History Of Acute Chest Syndrome Research Articles

Lipid and hemolysis parameters predicting acute chest syndrome in adulthood with sickle cell disease

Sickle cell disease (SCD) is a lifelong blood disorder affecting approximately 100,000 people in the United States and is one of the most common monogenic diseases. A serious complication of SCD is acute chest syndrome (ACS). ACS is a condition with a high rate of morbidity and mortality. The aim of the study was to assess hemolysis and lipid parameters in a cohort of confirmed SCD patients to predict ACS development in the following year.Standard lipid were performed (triglycerides, total cholesterol, high-density cholesterol, low-density cholesterol) panel to calculate of non-HDL-C, large buoyant LDL cholesterol (lbLDL-C) and small dense LDL cholesterol (sdLDL-C) with Sampson equation. Hemolysis and hematologic parameters were also evaluated.Among 91 patients included between September 2018 and June 2021, thirty-seven patients had history of ACS and 6 patients developed ACS during following year. In unadjusted logistic regression, total bilirubin was associated with ACS occurrence (RR: 1.2 [1.05–1.51] p = 0.013). Concerning lipid profile, non-HDL-C (RR: 0.87 [0.0.67–0.99] p = 0.04) and sdLDL-C (RR: 0.78 [0.49–0.96] p = 0.03) were associated with ACS occurrence decrease. C-reactive protein was associated with ACS occurrence (RR: 1.27 [1.065–1.85] p = 0.011).Based on these findings, this study demonstrated that several biomarker easily available can be used at steady state to predict ACS in the following year. The validation of these results are required to ensure the reproducibility of the findings.

Evaluating the effectiveness of COVID-19 vaccines in adults with sickle cell disease during the Omicron period of COVID-19 pandemic

Background and aimsThe Omicron variant, one of the variants causing the coronavirus disease of 2019 (COVID-19), was first identified in November 2021 and became the predominant variant in 2022. Although causing less severe disease, this variant and its subvariants have been associated with increased transmissibility and limited protection despite vaccination and prior infection. Individuals with sickle cell disease (SCD) are particularly at greater risk of severe illness and death, and studies regarding the effectiveness of COVID-19 vaccination have been limited in this population. The study aims to determine the effectiveness of COVID-19 vaccination during this period among individuals with SCD and to examine various factors that can influence the likelihood of COVID-19 infection and severity among SCD individuals.MethodsThis is a retrospective analysis of adult patients (≥18 years) with SCD who had emergency and inpatient encounters between January 1 and December 31, 2022. Multivariable regression analysis was performed to determine the effectiveness of the COVID-19 vaccine among this population.ResultsThe study found that COVID-19 vaccination lowered the infection risk among SCD individuals by over 70% if they have received at least one dose of the vaccine. The study also found that individuals with SCD and a history of acute chest syndrome were over 3 times more likely to have a COVID-19 infection diagnosis than those without a history of acute chest syndrome.ConclusionThe study confirms the effectiveness of the COVID-19 vaccine among individuals with SCD during the Omicron period of the COVID-19 pandemic.

Risk factors for acute chest syndrome among children with sickle cell anemia hospitalized for vaso-occlusive crises

Sickle cell anemia (SCA) is a globally prevalent inherited condition, with acute chest syndrome (ACS) being one of its most severe complications. ACS frequently leads to hospitalization, requires intensive care unit (ICU) admission, and can even result in death. This study aimed to discern the early indicators of impending ACS in children with SCA who were initially hospitalized due to painful vaso-occlusive crises (VOC). This was a retrospective, case‒control investigation of 120 patients aged 1–14 years seen at the King Saud Medical City in Riyadh, Saudi Arabia from January 2021 to December 2022. Patients were classified into cases and controls: those who developed and did not develop ACS during hospital stay, respectively. Demographic factors, laboratory results, vital and clinical signs, and treatment protocols were compared between these groups. The following were significant predictors of impending ACS: previous diagnosis of asthma, history of ACS, recent upper respiratory tract symptoms prior to admission, and need for a blood transfusion within the first 24 h of admission due to a drop in hemoglobin levels. Further regression analysis indicated that elevated steady-state mean corpuscular volume, leukocyte count, total bilirubin, and an increased absolute neutrophil count level 24 h after admission also foreshadowed impending ACS among patients admitted for VOC. The location of pain was also significant; the incidence of ACS was higher in patients with back pain, but lower in those with pain confined to the limbs. The ACS group had a longer average duration of hospital stay compared to those with VOC alone, (7.6 vs. 5.8 days). Among patients initially admitted for VOC, 15.7% were diagnosed with ACS. Most ACS cases were managed with transfusions and antibiotics, and nearly one-third of patients needed admission to an ICU or a high-dependency area.

The Role of Neighborhood Disadvantage, Systemic Inflammation, and Acute Chest Syndrome in Children with Sickle Cell Disease

Introduction: Acute chest syndrome (ACS) is a frequent pulmonary complication of sickle cell disease (SCD) and is a leading cause of morbidity and mortality in both children and adults with SCD. In addition to biological factors, there is increasing recognition that social and environmental factors, such as low socioeconomic status and air pollution, respectively, play a role in disease processes. Current evidence suggests that neighborhood disadvantage influences cardiopulmonary outcomes in non-SCD populations. The disproportionate presence of polluting industries and major roadways near disadvantaged neighborhoods could impact lung health in children with SCD, and exposure to toxic metals has also been linked to worsening systemic inflammation. Yet, the impact of neighborhood disadvantage on inflammation in ACS has not been assessed. The goal of this study is to investigate the effects of neighborhood disadvantage on inflammatory markers in children presenting with ACS. Methods: We enrolled children in our institution with SCD (all genotypes) aged 2-21 years of age with and without a history of ACS. We abstracted clinical information including sex, age, number of ACS episodes up to enrollment, and residential address. In addition, blood samples were collected during routine hematology appointments and hospitalizations for ACS. Plasma cytokine levels were measured using multiplex assays on a subset of participants. Using census tract-level data on poverty, education, housing and employment from the US Census, we computed the area deprivation index (ADI) for census tracts across the greater Houston area and assigned an ADI score to each study subject based on their geocoded address at the time of visit. We dichotomized ADI at the median value (99.0; minimum 42.4, maximum of 156.5) across the study area into “high” and “low” deprivation categories. Results: Forty-four participants met inclusion criteria with complete ADI, clinical and cytokine data. Mean age was 11.6 years (SD 5.1), 52% were male, and 66% lived in a high ADI tract. In children over 10 years of age (n=24), there were higher levels of IL-4, IL-6, IL-8, and IL-13 in those from high ADI areas compared to those from low ADI areas [median concentrations (pg/mL): 139.2 vs 75.7, p=0.53; 17.18 vs 11.92, p=0.67; 15.85 vs 5.38, p=0.20; 19.28 vs 8.30, p=0.38, respectively]. Similarly, IL-4, IL-6, and IL-13 levels were higher in children 10 years and younger from high ADI areas, though not statistically significant. There were no differences between median ADI for patients without a history of ACS and those with recurrent ACS (107.7 vs 108.1, p=0.9). Conclusion: In Houston children with SCD, especially 10 years and older, there were overall higher levels of systemic inflammation in those from high ADI areas compared to those from low ADI areas. However, these findings did not reach statistical significance. There was also no significant difference in ADI scores based on frequency of admissions for ACS. Future studies are needed to analyze cytokines from a larger cohort of patients with SCD and compare ACS outcomes to other regions for a more powered, comprehensive investigation.

Evaluating the Effectiveness of COVID-19 Vaccines in Adults with Sickle Cell Disease during the Omicron Period of COVID-19 Pandemic

BACKGROUND: The Omicron variant, one of the variants causing the coronavirus disease of 2019 (COVID-19), was first identified in November 2021 and became the predominant variant in 2022. Although causing less severe disease, this variant and its subvariants have been associated with increased transmissibility and limited protection despite vaccination and prior infection (PMID: 35622357). Individuals with sickle cell disease (SCD) are particularly at greater risk of severe illness and death (PMID: 35060794). As more people with SCD are getting vaccinated and restrictions are being lifted during the Omicron period of the pandemic, the impact on this group has yet to be extensively studied. The study aims to determine the effectiveness of COVID-19 vaccination during this period among individuals with SCD. Additionally, the study aims to examine various factors that can influence the likelihood of COVID-19 infection and severity among SCD individuals. METHODS: This multicenter retrospective study was conducted at three hospital centers in Michigan. A total of 101 SCD adult patients (age ≥ 18 years old) who had emergency and inpatient encounters from January 1 to December 31, 2022, were included in the study. Electronic medical records were reviewed to gather patient data such as demographics, details of COVID-19 infection, underlying comorbidities, and other clinical information, while the immunization registry in Michigan was used to obtain COVID-19 vaccination status. Multivariable regression analysis was conducted to determine the clinical correlation between COVID-19 vaccination status and infection and to examine various factors influencing COVID-19 severity. Statistical analyses were performed using SPSS version 28.0 statistical software, and a p-value of <0.05 was considered statistically significant. RESULTS: Of the 101 adults with SCD included in the study, 97 % were Black, with a mean age of 40 years. The majority had the hemoglobin SC (54%) or SS (35%) genotype. 42 individuals with SCD and confirmed COVID-19 were identified. The most reported chief complaints in the emergency rooms at the time of COVID-19 diagnosis were myalgia and chest pain. Interestingly, individuals with SCD and a history of acute chest syndrome were over 3 times more likely to have a COVID-19 infection diagnosis than those without a history of acute chest syndrome (OR=3.68, 95% CI=1.47-9.17). This was likely due to a significant overlap between the symptoms of acute chest syndrome and COVID-19 warranting emergency care visits. 47.5 % of the individuals with SCD were vaccinated by December 2022. Among these, 12.5% were partially vaccinated, 50% were fully vaccinated, and 37.5% had a booster. COVID-19 infection was significantly higher among the nonvaccinated compared to vaccinated individuals (55% vs. 27%, p=0.01). The mean interval days from the latest dose of COVID-19 vaccination to COVID-19 infection was 297.9 ± 160.5 days. The study found that COVID-19 vaccination lowered the infection risk among SCD individuals by over 70% if they have received at least one dose of the vaccine (OR=0.27, 95% CI=0.10-0.77). There was also a significant difference in preventing COVID-19 infection among the different vaccination subgroups of partial, full, and booster (33% vs. 25% vs. 28%, p=0.045).The results of the multivariable logistic regression analysis showed that none of the factors, such as obesity, pre-existing cardiac history, pulmonary history, renal disease, stroke, or transient ischemic attack, were found to be significantly associated with COVID-19 severity in this sample population. CONCLUSION: Receiving at least one dose of the COVID-19 vaccine can offer protection among individuals with SCD, even with the emergence of Omicron and its subvariants during the COVID-19 pandemic. Additionally, it is crucial that individuals with SCD remain vigilant and seek medical care if they experience chest pain, as this could be the only symptom of COVID-19 among this population.

Vitamin D Deficiency and Avascular Necrosis in Patients with Sickle Cell Disease: A Retrospective Cohort Study

Introduction Sickle cell disease (SCD) is an inherited hemoglobinopathy with complex systemic involvement. Avascular necrosis (AVN) is a devastating complication among patients with SCD. Vitamin D deficiency (VDD) is commonly found in SCD patients, but there is limited research on the potential role of VDD as a risk factor for AVN in SCD patients. This study aimed to assess the association between VDD and AVN and determine the patterns, risk factors, diagnosis, and treatment of AVN in SCD patients. Methods We conducted a retrospective cohort study of consecutive SCD patients diagnosed with VDD from January 2020 to December 2022 at Prince Sultan Medical Military City (PSMMC) in Riyadh, Saudi Arabia. Patients meeting the following criteria were included: (1) adults and children with confirmed SCD through hemoglobin electrophoresis and (2) tested for VDD. Patients who underwent bone marrow transplant were excluded. The main outcome measured was the occurrence of AVN. VDD was diagnosed in patients with 25-hydroxyvitamin D levels below 30 nmol/L. Magnetic resonance imaging was used to stage and confirm AVN diagnosis. Associations were assessed using the chi-square test, and logistic regression was performed to control for confounding. Results The study included 711 eligible SCD patients, with 271 (38%) being children. VDD affected 301 out of 711 patients (42.3%). Among these, 212 (70.4%) were adults (>18 years old). VDD was observed in 32.2% of children and 48.1% of adults. Of the total cohort, 127 (17.9%) patients experienced AVN, including 18 children. Among patients with VDD, 89 developed AVN, while VDD affected 212 patients without AVN. The time between VDD diagnosis and AVN presentation ranged from 3 to 12 months. Male patients accounted for 52% of AVN cases. The average age at AVN diagnosis was 30.9 ± 11 years. The most common clinical presentation of AVN was chronic joint pain in over 95% of patients. Other presentations included limping in 3.9% of patients and limited joint movement in one patient. Affected joints included the hip (86%), shoulder (16.5%), knee (4.7%), and sacroiliac joint (0.7%). Bilateral joint involvement was present in 50.4% of AVN patients. The majority of patients (76.4%) were diagnosed with advanced stage AVN (III/IV). Treatment of patients with AVN included joint replacement in 44 (34.6%) patients, while the remaining 83 patients managed with conservative therapy such as pain control and physiotherapy. Patients with a history of VDD were significantly associated with a higher risk of AVN (p < 0.001), as seen in Table 1. Multivariate logistic regression showed SCD patients with VDD had 9.79 times the odds of AVN compared to SCD patients without VDD (OR 9.79; 95% CI: 5.25-18.26). Other statistically significant risk factors for AVN included frequent vaso-occlusive crises (three or more episodes per year), older age, history of acute chest syndrome, and low hemoglobin F levels. Conclusion AVN is a significant cause of morbidity in our SCD cohort, with most patients having advanced AVN disease. VDD is an independent risk factor for AVN in patients with SCD. Well-designed randomized trials are needed to determine the effect of vitamin D supplementation in reducing AVN in children and adults with SCD.

MiRNA-369-5p within Small Extracellular Vesicles Correlates with Acute Chest Syndrome in Patients with Sickle Cell Disease

Introduction: Acute chest syndrome (ACS) is one of the leading causes of mortality in patients with sickle cell disease (SCD). Despite this, there are no biomarkers that can distinguish patients who present with a painful vaso-occlusive episode (VOE) and may rapidly develop ACS. Endothelial damage is a critical component of the pathophysiology of SCD. Small extracellular vesicles (EVs) are endocytic-derived vesicles that package protein and nucleic acid cargo for communication between cells. We and others have demonstrated that EVs have unique properties in patients with SCD. We have shown that EVs from SCD patients differentially affect endothelial integrity in vitro. We have previously performed miRNA sequencing and identified 15 miRNA that were differentially expressed based on a history of ACS. In this study we sought to closely assess how three of these miRNA, miR-let7c-5p, miR-122-5p, and miR-369-5p, differ across the timeline of patients with sickle cell, ie. at baseline, during ACS and during VOE. Methods: The SCD biobank at the University of Chicago Comer Children's Hospital and LaRabida Children's Hospital was queried for patients who had multiple blood samples over many years that included at least one each of a baseline (> 4 weeks from an acute event), a hospitalization for ACS and a hospitalization for a VOE. All subjects had been prospectively enrolled, with informed consent provided by parents or patients aged >18 years and assent obtained from subjects aged 9-18 years. Control samples (n=5) were obtained from patients without SCD who received bloodwork for routine check-ups or for follow-up of iron-deficiency anemia. Equal volumes of control samples were pooled for consistency across experiments. EVs were isolated via Total Exosome Isolation Kit (Thermo Fisher Scientific) per the manufacturer's guidelines. RNA was purified from samples using the miRNeasy Micro Kit (Qiagen). For quantitative PCR, complementary DNA was generated with the TaqMan Advanced miRNA cDNA Synthesis kit (Thermo Fisher Scientific). Specified miRNAs (hsa-miR-122-5p, hsa-miR-99a-5p, hsa-miR-369-5p, hsa-miR-let-7c-5p) were analyzed using TaqMan Fast Advanced Master Mix (Thermo Fisher Scientific) and TaqMan Advanced miRNA Assay primers (Thermo Fisher Scientific). Samples were analyzed in triplicate on a 7500 Fast Real-Time PCR machine (Applied Biosystems) and threshold cycle values were normalized to cel-miR-39 controls. Relative changes in expression for ACS and VOE samples were calculated using the respective baseline samples or non-SCD controls as reference values and theΔΔ quantification cycle method. Results: To determine whether exosomal miRNA levels correlated with the disease status of patients, normalized samples from all patients were aggregated and then stratified based on sample type (baseline, VOE, ACS, or ACS post transfusion). While there were no statistically significant differences in exosomal expression of miR-let-7c-5p and miR-122-5p between sample types, there was a promising trend for miR-122-5p. There was a 2.6-fold increase in miR-122-5plevels, relative to baseline, when patients experienced a vaso-occlusive episode. In contrast, miR-122-5p levels decreased 2.3-fold, relative to baseline, when patients were hospitalized with acute chest syndrome. Extravesicular miR-369-5p levels were differentially regulated and correlated with the disease status of patients. When patients were hospitalized with a VOE or ACS, there was a 2.9-fold and 10-fold increase in miR-369-5p levels, respectively, compared to their baseline. In addition, there was a statistically significant difference between VOE and ACS samples, which suggests that miR-369-5p levels can distinguish between VOE and ACS events (Fig. 3C). Interestingly, when ACS samples were obtained post-transfusion (ACS ptx), miR-369-5p levels decreased significantly to values near that of VOE samples. Conclusions: In this study, we report that the miRNA-369-5p levels in small EVs are differentially up-regulated in SCD patients during an ACS event. Furthermore, we show that these levels can distinguish patients presenting with a VOE from those who eventually develop ACS. Our findings demonstrate that it is possible to utilize extracellular vesicles and their contents to predict ACS. Further studies should be done so there is a tool to predict ACS and improve the clinical outcomes for patients with SCD.

Longitudinal Worsening of Left and Right Sided Cardiac Function in Patients with Sickle Cell Disease

Rationale: Sickle cell disease (SCD) is a genetic hemoglobinopathy characterized by hypercoagulability and accelerated mortality. Venous thromboembolism (VTE) occurs in 11-12% of SCD patients by age of 40 and increases mortality risk two to three-fold. Transthoracic echocardiography (TTE) can identify mortality risk factors in SCD including an elevated tricuspid regurgitant jet velocity (TRV) and diastolic dysfunction. We sought to characterize longitudinal changes in left and right sided cardiac function and to identify the impact of VTE in this process. Methods: We conducted a retrospective review of 402 consecutive SCD adults, 18 years of age and older, treated at our institution between 2003 and 2021. Deep venous thrombosis and/or pulmonary embolism with confirmatory diagnostic imaging defined VTE. Demographics, clinical history, laboratory data, and diagnostic evaluation were abstracted from the medical record. For echocardiographic data, clinical echocardiograms were individually re-analyzed with extensive coding of left ventricular (LV) and right ventricular (RV) systolic and diastolic function. Data were recorded at time of first contact or prior to VTE if applicable and were repeated at five years post-VTE. In the non-VTE group, baseline and five-year longitudinal data were obtained. Results: Within our cohort, 62% were HbSS/HbSβ 0, 56% were female, and 19% had a prior VTE. Prior history of acute chest syndrome, stroke, surgical splenectomy, and avascular necrosis was more common in the VTE group (p<0.01 for each comparison). Mortality was significantly higher in the VTE group compared to the non-VTE group (13% v 6%, p=0.04). In our cohort, 146 patients had initial and 5-year follow-up echocardiography (107/329 of non-VTE group, 39/75 of VTE group). Longitudinally, there were significant declines in both medial e ‘ and lateral e’ velocity and the E/A ratio, reflective of worsening left ventricular diastolic dysfunction. Right-sided cardiac function also worsened with a significantly increased TRV and right ventricular base dimension in follow-up echocardiograms. Of note, the baseline TRV was higher in the VTE group compared to the non-VTE group. In the VTE group, E/A ratio significantly decreased and RV base dimension significantly increased on follow-up study. In the non-VTE group, significant increases in TRV and RV base dimension were observed along decreases in left atrial ejection fraction, medial and lateral e', and E/A ratio on follow-up study (Table 1). Conclusions: Patients with SCD and VTE have increased mortality compared to those without VTE. Echocardiography demonstrates longitudinal worsening of left ventricular diastolic and right-sided cardiac function. These changes were more pronounced in the non-VTE group, and the lack of changes in the VTE group may reflect missing data. Our findings need to be confirmed prospectively but suggest the importance of a deeper evaluation of echocardiography to better understand the progression of SCD related cardiac dysfunction and pulmonary hypertension.

Evaluation of a prophylactic transfusion program on obstetric outcomes in pregnant women with sickle cell disease: A single centre retrospective cohort study

ObjectiveTo evaluate the effects of a prophylactic transfusion program (TP) on obstetric and perinatal outcomes in pregnant women with sickle cell disease (SCD). MethodsThis retrospective cohort study included all singleton pregnancies among women with SCD in a French university tertiary care center between 1 January 2004 and 31 December 2017. The TP group included patients selected according to the French guidelines who received regular red blood cell transfusions during pregnancy until delivery. The factors associated with TP indication [year of birth, SCD genotype, history of acute chest syndrome and delayed hemolysis transfusion reaction (DHTR) risk score] were taken into account in a propensity score. A composite obstetric adverse outcome was defined associating birth before 34 gestational weeks and/or pre-eclampsia and/or small for gestational age and/or abruption and/or stillbirth and/or maternal death and/or neonatal death. ResultsIn total, 246 pregnancies in 173 patients were analyzed. Twenty-two pregnancies with a history of DHTR were excluded. A higher frequency of TP was found before 2013 [119/148 (80.4%) vs 38/76 (50%); p < 0.001]. Rates of preterm birth before 34 gestational weeks (5.6% vs 19.7%; p = 0.001), vaso-occlusive crisis (36.5% vs. 61.8%; p < 0.001), and acute chest syndrome (6.1% vs. 14.5%; p = 0.04) during pregnancy were decreased significantly in the TP group. Among the groups with and without composite obstetric adverse outcomes, the frequency of TP was 52.6% and 74.7%, respectively [odds ratio (OR) 0.30, 95% confidence interval (CI) 0.09–1.02]. The multivariate analysis shows that the TP was associated with a significant reduction in the risk of composite obstetric adverse outcomes (OR 0.28, 95% CI 0.08–0.97; p = 0.04). ConclusionA red blood cell TP may have an independent protective effect on maternal and perinatal adverse outcomes during pregnancy in women with SCD.

Most adults with severe HbSC disease are not treated with hydroxyurea.

Sickle cell hemoglobin SC (HbSC) disease is the second most frequent sickle cell disease (SCD) genotype after sickle cell anemia (HbSS). Globally, ∼55 000 newborns with HbSC are delivered annually, with the highest HbC gene frequency in West Africa. In Ghana, 40% of adults visiting the Ghana Institute of Clinical Genetics SCD clinic have HbSC. Unlike HbSS, hydroxyurea use is not routinely recommended for individuals with HbSC because of the perceived high-risk to benefit ratio. To test the hypothesis that at least 5% of adults with HbSC will meet the American Society of Hematology criteria for severe disease, we conducted a retrospective descriptive cohort study of all individuals with HbSC (≥18 years) who visited the clinic in 2019. Adults with HbSC aged from 18 to 45 years were selected. We identified a comparison group of 639 individuals with HbSS and matched the frequency based on the age and sex of individuals with HbSC. Severe disease was defined as a history of ≥3 SCD-associated moderate or severe pain episodes per year, history of acute chest syndrome, and severe symptomatic chronic anemia that interferes with daily activities or quality of life. The study end points were the proportion of individuals with SCD who met the definition of severe disease and were eligible for hydroxyurea. In total, 64 of 639 (10.0%) individuals with HbSC met the eligibility criteria for hydroxyurea therapy compared with 154 of 639 (24.1%) individuals with HbSS. Less than 1% and 3% of individuals with severe HbSC and HbSS, respectively, were routinely prescribed with hydroxyurea in this tertiary care medical center.

Acute chest syndrome in adult patients with sickle cell disease: The relationship with the time to onset after hospital admission.

Data on acute chest syndrome (ACS) in adult sickle cell disease patients are scarce. In this study, we describe 105 consecutive ACS episodes in 81 adult patients during a 32-month period and compare the characteristics as a function of the time to onset after hospital admission for a vaso-occlusive crisis (VOC), that is early-onset episodes (time to onset ≤24 h, 42%) versus secondary episodes (>24 h, 58%; median [interquartile range] time to onset: 2 [2-3] days). The median age was 27 [22-34] years, 89% of the patients had an S/S or S/β0 -thalassaemia genotype; 81% of the patients had a history of ACS (median: 3 [2-5] per patient), only 61% were taking a disease-modifying treatment at the time of the ACS. Fever and chest pain were noted in respectively 54% and 73% of the episodes. Crackles (64%) and bronchial breathing (32%) were the main abnormal auscultatory findings. A positive microbiological test was found for 20% of episodes. Fifty percent of the episodes required a blood transfusion; ICU transfer and mortality rates were respectively 29% and 1%. Secondary and early-onset forms of ACS did not differ significantly. Disease-modifying treatments should be revaluated after each ACS episode because the recurrence rate is high.

Treatment of Individuals with Severe Sickle Cell Disease with OTQ923, an Autologous, Ex Vivo, CRISPR/Cas9-Edited, CD34+ Hematopoietic Stem and Progenitor Cell Product, Leads to Durable Engraftment and Fetal Hemoglobin Induction

Introduction: Increased levels of fetal hemoglobin (HbF; encoded by γ-globin [HBG1/HBG2]) are protective against complications of sickle cell disease (SCD). BCL11A is a transcription factor that binds to HBG1/HBG2 promoters and produces a γ-to-β globin (fetal-to-adult hemoglobin) switch. Inhibiting BCL11A binding to its target can reverse the switch and induce HbF expression in adult red blood cells (RBCs). OTQ923 is an autologous, ex vivo, CRISPR/Cas9-edited, CD34+ cellular product with a targeted disruption of the HBG1/HBG2 promoters on chromosome 11. Targeting this region in preclinical models led to HbF induction, phenotypically recapitulating hereditary persistence of fetal hemoglobin (a naturally occurring condition whose co-inheritance ameliorates SCD severity). This approach is more targeted than complete elimination of BCL11A expression in erythrocyte precursors for treating hemoglobinopathies. Additionally, unlike lentiviral vector gene addition, induction of endogenous γ-globin transcription could concur with reduction of βS-globin expression to avoid α- and β-like globin chain imbalance. Methods: Subjects with severe SCD, defined by a history of stroke, recurrent vaso-occlusive events (VOE), acute chest syndrome (ACS), chronic transfusions, recurrent priapism or red cell alloimmunization, were eligible to participate in the adult cohort (≥18-≤40 years old) of this clinical trial (NCT04443907). OTQ923 was manufactured from cryopreserved, peripheral blood derived CD34+ cells, collected after plerixafor mobilization. Prior to infusion, participants received myeloablative busulfan. Primary endpoints are to evaluate engraftment, long-term safety, and efficacy of HbF expression. Results: As of the data cut-off (July 8, 2022), 2 participants had received OTQ923, with follow-ups of 9 months (mos) and 3 mos, respectively. Here, we present initial clinical data from these 2 participants; additional data will be presented at the meeting. Both participants were homozygous for the sickle mutation. Participant 1 is a 22-year-old male with a history of silent cerebral infarcts, ACS, and priapism. At study entry, he was receiving chronic transfusions. He received 2.8x106 CD34+ cells/kg of OTQ923 (2 combined manufacturing batches). Participant 2 is a 21-year-old male with a history of ACS, and a silent cerebral infarct and was receiving hydroxyurea. He received 5.99x106 CD34+ cells/kg of OTQ923 (3 combined manufacturing batches). Time to neutrophil engraftment (the first of 3 consecutive days of absolute neutrophil count above 500 cells/mL after cell infusion) was 26 and 20 days for Participants 1 and 2, respectively. No OTQ923-related adverse events (AEs) were reported in either participant. All observed AEs were consistent with busulfan conditioning. Participants received RBC transfusions around conditioning and have received none after engraftment. For Participant 1, HbF level increased in the 6 mos after infusion and was stable at data cut-off (22.1% HbF at 9 mos after infusion). Induction of HbF was pancellular, with an F-cell percentage around 91% at 6 mos after infusion (Fig. 1A). Participant 2 had achieved an HbF level of 15.9% at 3 mos after infusion, the latest evaluable timepoint at data cut-off. Neither participant had any SCD-related VOEs after infusion of the cellular product. The proportion of edited alleles in the peripheral blood of Participant 1 was maintained at over 60% until Mo 6, which was the last evaluable timepoint (Fig. 1B). The indels were diverse, except for a predominant, large 5 kb deletion arising from simultaneous double-stranded DNA cleavage at HBG1 and HBG2 on-target sites, similar to previous reports. Conclusion: Preliminary data demonstrate clinically meaningful increases in HbF and evidence of benefit for both Participants 1 and 2 after OTQ923 infusion. Edited alleles were stable and maintained in the peripheral blood for >6 mos. The safety profile of OTQ923 was as expected after myeloablative busulfan and autologous hematopoietic stem cell transplantation. Taken together, these data suggest that this approach is safe and offers a potentially curative option for patients with severe SCD. Using cryopreserved, CD34+ cells as a starting material offers the advantage of centralizing manufacturing, scaling up the process to allow for improved patient access around the globe. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

Impact of Transfusion Program during Pregnancy on the Obstetrical Outcomes in Sickle Cell Disease Women

Introduction: Pregnancy in sickle cell womenis associated with adverse maternal outcomes. Studies evaluating the effects of the transfusion program (TP) during pregnancy are contradictory. The objective of this retrospective study was to evaluate the effect of the transfusion program on maternal and neonatal outcomes in Sickle cell disease (SCD) . Since the publications highlighting the frequency of delayed hemolysis transfusion reaction (DHTR) in SCD patients and particularly in pregnant women, transfusion(TF) indications have changed in the management of pregnancies. Transfusion indications have been limited since 2015 in view of the risks of alloimmunization and DHTR, associated with the lack of evidence of obstetrical benefit, in SCD pregnancies (10). Our objective was to evaluate the impact of the transfusion program during pregnancy on obstetric and neonatal outcomes with a propensity score to account for potential biases. Method: This is a retrospective cohort study based on analysis of electronic and paper medical records including all pregnancies in women with SCD (Hb SS, SC, S beta-thalassemia phenotypes) who received prenatal care delivered in a French tertiary care academic center (CHI-Créteil) and in Henri Mondor SCD referral center between January 2004 and December 2017. The DHTR risk score was defined for all patients. Confounding factors considered in a propensity score were delivery period, SCD genotype, history of acute chest syndrome (ACS), and delayed hemolytic transfusion reaction (DHTR) risk score. Results: We analyzed 246 pregnancies in 173 patients. Twenty-two pregnancies with a history of DHTR were analyzed separately. We found a higher frequency of TP before 2013 (119/148 [80.4%] vs 38/76 [50%], p<0.001). Patients with a history of ACS and a low DHTR risk score were significantly more represented in the transfusion program group. There was no difference between the two groups in the frequency of preeclampsia, eclampsia, Hellp syndrome, term of delivery , births <37 weeks, birth weight, and cesarean section. Punctual transfusions were more frequent in the group without TF program. Rates of preterm birth before 34 weeks, vaso-occlusives crisis(VOC) and ACS during pregnancy were significantly more frequent in the group without a transfusion program. There were 4 inaugural DHTRs in each of the 2 groups and 4 deaths in the TF Program group; this difference was not significant. Multivariate analysis weighted by propensity score showed that TF program was associated only with a significant reduction in the risk of preterm delivery before 34 weeks (OR= 0.05 95% CI [0.01-0.31], p = 0.001). Of the 22 pregnancies with a history of DHTR, 4 were complicated by a new DHTR event after emergency transfusion. The rates of delivery before 34 and 37 Weeks of gestation, neonatal death, frequency of ACS, hospitalization during pregnancy and in intensive care unit, and composite adverse obstetric outcome were significantly different between the group with a history of DHTR and all patients without known DHTR, confirming the potential seriousness of these patients. Conclusion: This study shows a trend toward reduced routine use of the transfusion program during pregnancy. There was no difference between the two groups( TP and without TP) in the frequency of pre-eclampsia, eclampsia, Hellp syndrome, term of delivery and births <37 weeks, birth weight and caesarean section. Propensity score-weighted analysis reveals an independent protective effect of the transfusion program on prematurity before 34 weeks as well as composite obstetric criteria (birth <34 weeks and/or preeclampsia and/or SGA and/or abruption and/or IUFD and/or maternal death and/or neonatal death). Although the benefit/risk balance of the transfusion program should be considered on a case-by-case basis with the DHTR risk score in early pregnancy. In patients with low transfusion risk, transfusions may be recommended upon discontinuation of HU or in case of VOC complications. Prospective studies are still needed on large homogeneous patient populations and the evaluation of alternative treatments to transfusion such as hydroxycarbamide seems important.

Venous Thromboembolism Is Associated with Right-Sided Cardiac Dysfunction and Increased Mortality in Patients with Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is a hypercoagulable state. Approximately 11-12% of patients with SCD have a venous thromboembolism (VTE) by age 40 which portends a nearly three-fold increased mortality risk compared to those without VTE. Additionally, echocardiographic findings of right-sided cardiac dysfunction and pulmonary hypertension (PH) are also independent mortality predictors in SCD. In the general population, VTE is a risk factor for PH; however, the association in SCD is uncertain. We hypothesized that patients with SCD and VTE have a greater frequency of right-sided cardiac dysfunction by transthoracic echocardiogram (TTE) and associated mortality risk compared to those without VTE. Methods: We performed a retrospective chart review of 402 consecutive SCD patients who received care at our institution between 2003 and 2021. VTE was defined as deep vein thrombosis (DVT) and/or pulmonary embolism (PE) by diagnostic imaging. Demographics, clinical and laboratory data, VTE diagnostic imaging, and TTE results were obtained from each subject. For those with VTE, we recorded data pre-VTE and 5 years post-VTE. For those without VTE, we recorded data at entry into the database and 5 years later. The atrial and ventricular size, right and left ventricular function, valvular function, and tricuspid regurgitant jet velocity (TRV) were collected from each echocardiogram. Data were analyzed using Fisher's exact, Sign-ranked and McNemar's tests. Results: In our cohort, 251 subjects (62%) were HbSS/HbSβ0 and 227 (56%) were female. VTE occurred in 75 individuals (19%) with deep vein thrombosis in 35 (47%), pulmonary embolism in 50 (67%), and both observed in 9 (12%). Prior history of acute chest syndrome, avascular necrosis, stroke, and surgical splenectomy was associated with VTE (p<0.01 for all). History of VTE was associated with an increased mortality rate during our study period compared to those without VTE (13% vs 6%, p=0.04). Within our cohort, 183 patients had initial and follow-up echocardiography (77% of VTE group, 38% of non-VTE group). In the VTE group, there was a higher frequency of right atrial enlargement five years post-VTE compared to pre-VTE (p=0.03). There was a non-significant trend towards decreased right ventricular function over five years in the VTE group (p=0.08) Neither of these findings occurred in the non-VTE group. There was no significant change in TRV after five years of follow-up in either group; however, only 45% of echocardiograms had TRV ascertained. Conclusions: Sickle cell disease patients who sustained a VTE had an increased risk of prior complications and subsequent mortality compared to those without a VTE. The presence of increased right atrial size and a trend towards right ventricular dysfunction five years post-VTE suggest development of pulmonary hypertension despite lack of change in the TRV. These findings need to be explored by a deeper analysis of the echocardiography, and in the future, a prospective study.

CLINICAL PREDICTORS OF VASO-OCCLUSIVE PAIN HOSPITALIZATION IN PATIENTS WITH SICKLE CELL DISEASE (SCD)

Vaso-occlusive painful episodes (VOE) are the most common clinical manifestation of sickle cell disease (SCD) and the primary reason for hospitalizations and emergency visits. This project aims to identify the clinical predictors of VOE hospitalization in adult participants of the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) Brazil SCD Cohort. The REDS-III Brazil SCD Cohort enrolled participants from 2013 to 2015 who were followed until 2018. Participants were randomly selected as eligible from public blood centers in 6 cities. Medical records were reviewed to abstract clinical data including the indications for all hospitalizations that occurred from one year prior to enrollment through the end of follow up. Adult cohort participants with 3+ hospitalizations per year due to VOE (cases) were compared to controls with less frequent VOE admissions to identify predictors of frequent VOE. Of the 2793 participants enrolled in the cohort, 184 (6.7%) had 3+ VOE admissions per year (5.5% of 1330 children <18yr and 7.5% of 1453 adults). Compared to adults with <3 VOE admissions/ year, the adults with frequent VOE had higher white blood cell counts (11,566 vs. 98,659 cells/uL), platelet counts (389,500 vs 357,333 cells/uL) and lower hemoglobinF (4.4% vs 6.9%) and were more likely to have received red blood cell transfusions (80% vs. 41%) and hydroxyurea (60% vs. 49%) in the past year. Acute chest syndrome, bacteremia, and asthma were also more common in adult cases compared to controls (83% vs 61%, 16% vs 8% and 17% vs 8%, respectively). Independent predictors of 3+ VOE admissions/year in multivariable models included higher white blood cell (OR 1 [1.000-1.001], history of acute chest syndrome (OR 2.8 [1.581-5.202] and treatment with hydroxyurea (OR 1.8 [1.123-3.038]. Frequent hospitalizations due to VOE are a marker of severe SCD used to identify patients for disease modifying therapy or even curative therapies such as bone marrow transplant. Understanding the significant predictors of frequent VOE in adults may identify other surrogate markers of severe disease that can be used to target therapies for high risk individuals. In this multi institutional cohort of SCD, white blood cell count and a history of acute chest syndrome were identified as significant independent predictors of frequent VOE while the association of hydroxyurea likely reflects treatment with this disease modifying therapy for frequent pain. Individuals with high white blood cell counts and acute chest syndrome should have close follow up to be monitored frequently and considered for early and aggressive treatment of pain as well as other disease modifying therapies.

Risk and protective factors for severe COVID-19 infection in a cohort of patients with sickle cell disease

Continued investigation of comorbid conditions that increase the mortality rate of COVID-19 is necessary to provide the best care for those affected. This continued push to find answers is even...

Risk Factors for Adverse Maternal and Fetal Outcomes in Pregnant Patients with Sickle Cell Disease

BackgroundApproximately 100,000 Americans are affected by sickle cell disease (SCD), an inherited hematologic disorder. In women with sickle cell disease, pregnancy is associated with increased maternal and fetal adverse outcomes (Elenga et al). However, there is a paucity of data on risk factors for adverse events in this population. This retrospective study seeks to add to the deficient repertoire of information regarding maternal and fetal outcomes in patients with sickle cell disease and their children.MethodsWe retrospectively evaluated pregnancy outcomes of women with SCD who had previously undergone echocardiography from the year 2000-2021. The associations between clinical variables and adverse hematologic (AHE), cardiac (ACE), obstetric (AOE) and fetal/neonatal (ANE) events were evaluated by the Generalized Linear Model (GLM). The adverse hematologic events were vaso-occlusive crisis (VOC) antepartum and postpartum, acute chest syndrome, venous thromboembolism antepartum and postpartum, and transfusion antepartum.ResultsWe identified 43 women/59 pregnancies with a median maternal age 27 years old (interquartile range [IQR] 20), pre-pregnancy BMI 25 kg/m2 (IQR 16). Maternal sickle cell genotype was SS in 31 (72%) women/37 (63%) pregnancies, SC in 8 (18%) women/18 (31%) pregnancies, and other genotype in 4 (9%) women/4 (7%) pregnancies. Prior venous thromboembolism was present in 12 (27%) women/15 (25%) pregnancies and prior acute chest syndrome (ACS) in 33 (80%) women/41 (75%) pregnancies. In the year before pregnancy, 24 (56%) women were admitted at least once for VOC. There were no maternal deaths during pregnancy or up to 1 year postpartum. AHE (n = 171) occurred in 43 (73%) pregnancies (Figure A), with a median of 2 (range 0-13) AHE per pregnancy. AHE were more common with genotype SS, history of ACS, history of ³ 10 lifetime transfusions, admission for VOC in the year before pregnancy, tricuspid regurgitation velocity (TRV) >2.5 m/s on echocardiogram, and increased maternal age, and less common with increased hemoglobin (Figure B). ACE were rare (n = 3) (Figure A) and weakly associated with increased maternal age (Figure C). AOE (n = 37) occurred in 27 (45%) pregnancies (Figure A) and were associated with lower pre-pregnancy maternal BMI (Figure D). ANE (n = 54) occurred in 27 (46%) of pregnancies, and were associated with maternal hypertensive disorders of pregnancy (Figure E).ConclusionsWe found that AHE during pregnancy in women with SCD were associated with genotype SS, history of ACS, ³ 10 lifetime transfusions, admission for VOC in the year before pregnancy, higher maternal age, and inversely related to hemoglobin. In addition, AHE during pregnancy were associated with TRV >2.5 m/s on echocardiogram, which has not been previously shown in women with SCD. These data may be useful to identify women at increased risk during pregnancy. Data show that patients with sickle cell disease who have more disease-related complications including history of acute chest syndrome, frequent pain crisis, elevated TRV on echocardiogram, and lower hemoglobin are at greater risk for AHE. This suggests that disease severity is directly related to outcomes. The association between increased maternal age and ACE has been demonstrated in the past in women without SCD (DeViti et al). The same can be noted for the association of AOE with lower maternal BMI (Verma et al), and ANE being associated with maternal hypertensive disorders of pregnancy (Lugobe et al). In the future, prevention of these complications will be key. Future directions include determining the effect of disease-modifying therapy on these outcomes, though safety during pregnancy has not yet been demonstrated for more novel agents such as voxelotor and crizanlizumab. With more information on these risk factors, we hope that modification and treatment can result in better outcomes. [Display omitted] DisclosuresDesai: Pfizer: Other: Publication Fee, Research Funding; Foundation for Sickle Cell Research: Honoraria; Forma: Consultancy; Novartis: Research Funding, Speakers Bureau; Global Blood Therapeutics: Honoraria, Research Funding.

COVID-19 and Sickle Cell Disease in the Province of Quebec: Morbidity and Mortality Rates Derived from the Provincial Registry

IntroductionApproximately 1500 people live with sickle cell disease (SCD) in the province of Quebec, Canada. Public health has recognized these patients as immunocompromised. SCD patients may be at higher risk of developing severe COVID-19 infection due to their underlying pro-inflammatory and thrombogenic state, splenic dysfunction and secondary organopathies. Descriptions about disease severity and mortality rates in SCD vary widely. From the SECURE-SCD registry, Mucalo et al. recently reported a 0.3% and 4.7% mortality rate in children and adults, respectively. In the French registry, Arlet and colleagues reported a 2.4% death rate among those hospitalized with COVID-19 and SCD, not different from the general population. As a result, the COVID-19 morbidity and mortality rates among the SCD population remain uncertain.ObjectivesThe primary objectives of our study are to describe the epidemiology, baseline characteristics and clinical outcomes of SCD patients with COVID-19 infection in the province of Quebec. In addition, we aim to identify risk factors for hospitalization and severe forms of COVID-19.MethodsWe built a web-based SCD-COVID-19 registry regrouping 7 adult and 4 paediatric tertiary care hospitals in the province of Quebec in June 2020. All SCD patients with a confirmed SARS-CoV-2 infection by PCR test were included in the study. We compared the prevalence of infection and hospitalization rates of SCD patients to the general population of Quebec using the epidemiological data from the INSPQ (National Institute of Public Health of Quebec) public database. We retrospectively analyzed data included between March 11, 2020 to March 1, 2021. Relative risk was calculated using bilateral association measures (exact fisher, mid-p or chi-squared tests, as appropriate) to compare the incidence of infection and hospitalization of SCD patients to the population of Quebec and to assess risk factors of hospitalization among SCD patients.ResultsDuring the first 12 months of the pandemic, 74 patients were included in the registry. The male to female ratio was 1:1.12. Median age was 23 years, ranging from 8 months to 68 years old. SS-Sbeta 0 genotypes were present in 51% of cases, while 49% were SC or Sbeta +. The majority of patients were on disease modifying therapy: 54% were on hydroxyurea and 17.5% on exchange transfusion therapy. The incidence of reported COVID-19 infection was significantly higher in SCD patients compared to the general population (4.9% vs. 3.5% p=0,002) (Table 1). Even more strikingly, SCD had rate of hospitalization 10-times greater than the general population (33.8 vs 3.2%, p<0,001). Nevertheless, the risk of admission to the intensive care unit was similar between SCD patients and the general population (24.0% vs. 24.1%, p=0.99). No death was recorded amongst SCD patients with COVID-19 compared to a death rate in the general population in Quebec of less than 70 years old of 48-78 for 100 000 infections (male-female).A history of acute chest syndrome (ACS) in the last year (OR 2.6 [1.5-4.6], p=0.04) and arterial hypertension (OR 3.3 [2.3-4.8], p=0.01) were associated with a higher risk of hospitalization (Table 2). On the other hand, there was no statistically significant association with age, sex, genotype, ABO blood group, baseline SCD therapy, or other comorbidities (chronic renal disease, obesity, pulmonary hypertension, chronic lung disease and previous admission to ICU) in our cohort.ConclusionsSimilar to other reports, we found that SCD patients were at much greater risk of hospitalization compared to the general population. We however found no increased risk of mortality or disease complication. This contrasts with results from other registries. A history of ACS and hypertension were associated with a higher risk of hospitalization. Whether social determinants of health could explain some of the outcome variability between different countries merit further investigation. Furthermore, we believe that registries are critical to monitor the impact of preventive measures. As vaccination is ongoing, it will be important to consider its impact on hospitalization and death rate among SCD population. Recruitment to the registry is ongoing and updated data will be presented at the meeting. [Display omitted] DisclosuresSoulieres: BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Forté: Novartis: Honoraria; Canadian Hematology Society: Research Funding; Pfizer: Research Funding.

Timed Average Mean Maximum Velocity (TAMMV) of Cerebral Blood Flow of Children and Adolescents with Sickle cell Disease: correlation with clinical and hematological profiles in country.

Detection of abnormal TAMMV with transcranial Doppler is fundamental in primary stroke prevention in children with sickle cell disease (SCD). The study aimed at evaluating TAMMV and correlating it with clinical and hematological profiles of children and adolescent with SCD. Transcranial Doppler was performed on subjects aged 2-16 years, using a 2 MHz probe placed over the transtemporal windows. Pulse oximetry was used to determine the peripheral oxygen saturation while clinical and hematological profiles were retrieved from their medical records. One hundred and thirty five patients were recruited. The mean TAMMV was 125cm/s. Patients with HbSS had a significantly higher TAMMV (131cm/s) than those with HbSC (107cm/s). Only one (0.74%) patient had abnormal TAMMV. TAMMV correlated inversely with oxygen saturation, Hct and patient's age, and positively with white cell and platelet counts. Previous history of acute chest syndrome (ACS) and recurrent painful crises increased the risk of development of abnormal and conditional velocity. Frequency of abnormal TAMMV in this study was low. Younger children and those with HbSS had higher TAMMV. Age, oxygen saturation and haematocrit correlated negatively while white cell and platelet counts correlated positively with TAMMV. Previous history of ACS and recurrent bone pain were associated with increased risk of having abnormal and conditional TAMMV.