Features Of Sickle Cell Disease Research Articles

Role of Vitamin D on Endothelial Function and Erythropoiesis: Implications for Sickle Cell

Endothelial dysfunction and chronic anaemia are key features of sickle cell disease (SCD), which significantly increases the risk of vaso-occlusive crises, pulmonary hypertension and stroke in affected individuals. Evidence indicates that vitamin D (VD), known for bone health, is linked to better endothelial function by increasing nitric oxide (NO) bioavailability, and promoting antioxidant and anti-inflammatory activities. It also regulates erythropoiesis by enhancing and prolonging red blood cell production and lifespan. VD deficiency is common in individuals affected by SCD, intensifying the already poor cardiovascular health. Up to date, only one study have investigated the effect of VD supplementation, and endothelial function outcome measures in SCD. The potential benefits of maintaining adequate circulating VD concentration in improving endothelial dysfunction and chronic anaemia would be of immense significance to affected individuals living in sub-Saharan Africa, who bear the greatest burden of the disease, with a substantial impact on morbidity and mortality. There is a lack of clinical data investigating the effect of VD on erythropoiesis in SCD. Therefore, this review aims to examine the current evidence regarding the influence of VD on both endothelial function and erythropoiesis and the clinical implications of enhancing endothelial function and erythropoiesis through VD supplementation in this at-risk group. A thorough search of databases, including PubMed, MEDLINE, and Google Scholar, was performed to gather relevant articles exploring the interplay between VD, endothelial function and erythropoiesis in SCD. Robust clinical evidence is warranted to show the impact of VD supplementation on improving endothelial function and erythropoiesis in SCD.

Evaluating the feasibility of delivering a pain management programme for adults living with sickle cell disease.

Pain is the prominent feature of sickle cell disease (SCD) and negatively affects quality of life. Delivery of pain management programmes (PMPs) has been suggested in clinical guidelines for pain management in SCD; however, further evidence of the feasibility and effectiveness of PMPs in this population is needed. This study explored the feasibility of delivering a sickle cell pain management programme (SCPMP) for adults within a haemoglobinopathies service. A single arm, repeated-measures observational design was used to determine feasibility of delivering the SCPMP at one study site. Primary feasibility outcomes were recruitment, completion of treatment and outcome measures, satisfaction, credibility and acceptability to participants. Secondary feasibility outcomes were treatment outcomes and processes, frequency of vaso-occlusive crisis (VOC) and healthcare utilisation. Four of five feasibility criteria were met. Annual recruitment of eight participants to a SCPMP was not achieved. Twenty-nine people began a SCPMP during the study period. Twenty-five (86.2%) participants attended ≥5/8 sessions and 21(84%) programme completers provided all end of programme questionnaires. Mean scores of >7 on ten-point scales were seen across satisfaction and credibility questions. At least moderate (Hedges g >0.5) effect sizes were seen in pre-post SCPMP measures of pain interference, anxiety, depression, self-efficacy, pain-related worry and acceptance. A small (Hedges g 0.4) effect size was seen in HRQoL. Following SCPMP attendance, mean frequency of self-reported VOC and hospital admissions reduced. This study suggests that, given an adequate source of referrals, a SCPMP is feasible to deliver and appears acceptable and credible to participants. Exploration of influences on recruitment, such as barriers to group interventions, would be illuminating, prior to investigating feasibility of an adequately powered randomised-controlled trial.

Clinical and demographic characteristics of sickle cell disease in colombian children

Clinical and demographic characteristics of sickle cell disease in colombian children

5613082 CD34+ HEMATOPOIETIC STEM CELL COUNT AS NOVEL BIOMARKER FOR PREDICTING VASCULAR EVENTS IN EGYPTIAN CHILDREN WITH SICKLE CELL DISEASE

Background: Vasoocclusion is the major clinical feature of sickle cell disease (SCD). It results in acute painful vasoocclusive crises and progresses to multiple organ failure (1). Severe SCD is defined as frequent pain, recurrent Acute Chest Syndrome (ACS), stroke and death(2). Therefore, it is essential to identify relevant predictive markers for clinical vascular events. Aim: Evaluation of circulating CD34 as a novel predictive marker of occurrence of vascular events in children with sickle cell disease in their steady state and to relate its levels to other clinical and laboratory parameters of SCD. Methods: 50 patients diagnosed with SCD aged 0.3-13 years old (median 2 years) in their steady state for at least 3 month were enrolled. History with emphasis on neurovascular and peripheral vascular events was taken then hematology, hemolysis, coagulation markers and flow cytometery for quantification of circulating CD34 were withdrawn at inclusion and compared to age and sex matches control then patients were prospectively followed up for 6 months where 2 groups of patients were compared depending on development of vascular events. Results: Results showed statistically significant higher level of circulating CD34+ in patients with SCD compared to control (p <0.001). Patients who developed peripheral vascular events on follow up (n=29) has statistically significant higher level of previous neurovascular events, previous history of vasooclussive crisis(VOC) and previous hospitalization for VOC (p-value 0.015, 0.001 and 0.001 respectively).As for laboratory markers, they have statistically significant higher level of total leucocytic count(TLC), neutrophil count, platelet count and CD34+ level with cut off value of >4340 cell/ ml and higher Time Averaged Mean Flow (TAMMAX)>115cm/sec(p-value 0.015, 0.008, 0.042 and 0.022, 0.028 respectively). There was negative correlation between CD34 and age of diagnosis (p<0.006), hemoglobin level at inclusion (p=0.045), while positively correlated with peripheral vascular events on follow up, TLC, platelet count and bilirubin level at inclusion(p=0.022, 0.01, 0.044, <0.001). Conclusion: Our data showed that circulating CD34 is a potential biomarker for predicting vascular events in children and adolescents with SCD at steady state.

Hemolysis scavenger proteins and renal function marker in children with sickle cell disease at steady state: A cross-sectional study.

Hemolysis is a fundamental feature of sickle cell disease (SCD) contributing to the vaso-occlusive crisis of patients. The objectives of the study were to assess the link between hemolysis proteins and hematological parameters, and to validate cystatin C(CYS C) as a potent renal marker in diagnoising SCD. Here, a cross-sectional study carried out at the pediatric SCD clinic of the Komfo Anokye Teaching Hospital comprised 90 SCDchildren (HbSC, HbSF, and HbSS). ANOVA, t-test, and Spearman's rank correlation analysis were done. Elevated proteins levels were compared to standard values; alpha-1 microglobulin (A1M) (1.8-65 µg/L), CYS C (0.1-4.5 µmol/L), and haemopexin(HPX) (500-1500 µg/mL). The mean (standard deviation) age of participants was 9.830 (±0.3217) years, and 46% of them were males. From simple descriptive analysis, we observed that all but one patient had their HPX level below the reference range (<500 µg/mL). Here, A1M levels were shown to be within the appropriate reference range for all the patients except few patients. CYS C levels were also all within the required reference values. A Spearman's rank correlation test between full blood count and HPX generally suggested a weak but positive correlation; RBC (coef. = 0.2448;p = 0.0248), HGB (coef. = 0.2310;p = 0.030), hematocrit(coef. = 0.2509; p = 0.020), and platelet(coef. = 0.1545;p = 0.160). Mean corpuscular volume(coef. = -0.5645;p = 0.610) had a stronger but negative correlation with HPX. This study depicts a positive and stronger association between CYS C and HPX levels (coef. = 0.9996;p < 0.0001), validating the use of CYS C as a useful marker of renal function in persons with SCDs. In the present study, we show that A1M levels were normal for most of the patients, hence CYS C levels are not alarming in this study. Further, there exists a correlation between hemolysis scavenger proteins and hematological parameters.

Depolarized Mitochondrial Membrane Potential and Elevated Calcium in Platelets of Sickle Cell Disease.

Hemolysis, a crucial feature of Sickle cell disease (SCD), is a key player for cellular activation leading to various complications including thrombosis. In response to hemolysis, platelets get activated and release components that are necessary for further platelet activation and aggregation. Thus, it is believed that platelets contribute to the development of thrombotic complications. Platelets in SCD are expected to be affected due to common cause of hemolysis. To measure the surface markers of platelets including P-Selectin, Phosphatidyl Serine and integrin αIIbβ3 in SCD patients and healthy controls in order to understand the status of the platelets in SCD. To measure the surface markers of activated platelets using flow cytometry. Since mitochondria and calcium play an important role in cellular functions, the mitochondrial membrane potential and calcium content of platelets in SCD were also evaluated using flow cytometry. In the present study, we have observed significant increase of calcium level in SCD platelets. Further, the loss of mitochondrial membrane potential in SCD platelets was found to be significantly higher when compared to platelets of healthy controls. Though the surface markers of activated platelets in SCD remain unchanged, increased level of calcium and mitochondrial membrane potential loss suggest that the platelets in SCD are more prone to become activated. In order to understand the status of the platelets in SCD, apart from the surface markers, it is also important to assess the calcium levels and mitochondrial membrane potential of platelets.

Association of Circulating Procoagulant Microvesicles with Painful Vaso-Occlusive Crisis in Sickle Cell Disease

Introduction: Thrombotic complication is one of the features of sickle cell disease (SCD), characterized by appearance of phosphatidylserine on the outer membrane of sickle-shaped red blood cells and most abundantly on membrane protrusions called microvesicles (MVs). However, the exact mechanism by which MVs may enhance coagulant activity in SCD patients has not been fully addressed. The aim of this study was to further investigate the procoagulant activity of circulating MVs in sickle cell crises. Materials and Methods: Subjects included in this cross-sectional study were 47 patients with SCD and 25 normal subjects with written informed consent obtained from all the participants. MV analysis was conducted by using CD61, CD235α, and Annexin-V monoclonal antibodies. The coagulant activity of MVs was determined by an ELISA-based procoagulant activity assay. Results: The majority of MVs were originated from platelets (CD61+) and erythrocytes (CD235+). These MVs demonstrated significantly enhanced levels during the painful crisis when compared with the steady-state period (p < 0.001) and controls (p < 0.001). Also, the procoagulant activity of MVs was significantly higher in crisis compared to those of steady state (p < 0.001) and positively correlated with the number of Annexin-V+ MVs (p < 0.001). Significant correlations were found between erythrocyte-derived MVs with hemolysis marker (r = 0.51, p < 0.001) and the hemoglobin level (r = −0.63, p < 0.001). Conclusion: The numbers of platelet- and erythrocyte-derived MVs are related to painful crisis, and their quantification in SCD may be helpful for identifying cases at increased risk of thrombotic complications.

Adhesion molecules and cerebral microvascular hemodynamic abnormalities in sickle cell disease.

Cerebrovascular abnormalities are a common feature of sickle cell disease that may be associated with risk of vaso-occlusive pain crises, microinfarcts, and cognitive impairment. An activated endothelium and adhesion factors, VCAM-1 and P-selectin, are implicated in sickle cell vasculopathy, including abnormal hemodynamics and leukocyte adherence. This study examined the association between cerebral expression of these adhesion factors and cortical microvascular blood flow dynamics by using in-vivo two-photon microscopy. We also examined the impact of blood transfusion treatment on these markers of vasculopathy. Results showed that sickle cell mice had significantly higher maximum red blood cell (RBC) velocity (6.80 ± 0.25 mm/sec, p ≤ 0.01 vs. 5.35 ± 0.35 mm/sec) and more frequent blood flow reversals (18.04 ± 0.95 /min, p ≤ 0.01 vs. 13.59 ± 1.40 /min) in the cortical microvasculature compared to controls. In addition, sickle cell mice had a 2.6-fold (RFU/mm2) increase in expression of VCAM-1 and 17-fold (RFU/mm2) increase in expression of P-selectin compared to controls. This was accompanied by an increased frequency in leukocyte adherence (4.83 ± 0.57 /100 μm/min vs. 2.26 ± 0.37 /100 μm/min, p ≤ 0.001). We also found that microinfarcts identified in sickle cell mice were 50% larger than in controls. After blood transfusion, many of these parameters improved, as results demonstrated that sickle cell mice had a lower post-transfusion maximum RBC velocity (8.30 ± 0.98 mm/sec vs. 11.29 ± 0.95 mm/sec), lower frequency of blood flow reversals (12.80 ± 2.76 /min vs. 27.75 ± 2.09 /min), and fewer instances of leukocyte adherence compared to their pre-transfusion imaging time point (1.35 ± 0.32 /100 μm/min vs. 3.46 ± 0.58 /100 μm/min). Additionally, we found that blood transfusion was associated with lower expression of adhesion factors. Our results suggest that blood transfusion and adhesion factors, VCAM-1 and P-selectin, are potential therapeutic targets for addressing cerebrovascular pathology, such as vaso-occlusion, in sickle cell disease.

First and Common Clinical Presentation of Sickle Cell Disease in Children

Background: sickle cell disease (SCD) is the most common inherited blood disease worldwide with the vast majority of cases occurring in sub-Saharan Africa. In Sudan, sickle cell anemia is one of the commonest chronic hemolytic anemias with high mortality and morbidity. Objective: the objective of this study is to determine the first and common presentation of sickle cell in children to assist early diagnosis, prevent complications and decrease morbidity and mortality of sickle cell disease in children. Methodology and Results: the study represented a combined descriptive study (hospital-based) and analytic study (cross-sectional observational) at Mohamed El-Amin Hamed Pediatric Emergency Hospital for Children in Omdurman, Khartoum State where 50 children diagnosed with sickle cell anemia, for the first time, aged 4 months -17 years were included during period of six months (January – June 2016). The commonest first presentation of SCD was sickle cell crises in 46%, features of infection in 18% and the rest 36% presented with combined symptoms. 62% of children presented with pallor as a feature of anemia, 32% with jaundice, 14% with fatigability, 14% with shortness of breathing and 6% presented with other symptoms related to anemia. Conclusion and Recommendations: It is clear that features of vaso-occlusive crises were the first presenting clinical features of sickle cell disease followed by features of infections and anemia. We believe that starting premarital screening, neonatal screening, expand and support SCD clinics and stablishing social support networks will help in decreasing morbidity and mortality from SCD.

Skeletal Muscle Satellite Cells in Sickle Cell Disease Patients and Their Responses to a Moderate-intensity Endurance Exercise Training Program.

We previously demonstrated that 8 weeks of moderate-intensity endurance training is safe and improves muscle function and characteristics of sickle cell disease (SCD) patients. Here, we investigated skeletal muscle satellite cells (SCs) in SCD patients and their responses to a training program. Fifteen patients followed the training program while 18 control patients maintained a normal lifestyle. Biopsies of the vastus lateralis muscle were performed before and after training. After training, the cross-sectional area and myonuclear content in type I fibers were slightly increased in the training patients compared to non-training patients. The SC pool was unchanged in type I fibers while it was slightly decreased in type II fibers in the training patients compared to non-training patients. No necrotic fibers were detected in patients before or after training. Therefore, the slight myonuclear accretion in type I fibers in trained SCD patients may highlight the contribution of SCs to training-induced slight type I fiber hypertrophy without expansion of the SC pool. The low training intensity and the short duration of training sessions could explain the low SC response to the training program. However, the lack of necrotic fibers suggests that the training program seemed to be safe for patients' muscle tissue.

Does glucose-6-phosphate dehydrogenase deficiency worsen the clinical features of sickle cell disease? A multi-hospital-based cross-sectional study

ABSTRACT Background The impact of glucose-6-phosphate dehydrogenase deficiency(G-6-PD) on the clinical course of sickle cell disease(SCD) is still controversial. The objectives of this study were to determine the prevalence of G-6-PD deficiency in patients with SCD and its effect on their clinical course. Methods A cross-sectional study of 122 SCD patients and 211 healthy blood donors was conducted in Kisangani city. Data were collected through clinical examination supplemented by patient medical records, and laboratory tests based on a survey form. G-6-PD activity was measured by spectrophotometry and the screening for SCD by the HemoTypeSC® rapid test. Statistical analysis was done using SPSS ver. 20.0. Results The prevalence of G-6-PD deficiency did not differ between SCD and non-SCD subjects, 35.2% vs. 33.6% respectively(p = .767). When comparing the hemoglobin level between SCD patients with and without G-6-PD deficiency, no significant difference was observed. However, in the 6 months prior to the study, SCD patients with G-6-PD deficiency had on average more transfusions than non-deficient SCD patients, 0.64 ± 0.897 vs. 0.24 ± 0.486(p = .004). Similarly, considering the clinical events of the last 12 months prior to the study, there were more hospitalizations, major vaso-occlusive crises and anemia requiring blood transfusion among G-6-PD deficient SCD patients compared to no-deficient, respectively 1.42 ± 1.451vs. 0.76 ± 1.112(p = .007); 1.37 ± 1.092 vs. 0.85 ± 1.014(p = .005); 0.74 ± 0.902 vs. 0.38 ± 0.739 (p = .007). Conclusion The prevalence of G-6-PD deficiency in SCD patients was high but did not differ from that observed in controls. In addition, G-6-PD deficiency appeared to worsen the clinical features of SCD. Nevertheless, prospective studies further clarifying this observation are needed.

Preventive measures of vaso-occlusive crisis among sickle cell disease patients in South-Eastern Nigeria: How much do our patients know?

Background: Vaso-occlusive crisis (VOC) is a feature of sickle cell disease (SCD), an inherited medical condition which is more common in Sub-Saharan Africa especially Nigeria and is saddled with multi-systemic complications. Knowledge and practice of preventive measures of VOC by patients may reduce the risk of morbidity and mortality. Aim: The purpose of this manuscript is to determine the knowledge, attitude, and practice of the various preventive measures of VOC by patients and their relationship with their frequency of painful crisis. Materials and Methods: A cross-sectional descriptive survey was used. This study was conducted between August, 2018, and February, 2019. Participants were selected consecutively as they came for clinic consultations. Demographic characteristics and the knowledge, attitude, and practice of various preventive measures of VOC were obtained using a structured interviewer-administered questionnaire. The analysis was performed using Statistical Package for the Social Sciences software version 23.0. Descriptive and inferential statistics were used with P < 0.05 which was considered statistically significant. Ethical clearance and informed consent were obtained before the commencement of the study. Results: A total of 154 SCD patients participated in the study and were made up of 73 (47.4%) males and 81 (52.6%) females, with a male-to-female ratio of 1: 1.1. Majority of the respondents (76.6%) had good knowledge of preventive measures toward VOC in SCD. This study also found that 59 (38.3%) participants had good practice of preventive measures toward VOC while 95 (61.7%) had fair practice. Majority (68% [40/59]) of those who had good practice of preventive measures were less likely to have more than three crises in a year compared to those who do not practice good preventive measures, though not statistically significant (OR = 2.489, P = 0558) (confidence interval = 0.480 – 0.637). Conclusion: Majority of the patients have good knowledge and practice of preventive measures of VOC and this appears to have reduced the frequency of their crisis in a year. Health education for sickle cell patients is an important tool that may reduce morbidity and mortality by reducing the frequency of crisis.

Revisiting anemia in sickle cell disease and finding the balance with therapeutic approaches

AbstractChronic hemolytic anemia and intermittent acute pain episodes are the 2 hallmark characteristics of sickle cell disease (SCD). Anemia in SCD not only signals a reduction of red cell mass and oxygen delivery, but also ongoing red cell breakdown and release of cell-free hemoglobin, which together contribute to a number of pathophysiological responses and play a key role in the pathogenesis of cumulative multiorgan damage. However, although anemia is clearly associated with many detrimental outcomes, it may also have an advantage in SCD in lowering risks of potential viscosity-related complications. Until recently, clinical drug development for SCD has predominantly targeted a reduction in the frequency of vaso-occlusive crises as an endpoint, but increasingly, more attention is being directed toward addressing the contribution of chronic anemia to poor outcomes in SCD. This article aims to explore the complex pathophysiology and mechanisms of anemia in SCD, as well as the need to balance the benefits of raising hemoglobin levels with the potential risks of increasing blood viscosity, in the context of the current therapeutic landscape for anemia in SCD.

Contribution of Vascular Cell Adhesion Molecule to Hemodynamics in Sickle Cell Disease

Vaso-occlusive events (VOEs) and pain crises are common clinical features of sickle cell disease (SCD) that result from sickle-shaped erythrocytes and leukocytes blocking blood flow, particularly in small vessels (Kato 2018). Activated endothelium also plays a role in the pathogenesis of VOEs in SCD. For example, VCAM-1 is expressed on blood vessels after activation by chemical and/or mechanical stimulation, which results in cytokine release. Studies have shown that patients with SCD have higher steady-state serum levels of soluble VCAM-1 compared to controls and that these levels are elevated during VOEs (White 2020). Furthermore, overexpression of these adhesion molecules on the endothelium results in prolonged adherence of white blood cells (WBCs), which has been shown to contribute to the development of VOEs and possibly cerebral vasculopathy. These findings raise the need to explore further the role of aberrant WBC- and/or RBC-endothelial interaction, mediated via VCAM-1, in the pathophysiology of cerebral microvascular hemodynamics and vasculopathy leading to cerebral microinfarcts in SCD. Therefore, we hypothesized that sickle cell mice will show greater cerebral cortical expression of VCAM-1 compared with age-matched controls and that this deposition will be associated with significant evidence of abnormal cerebral microvascular hemodynamic abnormalities.To examine the relationship between abnormalities in cerebral microvascular hemodynamics and VCAM-1 deposition in the cerebral microvasculature, we utilized a humanized sickle cell (with HbSS) and corresponding control (with HbAA). After cranial-window procedures, cortical capillaries, precapillary arterioles, and post-capillary venules were imaged using two-photon microscopy at two time points. In addition, this experiment included pre-and post-transfusion groups as we intend to study the impact of blood transfusion on hemodynamics. Using custom-written but well-validated MATLAB scripts, we analyzed line scans to identify the number and duration of rolling or adherent WBCs and RBCs, the RBC velocity in cerebral microvasculature, and the frequency and magnitude (mL/sec) of cerebral microvascular blood flow reversals. Rolling WBCs were defined as lasting two seconds or more, and adherent RBCs were defined as lasting 0.5 seconds or more. To quantify the expression of VCAM-1, we used immunohistochemistry to stain 50-micron sections of brain tissue for VCAM-1, Lectin to localize the vasculature, and Neun to localize neuronal nuclei. Images were analyzed using Phenochart and ImageJ software to examine the deposition of VCAM-1 throughout the brain tissue.As shown in Figure 1, at the first time point (baseline), we observed a significantly higher maximum RBC velocity (p<0.001) in the sickle cell mice compared to controls (figure 1a). We also found that there was significantly higher expression of VCAM-1 (p<0.001) (figure 1b) as well as significantly more leukocyte rolling (p<0.001) (figure 1c) in the sickle cell mice compared to controls. Additionally, we noted that the sickle cell mice have a significantly higher frequency of blood flow reversals (p<0.01) (figure 1d) as well as higher magnitude of microvascular blood flow reversals (p<0.001) (figure 1e) compared to controls. Interestingly, the sickle cell mice have a slightly lower average or mean capillary blood flow velocity compared to control (figure 1f), but this was not statistically significant (p=0.079). Since the mean capillary velocity is obtained as a smoothened difference between the forward flow and reversals, this decrease was surprising given the significant differences in frequency and magnitude of microvascular blood flow reversal in the sickle cell mice compared to controls (figs 1d and 1e).In conclusion, we see that the high velocity of blood flow might be a mechanical force, among other factors contributing to cerebral microvascular VCAM-1 expression in sickle cell mice. This might be responsible for the increased leukocyte-endothelial interactions and adhesion, ultimately leading to higher frequency and magnitude of cerebral microvascular blood flow reversal. Taken together, this may contribute to the observed slightly lower mean or effective microvascular forward blood flow. These pathophysiological changes might contribute to the reported higher rate of cerebral microinfarct and silent infarct in sickle cell disease. [Display omitted] DisclosuresArcher: Global Blood Therapeutics: Consultancy, Research Funding; Forma Therapeutics: Research Funding. Hyacinth: Novartis: Consultancy; Acuta Capital: Consultancy.

Incidence of Stroke and Other Brain Imaging Findings in Adult Patients with Sickle Cell Disease: A Retrospective Study

Background: Vaso-occlusion and hemolytic anemia are the main features of sickle cell disease. Central Nervous system complications of sickle cell disease (SCD) can include silent cerebral infarcts (SCI), hemorrhagic or ischemic strokes, seizures and Moyamoya syndrome. SCI is the most common neurological complications in SCD. SCI patients have abnormal Magnetic Resonance Imaging (MRI) of the brain with normal neurological examination and no history of stroke. More precisely, Casella et al in the Silent Cerebral Infarct Multi-Center Clinical trial (SIT) defined infarct as MRI signal abnormality that was at least 3 mm in one dimension and that was visible in two planes on fluid-attenuated inversion recovery T2 -weighted images, as determined by agreement of two of the three study neuroradiologists. SCI in children is associated with lower Intelligence Quotient and increased risk of stroke.Methods: In this retrospective study we reviewed 100 adult patients at our Comprehensive Sickle Cell Center. We looked at the incidence of documented stroke and other neurological complications in SCD patients. We reviewed the hospital records of SCD patients for any incidental brain imaging (MRI brain or Computed Tomography(CT) brain) findings, done as inpatient or in the emergency room as part of hospital visits.Results: Out of the 100 patients, 14 patients had documented stroke. On the review of other 86 patients, 10 patients had MRI brain, 23 patients had CT brain, and 53 patients had no brain imaging record. Out of the 10 patients with MRI brain, 7 patient had significant findings- 3 patients had small vessel ischemic changes, 1 patient with chronic petechial hemorrhage of cerebellar vermis, 1 patient with ischemic changes and Chiari malformation type 1 (CTM 1), 1 patient with CTM 1 and non-specific white matter changes and 1 patient with CTM 1 alone. Out of the 22 CT of the brain and 1 CT angiogram of brain, 2 imaging showed ischemic changes and the angiogram showed large cerebral vessel narrowing. Therefore, on our review, 19 patients out of 100 were found to have stroke and 24 out of 100 had significant neurological findings. However, only 14 out of 19 patients had documented stroke. 7 out the 10 patients with MRI brain had significant incidental neurological findings. The number of adult SCD patients with neurological findings in our cohort could have been higher, if we had brain imaging record for the 53 other patients.Conclusion: This study shows that there is a heavy burden of neurological complications in SCD patients and SCI is under-diagnosed. MRI brain is superior to CT brain in detecting neurological complications in SCD patients. SIT showed that regular blood-transfusion significantly reduced the recurrence of cerebral infarct in children with SCI. Finding of SCI in adults also warrants consideration for follow up brain imaging, neurology referral and discussion of treatment modalities including chronic blood transfusion and hydroxyurea therapy. CTM 1 can also be associated with SCD. In CTM 1, tonsil herniates 5 millimeter or below foramen magnum. SCD may cause increased thickness of calvarium from extramedullary hematopoiesis in skull, which can result in cranio-cephalic disproportion with cerebellar ectopia and subsequent CTM 1. Because of high incidence of neurological complications in SCD patients, routine screening with MRI brain should be considered in adult SCD patients. DisclosuresIdowu: Forma Therapeutics, Inc.: Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ironwood: Research Funding.

Mitapivat (AG-348) Demonstrates Safety, Tolerability, and Improvements in Anemia, Hemolysis, Oxygen Affinity, and Hemoglobin S Polymerization Kinetics in Adults with Sickle Cell Disease: A Phase 1 Dose Escalation Study

Background. Hemoglobin S (HbS) polymerization causes red cell sickling, hemolysis, and vaso-occlusion, key pathological features of sickle cell disease (SCD). Mitapivat (AG-348) has potential as an oral anti-sickling agent in SCD via increasing glycolytic activity, which reduces intracellular levels of 2,3-diphosphoglycerate (2,3-DPG) in parallel with increasing adenosine triphosphate (ATP). Reducing 2,3-DPG decreases HbS polymerization, while increasing ATP improves red cell membrane integrity. Here, we report the complete results of our single-center Phase 1 study of multiple ascending doses of mitapivat in subjects with SCD.Methods. We enrolled adult subjects (age ≥ 18 years) with confirmed SCD (HbSS) and baseline Hb ≥ 7 g/dL; with no recent transfusions, erythropoietin therapy, or changes in SCD-specific therapies including hydroxyurea (HU) and L-glutamine. Subjects received either 3 or 4 ascending dose levels of mitapivat (5 mg BID, 20 mg BID, 50 mg BID, 100 mg BID) for 2 weeks' duration each, followed by a 12-15 day drug taper. Safety and tolerability were assessed by frequency and severity of adverse events (AEs) and changes in hemoglobin (Hb) level and hemolytic markers. For each dose level, pharmacokinetics (PK), pharmacodynamics (PD; 2,3-DPG and ATP levels), and markers of oxygen (O 2) affinity (p50) and HbS polymerization (t50) were assessed pre-dose, post-dose, at end of taper, and at end of study. p50 is the partial pressure of O 2 at which 50% of the hemes in the Hb molecule have O 2 bound; t50 is the time at which 50% of erythrocytes are sickled in response to gradual deoxygenation with nitrogen to a final O 2 partial pressure of 38 torr.Results. Out of 17 subjects enrolled, 16 escalated to 50 mg BID. One subject, withdrawn 3 days after starting the study for a pre-existing pulmonary embolus, was not evaluable for response. After a protocol amendment, 9/10 eligible subjects completed the 100 mg BID dose level; 1 subject self-discontinued treatment after completing 3 dose levels. Mean age of the 17 subjects was 39 years (range 23-55 years); 11 were male, and 12 were on HU. Mitapivat was well tolerated; the most commonly reported drug-related AEs were insomnia (n=6 subjects, Grades 1-2), arthralgia (n=3, Grades 1-2), and hypertension (n=3, Grades 1-3). Six serious AEs (SAEs) were reported in 6/17 subjects, including 4 vaso-occlusive crises (VOCs), 1 non-VOC-related pain, and 1 pre-existing pulmonary embolism; 2/6 SAEs were deemed possibly drug-related. Of the 4 VOCs, 2 occurred during drug taper and were possibly drug-related, and 2 occurred during the 28-day safety follow up post-treatment in the setting of known VOC triggers.In 16 evaluable subjects, a dose-dependent decrease in mean 2,3-DPG levels and increase in mean ATP levels were consistently observed, followed by a return to near baseline by end of study (Figure 1A-B). There was a mean decrease in p50 and increase in t50 (Figure 1D-E), indicating increased oxygen affinity and slower sickling, respectively. The mean Hb increase at the 50 mg BID dose level was 1.2 g/dL (range -0.3-2.9 g/dL; Figure 1C). Over half (9/16, 56.3%) of subjects achieved a Hb response, defined as a ≥ 1 g/dL increase in Hb at any dose level compared to baseline. Subjects also experienced a mean reduction in the hemolytic markers of lactate dehydrogenase, total serum bilirubin, absolute reticulocyte count, and aspartate aminotransferase during the dose escalation period (Figure 1F-I), though responses were variable. Mean corpuscular volume (MCV) and HbF levels remained relatively stable throughout the study, supporting the notion that hydroxyurea exposure remained stable throughout the treatment period.Conclusion. During a 6-8 week treatment period, mitapivat demonstrated an acceptable safety and tolerability profile at multiple ascending dose levels in subjects with SCD. Mitapivat improved anemia, reduced markers of hemolysis, decreased 2,3-DPG and increased ATP levels, improved oxygen affinity, and decreased sickling rate, signaling its potential to improve clinically meaningful outcomes in SCD. Long-term disease modifying effects of mitapivat treatment in SCD are being evaluated in an ongoing extension study (ClinicalTrials.gov NCT04610866). [Display omitted] DisclosuresIyer: Novartis: Current equity holder in publicly-traded company; Agios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Mangus: Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Kung: Agios Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Dang: Agios Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Kosinski: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Hawkins: Bristol-Myers Squibb: Current equity holder in publicly-traded company; Agios: Current equity holder in publicly-traded company.

POS-067 UTILITY OF NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN (NGAL) IN DIAGNOSIS OF ACUTE KIDNEY INJURY AMONG CHILDREN WITH SICKLE CELL ANEMIA HOSPITALISED WITH VASO-OCCLUSION

Diagnosis of acute kidney injury (AKI) in low-income settings is challenging as creatinine testing is not routinely available and serum creatinine is affected by age, nutritional status and glomerular hyperfiltration, a feature of sickle cell anemia (SCA). Alternative point-of-care biomarkers are needed to facilitate early detection of AKI in at-risk populations. We evaluated the diagnostic accuracy of a semi-quantitative point-of-care test of urine neutrophil gelatinase-associated lipocalin (uNGAL) to diagnose AKI in SCA at hospital admission.

Moyamoya Syndrome Associated with Protein C and S Deficiency as a Neurological Complication in Children with Sickle Cell Disease

Background: Sickle Cell Disease (SCD) is an autosomal recessive hemoglobinopathy containing mutant sickle cell Hemoglobin (HbS). Acute and chronic organ dysfunction, chronic hemolytic anemia, and recurrent painful episodes are the main features of sickle cell disease. There is a wide variety of neurological complications, including: headache, cognitive difficulties, seizures, visual loss, ischemic and hemorrhagic stroke, transient ischemic attacks, soft neurological signs coma, altered mental status and covert or silent infarction. Moyamoya is an uncommon cerebral vasculopathy that’s also found in children with SCD. Case Presentation: Here, we reported two children diagnosed with SCD who presented with headache, recurrent ischemic strokes, seizures and cognitive decline. They showed abnormalities on different neuroimaging including: CT and /or MRI, MRA and/or CT angiography, also transcranial color coded duplex, EEG and Stanford-Binet Intelligence scales-Fifth Edition. They also showed abnormal level of protein C and protein S. They also had irregular blood transfusion and were diagnosed as Moyamoya syndrome. Conclusion: According to our findings, Moyamoya syndrome was a rare complication of SCD in children, but should be considered with proper approach, diagnosis and management.

The Effect of Crizanlizumab on the Number of Days Requiring Opioid Use for Management of Pain Associated with Vaso-Occlusive Crises in Patients with Sickle Cell Disease: Results from the Sustain Trial

The Effect of Crizanlizumab on the Number of Days Requiring Opioid Use for Management of Pain Associated with Vaso-Occlusive Crises in Patients with Sickle Cell Disease: Results from the Sustain Trial

Association of HIV infection with clinical and laboratory characteristics of sickle cell disease

BackgroundSickle cell disease (SCD) is a multisystem disorder characterized by a wide spectrum of clinical manifestations and severity. Studies investigating potential effects of co-morbid human immunodeficiency virus (HIV) and SCD have produced conflicting results, and additional investigations are needed to elucidate whether the interaction between the two disease states might impact both HIV and SCD clinical outcomes. The association of HIV infection with clinical and laboratory characteristics of patients with SCD was assessed.MethodsThis nested case-control study included individuals with SCD with HIV treated at six Brazilian SCD centers. Clinical and laboratory data were abstracted from medical records. HIV positive participants were compared to age, gender, center, and SCD genotype matched HIV negative participants (ratio 1:4). Individual clinical outcomes as well as a composite outcome of any SCD complication and a composite outcome of any HIV-related complication were compared between the two groups.ResultsFifteen HIV positive participants were included, 12 (80%) alive and 3 (20%) deceased. Most of the HIV positive patients had HbSS (60%; n = 9), 53% (n = 8) were female, and mean age was 30 ± 13 years. The frequency of individual SCD complications of acute chest syndrome/pneumonia, sepsis/bacteremia, pyelonephritis, ischemic stroke, hemorrhagic stroke, abnormal transcranial Doppler (TCD), and pulmonary hypertension was higher in HIV positive participants when compared to HIV negative, although analyzed individually none were statistically significant. HIV positive participants had significantly higher risk of any SCD complication and of a composite HIV-related complication compared to the HIV negative group (HR = 4.6; 95%CI 1.1–19.6; P = 0.04 and HR = 7.7; 95%CI 1.5–40.2; P = 0.02, respectively). There was a non-significant trend towards higher risk of any infections in participants with HIV positive (HR = 3.5; 95%CI 0.92–13.4; P = 0.07). Laboratory parameters levels were not significantly different in individuals with and without HIV.ConclusionsIn summary, our study in SCD patients shows that those with HIV have an increased risk of any SCD complication and HIV-related complications, as well as a suggestive but not significantly increased risk of infections.