusive crisis, while ET1GT/TT (rs5370) with chest pain, painful episodes, splenic sequestration and stroke. Interestingly, the NOS3GT/TT (rs1799983) alleles had a high stroke risk (RR:4.21), though, protection against bone disorders, cholelithiasis and less risk of hospitalization. We believed that our results indicate polymorphisms that may provide benefits in the treating Clinical Complications in SCD Patients, especially in vascular SCD pathophysiology, modulating vaso-occlusion crisis.

Overview of the Association Between the Pathophysiology, Types, and Management of Sickle Cell Disease and Stroke.

Sickle cell disease (SCD) is a genetic blood disorder that affects hemoglobin and increases stroke risk, particularly in childhood. This review examines the pathophysiological association between SCD and stroke, the classification of stroke types, risk factors, diagnosis, management, prevention, and prognosis. A comprehensive literature search was conducted via PubMed, Scopus, and Cochrane databases. Relevant studies on SCD and stroke pathophysiology, classification, epidemiology, diagnosis, treatment, and prevention were identified. Sickle cell disease causes red blood cells to become rigid and sickle-shaped, obstructing blood vessels. Recurrent sickling alters cerebral blood flow and damages vessel walls, often leading to ischemic or hemorrhagic strokes (HS). These occur most frequently in childhood, with ischemic strokes (IS) being more common. Key risk factors include a prior transient ischemic attack (TIA), low hemoglobin, and a high leukocyte count. Neuroimaging is essential for diagnosis and determining stroke type. Primary prevention centers on blood transfusions and hydroxyurea for those at high risk. Acute treatment involves promptly restoring blood flow and managing complications. However, significant knowledge gaps remain regarding stroke mechanisms, optimizing screening protocols, and improving long-term outcomes. This review synthesizes current evidence on SCD and stroke to highlight opportunities for further research and standardizing care protocols across institutions. Ultimately, a holistic perspective is critical for mitigating the high risk of debilitating strokes in this vulnerable patient population.

Pyruvate kinase activators: targeting red cell metabolism in sickle cell disease.

Hemoglobin S (HbS) polymerization, red blood cell (RBC) sickling, chronic anemia, and vaso-occlusion are core to sickle cell disease (SCD) pathophysiology. Pyruvate kinase (PK) activators are a novel class of drugs that target RBC metabolism by reducing the buildup of the glycolytic intermediate 2,3-diphosphoglycerate (2,3-DPG) and increasing production of adenosine triphosphate (ATP). Lower 2,3-DPG level is associated with an increase in oxygen affinity and reduction in HbS polymerization, while increased RBC ATP may improve RBC membrane integrity and survival. There are currently 3 PK activators in clinical development for SCD: mitapivat (AG-348), etavopivat (FT-4202), and the second-generation molecule AG-946. Preclinical and clinical data from these 3 molecules demonstrate the ability of PK activators to lower 2,3-DPG levels and increase ATP levels in animal models and patients with SCD, as well as influence a number of potential pathways in SCD, including hemoglobin oxygen affinity, RBC sickling, RBC deformability, RBC hydration, inflammation, oxidative stress, hypercoagulability, and adhesion. Furthermore, early-phase clinical trials of mitapivat and etavopivat have demonstrated the safety and tolerability of PK activators in patients with SCD, and phase 2/3 trials for both drugs are ongoing. Additional considerations for this novel therapeutic approach include the balance between increasing hemoglobin oxygen affinity and tissue oxygen delivery, the cost and accessibility of these drugs, and the potential of multimodal therapy with existing and novel therapies targeting different disease mechanisms in SCD.

Dietary Behaviors and Social Determinants of Health Among Adults Living with Sickle Cell Disease

Background: Social determinants of health (SDoH) may impact outcomes in sickle cell disease (SCD), and recent literature reports that particular SDoH, such as food insecurity and housing insecurity, may impact diet choices for individuals with SCD. Notably, health outcomes in SCD are linked to diet choices through increased protein and caloric needs, and through nutrients, such as polyphenols, omega fatty acids and micronutrients, which are involved in SCD pathophysiology. The connection between SDoH and diet quality may occur through multiple pathways including access to food, affordability, chronic pain and psychosocial factors at the individual and family level. Importantly, the impact of this connection may relate to outcomes such as pain frequency, hospitalizations, and SCD pathophysiologic biomarkers, such as inflammation. Study Design and Methods: The Diet and SCD Study (NCT: 05170412) is an observational mixed-methods study initiated in 2021 at the National Institutes of Health Clinical Center (NIH CC) in Bethesda MD with a target sample of 75 adults living with SCD in the United States. The purpose of the study is to evaluate associations between SDoH (food insecurity, neighborhood food access, education, employment, healthcare access), dietary intake, and population health related outcomes among adults living with SCD. Study inclusion criteria consists of adults (≥18 years of age) residing within the United States at the time of screening who have a confirmed diagnosis of sickle cell disease with any genotype, and are not hospitalized at the time of enrollment. To ensure participation from adults in diverse regions of the United States, the study has a hybrid design of in-person and telehealth procedures. In-person protocol visits are conducted at the NIH CC. The CC clinical visit includes a clinical assessment, anthropometric measurements, phlebotomy, as well as monitored/proctored electronic surveys that collect SDoH and disease severity variables. The telehealth protocol visit includes a virtual clinical assessment, phlebotomy at a local laboratory center, as well as the same monitored/proctored electronic surveys completed by CC clinical visit participants. A dietary behavior semi-structured interview is conducted at both the CC clinical visit and telehealth protocol visit to garner participants' personal stories related to food choices and diet. Laboratory variables include SCD disease specific markers, amino acid levels, and measurement of inflammatory cytokine markers. All participants undergo two unannounced phone-administered 24-hour dietary recall interviews with trained NIH nutrition staff to measure recent dietary intake. Data from 24-hour recall interviews are used to determine fluid, caloric, macro and micronutrient, and polyphenol intake. Usual dietary intake of foods of potentially related to SCD pathophysiology (cruciferous vegetables and thiocyanate-rich foods) is measured through self-administered electronic 12-month food frequency questionnaires. Primary objectives are to evaluate social determinants of health related to food security and access relevant to disease severity among adults living with sickle cell disease in the U.S. Secondary outcomes are to evaluate the association of dietary quality, specific dietary nutrient intake and serum levels, including amino acids and polyphenols, with disease severity. Tertiary outcomes include evaluating inflammatory and glucometabolic biomarkers with measures of social determinants of health. When completed, the Diet and SCD study will provide important information on the associations between SDoH, dietary quality, inflammatory biomarkers and disease severity for adults living with SCD and provide initial data for future cohort and intervention studies.