Dysfunction In Sickle Cell Disease Research Articles

Determinants of cognitive dysfunction in adults with sickle cell–related stroke or suspected neurological morbidity

AbstractThe prognosis of sickle cell disease (SCD) in adults is determined primarily by damage to targeted organs such as the brain. Cognitive dysfunction in SCD is a common chronic neurological manifestation, but studies remain mostly descriptive in adults. The objective of this study was to better characterize the cognitive profile and the association between cognitive dysfunction and brain lesions. We included adult patients with SCD referred for a neurological assessment. An adapted battery of neuropsychological tests was used to assess cognitive deficits. Brain or arterial abnormalities were assessed using brain magnetic resonance imaging/magnetic resonance angiography and a cervical and transcranial Doppler ultrasound. The cognitive profile of 96 patients was characterized by deficits in processing speed (58%), short-term memory (34%), and working memory (24%). Brain infarcts were found in 56% of patients and intracranial vasculopathy in 49%. Twenty percent of patients had no brain abnormalities. Processing speed dysfunction was associated with territorial infarcts (odds ratio [OR], 3.1; P = .03) and education outside of France (OR, 4.7; P = .02). Short-term memory dysfunction was associated with territorial infarcts (OR, 3.4; P = .01) and a low educational level (OR, 8.2; P = .01). Working memory dysfunction was associated with a low educational level (OR, 4.3; P = .05) and vasculopathy (OR, 3.7; P = .03). Cognitive dysfunction appears to be a hallmark sign of SCD, particularly for adults with sickle cell-related stroke or suspected neurological morbidity. Assessment of such dysfunction could be used in longitudinal follow-up and clinical trials.

Endothelial Dysfunction Linked to Ventricular Dysfunction in Children With Sickle Cell Disease, a 3D Speckle Tracking Study.

Sickle Cell Disease (SCD) is not a hematologic disease that occurs in isolation; it results in multi-organ complications. There is growing evidence of vascular stiffness as its underlying cause. This study aimed to investigate the relationship between endothelial stiffness and LV dysfunction in SCD patients and to explore its pathophysiology, particularly regarding the depletion of vasodilators such as Nitric Oxide (NO). 32 patients with established criteria for SCD and 40 healthy control subjects were selected for this case-control study. Comprehensive clinical assessment and assessment of endothelial function using Brachial Flow-mediated dilation (FMD) were performed, along with serum NO measurement, which was followed by diagnosis and echocardiographic assessment using 3D speckle tracking echocardiography (STE) and tissue Doppler imaging (TDI). Collected SCD cases showed echocardiographic features of Systo-diastolic dysfunction with reduced FMD compared to controls, denoting endothelial dysfunction in those patients. LDH showed a marked elevation, while serum NO showed a significant reduction in cases compared with controls. We also noted a positive correlation between FMD on the one hand and measures of ventricular dysfunction and level of serum NO on the other hand, the latter proving that reduction of NO is responsible for reduced endothelial function. We present the first report to date to outline the role of vascular stiffness as measured by brachial FMD in the induction of left ventricular dysfunction in SCD. We recommend that more research be conducted regarding possible strategies to replenish serum NO stores to delay microvascular injury and, in turn, ventricular dysfunction in SCD.

CASE-SA-09 - The Role of CMR in Assessing the Aetiology of Left Ventricular Systolic Dysfunction in Sickle Cell Disease: Three "Contrasting" Cases

CASE-SA-09 - The Role of CMR in Assessing the Aetiology of Left Ventricular Systolic Dysfunction in Sickle Cell Disease: Three "Contrasting" Cases

Comfort Therapy with Companionship Improves Learning Memory and Reduces Hyperalgesia in Sickle Mice

Chronic and unpredictable acute pain coexist with cognitive dysfunction in sickle cell disease (SCD). Managing chronic pain is crucial, though efforts are complicated by both physiological and affective contributors to pain. The affective state, which is severely impacted by the environment including stigma and social isolation, plays a substantial role in pain perception and may further exacerbate psychological factors. Therefore, we examined if companionship and social isolation influence cognitive function and pain in SCD. In the present study, we examined the effects of social isolation on hyperalgesia, learning memory, and anxiety in humanized transgenic homozygous BERK mouse model of SCD. At ~3.5 months of age, BERK male mice were paired with age-matched female BERK companions (1 male + 1 female/cage; called companion group) and another group of BERK males were placed into isolation (one male/cage; called isolation group) for ~14 months. Isolation and companion groups were maintained in general housing conditions in the same room. Both groups were assessed for body weight, hyperalgesia and cognitive behaviors. Mechanical hyperalgesia was assessed by counting paw withdrawal frequency (PWF) following 10 applications of a 1.0 g von Frey monofilament (Semmes Weinstein, Stoelting, Wood Dale, IL, USA) to the plantar surface of the hind paw. Cold hyperalgesia was assessed following placement of mice onto a 4°C cold plate chamber (Stoelting) and by measuring PWF over a 2-minute period. Musculoskeletal hyperalgesia was measured by testing grip force of each mouse's peak forepaw grip to a computerized grip force meter (SA Maier, Milwaukee, WI, USA) and normalizing by body weight. The cognitive behavioral assessment consisted of an open field test to assess anxiety-related behaviors, which measured time spent and number of crosses through a central region. Working memory was assessed using novel object recognition and novel placement recognition tests to measure discrimination of novel objects and location. Data are shown as mean ± SEM and comparisons between companionship and isolation groups were performed using unpaired, two-tailed T-tests to determine statistical significance (P<0.05) We observed a significant increase in the body weights of males housed with females ( Companion group) compared to males in isolation (p<0.05). It is likely that males living with a companion were eating more compared to those under isolation. Isolated male sickle mice experience greater hyperalgesia than male mice housed with a female companion. Isolation induces greater PWF to mechanical (P<0.05) and cold (P<0.005) stimuli, indicating exacerbated hypersensitivity to mechanical and cold stimuli. Spontaneous, non-evoked musculoskeletal hyperalgesia was not significantly altered by isolation (P>0.05). Isolation also appeared to impact working and learning memory. Novel object recognition and novel object placement tests revealed reduced discrimination ratios in isolated mice (~25%, P<0.05 and ~25%, P<0.05), which are suggestive of impaired learning and memory function compared to mice with companionship. Open field test showed no significant difference (P>0.05) between isolation and companionship groups in time spent and number of crosses in the open field center area, indicating no detectable differences in anxiety-like behaviors. According to cognitive tests, mice in companionship showed greater novel object and place detection and greater cognitive ability compared to those in isolation. For the first time we show the causal role of social isolation on hyperalgesia and memory in a humanized mouse model of SCD. “ Comfort therapy” with companionship can ameliorate the perception of pain through the higher brain centres. It is also likely that mice in companionship eat more as evinced by a significant increase in their weight, which may provide additional comfort and meet the increased nutritional/calorie demands of SCD due to altered metabolism. Our observations suggest that “ comfort therapy” with improved living conditions and reducing isolation and loneliness may improve pain-related outcomes in SCD.

Portosinusoidal Vascular Disorder: A Heretofore Unrecognized Manifestation of Sickle Cell Disease?

Portosinusoidal vascular disorder (PSVD) is a recently proposed histopathologic entity that encompasses a spectrum of often subtle hepatic microvascular lesions and related microarchitectural abnormalities. Clinical manifestations may arise years after histologic diagnosis and include extrahepatic portal vein thrombosis and portal hypertension. While the histopathologic features of PSVD have been associated with numerous clinical conditions, most notably prothrombotic/vasculopathic disorders, PSVD has not yet been described in sickle cell disease. This gap is striking given the central role of microvascular dysfunction in sickle cell disease and well-described patterns of hepatic injury and dysfunction in this population. This case series is the first to explore the prevalence and pathogenesis of PSVD in sickle cell disease. Forty-one diagnostically adequate liver biopsies from patients with sickle cell disease were identified across the archives of 5 tertiary medical centers. All biopsies exhibited at least 1 histopathologic feature associated with PSVD (mean 3.8 features/case). Overall, 90.2% of patients met the criteria for a diagnosis of PSVD based on the presence of specific histopathologic and/or clinical findings. Immunohistochemical stains for von Willebrand factor, CD34, and glutamine synthetase were performed on 36 cases (87.8%). Aberrant (centrilobular sinusoidal) CD34 and von Willebrand factor staining was present in 97.2% and 86.1% of cases, respectively. Glutamine synthetase reactivity was at least mildly decreased in zone 3 hepatocytes in 52.8% of cases. We posit that chronic erythrocyte sickling results in dysfunction and remodeling of the portal microvasculature, culminating in regression of zone 3 hepatocytes. The presence of PSVD may explain, at least in part, the hepatic dysfunction observed in this patient population. These patients may also benefit from extended clinical surveillance for portal hypertension and other complications. While subtle and prone to overdiagnosis, the features of PSVD should be carefully considered when interpreting liver biopsies from patients with sickle cell disease.

PB1403 Physiological Levels of Vascular Turbulence Increase Hemolysis with Implications for Vascular Dysfunction in Sickle Cell Disease

PB1403 Physiological Levels of Vascular Turbulence Increase Hemolysis with Implications for Vascular Dysfunction in Sickle Cell Disease

Impact of Sickle Cell Disease on Affected Individuals in Nigeria: A Critical Review.

Sickle cell disease is an autosomal recessive disorder of the beta-globin gene, with resultant deformation of the red blood cells and variable clinical outcomes. Nigeria is recognised as the country with the highest burden of sickle cell disease globally. This study aimed at critically reviewing available literature on impact of sickle cell disease in Nigeria. A literature search was carried out on four databases, and a total of 116 articles that met the inclusion criteria were included in the critical review. It was observed that majority of the studies were carried out in South-Western part of Nigeria (47.4%), whilst the North-East had the least number of studies undertaken in this area, more than a quarter of the studies (27.6%) were related to hematologic and serologic screening. Major themes that emerged from this review were morbidity and mortality; prevalence of sickle cell disease; issues relating to blood transfusion; psychosocial impact; and anatomical dysfunction in sickle cell disease. Intervention programs from both government and non-governmental organizations aimed at reducing the burden of sickle cell disease and its socio-economic impact were identified as key to strategies aimed at overcoming challenges associated with the disease. Findings from this study also revealed that education and awareness interventions were central to reducing the prevalence of sickle cell disease in this setting.

Evaluation of left ventricular systolic function in children with sickle cell anemia: contribution of 2D strain.

Children with sickle cell anemia (SCA) are at an increased risk of cardiovascular complications. The aim of this study was to assess the role of speckle tracking echocardiography in detecting subclinical myocardial damage in children with SCA. A cross-sectional case-control study was conducted at the echocardiography laboratory of the military hospital of Tunis between July and December 2018. Thirty patients with SCA were included. A control(C) group including 30 normally developing children was selected and matched to the SCA group by sex and age. We compared between the two groups: conventional echocardiographic parameters including cardiac output, left ventricular ejection fraction (LVEF), thickness and the global longitudinal strain (GLS). The echocardiographic measurements were indexed according to body surface area. The left ventricular (LV) GLS association with clinical characteristics and echocardiographic parameters were also evaluated. Patients and controls were matched for age and sex: the mean age was (11± 2years) in SCA group versus (12± 1 years) in C group with a sex ratio of (1.31 versus 1.27, respectively). Body surface area was comparable. LV hypertrophy and dilation were revealed in the SCA group, whereas measurements were normal in the C group. No significant differences were observed for cardiac output (p=0.4). LVEF were preserved in both groups. However, two-dimensional (2D) LVGLS was impaired in 46% of SCA group (n=14) with mean value of (-21%±3.07 vs -25%±2.98; p<0.01).In SCA group, impaired LVGLS was significantly associated with LVmass (r = - 0.399, p<0.01), LV tele diastolic diameter(r= -0.419, p<0.01) and left atrial volume (r= - 0.399, p< 0.04). In multivariate analysis, LV mass was the only independent factor. In the present study, LVGLS measurement revealed subclinical LV systolic impairment in patients with SCA. Therefore, 2D strain could be beneficial to detect the natural history of LV dysfunction in SCA.

Diffuse myocardial fibrosis occurs in young patients with sickle cell anemia despite early disease-modifying therapy

Letter to Blood| March 16, 2023 Diffuse myocardial fibrosis occurs in young patients with sickle cell anemia despite early disease-modifying therapy Clinical Trials & Observations Cara E. Morin, Cara E. Morin ∗ 1Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH2Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN https://orcid.org/0000-0003-1953-4486 Search for other works by this author on: This Site PubMed Google Scholar Akshay Sharma, Akshay Sharma ∗ 3Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN https://orcid.org/0000-0003-3281-2081 Search for other works by this author on: This Site PubMed Google Scholar Subodh Selukar, Subodh Selukar 4Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN https://orcid.org/0000-0002-3802-488X Search for other works by this author on: This Site PubMed Google Scholar Gary Beasley, Gary Beasley 5Division of Pediatric Cardiology, University of Tennessee Health Science Center, Le Bonheur Children’s Hospital, Memphis, TN https://orcid.org/0000-0001-6137-6114 Search for other works by this author on: This Site PubMed Google Scholar Anthony Merlocco, Anthony Merlocco 2Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN5Division of Pediatric Cardiology, University of Tennessee Health Science Center, Le Bonheur Children’s Hospital, Memphis, TN6Division of Pediatric Radiology, University of Tennessee Health Science Center, Le Bonheur Children’s Hospital, Memphis, TN https://orcid.org/0000-0001-6228-0229 Search for other works by this author on: This Site PubMed Google Scholar Chris Goode, Chris Goode 2Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN Search for other works by this author on: This Site PubMed Google Scholar Parul Rai, Parul Rai 7Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN https://orcid.org/0000-0002-5770-7280 Search for other works by this author on: This Site PubMed Google Scholar Jeffrey A. Towbin, Jeffrey A. Towbin 5Division of Pediatric Cardiology, University of Tennessee Health Science Center, Le Bonheur Children’s Hospital, Memphis, TN Search for other works by this author on: This Site PubMed Google Scholar Jane S. Hankins, Jane S. Hankins † 7Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN https://orcid.org/0000-0003-4439-7321 Search for other works by this author on: This Site PubMed Google Scholar Jason N. Johnson Jason N. Johnson † 2Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN5Division of Pediatric Cardiology, University of Tennessee Health Science Center, Le Bonheur Children’s Hospital, Memphis, TN6Division of Pediatric Radiology, University of Tennessee Health Science Center, Le Bonheur Children’s Hospital, Memphis, TN https://orcid.org/0000-0003-0712-1123 Search for other works by this author on: This Site PubMed Google Scholar Blood (2023) 141 (11): 1358–1362. https://doi.org/10.1182/blood.2022018209 Article history Submitted: August 26, 2022 Accepted: November 14, 2022 Connected Content This is a related article to: Heart failure in SCA: still challenging Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Request Permissions Cite Icon Cite Search Site Citation Cara E. Morin, Akshay Sharma, Subodh Selukar, Gary Beasley, Anthony Merlocco, Chris Goode, Parul Rai, Jeffrey A. Towbin, Jane S. Hankins, Jason N. Johnson; Diffuse myocardial fibrosis occurs in young patients with sickle cell anemia despite early disease-modifying therapy. Blood 2023; 141 (11): 1358–1362. doi: https://doi.org/10.1182/blood.2022018209 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBlood Search Subjects: Clinical Trials and Observations, Pediatric Hematology, Red Cells, Iron, and Erythropoiesis, Sickle Cell Disease, Transplantation TO THE EDITOR: We read with great interest the recent report from Niss et al.1 Our group has recently reviewed data from a similar population at our institution, which does not support the conclusion of Niss et al that diffuse myocardial fibrosis is prevented by early initiation of disease-modifying therapy (DMT). Cardiovascular complications are the leading cause of early mortality in patients with sickle cell anemia (SCA).2 Yet, the pathobiology of sickle cell cardiomyopathy is incompletely understood and likely multifactorial.3 Chronic anemia leads to global cardiac enlargement and myocardial hypertrophy. Global cardiac chamber dilation is a common feature in patients with SCA, and enlarged left atrial (LA) volume is a marker of diastolic dysfunction in SCA.4 Repetitive microvascular ischemic insults and associated reperfusion injury may contribute to diffuse myocardial fibrosis and myocardial remodeling in individuals with SCA....

The Role of TSP-1, TGF-B1 and Galectin-3 in the Pathogenesis of ACS in Sickle Cell Disease

Sickle cell disease (SCD) is a hereditary blood disorder characterized by painful vaso-occlusive episodes (VOE), acute chest syndrome (ACS), stroke and other clinical complications. Seventy-six percent of the primary and secondary complications of SCD are pulmonary and are strongly associated with hemolysis. ACS is the main acute pulmonary complication of SCD and is characterized by critical lung injury from vaso-occlusion in the pulmonary vasculature, release of inflammatory mediators, and alveolar edema decreasing gas exchange. Endothelial dysfunction, characterized by increased production of inflammatory mediators, increased oxidative stress, and aberrant cellular proliferation via platelet-derived thrombospondin-1 (TSP-1) and transforming growth factor-1 (TGF-B1) is increasingly implicated in pulmonary vascular pathology in other diseases. In addition, a mediator of TGF-B1, galectin-3, has been shown to be induce tissue-specific fibrosis via fibroblast activation in animal disease models. However, the mechanisms by which human pulmonary artery endothelial cell (HPAEC) dysfunction is instigated remains unclear. We hypothesized a novel theory that TSP-1, TGF-B1, and galectin-3 play a causal role in the pathogenesis of ACS in SCD. We set out to test our hypothesis by measuring TSP-1, TGF-B1 and galectin-3 plasma levels in a cohort of patients with SCD with (n=10) and without history of ACS (n=20), and healthy, race and age-matched controls (n=10). Patients with ACS had significantly higher plasma levels of active TGF-B1 (11.34 ng/mL) than those of patients without ACS (5.2 ng/mL) and healthy controls (3.4 ng/mL). Similarly, we found that SCD patients with a history of ACS had significantly higher levels of TSP-1 (642.7 ng/mL) and galectin-3 (8.87 ng/mL) as compared to patients without ACS (285.9 ng/mL and 6.02 ng/mL, respectively) and controls (133.36 ng/mL and 5.2 ng/mL, respectively). We also found a significant correlation between TSP-1 and TGF-B1 levels in non-ACS SCD patients and patients with ACS as well as galectin-3 and TGF-B1 levels in the plasma of all SCD patients combined. Given that platelets are a significant source of TSP-1 and TGF-B1, we next tested whether platelets mechanistically potentiate endothelial cell dysfunction in SCD. HPAECs were co-cultured with platelets isolated from healthy vs steady-state SCD individuals. Platelets in co-culture were quiescent or activated with the agonists 0.1 U/mL thrombin, 25 ug/mL collagen, and 2.5 uM free heme for 6 hours, and HPAEC proliferation was measured via crystal violet staining 48 hours after exposure. We found HPAEC proliferation upon control and SCD platelet exposure to free heme, but SCD platelets exposed to heme induced a more robust response in HPAEC proliferation. In addition, we found that collagen only significantly promoted HPAEC proliferation in the presence of SCD platelets and not control platelets. Activated platelets, in the presence of hemolysis, release large amounts of TSP1 and TGF-B1 that may lead to enhanced endothelial cell proliferation and fibrosis in SCD, possibly via increased response to collagen by activated platelets. We will conduct further experiments to determine whether blockers of TSP-1 or its canonical CD47 endothelial receptor may abrogate aberrant cellular proliferation in SCD. Overall, the roles of TSP-1 and galectin-3 in pulmonary fibrotic injury via the TGF-B1 signaling pathway in SCD need to be further elucidated for therapeutic targeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Molecular mechanisms of hepatic dysfunction in sickle cell disease: lessons from Townes mouse model.

Sickle cell disease (SCD) is an autosomal recessive genetic disorder that affects ∼100,000 Americans and millions of people worldwide. Erythrocyte sickling, vaso-occlusion, sterile inflammation, and hemolysis are the major pathophysiological pathways leading to liver injury in SCD. Although hepatic dysfunction affects up to 10%-40% of patients with SCD, therapeutic approaches to prevent liver injury in SCD are not known, and the molecular mechanisms promoting progressive liver injury in SCD remain poorly understood. Animal models have been beneficial in bridging the gap between preclinical and translational research in SCD. Recent advances in methodology have allowed the development of several humanized animal models to address various aspects of SCD-related liver diseases. This review provides an overview of current knowledge of the molecular mechanisms and potential therapeutic options of SCD-associated liver dysfunction using the Townes mouse model.

PB2218: ASSESSMENT OF CYSTATIN C IN PEDIATRIC SICKLE CELL DISEASE AND B-THALASSEMIA AS A MARKER OF SUBCLINICAL CARDIOVASCULAR DYSFUNCTION: A CASE-CONTROL STUDY

Background: Cardiovascular complications represent the main determinant of survival in patients with hemoglobinopathies. Serum cystatin C is a well-known marker of nephropathy in sickle cell disease (SCD) and b-thalassemia patients that has recently emerged as a strong predictor of cardiovascular dysfunction in patients with and without kidney disease. Aims: We performed a case control study to determine the role of cystatin C as a predictor of subclinical cardiovascular dysfunction in SCD and b-thalassemia patients. Methods: We enrolled 40 SCD patients with a mean age of 12.4 years, 40 b-thalassemia patients with a mean age of 11.4 years and 40 age and sex-matched controls. We assessed hematological profile, serum ferritin, urinary albumin–creatinine ratio (UACR), serum cystatin C, echocardiography and carotid intima media thickness (CIMT). Results: UACR, cystatin C and CIMT were higher in SCD and b-thalassemia patients compared to controls (p < .001). Significantly higher cystatin C levels were observed in SCD and b-thalassemia patients with nephropathy or left ventricular systolic dysfunction (shortening fraction <30%, or ejection fraction <55%; p < .001). Moreover, SCD patients with pulmonary hypertension had significantly higher cystatin C levels. Cystatin C levels were positively correlated with CIMT in SCD (p = .02) and b-thalassemia patients (p < .001) while negatively correlated with ejection fraction and shortening fraction (p < .001). The cutoff values of cystatin C ≥ 16.03 and ≥ 13.2 (ng/mL) could detect subclinical cardiac dysfunction risk among SCD and b-thalassemia patients respectively. Summary/Conclusion: Cystatin C appears to be a promising marker for subclinical cardiovascular dysfunction in SCD and b-thalassemia patients.

Increased Circulating Copeptin Levels Are Associated with Vaso-Occlusive Crisis and Right Ventricular Dysfunction in Sickle Cell Anemia

Objective: Vaso-occlusive crisis (VOC) is a common clinical manifestation of sickle cell anemia (SCA) and is associated with increased proinflammatory mediators. Copeptin is the C-terminal part of the prohormone for provasopressin and seems clinically relevant in various clinical conditions. Right ventricular (RV) dysfunction significantly appears in SCA patients due to pulmonary hypertension. This study aimed to investigate the association of copeptin levels in VOC patients and evaluate RV dysfunction. Materials and Methods: A total of 108 patients were enrolled in the study. Twenty-eight SCA patients in steady state (30.2 ± 0.9 years), 25 SCA patients in VOC (36.8 ± 11.8 years), and 55 healthy individuals (31.9 ± 9.4 years) with HbAA genotype were included. Clinical, echocardiographic, and laboratory data were recorded. ELISA was used for the determination of serum levels of copeptin. Results: VOC patients had significantly higher copeptin level compared both with controls and SCA subjects in steady state (22.6 ± 13.0 vs. 11.3 ± 5.7 pmol/L, 22.6 ± 13.0 vs. 12.4 ± 5.8 pmol/L, p = 0.009 for both). Additionally, the copeptin level was significantly higher in SCA patients with RV dysfunction than those without RV dysfunction (23.2 ± 12.2 vs. 15.3 ± 9.5 pmol/L, p = 0.024). Multiple logistic regression analysis revealed that high-sensitivity C-reactive protein and copeptin levels were found to be associated with VOC. Conclusion: This study showed that copeptin and hs-CRP levels were increased in patients with VOC, and it was found that RV dysfunction was more common in SCA patients with VOC than in the control group. Copeptin can be considered for use as a potential biomarker in predicting VOC crisis in SCA patients and in the early detection of patients with SCA who have the potential to develop RV dysfunction.

Global Longitudinal Myocardial Strain Correlates with Degree of Anemia in Sickle Cell Disease but Not Transfusion-Dependent Thalassemia

Cardiac failure is one of the leading causes of death in sickle cell disease (SCD) and transfusion-dependent thalassemia (TDT). For this reason, early detection of silent cardiac dysfunction is crucial for treatment and prevention of heart failure. Speckle-tracking echocardiography (STE) is an easily accessible tool for analyzing myocardial function and this modality has increased sensitivity in detecting asymptomatic disease. Attenuation in cardiac strain has been correlated to early systolic dysfunction among patients with cardiomyopathies. This technique has not been consistently evaluated in children with SCD and TDT. Due to the role of anemia and siderosis in the pathology of cardiac dysfunction, we hypothesized that early myocardial dysfunction correlates with the degree of anemia and hyperferritinemia in SCD. We analyzed the clinical, echocardiographic, STE and laboratory parameters in SCD and compared them to children with TDT and normal controls.We retrospectively analyzed date from consecutive patients with SCD and TDT who received treatment at our institution from 2008 to 2018. Echocardiographic data from children with benign murmurs served as normal controls (NC). Data was independently verified by a pediatric cardiologist. Descriptive and correlation analysis were used; a p-value < 0.05 was considered significant.Echocardiographic data were available for 77 SCD (HbSS and HbS/ ß 0 Thal), 25 TDT (ß 0/ ß 0 and ß +/ ß + Thal)and 138 NC. Mean hemoglobin (Hg) and ferritin values were 9.8 g/dl (6.8-14.6 g/dl); 392 ng/ml (19.3-8,3437.67 ng/ml), respectively for SCD patients and 9.3 g/dl (7-17.03 ng/dl); 2,960 ng/ml (13-13,831 ng/ml), respectively for TDT. Standard echocardiographic parameters left ventricular ejection fraction (LVEF), right VEF and LV shortening fraction (LVSF) were within the normal limits in SCD, TDT, and NC children. Significant differences were observed in the steady-state global circumferential strain (GCS) between the three groups SCD, TDT and NC [-26.5 (mean), 3.6 (SD); -27.6 (mean), 4.8(SD); -25.0 (mean), 3.6 (SD), respectively; p = 0.002] (Table 1). Subset analysis based on ferritin levels (> or < 1000 ng/ml), revealed no significant difference in GCS between the SCD or TDT groups (Table 2). However, global longitudinal strain (GLS) was significantly lower among SCD compared to TDT with ferritin levels greater than 1,000 ng/ml (Table 2). A positive correlation (r = 0.25, p = 0.046) was found between GLS and Hg in SCD patients (n=63) (Figure 1). No significant correlation was found between Hg and GLS in the TDT group (Figure 2). No significant correlation was found between GCS and Hg (r = 0.1, p = 0.42); GLS and GCS and ferritin in the SCD group. LVEF was found to be normal in patients with abnormal strain indices.Cardiac strain indices are abnormal in children with SCD and TDT compared to normal children. Significantly abnormal GLS was noted in hyperferritinemic SCD patients compared to TDT patients. A positive correlation between severity of anemia and GLS was observed in this study in SCD children. Based on these results, we speculate that therapies aimed at ameliorating anemia can potentially improve GLS and thus, early cardiac dysfunction in SCD patients. However, further studies are warranted to understand the contributory role of anemia and hyperferritinemia and its therapeutic implications on early myocardial dysfunction in SCD. [Display omitted] DisclosuresSathi: Vertex Pharmaceuticals: Consultancy.

Cortical Thinning and White Matter Loss in Sickle Cell Anemia Despite Chronic Exchange Transfusion Therapy

Neurovascular complications are a common and major cause of morbidity and mortality in patients with sickle cell disease (SCD). Prior studies have demonstrated cortical thinness (Kim et al. 2016) as well as reduced cerebral volume in children with SCD (Kawadler et al. 2013) when compared to age-matched controls. There is very limited data regarding cerebral volume in adults with SCD. Recently, our group showed that adults with SCD have reduced cerebral volumes when compared to race and age-matched controls (Santini et al. 2021a). A prior prospective study by Nitkunan et al. 2011. demonstrated brain atrophy rate of −0.914%±0.8% in older adults (mean 68 years old) with Small Vessels Disease, which is about twice the rate of healthy controls. Transfusion therapy has been effective in the primary and secondary prevention of strokes and silent infarcts in SCD. Automated erythrocytapheresis (exchange transfusion), in particular, is the most aggressive disease modifying-treatment in SCD, by rapidly diluting sickle hemoglobin and replacing it with normal hemoglobin. We hereby present a case of a 42 -year-old woman with sickle cell anemia (HbSS) who developed accelerated loss of cerebral volume within a three-year period despite chronic exchange transfusion therapy. The patient underwent brain MRI in 2016 and 2019 as part of an NIH-funded, prospective, longitudinal study of the neuroradiological correlates of cognitive dysfunction in SCD. Past medical history is notable for prior right hemispheric stroke for which she was placed on chronic exchange transfusion monthly with the goal of reducing HbS to <30%. T1-weighted images were acquired at 7T MRI using a customized RF coil (Santini et al. 2021b) and with the following parameters: 3D MPRAGE, TE/TI/TR = 2.17/1200/3000 ms, resolution 0.75 mm isotropic, total acquisition time = 5 min. The extent of atrophy was estimated using the longitudinal analysis as part of the Freesurfer package (version 7.1.1) and ITK-snap (version 3.8.0). The pre-exchange HbS was reliably maintained <30% throughout the observation period, during which the patient did not develop new strokes or neurological complications. Unfortunately, in spite of the patient's excellent adherence with the treatment and the achievement of the target HbS values, we observed progression of cerebral atrophy of 2.47% in volume in the hemisphere contralateral to the stroke between the two time points. The differences are also visible in the raw data (Figure 1). Chronic exchange transfusion is the most aggressive preventive treatment for the neurological sequelae of sickle cell disease. This case demonstrates an accelerated brain atrophy, suggesting that this treatment may not be fully protective against progressive cerebral atrophy. Unfortunately, the mechanism of brain atrophy in SCD is not fully understood. More longitudinal studies are needed to assess cortical changes and cerebral volume changes as this can lead to further understanding of their pathophysiology and to the development of therapeutic options to arrest the progression of cerebrovascular disease in this population. [Display omitted] DisclosuresNovelli: Novartis Pharmaceuticals: Consultancy.

Age-Associated Decline in Blood Parameters in Individuals with Sickle Cell Disease

IntroductionIndividuals with sickle cell disease (SCD) in resource-rich countries are now living longer due to the implementation of newborn screening, use of prophylactic penicillin, and introduction of hydroxyurea. The impact of SCD on the bone marrow and peripheral blood counts as individuals with SCD age is not well described in the hydroxyurea era. As a result of increased red blood cell (RBC) turnover due to hemolysis in SCD, potential ineffective erythropoiesis, and well-described systemic inflammatory processes, the increased stress in the bone marrow may manifest as decreased peripheral blood cell counts over time in a during an aging process unique to those with SCD.ObjectiveThe objective was to model routine clinical blood measurements (n=5,328) with a longitudinal cohort of 447 patients, resulting in models of circulating blood counts as a potential marker of bone marrow function across the lifespan in adults with SCD. Our working hypothesis was that increasing age would be associated with decreases in certain blood counts, with trends modified by SCD genotype severity.MethodsIn this large, single institution retrospective cohort study, we analyzed blood count measurements from adults with SCD. We used an accelerated longitudinal cohort design to examine changes in white blood cell count (WBC), hemoglobin (HGB), absolute reticulocyte count (ARC), and platelet count over time. Genotypes were grouped as severe (HbSS or HbSβ 0-thalassemia; n=301), non-severe (HbSC or HbSβ +-thalassemia; n=136), or other (n=10). For HGB and ARC, we adjusted for estimated glomerular filtration rate (eGFR) and serum creatinine.ResultsPatients ranged in age at enrollment from 18 to 84 (M = 31.9, SD=12.9), with median follow-up time of 3.6 years and a median of 6 measurements per patient. Overall, HGB and ARC decreased across the lifespan; however, trends were moderated by genotype. Compared to individuals with non-severe genotypes, those with the severe genotypes had consistently lower HGB levels that did not differ by age. For ARC, the severe genotypes had higher levels in young adulthood, which slowly decreased with age. WBC also decreased with age for this group. In contrast, individuals with the non-severe genotype showed an increase in WBC by age. Platelet counts decreased with increasing age for those with the severe genotype while those with non-severe genotypes showed an increase with age.ConclusionSevere SCD genotypes are associated with decreases in HGB, ARC, WBC, and platelet count by age. For HGB and ARC, these declines are significantly attenuated by renal function, suggesting that such declines are largely related to worsening renal function with age. However, an intrinsic bone marrow contribution to this aging process should also be explored in future studies. Decreases in WBC and platelet count with time, observed in the severe genotypes, support the presence of pathological processes of bone marrow dysfunction that may worsen with age. A possible etiology of the increasing bone marrow dysfunction in SCD may be a result of bone marrow exhaustion or cellular senescence. Prospective studies to explore contributors to reduced blood counts during the aging process in individuals with SCD are needed. We are actively exploring potential biomarkers associated with this process. [Display omitted] DisclosuresCarden: Forma Therapeutics: Current Employment. Derebail: Novartis: Consultancy; UpToDate: Patents & Royalties; Travere Therapeutics: Consultancy; Bayer: Consultancy. Ataga: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Multiple inducers of endothelial NOS (eNOS) dysfunction in sickle cell disease.

A characteristic aspect of the robust, systemic inflammatory state in sickle cell disease is dysfunction of endothelial nitric oxide synthase (eNOS). We identify 10 aberrant endothelial cell inputs, present in the specific sickle context, that are known to have the ability to cause eNOS dysfunction. These are: endothelial arginase depletion, asymmetric dimethylarginine, complement activation, endothelial glycocalyx degradation, free fatty acids, inflammatory mediators, microparticles, oxidized low density lipoproteins, reactive oxygen species, and Toll‐like receptor 4 signaling ligands. The effect of true eNOS dysfunction on clinical testing using flow‐mediated dilation can be simulated by two known examples of endothelial dysfunction mimicry (hemoglobin consumption of NO; and oxidation of smooth muscle cell soluble guanylate cyclase). This lends ambiguity to interpretation of such clinical testing. The presence of these multiple perturbing factors argues that a therapeutic approach targeting only a single injurious endothelial input (or either example of mimicry) would not be sufficiently efficacious. This would seem to argue for identifying therapeutics that directly protect eNOS function or application of multiple therapeutic approaches.

Hidden brain iron content in sickle cell disease: impact on neurocognitive functions

Children with sickle cell disease (SCD) are at a high risk for neurocognitive impairment. We aim to quantitatively measure cerebral tissue R2* to investigate the brain iron deposition in children and young adults with SCD in comparison to beta thalassemia major (BTM) and healthy controls and evaluate its impact on neurocognitive functions in patients with SCD. Thirty-two SCD, fifteen BTM, and eleven controls were recruited. Multi-echo fast-gradient echo sequence brain MRI was performed, and brain R2* values of both caudate and thalamic regions were calculated. SCD patients were examined for the neurocognitive functions. SCD had high iron overload 0.30 ± 0.12mg/kg/day. 68.9% of SCD had under-threshold IQ, 12.5% had moderate to severe anxiety, and 60.8% had depression. There were no differences between SCD, BTM, and controls in brain MRI except that left thalamus R2* higher in BTM than both SCD and controls (p = 0.032). Mean right caudate R2* was higher in female than male (p = 0.044). No significant association between brain R2* and LIC or heart R2* values in SCD. Left caudate R2* directly correlate with age and HbS%, and negatively correlate with HbA% while right thalamus R2* negatively correlate with transfusion index and among SCD patients.Conclusion: Neurocognitive dysfunction in SCD could not be explained solely by brain iron overload. What is Known: • Children with sickle cell disease are at great risk of brain damage due to their irregularly shaped red blood cells that can interrupt blood flow to the brain. • There are a number of factors that have negative brain effects that result in learning difficulties, and this not only due to increase brain iron content. What is New: • Assessment of quantitative brain iron content using MRI R2* in children and young adults with SCD in comparison to beta thalassemia major and healthy controls. • Impact of brain iron content on neurocognitive functions of children and young adults with SCD.

Platelet Aggregation Dysfunction in Sickle Cell Disease

Acute systemic painful vaso-occlusive crisis (VOC) is the predominant clinical event requiring sickle cell disease (SCD) patients to seek emergency medical care. VOC often serves as an antecedent to acute chest syndrome (ACS), which is a type of acute lung injury and the leading cause of mortality in SCD. Current treatments for ACS are primarily supportive, and there is a critical need for rescue strategies to prevent the progression of VOC to ACS. ACS involves thrombosis across pulmonary artery branches, but the pathophysiology of thrombosis in SCD is largely unknown. Adenosine diphosphate (ADP) released from lysed erythrocytes can activate platelets by stimulating the purinergic receptors P2Y1 and P2Y12, suggesting that blocking these receptors may prevent VOC. Surprisingly, P2Y12 receptor blockade was unsuccessful in preventing VOC in a recent DOVE trial, justifying the need for better understanding of purinergic signaling in SCD.We used a novel intravital microscopy enabled experimental model of vaso-occlusive pulmonary thrombosis in transgenic SCD mice triggered by an intravenous (IV) administration of ADP. This method allows real time in vivo visualization of platelet aggregation in the lung of live SCD mice using multi-photon-excitation based quantitative fluorescence intravital lung microscopy (qFILM). We discovered that vaso-occlusive thrombosis involves entrapment of large circulating platelet aggregates in the bottle-necks located between the pulmonary arterioles and capillaries. Surprisingly, the dose of ADP that led to the pulmonary vaso-occlusive thrombosis in control mice, failed to induce vaso-occlusive thrombosis in SCD mice. Remarkably, further in vivo and in vitro platelet aggregation studies confirmed that SCD mouse platelets were indeed refractory to ADP but not collagen.Our preliminary findings suggest that therapeutic inhibition of P2Y1 and P2Y12 platelet receptors will not be a successful therapy in SCD. Our findings also warrant the need for further studies to understand the role of purinergic signaling in SCD DisclosuresNo relevant conflicts of interest to declare.

Assessment of cystatin C in pediatric sickle cell disease and β-thalassemia as a marker of subclinical cardiovascular dysfunction: a case-control study

Cardiovascular complications represent the main determinant of survival in patients with hemoglobinopathies. Serum cystatin C is a well-known marker of nephropathy in sickle cell disease (SCD) and β-thalassemia patients that has recently emerged as a strong predictor of cardiovascular dysfunction in patients with and without kidney disease. We performed a case control study to determine the role of cystatin C as a predictor of subclinical cardiovascular dysfunction in SCD and β-thalassemia patients. We enrolled 40 SCD patients with a mean age of 12.4 years, 40 β-thalassemia patients with a mean age of 11.4 years and 40 age and sex-matched controls. We assessed hematological profile, serum ferritin, urinary albumin–creatinine ratio (UACR), serum cystatin C, echocardiography and carotid intima media thickness (CIMT). UACR, cystatin C and CIMT were higher in SCD and β-thalassemia patients compared to controls (p < .001). Significantly higher cystatin C levels were observed in SCD and β-thalassemia patients with nephropathy or left ventricular systolic dysfunction (shortening fraction <30%, or ejection fraction <55%; p < .001). Moreover, SCD patients with pulmonary hypertension had significantly higher cystatin C levels. Cystatin C levels were positively correlated with CIMT in SCD (p = .02) and β-thalassemia patients (p < .001) while negatively correlated with ejection fraction and shortening fraction (p < .001). The cutoff values of cystatin C ≥ 16.03 and ≥ 13.2 (ng/mL) could detect subclinical cardiac dysfunction risk among SCD and β-thalassemia patients respectively. Cystatin C appears to be a promising marker for subclinical cardiovascular dysfunction in SCD and β-thalassemia patients.