key: cord-0074649-y12z03x4
authors: nan
title: Abstract Book for the 2nd Sickle Cell & Thalassaemia Virtual Conference
date: 2022-01-31
journal: Hemasphere
DOI: 10.1097/01.hs9.0000821768.32988.8d
sha: 7ea61fb1e021093e4b7d0efb4b17fdefc84e880e
doc_id: 74649
cord_uid: y12z03x4

nan

Transferrin (TF) is a bilobed 80kD glycoprotein with N-and C-lobe iron binding sites. TF circulates as four forms: unbound to iron (apo-TF), iron bound to the N-lobe (monoferric N-TF), the C-lobe (monoferric C-TF), or to both lobes (diferric-TF). Most circulating TF under physiological conditions is monoferric. The iron-bound TF forms interact with TF receptor-1 (TFR1), which is ubiquitously expressed and serves as the main mechanism for cellular iron delivery. Iron-bound TF also interacts with TF receptor-2 (TFR2) which is expressed on hepatocytes, erythroblasts, and bone cells. Whereas TFR1 serves primarily as a cargo receptor, TFR2 serves primarily to influence cellular signaling events regulating hepcidin expression, erythropoiesis, and bone formation. We proposed that different transferrin forms provide differential signaling properties in this regulation. We thus generated TF mutant mice in which all iron-containing TF was either monoferric N (Tf monoN ) or monoferric C (Tf monoC ). Compared with Tf monoC mice, the Tf monoN mice demonstrated increased RBC production and increased hepcidin expression relative to iron status (Parrow et al. Blood). Based on observations in β-thalassemic mice treated with exogenous TF (Li et al. Nat Med), we hypothesized that β-thalassemic mice obligate for monoN TF would demonstrate improved erythropoietic and iron parameters compared with β-thalassemic mice obligate for monoC TF.

To address this hypothesis, we crossed Hbb th3/+ mice, a mouse model of β-thalassemia intermedia (BT), with Tf monoN and Tf monoC mice. Compared with Hbb th3/+Tf+/+ mice, in Hbb th3/+ Tf monoN mice demonstrated significantly increased RBC counts, elevated hemoglobin, improved erythrocyte morphology ( Figure 1A -B), decreased splenomegaly, fewer bone marrow erythroblasts, and improvement of ineffective erythropoiesis (as measured by the ratio of progenitors to RBC in the bone marrow). Additionally, serum erythroferrone (ERFE) was significantly reduced and hepcidin levels were increased in Hbb th3/+ Tf monoN relative to Hbb th3/+Tf+/+ controls. Conversely, hematological parameters from Hbb th3/+ Tf monoC mice were comparable to Hbb th3/+Tf+/+ mice. Similarly, Hbb th3/+ Tf monoC mice had no improvements in markers of ineffective erythropoiesis in the bone marrow compared with Hbb th3/+Tf+/+ mice.

In summary, we demonstrate that the differential regulatory effects of monoN and monoC TF on erythropoiesis are relevant not only in steady-state, but also in the ineffective erythropoiesis that is characteristic of β-thalassemia. Because both monoN and monoC TF forms can deliver only one iron atom per TF-TFR1 binding event, our findings suggest that the improvements observed only in the Hbb th3/+ Tf monoN mice were not due to iron restriction alone. We are now elucidating the mechanisms by which the two TF lobes exert their differential effects on ineffective erythropoiesis and exploring the translational potential of obligate monoN TF in the treatment of β-thalassemia.

Background: Transfusion-dependent ß-thalassemia (TDT) is a disorder due to mutations in the gene encoding the ß-globin chain causing a reduced or absent production of haemoglobin A leading to severe anaemia and lifelong transfusion dependence. Gene therapy has now been accepted as a possible alternative cure to allogeneic bone marrow (BM) transplantation. Aims: We developed a gene therapy approach based on autologous mobilized hematopoietic stem cell transduced by lentiviral vector, expressing human ß-globin gene, administered by intrabone injection, following a myeloablative conditioning (NCT02453477). Methods and Results: Nine patients with severe TDT with different genotypes have been treated with a drug product with a median cell dose of 19 .5x106 CD34+ cells/kg, a transduction efficiency from 38 to 77% and a median vector copy number/genome (VCN) in bulk CD34+ cells of 0.9 (range: 0.7-1.5). Overall, gene therapy was generally well-tolerated with no adverse events related to the investigational product. No severe infectious-related adverse events were reported, except for those related to neutropenia as expected after myeloablative conditioning. Polyclonal vector integrations profiles with no evidence of clonal dominance have been detected in all patients with the expected genomic distribution for lentiviral vectors. Clinical outcome showed a reduction of transfusion requirement both in frequency and volume in adult patients up to more than 50%. Among the pediatric patients, 4 out of 6 discontinued transfusions shortly after gene therapy and are transfusion-independent at the last follow-up (up to 75 months). A robust and persistent engraftment was observed in 7 out of 9 patients, with a marking of BM progenitors that, in engrafted patients, ranged between 25.3 and 79.8% and with a median VCN in CD34+ cells of 0.53 (range: 0.34-2.21). As a relevant target for transgene expression, BM erythroid cells were stably marked (VCN range 0.3 -2.5).

A longer follow-up will provide further results on long-term clinical efficacy and safety of this approach. endothelial P-Selectin from Weibel-Palade bodies to the cell surface, a process promoting sickle Red Blood Cell (SS RBC) adhesion to vessel walls. Up-regulation of P-selectin contributes to cell-cell interactions, as activated platelets bind to neutrophils to form aggregates in a P-selectin-dependent manner. Previous studies have shown that anti-P-selectin agents decrease SS RBC adhesion in vivo, increase microvascular flow, and reduce adhesion of the leukocyte to endothelium, showing the potential of P-selectin as a therapeutic target. In November 2019, the FDA approved the first P-selectin inhibitor, crizanlizumab-tmca (Adakveo, Novartis), to reduce the frequency of vaso-occlusive crises (VOCs) in adults and pediatric patients with SCD. Different types of P-selectin inhibitors can offer physicians and patients new treatment options enhancing the arsenal of drugs to combat SCD. Inclacumab (Global Blood Therapeutics) is a fully human monoclonal antibody designed to bind to and selectively inhibit P-selectin. Differences in static cell adhesion to P-selectin substrate due to inclucumab were shown previously. The present study aimed to validate the dose-dependentability of inclacumab in blocking P-selectin cell adhesion in samples from SCD patients using in-vitro Whole Blood (WB) and Isolated White Blood Cell (I-WBC) assays. Methods: Five deidentified samples from SCD patients undergoing phlebotomy prior to blood exchange had been collected at the Children's Hospital of Michigan with Flow Adhesion on P-selectin measured using proprietary assays in both Whole Blood (WB) and in Isolated WhiteBlood Cells (I-WBC), with and without Inclacumab after 5 minutes incubation at room temperature. Microfluidic channels were coated with P-selectin, and I-WBC (5x10 6 /mL) suspension or WB sample diluted 1:1 with phosphate buffer was passed through the channel for 6 (I-WBC) or 10 (WB) minutes at a shear rate of 1 dyne/cm and pulsatility of 1.67 Hz. The channel was washed for 5 minutes with the same buffer, and the number of cells adherring to the channel surface was quantified. Results: Incubation of either WB or I-WBC with inclacumab significantly reduced flow adhesion to P-Selectin with the overall inhibition being stronger when assessed on isolated white cells (ab. 35% inhibition on WB vs. ab. 55% on I-WBC after incubation with 40 mM Inclacumab as compared to baseline Flow Adhesion values, Fig. 1 ). Adhesion on P-selectin showed a pronounced dose response that followed logarithmic response curve, with changes in adhesion with I-WBC better correlated with inclacumab dose, than those measured using WB. Decrease in adhesion on P-selectin was reliably detected at 2 μg/mL treatment dose for 3 out of 5 samples, with dose-depemdent decrease in adhesion in all samples at 10 and 40 μg/mL treatment doses (for I-WBC; and similar for WB). For flow adhesion with both WB and I-WBC elevated adhesion at lower doses was observed in some samples. Conclusions: Both WB and I-WBC adhesion to P-Sselectin show a dose dependent inhibition by inclacumab, with clinically relevant doses likely demonstrating greater inhibition. P-selectin adhesion assays described in this study may serve as potential surrogate biomarkers of clinical response tp p-selectin inhibitors, like inclacumab.

pain events, such as back pain, chest pain and myalgia. Pain events are known adverse drug reactions in the crizanlizumab label, however, pain events occurring during/within 24 hours of crizanlizumab infusion in SUSTAIN were not identified as potential IRRs. 3 For SCD patients, IRRrelated pain events may differ in location, severity and/or nature from their usual SCD/VOC pain. Aims: We reviewed PM data on IRRs presenting as pain events in SCD patients treated with crizanlizumab. Methods: A custom search of the Novartis safety database (comprising PM reports [spontaneous] and managed access/patient orientation program reports) was performed for reports received in November 2019-June 2021, using ~111 MedDRA terms associated with potential signs/symptoms of IRRs presenting as pain events. IRRs must have occurred during/within 24 hours of the most recent crizanlizumab infusion, and pain could differ from a patient's usual SCD/VOC. As reports were not gathered via a uniform data collection system, potential limitations include underreporting, incompletely documented cases, or bias towards reporting severe events. Results: IRRs presenting as pain events were experienced by 28 patients (Table) , and most commonly presented as back pain, pain in extremity, arthralgia, musculoskeletal chest pain and headache. Reporting rate was 1.67 cases per 100 patient-years (95% CI 1.11-2.42). Most patients (n=24) initially experienced IRR at the first or second infusion. IRR recurred on subsequent infusion(s) in six patients. Twenty patients (71%) were hospitalized for treatment, including analgesics, antihistamines, IV fluids and/or steroids. Nine patients (32%) reported known complications of SCD following IRR (Table) . Crizanlizumab was discontinued in 23 patients (82%) after their most recent IRR, including all who experienced secondary SCD complications. All patients recovered (the majority within 3 days; one with sequelae), except one who died following SCD complications and refusal of blood transfusions for personal reasons. Resolution time was prolonged for patients who reported SCD complications following IRR. Causal analysis of complications was confounded by the underlying disease and use of steroids to treat IRR (systemic corticosteroid exposure in SCD patients has been associated with pain, complications [including severe VOCs and hemorrhagic stroke] and death). We do not know whether the 28 patients had an active VOC or other SCD complications before receiving crizanlizumab. Summary -Conclusion: Although rare, based on review of PM data, healthcare professionals should be aware of the possibility of IRRs presenting as pain events during/after crizanlizumab infusion. Crizanlizumab labels have been/are being updated by Novartis to provide information on monitoring, management and prevention of IRRs, including a statement recommending caution when using corticosteroids. Given the limited data available regarding IRRs, Novartis is committed to further understanding these events. 9 Children's Healthcare of Atlanta, Atlanta, UNITED STATES Background: Etavopivat, an investigational, once daily (QD), selective, erythrocyte pyruvate kinase (PKR) activator, increases PKR activity, resulting in ↓2,3-DPG and ↑ATP in RBCs of healthy volunteers (HV) and patients (pts) with sickle cell disease (SCD) [1, 2] . Aims: Multiple-dose studies in pts with SCD (NCT03815695): 2-wk multiple ascending dose (MD) cohorts to identify the etavopivat QD dose providing maximum PD activity with an acceptable safety profile and a 12-wk open-label (OL) study to characterize safety and clinical activity at the maximum pharmacodynamic (PD) dose. Methods: Completed MD cohorts: 20 pts with SCD were randomized 8:2 to etavopivat (300 mg, then 600 mg) or placebo (PBO) QD for 2 wks. Ongoing OL study: ≤20 pts will receive etavopivat 400 mg QD for 12 wks. Assessments: safety, PK, PD, and RBC health. All pts provided written informed consent. Results: MD cohorts (n=17 HbSS, n=2 HbSβ+thalassemia, n=1 HbSC) completed enrollment and data unblinded (300 and 600 mg etavopivat, n=8 each; PBO, n=4). OL cohort: As of July 13, 2021, 11 pts (HbSS/SC, n=10/1) were treated: median treatment (Trt) duration was 12 (range 1-12) wks; 6 pts completed 12 wks of Trt. In MD pts, etavopivat demonstrated dose-proportional PK with overlapping PD response (↓2,3-DPG; ↑ATP), confirming prior results in HVs that etavopivat 400 mg QD provides maximal PD activity. Etavopivat was well tolerated. AEs were reported in 1/4 (25%) MD PBO pts, most were grade (Gr) ≤3, with 1 Gr4 blood creatine phosphokinase (CPK) increase. AEs were reported in 13 For both adult and paediatric acute pain presentations, the majority of centres provided care in their hospital emergency department (ED), and only a small number offered direct access to a ward (5%) or an ambulatory facility (12%). Ambulatory facilities' opening days ranged from 5 -7, with 64% only operating during standard hours. Access to an acute pain service (APS) was available in 83% and 65% for adult and paediatric departments respectively. Generic pain protocols were available in 50 services. The protocols vary, but the most common analgesia prescribed in adults was morphine (oral or subcutaneous or). In children, morphine (oral or intranasal) was widely used. Individual pain protocols were used in 61% of responding centres. The NICE standard '<30 minutes time to first analgesia' were not met in the majority of centres (range 30-60, outliers 80-128 min). Overall, the time to first analgesia was lower in services with ambulatory care facilities. The length of stay ranged between 3-5 days. Between 1-5% of the patients experienced a prolonged admission (>21 days). Frequent re-admissions occurred in 2-10% of the patient population (≥3 admissions/year). Education and teaching sessions were infrequently delivered for ED consultants, ED nurses, Acute Medicine consultants and pharmacists (30%, 40%, 21% and 5%). Summary: Hospital management of acute sickle pain is a significant challenge to NHS services and needs to be re-evaluated.

The questionnaire results will inform the objectives and work plans of four working groups within the NSPG (acute pain, chronic pain, education and research). In order to develop national policies, it will be necessary to generate evidence through a more detailed audit of outcomes in scenarios of best practices identified here. No references, but a more detailed summary Summary: Hospital management of acute sickle pain is a significant challenge to NHS services and needs to be re-evaluated at local and national level. Despite publication of NICE guidelines in 2012, few services in the NHS are able to consistently provide timely pain relief. The range of policies for analgesia management is surprisingly broad.

The availability of ambulatory care in some centres could function as an exemplar for national practice. There may be alternative models of care which could be effective. Patients with frequent attendance and prolonged hospital stay are present in most centres and, although relatively small as a proportion of the service, are especially challenging to manage. The management of these patients requires a multidisciplinary approach and the development of national guidance, as often this is outside the expertise of haematologists. This may be helpful in improving outcomes in this patient cohort. Background: Brain involvement in hereditary hemoglobinopathies (e.g. sickle cell disease, beta-thalassemia, spherocytosis) is commonly attributed to anemia-related relative hypoperfusion. Supratentorial and infratentorial vascular watershed regions seem to be especially vulnerable, but data are very scarce. Aims: We investigated a large beta-thalassemia sample with arterial spin labelling in order to characterize regional perfusion changes and their correlation with phenotype and anemia severity.

We performed a multicenter single-scanner cross-sectional MRI study analyzing non-invasively in 71 beta-thalassemia patients and 56 healthy controls the brain perfusion changes. Clinical phenotype, age, hemoglobin levels, cognitive functioning and parenchymal lesions were also recorded. Results: Brain perfusion was globally increased in beta-thalassemia patients compared to healthy controls; using age and sex as covariates and scaling the perfusion maps for the global cerebral blood flow, beta-thalassemia patients showed: hyperperfusion in the white matter of the centrum semiovale bilaterally, located in the watershed regions between the vascular territories of the main cerebral arteries (Fig-1a) and in the cerebellar white matter corresponding to the cerebellar watershed regions. Subdividing patients according to anemia severity (hemoglobin level < or > 9.5g/dL), the hyperperfusion clusters persisted exclusively in the subgroup with lower hemoglobin levels.

The relative hyperperfusion observed in vascular watershed territories does not support the previous hypothesis of a selective parenchymal hypoperfusion in the pathogenesis of brain injury in hereditary hemoglobinopathies. A careful management of anemia severity seems to be pivotal for preventing perfusion dysfunction, at least in beta-thalassemia. Among 749 SCA children, 86 were splenectomized at mean (SD) age of 6.4 years (3.9). As expected, mean (SD) Howell-Jolly bodies score was significantly higher at check-up in splenectomized than in non-splenectomized SCA-patients: 1.73 (1.2) vs 1.1 (1.0), p<0.001. However, the difference between both populations decreased during aging because of the progressive functional splenic dysfunction in non-splenectomized patients ( Figure 2 ) Among SCA-children, 138 were transplanted with matched sibling donor at mean (SD) age of 9.0 years (4.9y). At each age of assessment, Howell-Jolly bodies score was strongly significantly (p<0.001) lower in transplanted than in non-transplanted children (Figure 3 ). At check-up performed during the 18th year of life, mean (SD) Howell-Jolly bodies score was 1.57 (1.0) in 241 non transplanted vs 0.54 (0.9) in 70 transplanted children (p<0.001) and the score in transplanted children was significantly positively correlated with the age at transplant (r=0.335, p=0.002). Seven children with splenic sequestration history or hypersplenism and available MSD-donor had partial splenectomy before transplant in order to try to preserve splenic function. Mean (SD) Howell-Jolly bodies score was 1.83 (1.2) before and was nul after transplant in all seven children.

This cohort study clearly shows that splenic dysfunction increases during aging in SCA children and that stem cell transplantation allows to preserve splenic function especially since the transplant is performed early. In children with indication of splenectomy for recurrent splenic sequestrations or hypersplenism who have an available matched sibling donor, the present study encourages to propose partial vs total splenectomy just before stem cell transplantation in order to preserve splenic function. 1) . Prior to SCT, the patient underwent sperm cryopreservation, he received one dose of Rituximab for EBV prophylaxis, and he underwent exchange transfusion to target a Hb S <30%. Additional supportive therapy included: levetiracetam; ursodiol; and infection prophylaxis with posaconazole, levofloxacin, and valacyclovir. A total of 5.41 x 106/ kg CD34+ PBSC were infused. No G-CSF was planned but it was added on day +15 due to slow engraftment. Neutrophil engraftment occurred at day +27. Platelets were kept above 50k and engraftment occurred at day +48. Pre-engraftment adverse events included radiation-induced parotiditis, neutropenic fever, and medication-induced rhabdomyolysis with muscle pain attributed to posaconazole (CK peaked on day +13 with levels >7800; posaconazole was switched to micafungin with adequate resolution). Upon discharge pen-VK, Valtrex and fluconazol were continued and he started SMZ-TMP. He was re-admitted twice -once for SVT, and again for pneumonia. Chimerism studies revealed a 96% donor chimerism on day +30, with subsequent sustained 100% donor chimerism from day +100. Hb electrophoresis has been normal. CD4 count at day +120 was 1795 cells/ul. Our patient has had no GVHD. Tapering of immunosuppression started at 9 months and completed at 11 months post-SCT. His new baseline Hb is 14 g/dl, his last RBC transfusion was on day +33 and monthly therapeutic phlebotomies were started at 9 months. The patient is currently 1.4 yrs post-SCT. Renal transplant evaluation is underway.

Haploidentical transplantation with post-transplant Cy is a feasible approach for patients with severe SCD and ESRD. Patients require very close monitoring for complications by a specialized multidisciplinary team, but it can be a curative therapy with significant improvement in quality of life. Background: Thalassemia is characterized by ineffective erythropoiesis and hemolysis that occur due to imbalanced production and precipitation of globin chains. 1,2 Thalassemic red blood cells (RBCs) have insufficient levels of ATP to meet increased energy demands associated with globin chain imbalance, protein degradation, and cellular oxidative stress responses. 3, 4 Mitapivat is an oral activator of RBC pyruvate kinase (PKR), a key glycolytic enzyme regulating ATP production. 5 In a phase (ph) 2, open-label trial of mitapivat in adults with α-or β-non-transfusion-dependent (NTD) thalassemia (NCT03692052), 80% of patients (pts) met the primary endpoint of a hemoglobin (Hb) response (≥1.0 g/dL increase from baseline [BL] at ≥1 assessments between Weeks (Wks) 4-12, inclusive). Improvements in markers of hemolysis and ineffective erythropoiesis were also observed and mitapivat was generally well tolerated. 6 Aims: To report data from the ongoing long-term extension (LTE) period (up to Wk 72; data cutoff 27Mar2021). Methods: Pts aged ≥18 yrs with a known medical history of α-or β-thalassemia, Hb concentration ≤10.0 g/dL, and ≤5 RBC units transfused in prior 24 wks and none in 8 wks prior to study drug were eligible. All pts started mitapivat 50 mg twice daily (BID), escalating to 100 mg BID based on individual safety and Hb assessments. Background: Sickle cell disease (SCD), a lifelong, inherited blood disorder, leads to sickle hemoglobin (HbS) formation. HbS polymerization causes red blood cell sickling, leading to hemolysis, chronic anemia, and vaso-occlusive crises (VOCs). Patients with SCD are at higher risk of end-organ damage, increased morbidity, and early mortality due to low hemoglobin (Hb) and increased hemolysis. 1 Voxelotor, a HbS polymerization inhibitor, is approved in the US for SCD treatment in adults and adolescent patients aged ≥12 years. 2 The randomized, placebo-controlled HOPE trial showed that significantly more patients on voxelotor 1500 mg had a >1 g/dL Hb increase than those on placebo at any time to week 72. These Hb increases were associated with reduced hemolysis markers. 3 Here we report an interim analysis of an ongoing open-label extension (OLE) of the Methods: Patients who completed the phase 3 HOPE trial were eligible to enroll in the multicenter OLE study and receive treatment as long as they continued to receive clinical benefit and/or until they had access to voxelotor through commercialization or a managed access program. Background: Inclacumab, a fully human IgG4 anti-P-selectin monoclonal antibody, is being developed for the reduction of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD). P-selectin-mediated platelet-leukocyte aggregate (PLA) formation has been shown to contribute to vaso-occlusion. Safety and pharmacology of inclacumab have previously been well characterized in over 700 subjects (healthy volunteers and patients with cardiovascular disease), at doses up to 20 mg/ kg every 4 weeks for up to 9 months. The current Phase 1 study was initiated to evaluate the safety and pharmacology of inclacumab at doses of 20 mg/kg and 40 mg/kg in healthy subjects in support of a target Phase 3 dose of 30 mg/kg administered every 12 weeks to patients with SCD. Methods: Healthy adult subjects over 18 years of age without significant current or prior health conditions received a single intravenous (IV) dose of 20 mg/kg inclacumab infused over approximately one hour (Cohort 1). Following a review of safety, a second cohort received a single IV dose of 40 mg/kg infused over approximately one hour (Cohort 2). The total study duration and sample collection period was 29 weeks. Final safety and preliminary pharmacokinetics (PK), anti-drug antibody (ADA), and ex vivo thrombin receptor-activating peptide (TRAP)-activated PLA formation data are reported. Results: Fifteen subjects received a single dose of inclacumab 20 mg/ kg (n=6) or 40 mg/kg (n=9). Median age was 42 years (range 22-52 years); median body weight was 73.6 kg (range 63.7-89.3 kg). Through the prespecified 72-hour post-infusion safety assessment period in both cohorts, no treatment-emergent adverse events (AEs) > grade 1 (mild) nor dose-limiting toxicities were reported. Across the duration of the study, there were no serious AEs, infusion-related reactions, or hypersensitivity reactions. Additionally, no clinically significant changes in vital signs, laboratory findings, or ECGs were observed. The most common AEs were upper respiratory tract infections, headache, myalgia, back pain, and contact dermatitis. The only events assessed by the investigator as potentially related to inclacumab were headache and dizziness, which were experienced by one subject (20 mg/kg) and occurred 4 hours following the end of infusion. In healthy subjects, inclacumab demonstrated dose-proportional PK over the dose range tested; PK parameter estimates were consistent with those reported for monoclonal antibodies. Geometric mean Cmax following single doses of 20 and 40 mg/kg were 402 and 970 µg/mL, respectively. Mean TRAP-activated pre-dose PLA formation was 33-39% across cohorts and decreased to 9-14% at 2 hours following end of infusion. PLA inhibition was sustained up to 23 weeks for both the 20 and 40 mg/kg doses. Two subjects in the 40 mg/kg cohort were ADA-positive on Week 12 and thereafter; a preliminary analysis demonstrated no apparent impact on PK or safety in these subjects. a key role in the multicellular interactions that can lead to VOCs. [3] [4] [5] Crizanlizumab is a first-in-class humanized monoclonal antibody that blocks P-selectin, and is approved in several regions to prevent/reduce VOCs for SCD pts aged ≥16 years. Since June 2018, SCD pts in some countries have been able to obtain early access to crizanlizumab before health authority approval via a MAP (NCT03720626). Aims: To describe the rate of home-and healthcare-managed VOCs and use of opioids for VOC-related pain relief pre-and post-crizanlizumab initiation in SCD pts who participated in the MAP (in countries where publication of these data is allowed).

The MAP provided access to crizanlizumab for pts with serious or life-threatening disease (SCD) for which no comparable or satisfactory alternative to crizanlizumab was available as treatment in their country. Other eligibility criteria included: aged 16-70 years (18-70 years in Italy); history of VOCs as determined by the treating physician (including recurrent VOCs while taking preventative therapies eg hydroxyurea [HU]); and ineligibility for a crizanlizumab clinical trial. VOC and opioid use frequency are described for pts with available data 12 months pre-crizanlizumab initiation and after ≥12 months of treatment with crizanlizumab, overall and stratified by SCD genotype and history of HU use. In the 12 months pre-crizanlizumab initiation (baseline), all 37 pts (100%) had ≥1 home-managed VOC and 95% had ≥1 healthcare-managed VOC. In the 12 months post-crizanlizumab initiation, 68% and 59% of pts had ≥1 home-and ≥1 healthcare-managed VOC, respectively. Median (IQR) absolute reductions from baseline in home-and | 2022; 6:S1

healthcare-managed VOCs after ≥12 months of crizanlizumab treatment were -4.0 (-6.0 to -2.0) and -3.0 (-4.0 to -1.0), respectively. The lower rates of VOCs post-vs pre-crizanlizumab were also observed when stratifying the data by SCD genotype/prior HU use ( Figure) . Of note, a small number of pts are included in some groups when stratifying the data. Opioids were taken for VOC management by 95% of pts (n=35/37) in the 12 months before crizanlizumab initiation and by 68% (n=25/37) in the 12 months after; the most common opioid taken was morphine (74% [n=26/35] and 56% [n=14/25], respectively). Summary -Conclusion: Pts participating in the crizanlizumab MAP had a high burden of home-and healthcare-managed VOCs, as well as SCD-related complications at baseline, despite many pts reporting a history of HU use. Most pts reported using opioids for VOC management. Crizanlizumab substantially reduced the median annualized rates of home-and healthcare-managed VOCs and use of opioids from baseline in this real-world setting, consistent with results from SUSTAIN. 6 Background: Vaso-occlusive crises (VOCs) are the hallmark of SCD. P-selectin, a cell adhesion molecule, plays a key role in the multicellular interactions leading to VOCs. In the SUSTAIN trial, crizanlizumab 5 mg/kg, a first-in-class humanized monoclonal antibody that blocks P-selectin, significantly reduced the annualized rate of VOCs versus placebo and had a favorable safety profile in adults with SCD. Aims: To describe the initial safety and efficacy results for patients with SCD aged 12 to <18 years treated with crizanlizumab 5 mg/kg in the SOLACE-kids trial (ClinicalTrials.gov: NCT03474965; EudraCT: 2017-001747-12). Methods: SOLACE-kids is an ongoing Phase II study to establish and confirm appropriate dosing (Part A) and evaluate long-term safety and efficacy (Part B) of the confirmed dose of crizanlizumab, with or without hydroxyurea, in pediatric patients with SCD (any genotype) and ≥1 VOC leading to a healthcare visit within 12 months prior to screening. Patients (target enrollment N≥100) are stratified by age: Group 1 (12-<18 years), Group 2 (6-<12 years) and Group 3 (6 months-<6 years). Patients receive crizanlizumab on Day 1, Day 15, then every 4 weeks (up to 2 years). This analysis reports initial safety and efficacy results for Group 1 patients receiving crizanlizumab 5 mg/kg. Results: As of 28 August 2020, 50 patients have been enrolled in Group 1 (median [min-max] age 14.9 [12.0-17.9] years; 58% female; 88% HbSS genotype; 64% Black/African American; 84% receiving hydroxyurea). Median (range) duration of crizanlizumab exposure was 36.6 (6-98) weeks; 88% of patients received treatment for ≥26 weeks. The most common adverse events (AEs) regardless of causality with study treatment were headache (n=14 [28%]), vomiting (n=12 [24%]) and back pain (n=9 [18%]). Treatment-related AEs occurred in 12 (24%) patients. Grade ≥3 AEs occurred in 13 (26%) patients, most commonly anemia (n=3 [6%]) and back pain (n=2 [4%]). Grade ≥3 treatment-related AEs (back pain and pain in extremity) were reported in one (2%) patient. Eleven (22%) patients had serious AEs; none were deemed treatment related. No AEs led to treatment discontinuation except one patient who died of suspected meningitis (considered unrelated to treatment). The incidence of AEs of special interest (AESI) is shown in Table 1 . No infusion-related reactions were serious, and all had resolved at data cutoff, except for one case of Grade 1 dizziness. There were no cases of anaphylaxis to crizanlizumab. No pain events were serious, and all had resolved or were resolving by data cut-off. The median (Q1-Q3) number of VOCs leading to a healthcare visit at baseline was 3.0 (1.0-5.0) versus 1.6 (0.0-3.7) while on treatment, a median absolute reduction from baseline of -1.0 (-3.0 to 0.5). At baseline, the median (Q1-Q3) rate of hospitalizations/emergency room visits was 4.0 (2.0-8.0) versus 1.5 (0.0-2.7) while on treatment, a median absolute reduction from baseline of -2.4 (-5.0 to 1.0). Eighteen (36%) patients did not experience a VOC leading to a healthcare visit during crizanlizumab treatment. Summary -Conclusion: In this initial analysis, crizanlizumab 5 mg/kg was safe and well tolerated in patients with SCD aged 12-<18 years, consistent with the established profile of crizanlizumab in adults. No new safety signals were identified. Crizanlizumab 5 mg/kg led to a clinically relevant reduction in VOCs in this patient population compared with baseline. Background: Patients with beta-thalassemia may need regular red blood cell transfusions in infancy.1 In the absence of iron chelation therapy, frequent transfusions cause iron to accumulate, which can lead to morbidity, organ damage, and death. However, in very young children, current practice is to delay chelation therapy until receipt of 10-20 transfusions, or until serum ferritin (SF) has reached 1000 μg/L, due to concerns over excessive iron depletion with deferoxamine. 1,2 Unfortunately, this delay may increase the risk of iron accumulation in endocrine glands where toxicities could later manifest. 3 Aims: START (NCT03591575) evaluated the safety and efficacy of the oral iron chelator deferiprone (DFP) in children with transfusion-dependent beta-thalassemia who did not yet meet the criteria for starting chelation therapy per standard practice. Methods: Infants and children receiving regular blood transfusions (2 minimum) and whose SF level was between 200-600 μg/L were randomly assigned 1:1 to DFP oral solution or placebo until SF exceeded 1000 μg/L at 2 consecutive visits or 12 months of therapy. DFP was initiated at 25 mg/kg/d and increased to 50 mg/kg/d after 2 weeks; based on iron load, DFP was increased to 75 mg/kg/d. Efficacy was assessed by monthly SF measurements to monitor iron load. The primary endpoint was the percentage of patients in each group with SF <1000 μg/L. All patients provided informed consent or assent. Results: The study enrolled 64 patients; 32 per group. The mean (SD) age was 3.03 (2.42) years in the DFP group and 2.63 (1.70) years in the placebo group; participants were 62.5% and 65.6% male in the DFP and placebo groups, respectively. There were no group statistical differences in the baseline demographics. The primary reason for withdrawal was SF levels that exceeded 1000 μg/L at 2 consecutive visits, which occurred in 25% of patients receiving DFP vs 63% of patients receiving placebo (P=0.0051). After completing 12 months of treatment, 65.6% of patients receiving DFP had a SF level <1000 mg/L vs 37.5% receiving placebo (P=0.0446). The percentage of patients who reached the 1000 mg/L SF threshold increased more rapidly in the placebo group vs the DFP group, and the difference in rates between the 2 groups was significant (P=0.0407). A summary of adverse events (AEs) is shown in Table 1 . There were no significant group differences in the number of overall AEs (P=1.0000), serious AEs (P=0.4258), or the number of AEs that were considered to be at least possibly related to the study treatment (P=1.0000). Two patients receiving DFP withdrew from the study due to AEs: 1 patient experienced agranulocytosis and 1 patient experienced neutropenia of moderate severity and both patients recovered. Conclusions: Initiation of DFP chelation therapy at a lower threshold of SF values than currently recommended was safe and efficacious in preventing iron overload in most transfusion-dependent children. After 12 months of treatment, the number of patients with a SF level <1000 μg/L was significantly higher in the DFP group vs the placebo group. Moreover, there were significantly more patients who withdrew due to elevated SF levels in the placebo group (62.5%) vs the DFP group (25%). The safety and tolerability profile of DFP administered for up to 12 months in infants and young children was comparable to the profile established in older age groups and there were no instances of iron depletion. Background: Patients with transfusion-dependent-thalassemia (TDT) are considered as increased risk population for severe and/or morbid COVID-19 infection. Timely vaccination is the main preventive method for severe COVID-19. Different adverse events and reactions following vaccination have been reported, with severe ones being extremely rare. TDT patients may have altered immunity due to chronic transfusions, iron overload and chelation therapy, and splenic dysfunction. The safety profile of vaccination in chronically transfused patients with thalassemia has not been reported. Aim: To evaluate the safety profile of COVID-19 vaccines in TDT patients. Patients and Methods: This is a single institution's, retrospective analysis evaluating all TDT patients, older than 18 years old, who had completed the vaccination protocol at least 30 days before data cut-off time (July 20th 2021). Adverse events were reported by patients up to 30 days post each dose. Demographic data and hematological data, including mean hemoglobin levels before and up to 90 days after each dose, were recorded. T-test was performed to investigate changes in hematological profile and transfusion burden post vaccination. Results: 186 patients (median age:45; range:18-61 years old; male/ female:87/99) were included for data analysis corresponding to 53% of all TDT patients followed in our Thalassemia Unit. Distribution of vaccine types were: Comirnaty-BNT162b2 (Pfizer Inc. and BioNTech)90.86% (n =168), Vaxzevria (previously COVID-19 vaccine, AstraZeneca) 1.61% (n=3), Moderna (Moderna TX Inc.) 6.99% (n =13) and JNJ-78436735 (Janssen Pharmaceuticals Companies of Johnson & Johnson) 0.54% (n =2). No patients had confirmed or suspected previous COVID-19 infection. Adverse events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The incidence of adverse events after 1st and 2nd dose were 43.5% (81/186) and 54.8% (102/186), respectively. Adverse events after 1st dose included pain at injection site 26.3% (n=49), fatigue 9.7%(n=18), fever 5.4% (n=10),headaches 4.3% (n=8), arthralgia and myalgia 2.2% (n=4), and lymphadenopathy 0.5% (n=1). Adverse events after 2nd dose included fever 28.5% (n=53), fatigue 17.7% (n=33), pain at injection site 15.6%(n=29), arthralgia and myalgia 11.3% (n=21), headaches 9.1% (n=17), lymphadenopathy 3.2% (n=6), dizziness 0,5% (n=1), tachycardia 0.5% (n=1), diarrhea/ vomiting 0.05% (n=1) and amaurosis fugax 0.5%: (n=1). No grade 4-5 events or anaphylaxis were observed. Two patients (both males, 51 years and 45 years old, respectively) presented with acute hemolytic crisis with hemoglobinuria in 3rd and 20th day after the second dose with Pfizer/ BioNTech, respectively. They are receiving treatment with corticosteroids without partial response. Both patients had a history of acute hemolysis crisis within the last 3 years. A slight decrease in patients' mean hemoglobin levels was observed three months after vaccination compared to the mean hemoglobin levels before vaccination (mean=9.9 /sd=0.63 g/dL vs mean=9.81 /sd=0.64 g/dl, respectively, p= 0.05). Conclusions: Compared to the vaccine trials, we observed some lower incidence of vaccine-related adverse events in our cohort of TDT patients. A temporary drop in hemoglobin levels may be noted. Of interest, two patients with previous history of alloimmunization, developed hemolysis. Close follow up is required in TDT patients post vaccination. | 2022; 6:S1 severity. The main search was conducted, separately, by a MSc Student and a PhD student, both in Human Genetics and reviewed by a medical and human geneticist with expertise in SCD and a clinician-scientist with expertise in molecular biology and microbiology. A total of 229 articles was compared and screened for duplications. The abstracts of the remaining articles were screened for suitability to the study. Articles were excluded based on its relevance to the scope of the review. Results: This systematic review examines available data on the role of the microbiome in SCD clinical events. A total of 13 published articles were selected; most were observational human studies (n =10), and five included SCD mouse models. Few studies performed microbiome 16S rRNA analysis, to identify/classify uncultured microbes (n = 8/13). Results showed that the microbiome influences inflammation, and vaso-occlusive crises (VOC) in SCD, and is disrupted by medication and diet. This review was able to provide insight on how immunity can be maintained by the microbiome through TLRs and Myd88 mechanisms. The exploration of bacterial translocation may be regulated by an altering intestinal permeability and the microbial density, which is managed by the damage-associated molecular pattern (DAMPs). This may give insight into treating an altered intestinal microbiome in SCD patients. Whereas in SCD mouse models, neutrophil adhesion, Mac-1 activation, and heterotopic interaction in red blood cells were significantly influenced by microbiota. Conclusion: Data suggest that the microbiome can be disrupted by the SCD endophenotypes, specifically by triggering inflammation pathways, which could promote a cycle of VOC. This review emphasizes the need for investigating microbiome effects on SCD throughout the lifespan of patients. 1. To compare a baseline gap analysis at the commencement of the project in 2019 with an interim gap assessment 2 years into the project, following secondments to UK laboratories from Nigeria 2. To identify areas of increased focus and support during planned secondments, workshops, and virtual lectures • Working towards accreditation -2/6 versus 3/6: There is the need for each laboratory to progress towards an application for accreditation. • SOP's available for tests and processes -38 versus 32: This might suggest standardisation and rebranding of documents previously labelled as SOP's.

• No schedule of SOP revisions in 0/6 laboratories versus 4/6 laboratories: This clearly demonstrates an understanding that SOP's need to be updated via a document management system. • Scientist certified competences -22 versus 22.

• Self -assessed improvement targets -18 versus 15. • Laboratory lead for QA -3/6 versus 6/6: The importance of QA leadership for each laboratory identified prior to interim assessment.

Early evidence suggests that ARISE secondments have facilitated improved approaches to laboratory governance procedures and QA. Mentoring by EU partner laboratories will further enhance this. ARISE related workshops and train -the-trainer programmes will support capacity building and skills transfer.

A final assessment will be undertaken at the end of the ARISE initiative.

The ARISE initiative will build on the early success of improvement in laboratory systems, to further support service development and capacity building. The target for each partner laboratory will be a timeline of application to full accreditation Background: Sickle cell disease (SCD) is an inherited blood disorder that causes abnormalities in the oxygen-carrying protein hemoglobin found in red blood cells, leading to severe long-term health effects. According to the World Health Organization, more than 300,000 babies are born each year with SCD globally with majority in sub-Saharan Africa failing to reach the age of five. With early identification, low-cost treatments known to be effective in high-income settings for several years, can improve the health of children with SCD. Yet, SCD has not received much funding in many African countries as a health priority limiting available diagnostic and treatment services for it. The Consortium on Newborn Screening in Africa for SCD (CONSA), established in 2018, is a part of the American Society of Hematology's broad initiative to strengthen the SCD response globally through advocacy and research generation.

• Demonstrate the effectiveness of early identification and clinical interventions for newborns with SCD • Create sustainable, expanded networks for newborn screening and clinical interventions • Foster collaboration between African hematologists and public health services to develop an organized network of researchers for conducting quality studies and publishing results • Increase hematology capacity throughout sub-Saharan Africa CONSA introduces standard-of-care practices for screening and early intervention therapies (including antibiotics and malaria prophylaxis, folic acid supplements, family education and counseling, and immunizations) at participating clinical institutions, screening 10,000 -16,000 babies per year in each country, and providing clinical follow-up for babies diagnosed with SCD. A shared registry captures data from CONSA institution sites, which will be used to estimate the prevalence of SCD in member countries and evaluate the effectiveness of the interventions for the survival of newborns to five years of age. Currently, CONSA is working in seven countries, Ghana, Kenya, Liberia, Nigeria, Tanzania, Uganda, and Zambia. Hematologists and public health officials participating in the consortium have mobilized networks of screening laboratories, SCD or pediatric hematology clinics, teaching hospitals, regional referral hospitals, universities, and satellite clinics to screen newborns and provide clinical services protocol. Alongside the research showcasing the health outcomes of newborns screened and delivered early interventions, the consortium is working to ensure the long-term sustainability of programs through government, corporate, and other partner support. All country sites launched screening in 2021. As of November 15, over 17,000 babies have been screened with over 150 found to be living with SCD. Despite challenges from the COVID-19 pandemic, including population concerns of going to health clinics, need to protect SCD patients from transmission, and supply chain breakdowns, CONSA looks forward to continuing to expand newborn screening efforts for the next several years. Conclusion: The presentation will provide an overview of CONSA's goals and current work to screen and provide care for newborns with SCD, despite challenges from the COVID-19 pandemic. The presentation will also include details from the Nigeria clinical sites, case studies of current babies with SCD, and recent work done to strengthen Nigeria's national newborn screening and clinical eff Background: Sickle cell disease (SCD) is characterised by severe episodic pain requiring prompt and effective analgesia. However, SCD patients frequently experience poor quality of care due to lack of awareness of the condition among non-specialist staff, pre-conceived biases and unfounded allegation of drug-seeking behaviour. Several reports and surveys using Patient Reported Experience Measure (PREM) tools indicate widespread prevalence of ineffective pain relief in emergency department(ED), poor access to psychological therapies and poor funding for service development. Aims: To use a validated PREM tool to survey patients or carers of sickle cell disease within the paediatric service of a Specialist Haemoglobinopathy Team. To use an established Continuous Quality Improvement (CQI) methodology (5-D's-define, describe, design, deliver, digest) to ensure sustained improvement in patient-reported areas of service deficit. Methods: The PREM survey was conducted as part of a network-wide initiative in 2018. The survey responses were analysed and problem scores created for specialist care, emergency care, ward-based care, information and support. These problem areas were categorised into domains where further improvement action was needed. CQI tools were used to map the patient journey within Emergency Department (ED) when presenting with pain followed by thematic analysis to identify potential improvements in the patient journey. Results: The PREM survey analysis identified three domains for improvement:

• Domain A: To improve the effectiveness of pain relief and quality of empathic and informed care to paediatric sickle cell patients and their families in ED.

We developed multi-disciplinary teaching videos with patient involvement and patient information material based on ED/pain/sickle staff feedback. Excellent engagement from all staff groups obtained. Patient involvement in ED teaching video was well received. Thematic analysis of ED process mapping highlighted need for sustained staff education and re-writing ED pain protocol to align with current practice. Pre-conceived biases were identified among staff with respect to attributing drug-seeking behaviour to patients during severe sickle cell pain.

• Domain B: To improve the information presented to children regarding SCD and the care services available in our trust

We developed child friendly Information leaflets targeting primary school age and secondary school age readers • Domain C: To improve the availability of, and access to, mental health services for paediatric SCD patients. | 2022; 6:S1

We developed virtual parent support groups and psychological health screening for adolescent patients in clinics. We organised a 'Tree of Life' (ToL) patient empowerment workshop. The parent support groups were well attended. Plans are in place to continue ToL workshops and support groups on a regular basis. Future work: A rapid improvement workshop is being planned to engage a wider multi-disciplinary team to engender a culture of empathy in line with our trust values. Further input from workshop is expected to identify and implement sustainable goals. We plan to undertake a repeat PREM survey following the end of this CQI project to understand the impact and the implemented improvements. Our findings demonstrated that young people with SCD experienced significant decline in processing speed over time, with a larger decline occurring in participants aged under 9 years, regardless of infarct status. These findings highlight the importance of researching and monitoring PSI longitudinally in young people with SCD, to better understand the impacts of SCD an individual's cognition, identify potential treatment effects and to ensure appropriate support is put in place. Note: Mean processing speed index in a typically developing sample is 100. SCI = silent cerebral infarction; T1 = timepoint 1; T2 = timepoint 2. Background: SCD has a high clinical burden, results in poor quality of life (QoL) and reduces life expectancy in many patients (pts). To improve treatment/management, it is important to gain a deeper understanding of pt and HCP experiences. Aims: SWAY was a cross-sectional survey that assessed pt and HCP experiences of SCD. Here we focus on the experiences of HCPs from various regions on SCD symptoms and complications, impact of SCD on QoL, treatment goals and treatment satisfaction. Methods: SWAY was an international cross-sectional survey developed by international expert physicians, pt advocates and Novartis to assess pt and HCP experiences of SCD. Here we focus on the experiences of 365 HCPs who manage ≥10 SCD pts (≥5 in Canada, ≥2 in the Netherlands) and who completed the survey in April-October 2019. Responses to questions on how much SCD impacts pts' emotional wellbeing, QoL and daily life, as well as HCP treatment satisfaction, were ranked on a Likert scale (1-7: 1=not at all/strongly dissatisfied, 7=a great deal/strongly satisfied; 5-7 indicated high impact/satisfaction). Results: HCPs in all six regions recognized the prevalence of acute and chronic pain (although less frequently in Africa vs other regions; Table) . Acute chest syndrome and joint issues were among the five most common complications reported by HCPs in all regions. Globally, HCPs noted the high impact of SCD on emotional wellbeing (71-97%) and of symptoms/ complications on QoL (79-100%). Fewer HCPs in the Middle East (ME) reported a high impact of SCD on physical and sexual activity compared with other regions (Figure) . Around 40% of HCPs in the ME and Asia thought that SCD has a high impact on daily activities, compared with 77-90% in other regions. In Asia, fewer HCPs reported that SCD has a high impact on pts' education (48%) and ability to maintain a job (43%) compared with other regions (69-90% and 56-90%, respectively). Hydroxyurea (HU) was among the three most common therapies ever initiated and the therapy most likely to be initiated in any age group by HCPs in all regions except Africa (Table) . Improving pts' QoL was the top treatment goal for HCPs across all regions (51-84%). Fewer HCPs in North America (32%), South America (27%) and Europe (46%) were highly satisfied with current SCD treatments compared with other regions (62-72%); the main reason for dissatisfaction was limited treatment options in all regions except Asia. Summary: The most frequent SCD symptoms/complications that HCPs reported were similar across all regions. However, regional differences in HCP experiences of how SCD impacts pts' daily life exist (eg fewer HCPs reported a high impact on physical/sexual activity in the ME, on daily activities in the ME/Asia, and on education/work in Asia, vs other regions), which may be explained by cultural variations. HU was one of the three most common prior treatments in all regions except Africa, which may indicate an educational knowledge gap, particularly as the HCPs from Africa who completed the survey were primarily non-specialists. This could also reflect poor access to HU and/or its high cost in Africa. HCPs in most regions were dissatisfied with SCD treatments because of limited options, indicating a global unmet need for additional treatment choices. Improving QoL was the main treatment goal for HCPs in all regions, which may be indicative of a high negative impact of SCD on pt QoL and the ongoing need to address this. | 2022; 6:S1 Background: Sickle cell disease (SCD) is one of the most prevalent genetic diseases, affecting between 20 and 25 million people worldwide. In the Sub-Saharan Africa, where it is more prevalent, it contributes to 50-80% of under-5 mortality. Clinical manifestations of SCD are very heterogeneous and the intestinal microbiome appears to be crucial in the modulation of inflammation, cell adhesion and induction of aged neutrophils, which are the main interveners of recurrent vaso-occlusive crisis. Enterocyte injury, increased permeability, altered microbial composition, and bacterial overgrowth have all been documented as microbial and pathophysiologic changes in the gut microbiome of SCD patients in recent research studies. Microbiota analysis in SCD populations will be essential to demonstrate the importance of specific bacteria and their function in this disease and provide new insights for attenuating symptoms and new drug targets. Aims: Given this, our aim is to sequence by NGS bacterial 16S RNA gene in order to characterize the gut microbiome of SCD children and healthy siblings, as a control. A written informed consent was presented and explained to all the guardian participants prior to the data collection. A total of 72 stool samples were obtained from children between 3-14 years old. Results: Our preliminary results showed that the SCD and control samples exhibit some notable differences in microbiota relative abundance, at different levels of classification. Children with the disease have a higher number of the phylum Actinobacteria (p=0.013) with a mean of sequences of 5.47% (± 3.49), while the siblings have a mean of 3.25% (± 2.98). As for the genus level, only Clostridium cluster XI bacteria was more prevalent in the SCD children, whereas the siblings had higher numbers of Blautia, Aestuariispira, Campylobacter, Helicobacter, Polaribacter and Anaerorhabdus. Conclusion: There is still much to learn before fully relying on the therapeutic approaches for gut modulation, which is why more research in this field is crucial to making this a reality. This works as been supported by FCT/Aga Khan (project nº330842553) and FCT/MCTES (UIDB/05608/2020 and UIDP/05608/2020) -H&TRC. Background: Sickle Cell Anemia (SCA), a quite common hemoglobinopathy in Greece, is a consequence of abnormal hemoglobin S production (HbS). When the oxygen tension is low, HbS polymerization occurs, resulting in red blood cells (RBC) sickling that affects membrane integrity, cell deformability and rheological behavior. Thus, SCA provokes reduced RBCs survival, chronic hemolytic anemia, oxidative stress and microvascular occlusion. Currently, RBC transfusion and hydroxyurea supplementation are the major disease-modifying therapies available for SCD. In addition, L-glutamine oral therapy has been proposed as an anti-oxidative agent for SCA. Aims: The purpose of this study is to measure the oxidative status of RBCs and hemolysis in SCA patients under simultaneous hydroxyurea and L-glutamine therapy. Methods: Eighteen SCA patients (52±12 years old, HbS=68,02±9.40%, on average) as well as sixteen similar age-and gender-matched healthy volunteers (controls) participated in the present study. Six patients were under no therapy before glutamine intake, eight patients were under single hydroxyurea therapy and four patients were under blood transfusion therapy. After signing an informed consent, patients took a dose range of 10-30g glutamine (Glutamine DB EXTRA supplement) daily for a 4-month period. Blood sampling were taken before glutamine intake and during a period of 2-4 months after it. Intracellular RBC Reactive Oxygen Species (iROS) were measured by Flow Cytometry. Osmotic Fragility test (mean corpuscular fragility, MCF) and plasma free hemoglobin (p-F-Hb) were also determined. Statistical analysis was performed by GraphPad Prism 8.0.3 and SPSS v.27 software. Results: All patients had significantly increased iROS levels (632,30±44,83 AU) compared to controls (443.07±69.40 AU, p<0.01), while these under transfusion therapy had only slightly increased values (506.50±31.80 AU, p<0,05). The group of hydroxyurea treatment had lower iROS levels (584.00±87.00 AU) compared to the no therapy group (614.34±23.56 AU, p<0.05). Co-administration of hydroxyurea and glutamine resulted in a 22% decrease in iROS within a two-month period, which was preserved until the end of the four-month period. All patients had decreased RBC MCF (MCF=0.337±0.040% NaCl) compared to controls (MCF=0.46±0.01% NaCl), a finding that was unaffected by hydroxyurea intake (MCF=0.338±0.044% NaCl), a two (MCF=0,331±0,054% NaCl) and four-month (MCF=0.337±0.047% NaCl) glutamine intake period and transfusion therapy (MCF=0.326±0.031% NaCl) (p<0.01). Total bilirubin (T-BIL) was increased in the no therapy group (2.46mgr/ dl±0.28) compared to controls (0.63mgr/dl±0.17), while p-F-Hb was increased in all patients (24.34mgr/dl±11.98 vs controls 7.12mgr/ dl±2.90) (p<0.01). Patients under hydroxyurea treatment showed a 19.02% decrease in T-BIL levels but not significant different p-F-Hb levels. Finally, concomitant hydroxyurea and glutamine administration seemed to cause a further decrease in T-BIL and p-F-Hb levels (T-BIL;23.24%, p-F-Hb;65.38% after a two-month period intake). Summary-Conclusion: RBCs of patients under simultaneous hydroxyurea and glutamine supplementation scheme cope better with oxidative and hemolysis stresses. L-glutamine seems to be a candidate antioxidant supplement able to deal with basic symptoms of SCA. Sickle Cell Disease (SCD) is an inherited blood disorder that affects millions of people worldwide, and it is caused by a mutation of the β-globin gene which results in the polymerization of HbS when deoxygenated. Sickle cell patients experience severe pain, multi organ damage, and shortened life span. Changes arising from sickle hemoglobin (HbS) inside the red blood cell (RBC) leads to an imbalance of the oxidative reactions which increases reactive oxygen species (ROS) formation. Consent was obtained from people with SCD and people with SCD. Our lab discovered that SCD patients have a significant fraction of RBCs retaining-mitochondria which were associated with excessive levels of ROS1. We also noticed and increase in immature mitochondria containing reticulocytes in peripheral blood of SCD patient compared to control subjects. The percentage of mitochondria retaining RBCs directly correlated with absolute number of reticulocytes (n=18,r=0.69, P< 0.001). As would be expected we were able to link mitochondria-retention with hemolysis. In addition when we investigated energy metabolism we made the novel finding that SCD RBC have increase oxygen consumption rate (OCR). Mitochondrial-RBC retention and markers of hemolysis (serum bilirubin, and LDH) were compared by using Pearson's correlation coefficient analysis. The total serum bilirubin was directly associated with the percentage of mitochondria-containing RBCs in SCD patients' blood samples (r=0.31, n=41, p<0.04). A subgroup analysis showed a strong association between bilirubin and mitochondria-retaining RBCs in SCD patients who were not taking Hydroxyurea (r=0.55, n=17, P<0.02). There was a less significant association of percentage of mitochondria-containing RBCs in SCD with serum LDH (r=0.02, n=40, P<0.2) when all patients were analyzed, however, a strong association was seen with serum LDH and mitochondria retaining RBCs in SCD patients who were not taking Hydroxyurea (r=0.67, n=17, P<0.002). Lactate dehydrogenase (LDH) is a known biomarker for hemolysis-and associated disease complications and early mortality in patients with SCD. Percentage of mitochondria retaining RBCs also directly correlated with absolute number of reticulocytes (n=18,r=0.69, P< 0.001).We next investigated the mitochondrial RBCs energy metabolism in SCD as compared to controls in both human and mice. RBCs obtained from Townes SCD or control mice were seeded in an Agilent Seahorse XF 24-well plate using the Seahorse XF Base Medium with supplements and we monitored the OCR and extracellular acidification rate (ECAR), in real time by Seahorse XFe-extracellular flux analyzer. OCR is significantly higher in sickle cell RBCs of both human and mice origin compared to control. OCR was reduced to normal levels with oligomycin which is a known blocker of mitochondrial respiration. The mechanism responsible for mitochondrial retention in SCD is unknown. We further investigated that stress erythropoiesis is responsible for abnormal mitochondrial retention in erythrocytes. Terminal erythrocyte precursors and reticulocyte from bone marrow and spleen and peripheral blood had ROS and mitochondrial content by FACS2. Phlebotomized showed similar increased in erythrocyte mitochondrial retention and similar pattern of precursor erythrocyte in bone marrow to SCD mice precursors. Conclusion: Our data suggest a novel pathophysiology of stress erythropoiesis in SCD. Aims: HbE/β-thalassemia is the commonest form of severe β-thalassemia, and comprises approximately 50% of all cases worldwide 1 . HbE/β-thalassemia is caused by the HbE codon 26 G>A mutation on one allele and any β0-thalassemia mutation on the other. There is a reduction in β-globin production, resulting in a relative excess in α-globin chains that leads to ineffective erythropoiesis. Importantly, individuals with a mutation on one, but not two, alleles have β-thalassemia trait, a carrier state with a normal phenotype shared by 1.5% of the world's population 2 . Recent gene therapy and gene editing approaches have been developed to treat β-thalassemia but do not directly repair the causative mutation in-situ. Gene replacement approaches rely on lentiviral vector-based sequence insertion or homology directed repair (HDR). HbF induction strategies rely on non-homologous end joining targeting of enhancers in-trans. These approaches, whilst variably successful, are associated with potential safety concerns. Methods: Adenine base editors (ABEs) circumvent these problems by directly repairing pathogenic variants in-situ through deamination. ABEs catalyse A-T to G-C transitions. Conversion of the HbE codon to WT through base editing is an attractive strategy to recapitulate the phenotypically normal β-thalassemia trait state without potentially harmful double-strand breaks or random vector insertions. ABEs are able to convert the HbE codon (AAG) to wild-type (GAG), but also to GGG or AGG (Fig A) . GGG at codon 26 is found in a naturally occurring haemoglobin, Hb Aubenas 3 . Heterozygotes have normal red cell indices and are phenotypically normal. We electroporated the latest generation of ABE8 editors 4 as mRNA into 3 different severe HbE/β-thalassemia donor HSPCs with sgRNAs targeting the HbE codon. Results: The mean conversion from the HbE codon to a normal or normal variant in unselected cells was 86.2 (SD±8 .1%, Fig B) . The indel rate from inadvertent on-target Cas9 cleavage was below 0.5%. Edited cells did not show any perturbations in erythroid differentiation as assessed by Immunophenotyping and cellular morphology. In differentiated erythroid cells, RT-qPCR showed a mean fall in the α/β mRNA ratio to 0.65±0.08 (unedited patient cells normalised to 1, n=5, Figure C) , indicating a reduction in the excess α-globin gene expression. Protein analysis by CE-HPLC showed a 3.6-fold reduction in HbE levels (SD±1.3) and a 13.5-fold increase in HbA/Hb Aubenas (SD±2.4, Fig D & E) . In serial NSG-murine xenotransplantation experiments, base edited cells were found to persist in secondary transplants, showing editing is possible in long-term HSCs (mean editing efficiency 34.5%, Fig F) . Potential off-target effects were assessed in-vitro by CIRCLE-seq 5 ; most candidate sites were in intergenic and intronic regions (Fig G & H) . The top 250 sites were sequenced using deep targeted NGS. Only 5 sites showed OT deaminations at low levels in patient cells (mean 1.5%). We developed a machine learning model to assess potential OT-effects on chromatin accessibility, at all candidate sites in 49 different blood cell types 6 . Only 17 potential edits were predicted to result in a significant change in chromatin state (Fig I) . 3 of these were in the top 250 sites sequenced previously, and none showed deamination in-vivo. Conclusion: Together these data provide robust evidence for base editing being used as an effective and safe therapeutic strategy for HbE/β-thalassemia. Methods: Clinically diagnosed homozygous SCA patients from the Tunis national bone marrow transplant center and healthy donors were sampled for hematological and cellular assays. Flow cytometry was performed in to quantify apoptotic MVs derived from erythrocytes, platelets and endothelial cells using specific fluorescent antibodies and dyes.

Our results showed a statistically significant increase in the number of apoptotic MVs which suggests a high apoptosis rate in patients' cells comparing to healthy donors. We also found that MVs derived from erythrocytes, platelets and endothelial cells were clearly elevated in SCA patients which suggests their potential contribution in thrombotic risk and chronic hemolytic anemia. Our findings suggest then that microvesicles can be considered as hemolytic biomarkers for a predictive diagnosis so that disease complications could be avoided.

Background/Aims: Sickle cell disease (SCD) also known as sickle cell anemia is one of the most worldwide-disseminated hereditary hemoglobinopathies. It is caused by a single amino acid substitution at the sixth residue of β globin gene (Glu6Val), which results in an abnormal hemoglobin called hemoglobin S (HbS). The acceleration of HbS polymerization induces rigid and dysfunctional erythrocytes that play a central role in acute and chronic clinical manifestations of SCD (Conran et al.,2009 ). Vaso-occlusion and hemolytic anemia are the hallmarks of SCD. We aim to explore the cellular environment of red blood cells to explain the physiopathology of SCD. In fact, the life span of circulating erythrocytes in healthy individuals vary from 100 to 120 days. In SCD, red blood cells undergo a form of cell death, namely, eryptosis before they reach their full life span. Eryptosis is triggered by a wide variety of factors as hyperosmolarity, oxidative stress and energy depletion. It is characterized by the presence of membrane blebbing, cell shrinkage, and phosphatidylserine (PS) exposure (Lang et al.,2012) . In this study, we will explore the mechanism of triggering of eryptosis in Sickle cell disease. Methods: Following clinical diagnosis, 50 homozygous SCD patients and 30 healthy donors were identified for hematological and cellular assays. Flow cytometry was performed in order to determine the viability parameters of erythrocytes. The morphology of red blood cells and the externalization of phosphatidylserine was detected by labeling red blood cells with Annexine V. Moreover, we had identified intracellular calcium concentration and ceramide level by labeling erythrocytes with Fluo3-am and anti-ceramide antibodies. Finally, we had quantified reactive oxygen species (ROS) by labeling red blood cells with CM-H2DCFDA. Results and Discussion: Eryptosis in sickle cell patients is accelerated. In fact, PS (+) red blood cells are more present in patients than in healthy subjects. Therefore, eryptosis is triggered by oxidative stress, which stimulates the increase of calcium activity and subsequent externalization of PS and red blood cells shrinkage in sickle cell patients. However, the pathway of ceramide can also be considered a potential stimulating factor of eryptosis in SCD. Eryptosis ensures healthy erythrocyte quantity in circulation, whereas excessive eryptosis is the cause of acute anemia and may contribute to vaso-occlusive crisis in SCD patients.

The key pathology in sickle cell disease (SCD), a life-threatening, hereditary hemoglobin (Hb) disorder, is red blood cell (RBC) sickling due to polymerization of deoxygenated sickle Hb (HbS), which can be exacerbated by increased levels of the glycolytic metabolite 2,3-diphosphoglycerate (2,3-DPG), and decreased ATP. [1] [2] [3] Sickled RBCs are rigid, not deformable, and fragile, resulting in vaso-occlusion triggering pain and chronic hemolysis. 4-6 SCD treatment options are limited, with an unmet need for safe and effective therapies to improve anemia and reduce pain. Mitapivat is an oral, activator of RBC pyruvate kinase (PKR), a key glycolytic enzyme. PKR activation decreases 2,3-DPG and increases ATP, which may reduce HbS polymerization, RBC sickling, and hemolysis in SCD. 3, [7] [8] [9] Data from the phase (ph) 1 National Institutes of Health multiple ascending dose study of up to 100 mg mitapivat twice daily (BID) in SCD (NCT04000165) showed that mitapivat was safe and tolerable, increased ATP and decreased 2,3-DPG in a dose-dependent manner, and improved anemia and hemolysis. 8, 10 Aims: To report the study design of RISE UP (NCT05031780, EudraCT: 2021-001674-34), a ph 2/3, double-blind, randomized, placebo-controlled, multicenter study evaluating the efficacy and safety of mitapivat in patients (pts) with SCD. Methods: Eligible: pts aged ≥16 yrs with documented SCD (HbSS, HbSC, HbSβ 0 /HbSβ + thalassemia, other SCD variants), 2-10 sickle cell pain crises (SCPCs; acute pain needing medical contact, acute chest syndrome, priapism, hepatic or splenic sequestration) in the prior 12 months, and Hb 5.5-10.5 g/dL. If taking hydroxyurea (HU), the dose must be stable for ≥90 days before starting study drug. Ineligible: pts receiving regularly scheduled blood transfusions, with severe kidney disease or hepatobiliary disorders, currently receiving SCD therapies (excluding HU) or who have received gene therapy, bone marrow or stem cell transplantation.

In the double-blind ph 2 part, 69 pts will be randomized (1:1:1) to 50 mg or 100 mg mitapivat, or placebo BID for 12 weeks (wks). The primary objective of ph 2 is to determine the recommended ph 3 mitapivat dose by evaluating anemia and safety vs placebo via the following endpoints: Hb response (≥1.0 g/dL increase in average Hb concentration over Wks had good knowledge on SCD. The odds of good knowledge was 82% lower in nurses than clinicians (AOR= 0.177; 95% CI: 0.090, 0.349; p = 0.000); 95% lower in diploma than Master degree holders (AOR = 0.049; 95% CI: 0.008, 0.300; p = 0.001) and 4.6 times higher in those with 5 -9 years than ≥ 10 years of experience (AOR=4.564; 95%CI: 1.341, 15.525; p=0.015). The regional-level hospitals lacked diagnostic tests and Hydroxyurea. Conclusion: There was a general lack of knowledge on SCD among healthcare workers and limited availability of critical resources for the diagnosis and care of SCD, especially at regional-level hospitals. Efforts are needed for their improvement in order to enhance care to patients, thus reducing the morbidity and mortality due to SCD in Tanzania.

India has been identified as having the second largest number of births with sickle cell anaemia(SCA) in the world after Africa and exhibits wide clinical diversity (1) . We therefore introduced a scoring system to evaluate the severity of SCA in India children using simple clinico-laboratory parameter.

Objective and work plan: The main aim is to see if Indian score is different from international scores -tweel et al., (2) In India, the disease is largely undocumented. Thus, there is an urgent need to document the features of Indian disease so that locally appropriate models of care may be evolved across other countries too. We used cluster analysis of clinical parameters like avascular necrosis,stroke, hepatic or splenic sequestration, acute chest syndrome, vaso-occlusive crisis, number of blood transfusions with combined clinical and laboratory parameters of internationally validated score. The idea is to clinically categorise the children based on expert opinion into mild,moderate and severe using several clinical parameters and to match this with a validated international scoring system. The total severity score of 173 patients ranging from 0 to | 2022; 6:S1

70 with mean ± standard deviation of 27.69 ± 24.51. Approximately 63.7% had mild disease, 13.2% moderate disease, and 35.7% severe disease, according to our severity score grading system. Comparison of international score with our score was done with a matching of 64.9%. Some minor modifications was done in a validated score due to local factors and clinical diversity.Present samples cohort (171) was divided randomly into two groups; Discovery group (N=100) and Validation group (N=71). Validation was done with overall matching of 81.5% after including parameters which was not present in an international score as per Indian patients. Score matching increased from 65% to 82% All weightings demonstrated a significant difference between the scores of mild, moderate, and severely affected patients, as classified by a subjective rating or with an existing index (P < 0.01). Conclusion: Routine evaluation of disease severity in children with SCA will help to prospectively identify children at higher risk for a turbulent clinical course who may need more active management and monitoring. Assessment of patients objectively after any type of intervention like counselling, treatment(pre and post hydroxyurea) can be done by score.

Introduction SCA is a common genetic disorder in Saudi Arabia with estimate of 1.4 % of population (1, 2) . The prevalence of SCD in Jazan region is around 24 per 10,000 which consider the second region with high prevalence of SCD after eastern province. COVID 19 infection outbreak has affected SCD with different outcome.

Objectives: This research aims to determine the clinical picture of COVID-19 in patients with sickle cell disease SCD. The study represented the risk factors for severe COVID-19 presentation and predictors for poor prognosis in this group of patients. Methods: This study is a retrospective, descriptive, observational study of SCD adult and pediatric patients in Prince Mohammed Bin Nasser Hospital, Jazan, Saudi Arabia, who were diagnosed with COVID-19 virus infection at the study center from March 2020 to September 2021.

To describe clinical presentation of SCD patients of different severities, who got COVID-19 during the study, socio-demographic data, clinical presentations, laboratory parameters, medications use, as well as COVID-19 symptoms and severity were extracted and analyzed from the medical record files. Results: 43 medical records for adult and pediatric sickle cell patients with COVID-19 were collected, in order to determine the impact of COVID-19 on the clinical presentation of SCD patients. (53%) were females, (47%) were males with a mean age of 24 years (±1.9). (37%) of the sample suffered from major comorbidities, out of which 44% had ACS. and 11.6% have pulmonary embolism. The most prevalent clinical symptoms were fever (56%) and Shortness of Breath (37%). (16%) of included patients were admitted to the ICU with an average length of stay equals to 3.9 days (±0.6). CBC showed normal averages of PLT with a mean equal to 327 K/uL (±21.6), Basophils 0.05 K/uL (±0.01), Lymphocytes 3.6 K/uL (±0.4). High averages were found for WBC 13.8 K/uL (±1.1), Neutrophils 8.8 K/uL (± 0.9) and PT 14.2 seconds (±0.3). The only laboratory parameter that showed low average reading was Hemoglobin, with a mean equal to 8 g/dl (±0.2). Out of the 41 patients who undergone CRP test, 85% were positive. The main CT chest finding were ground glass appearance in 30% of the patients 88% of the studied patients were on Hydroxyurea, 76% were on 1000 mg dose. For COVID-19 management, majority of patients were on Antibiotics 93%, 70% of patients started Anticoagulants, 51% of the patient has received antiviral treatment. 32.5% of the patient were treated with steroids. 70% of the patients have received blood transfusion. 5 patients 12% were managed at home. One patient had coinfection with falciparum malaria. Total deaths was 2 patients represented 4.6 % out of total SCD patients with COVID-19 who were included in the study.

After exploring the impact of COVID-19 on SCD patients, the main presenting symptom were fever and shortness of breath. The major complication were acute chest syndrome 44% and pulmonary embolism in 12%. The overall prognosis was excellent and most of the patient have recovered. The death was reported in 2 patients only. Outpatient treatments were feasible in 12% of the patients. Table 1 . None of the patient had cardiac iron overload, 2 had medium and 1 severe hepatic iron overload. Five patients had commorbidities (pulmonary hypertension 2, heart failure 1, atrial fibrillation 3, diabetes mellitus 2, arterial hypertension 1, malignant disease 1). Five patients had been vaccinated for COVID-19 before they presented with disease. The majority of patients (32/33) devepoped symptomatic disease of mild (26) or moderate (6) severity according to established criteria. Only one patient presented severe disease. Only 6/33 patients required hospitalization (4 thalassemic and 2 with SCD). In 4/6 hospitalized patients oxygen therapy with a nasal cannula was required and only one patient required a Venturi mask. None of the patients were intubated. One of the SCD patients developed an acute painful episode but there was no ACS post COVID-19. No increase in transfusion requirements was observed. There were no deaths in our patient population. All but one patients completely recovered whereas one SCD patient who was hospitalized is suffering from long-COVID. History of heart failure was associated with severe disease (p=0.03) and history of AF was associated with need for hospitalization (p=0.02). History of splenectomy, pulmonary hypertension or ACS and the degree of iron overload were not associated with disease severity or hospitalization requirement. Conclusion: COVID-19 had mild to moderate severity in the majority of our patients and only a minority of the patients required hospitalization.

No ICU admissions or deaths were observed, comparing favourably to published data. Factors predisposing for severe COVID-19 in the general population, especially cardiac disease, seem to play a role also in patients with hemoglobinopathy. Background: Thalassemias are characterized by imbalanced globin-chain production resulting in excess α-or β-globin precipitation, hemolytic anemia, and ineffective erythropoiesis. 1,2 ATP levels are reduced in thalassemic red blood cells (RBCs), despite increased energy demands. 3, 4 Mitapivat is an oral activator of RBC pyruvate kinase (PKR), a glycolytic enzyme that regulates ATP production. 5 In a phase 2 study of patients with α-or β-non-transfusion-dependent thalassemia (NTDT), twicedaily (BID) dosing with mitapivat increased hemoglobin (Hb) levels by ≥1.0 g/dL in 80% of patients, 6 supporting the broadening of mitapivat's development in thalassemia. Aims: To report the study designs of ENERGIZE (2021-000211-23) and ENERGIZE-T (2021-000212-34), two phase 3 trials to assess the efficacy and safety of mitapivat in adults with α-or β-NTDT or transfusion-dependent thalassemia (TDT), respectively. Methods: Both studies are phase 3, multicenter, randomized, double-blind, placebo-controlled trials (Figure) . In ENERGIZE, approximately 171 eligible adults with NTDT will be randomized (2:1) to receive 100 mg mitapivat BID or placebo for 24 weeks. Upon completion, eligible patients can transition to a 5-year, open-label extension. Key inclusion criteria: documented diagnosis of thalassemia (β-thalassemia ± α-globin mutations, Hb E β-thalassemia, or α-thalassemia [Hb H disease]), Hb concentration ≤10.0 g/dL, and NTDT defined as ≤5 RBC units during the 24-week period before randomization and no RBC transfusion ≤8 weeks prior. The primary endpoint is an Hb response defined as a ≥1.0 g/dL increase in average Hb concentration from Week 12 through 24 compared with baseline. Secondary endpoints include patient-reported outcomes, changes in Hb, markers of hemolysis and erythropoiesis, and safety. In ENERGIZE-T, approximately 240 eligible adults with TDT will be randomized (2:1) to receive 100 mg mitapivat BID or placebo for 48 weeks. Upon completion, eligible patients can transition to a 5-year, open-label extension. Key inclusion criteria: documented diagnosis of thalassemia (same genotypes as detailed for the ENERGIZE study), and TDT defined as 6-20 RBC units transfused and no transfusion-free period ≥6 weeks during the 24 weeks before randomization. The primary endpoint is a transfusion reduction response, defined as a ≥50% reduction in transfused RBC units with a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through Week 48 compared with baseline. Secondary endpoints include additional measures of transfusion burden, changes in iron markers, and safety. Results: Not yet available. Conclusions: ENERGIZE and ENERGIZE-T are the first pivotal studies to assess a potential treatment across a broad spectrum of patients with thalassemia (ie, patients with TDT and NTDT; α-and β-thalassemias). ENERGIZE and ENERGIZE-T will evaluate the efficacy and safety of mitapivat, a novel, first-in-class oral activator of PKR. Both studies are actively recruiting. | 2022; 6:S1 Background: The paper presents results of 27-year epidemiological study of screening and follow-up haemoglobinopathies in Slovakia. Aims: The incidence of haemoglobinopathies in Slovek Republic Methods: Between 1993 -2020, in two centres in Bratislava and in one centre in Kosice, carriers of beta-thalassaemic genes or other haemoglobinopathies were searched for. Patients with a probability of having a haemoglobinopathy were sent to the research facilities. Diagnosis was performed by haematologists, whereby the family history was evaluated, together with overall clinical condition, blood count and blood smear, iron and haemolysis parameters, mutations of hereditary haemochromatosis, and haemoglobin electrophoresis testing. Results: A clinical suspicion of the heterozygous form of beta-thalassaemia or other haemoglobinopathies was documented in 694 patients. Of them 25 (6.04%) patients were foreigners. 415 (59.85%) patients were genetically examined. In 385 (92.99%) of them heterozygote beta-thalassaemia was confirmed (in 98 families). Five patients (1.21%) were diagnosed for delta,beta-thalassaemia, 4 patients (0,97%) for delta,beta-gama1-thalasaemia or persistent hereditary fetal haemoglobin. In total we diagnosed 20 mutations of beta-globin gene. The most frequent mutations were IVS 1.110 (G-A), IVS II-1(G-A) and codon 39. Evidence of haemoglobin S (heterozygote sickle cell anaemia) was also notable in two non-relative children, whose fathers were of African origin, in one patient of Ghana and in one patient from Nigeria. One female patient was followed up for haemoglobin Santa Ana (mutation de novo), one family for haemoglobin Bishopstown and one patient for mutation KLF1 gene. In our group were 14 patients (3.14%) diagnosed for alpha-thalassaemia. All patients were heterozygotes, only one female patient from Macedonia was a double heterozygote for beta-thalasaemie. Clinicaly all of the patients had a minor or intermedia form. In the years of 2012-2019 we observed 12 pregnant patients with beta-thalasaemie. One of them had multiple pregnancies, all deliveries were without haematological complications.

The study showed that in the west and eastern Slovakia there is a higher number for thalassaemia and other haemoglobinopathies. Mutations are of historical origin or over the past years we have recorded an increase number of mutations from areas with high incidence of haemoglobinopathies. It is necessary to continue in search of pathological gene carriers to avoid serious forms of the disease. Key words: thalassaemia -sickle cell disease -prevention-epidemiological study -Slovakia

The global annual population of newborns with structural haemoglobin disorders is estimated at five million. Nigeria accounts for more than 30% of these in Sub-Saharan Africa with under-five mortality from haemoglobinopathies reaching 50-90%. Despite this huge burden and a 15-fold reduction in deaths from haemoglobinopathies in countries that conduct newborn screening, most sub-Saharan Africa countries do not have a screening program. Haemoglobin electrophoresis is also not sensitive for newborn screening. Objectives: This study was carried out to determine haemoglobin phenotype patterns and frequency in neonates attending routine immunization clinics in Bida, and to identify factors associated with the occurrence of haemoglobinopathy. Methods: It was a descriptive cross-sectional study that recruited 254 neonates by multi-staged sampling technique from nine immunisation centres. Heel prick blood sample collected on Guthrie cards were tested using High-Performance Liquid Chromatography (HPLC). The relationship of various risk factors with the occurrence of an abnormal haemoglobin variant was analysed with the Statistical Package for Social Sciences. Results: The Hb phenotypes found in this study were HbFA-73.6% (187/254), HbFAS-23.2% (59/254), HbFAC-1.6% (4/254), HbFS-1.2% (3/254), and HbFAD-0.4% (1/254). There was an almost equal abnormal haemoglobin occurrence in both genders. The majority (89%) of mothers did not know their Hb phenotype, one-quarter of these had a newborn with an abnormal phenotype and 20% married in consanguineous marriages. Wrong perception of sickle cell disease was common. Conclusion: Abnormal haemoglobin variants were present in more than one-quarter (26.4%) of the neonatal population studied in Bida. Most parents were not aware of their haemoglobin phenotype and had a wrong perception of sickle cell disease. Consanguinity though common in the population did not significantly affect the occurrence of an abnormal haemoglobin phenotype. Background: Oxidative stress is a key contributors to the pathophysiology of sickle cell disease (SCD) and related complications including acute pain (vaso-occlusive crisis VOC) and acute chest syndrome (ACS) [ 1, 2 ] . L-glutamine (L-Gln), a precursor of nicotinamide adenine dinucleotide (NAD), has been shown to play a key role in the regulation of oxidative stress [ 3 ] . In a pivotal Phase 3 trial, L-Gln demonstrated significant reduction in VOCs, hospitalizations, and ACS events compared to placebo in patients with SCD, with or without hydroxyurea (HU) use, over a 48-week period [ 4 ] . In September 2021, a re-analysis of the trial data revealed that L-Gln decreased the number of VOCs by 45% [ 5 ] . Aims: To confirm the efficacy of pharmaceutical-grade L-glutamine in pediatric and adult patients with SCD at follow-up time points of 24, 48 and 72 weeks. Methods: In a retrospective study conducted from October 2019 to April 2020, 19 patients (4 patients from Qatar and 15 patients from French Guyana) were treated orally with L-Gln (0.3mg/kg) twice daily. Laboratory parameters (hemoglobin levels (Hg), hematocrit proportion (Ht), WBC counts, reticulocyte counts, and LDH levels) were measured at baseline and follow-up time points. Clinical parameters (number of VOCs, hospitalizations, days hospitalized, ACS events, and blood transfusions) were documented for the year prior to treatment initiation as baseline values. These parameters were also collected at 24, 48, and 72 weeks from treatment initiation. Adverse events (AEs) were also collected during the treatment period. The data values at 24, 48, and 72 weeks have been annualized. Statistical analysis was performed using MedCalc Version 20.015. Results: 19 patients (HbSS, age range, 8-54 years; 53% patients <18 years) were retrospectively analyzed. 63% of the patients were receiving HU at baseline and 47% received concomitant HU during the study. Compared to baseline, patients had significantly fewer VOCs at 24, 48, and 72 weeks following L-Gln therapy (median change from 3.0 to 0; P<0.00001). Compared to baseline, there were fewer hospitalizations (median change from 3.0 to 0; P<0.00001) and patients spent fewer days in hospital (median change from 15.0 to 0; P<0.00001). Moreover, at 24, 48, and 72 weeks, the number of blood transfusions was considerably lower than at baseline (median, from 3.0 to 0; P<0.00001). In the year prior to treatment initiation, 2 patients reported a single ACS event, but, no such events were observed during therapy. Following treatment with L-Gln, the mean Hg level increased significantly from baseline to 72 weeks (8.2 to 8.8 g/dL; P<0.001) with peak mean increase from baseline of 11.2% at 48 weeks. A similar increasing trend was observed for Ht from baseline to 72 weeks (24% to 27%; P<0.001) with highest mean improvement from baseline of 15.5% at 48 weeks. Conversely, mean reticulocyte counts and LDH levels were significantly reduced at follow-up time points compared to baseline (P=0.003 and P<0.001, respectively). Only few AEs occurred and were mild. No compliance issue was reported. Conclusions: This study demonstrated that L-Gln therapy in SCD patients from Qatar and French Guyana resulted in significant and sustained improvements in clinical outcomes (number of VOCs, number and duration of hospitalizations, and number of blood transfusions) and an increase in Hg and a reduction of hemolysis. 2 patients with a history of ACS did not experience any of those events during L-Gln therapy. (Colombatti 2016) . Transcranial Doppler ultrasound (TCD) is a validated screening tool to identify pediatric SCD patients with the highest risk of stroke, to start on a preventive chronic blood transfusion regimen (Estcourt 2020; Inusa 2019). We aimed to evaluate the distribution of TCD velocities in a pediatric natural history cohort and investigate their correlation with hematological variables and treatments. Methods: We performed a retrospective analysis on data from a prospective pediatric cohort followed from January 1, 2009, to December 31, 2020 (censoring date). We used transcranial Doppler imaging (TCDi) and classified results according to STOP criteria, considering terminal internal carotid artery (TICA) and middle cerebral artery (MCA) time-averaged maximum mean velocities (TAMMVs). Hematological, clinical, and treatment variables were available from the natural history cohort database. Two-sample and Welch t-tests for unequal variances were used to compare mean hemoglobin (Hb) values and hemolysis markers in patients with and without abnormal/conditional TCDi results. Fisher and chisquare tests were used to compare categorical variables. Linear regression models were used to assess the effects of MCA and TICA TAMMVs as continuous variables on Hb. Odds ratios (ORs) for neurological events at different Hb levels were estimated using generalized estimated equations (GEE) with a binomial distribution, logistic function, and exchangeable correlation structure, allowing for correlation among repeated observations for the same patient. Multivariable GEE including characteristics and treatment variables were used to evaluate the association between neurological events and Hb. (Figure 1A and 1B) . Univariate analysis showed significant inverse correlation between abnormal/conditional TCDi results and Hb considered as a continuous variable (OR: 0.484, P<0.001). In the multivariate analysis, the correlation between TCDi results and Hb remained significant; moreover, the risk of presenting abnormal/conditional TCDi results decreased with age (OR: 0.833, P<0.0064). Conclusions: This analysis from our natural history cohort shows a significant inverse correlation between Hb and MCA and TICA velocities, supporting the beneficial effect of higher Hb levels in reducing TAMMV. Background: SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, resulting in the production of hemoglobin S (HbS). HbS polymerizes within RBCs under certain conditions, leading to the distortion of the RBC membrane and generation of dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions, which may present as acute, painful episodes called VOEs. Although most VOEs are managed at home, >70% of emergency department visits and >90% of hospitalizations for SCD are VOE-related. 1,2 Additionally, acute chest syndrome is one of the most severe complications of VOEs and is a leading cause of mortality. 3, 4 As there are no targeted therapies for the management of VOEs, treatment is currently limited to pain management, blood exchange transfusion (with the risk of complications), and other supportive care, which represents a significant unmet medical need. Overall, accumulating nonclinical data suggest a multimodal role for complement dysregulation in the pathophysiology of SCD including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage. 5 Complement pathway activation has been described in pts with SCD at baseline, in acute pain crises, and in pts with delayed hemolytic transfusion reaction. The complement pathway can be targeted with crovalimab, which is a novel, engineered, anti-complement C5 monoclonal antibody. In a Phase 1/2 paroxysmal nocturnal hemoglobinuria (a complement-mediated disorder) study, crovalimab showed rapid and sustained complement inhibition with promising efficacy and safety. 6 Aims: CROSSWALK-a (NCT04912869) is a randomized, double-blind, placebo-controlled, Phase 1b study evaluating the safety of crovalimab in managing acute uncomplicated VOEs in pts with SCD. Methods: Pts aged 12 to 55 years, weighing ≥40 kg, and with a confirmed diagnosis of SCD homozygous hemoglobin S (HbSS) or sickle cell β 0 thalassemia (HbSβ 0 ) will be enrolled (Figure) . Pts must present with an acute uncomplicated VOE, requiring hospitalization and treatment with parenteral opioid analgesics. Vaccinations against Neisseria meningitidis, Hemophilus influenzae type B, and Streptococcus pneumoniae must be current. Eligible pts will be randomized 2:1 to receive either a single intravenous weight-based tiered dose of crovalimab or placebo. All pts will continue with pain management and other supportive care for their VOE, and may continue concurrent SCD-directed therapies. Pts will be followed during hospitalization until discharge and will also be followed post-discharge during an observational period. The maximum total study duration for an individual pt, including the hospitalization and observational periods, will be 12 weeks. The primary objective is to evaluate the incidence and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0, incidence and severity of infusion-related reactions and hypersensitivity, and change from baseline in targeted vital signs and clinical laboratory test results. Efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and exploratory biomarker endpoints will also be evaluated. Results: CROSSWALK-a is scheduled to be completed in September 2023. Summary: CROSSWALK-a is enrolling pts with SCD in 5 countries.

Background: SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, with either homozygous inheritance or heterozygous co-inheritance with other pathogenic variants of the β-globin gene. Hemoglobin S, produced as a result of this point mutation, polymerizes within RBCs under certain conditions, distorting them and generating dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions, which may present as acute painful episodes called VOEs. Pts with SCD may also have severe chronic anemia, chronic pain, immune dysfunction, and progressive multi-organ damage. Current therapies for SCD include hydroxyurea, as well as newer treatments such as L-glutamine, crizanlizumab, and voxelotor. Despite these treatments, considerable morbidity and mortality among pts with SCD represents a significant unmet medical need. Complement pathway activation has been reported in pts with SCD at baseline, in acute pain crises, and in delayed hemolytic | 2022; 6:S1 transfusion reaction. Accumulating nonclinical data suggest the potential multimodal role for complement dysregulation in the pathophysiology of SCD, including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage. 1 The complement pathway can be targeted with crovalimab, a novel anti-C5 monoclonal antibody that allows for small-volume subcutaneous (SC) self-injection. In a Phase 1/2 paroxysmal nocturnal hemoglobinuria (a complement-mediated disorder) study, crovalimab showed rapid and sustained complement inhibition with promising efficacy and safety. 2 Aim: CROSSWALK-c (NCT05075824) is a randomized, double-blind, placebo-controlled, Phase 2a study evaluating the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs in pts with SCD. Methods: Pts aged 12 to 55 years, weighing ≥40 kg, with a confirmed diagnosis of SCD, homozygous hemoglobin S (HbSS) or sickle cell β 0 thalassemia (HbSβ 0 ), and presenting with 2 to 10 VOEs are eligible, including pts on concurrent SCD-directed therapies. Vaccinations against Neisseria meningitidis, Haemophilus influenzae type B, and Streptococcus pneumoniae are required. Pts with a history of hematopoietic stem cell transplant will be excluded. Eligible pts will be randomized 1:1 to the crovalimab or placebo arms (Figure) . An initial intravenous loading dose of crovalimab or placebo will be given on Week 1, Day 1, followed by SC dose on Week 1, Day 2, and then weekly SC doses on Weeks 2-4. Starting Week 5, a maintenance dose will be given every 4 weeks for 48 weeks. All study treatment will be given according to a weight-based tiered dosing schedule (pts weighing ≥40 kg to <100 kg and pts >100 kg). The primary objective is to evaluate the efficacy of crovalimab vs placebo based on the annualized rate of medical facility VOEs. Key secondary efficacy objectives are the annualized rate of acute chest syndrome, the annualized rate of home VOE, and change in urinary albumin-creatinine ratio, tricuspid regurgitant jet velocity, and Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue score in adults, from baseline to Week 49. Safety, pharmacokinetics, immunogenicity, and exploratory biomarker objectives will also be evaluated. Results: Primary results for CROSSWALK-c are expected in July 2024. Summary: CROSSWALK-c is enrolling pts with SCD and chronic VOEs in 6 countries. Background: Thalassemia major has various complications that can increase morbidity and mortality. Osteoporosis is a common complication in thalassemia major and has a multifactorial pathogenesis. Osteoporosis can cause vertebral compression fractures and lead to disability. In TIF recommendation, a DEXA-scan is used to measure bone density in thalassemia patients. However, most patients in Indonesia could not afford the DEXA-scan examination because it is not covered by insurance. The 2019 ISCD Pediatric Positions Task Forces stated that the diagnosis of pediatric osteoporosis included the presence of a nontraumatic vertebral compression fracture (VF), without the need for BMD criteria. In Indonesia, there has been no study for the prevalence of hypovitaminosis D and vertebral compression fractures in children with thalassemia major and its correlation. Objective: To describe the prevalence of VF and hypovitaminosis D in children with thalassemia major. Methods: A cross-sectional study design was conducted in children with thalassemia major aged 7-18 years at the Thalassemia Center at Cipto Mangunkusumo National Hospital. Detection and evaluation techniques for vertebral fractures were using plain radiograph from Siemens Healthineers -Ysio Max -X-ray. The classification is based on Global Consensus Recommendations on Prevention and Management of Nutritional Rickets, whereas <30 nmol/L or <12 ng/mL are deficient, 30-50 nmol/L or 12-20 ng/mL are insufficient. Results: This study obtained 165 subjects (50,1% boys, 66% homozygous beta-thalassemia). Fifty-two subjects (31,5%) have VF, and three of them have both thoracal and lumbar fractures. The most common sites of VF were lumbar five and thoracic 11-12. The youngest subject who has VF is seven years old. Osteopenia was found in 67,3% of patients. There were no subjects with fractures who had complaints of pain or a history of previous trauma. Vitamin D levels [25(OH)D] were measured in 122 subjects, and hypovitaminosis D occurred in 77,9% of the subject (32,8% deficiency, 45,1% insufficiency). Our study found no significant relationship between vitamin D levels on the incidence of vertebral compression fractures (p>0,05). Conclusion: To our knowledge, this is the highest prevalence of VF among various studies that have been conducted. Vertebral X-ray is beneficial to detect bone density from osteopenia to fracture in children with thalassemia major. Hypovitaminosis D is common in thalassemia, requiring regular vitamin D administration. Further research is needed to consider the other contributing factors.

Background: In Sickle Cell Disease (SCD), spleen enlargement happens frequently in children. Acute splenic sequestration occurs when the red pulp of the spleen filtering action is exaggerated and the red blood cells are trapped, which causes the spleen sudden enlargement. If left untreated, this condition can be life-threatening. The spleen length is typically measured in the clinic, including manual palpation and following ultrasound examination. However, the common clinical workflow is non-quantitative (manual palpation) and suffers from inter-and intra-experts variability (ultrasound examination). In the developing area, where there is a high prevalence of SCD, there is often a lack of experienced sonographers to conduct the length measurement while ultrasound examination. To address this problem, we set out to use a deep learning-based strategy to develop a full pipeline, which consists of a quality control system and an automated length measurement for spleen assessment. Methods: We investigated the use of deep learning to automate the process of spleen length measurement. A deep learning model based on the ResNet was developed to classify whether the input ultrasound image could be used to measure the length. A U-net based network was trained to automatically segment the spleen. The principal components analysis was then applied to the segmentation to find the longest axis of the spleen, and the splenic length was computed based on the projection of the points within the segmentation to the axis.

: 475 ultrasound images of the spleen were used in this study. 475 images were used to train the quality control network (420 good quality images and 55 bad quality images), and 420 images (good quality images) were used in developing the automated spleen length measurement system. These images were obtained from SCD patients and were acquired as part of routine examinations at the Evelina Children's Hospital, London. 108 images were manually measured by three experienced sonographers to computer the inter-expert variability as a comparison to our methods. The mean percentage error of our length measurement has reached 4.58% on good quality images which was within the human expert error (5.78%). Our quality control system has reached 0.964 sensitivity and 0.636 specificity. After incorporating bad quality images and the quality control system, the full pipeline reached 4.88% percentage length error, which is still within the human expert variability. Conclusion: We have demonstrated that deep learning can be used for automating the length measurement for the spleen from ultrasound images. The performance of the developed pipeline has reached the human expert level. This can be potentially used in a real clinical scenario. Aim: The aim of this study was to identify the reasons for the poor uptake and adherence to hydroxycarbamide from the perspective of people with sickle cell disease, parents of children with sickle cell disease and clinicians of people with sickle cell disease. Background: Children and adults with sickle cell disease have health related complications which impact on their health, quality of life and life expectancy. Hydroxycarbamide has been demonstrated to offer clinical benefits with minimal toxicities but uptake and adherence to hydroxycarbamide remains poor. Method: This study was a systematic review. A search strategy covered several databases including Academic Search Complete, Medline, CINAHL Complete, SocIndex, PubMed, Psych Info, British Nursing Index, Cochrane and Science Direct. An inclusion and exclusion criteria was applied and 9 studies were then critically appraised using validated appraisal tools. Data was extracted, themes identified and results and findings synthesised. Results: Four key themes and further subthemes were identified.

• Safety of hydroxycarbamide, subthemes: side effects, long term side effects, still experimental • Knowledge and Understanding, subthemes: knowledge of hydroxycarbamide, knowledge of sickle cell disease, perceived effectiveness of hydroxycarbamide, perception of disease severity, perception of therapeutic effect in the community • Clinician/healthcare, subthemes: clinician choice, clinician relationship trust in medical system • Burden of taking, subthemes: remembering to take, aversion to taking pills, clinic reviews (missed work, school), number of blood tests, obtaining prescriptions/refills, costs, transport Conclusions: Whilst scientific evidence suggests that the benefits of hydroxycarbamide far outweigh the risks, the participants in the nine included studies report barriers that effect its utilisation. Whilst many of the concerns have been reported previously this systematic review confirms that these barriers still exist. Clinicians and healthcare professionals must explore barriers with their colleagues, patients and families and need to make provisions to help reduce the burden of treatment with hydroxycarbamide. Continuing discussions and education throughout childhood, transition and into adulthood will enable patients and families to make informed decisions. Further qualitative studies would enhance the findings of this research. | 2022; 6:S1 this topic is heterogeneous and we urgently require an evaluation of the evidence supporting efficacy of non-pharmacological interventions in reducing the frequency and intensity of sickle cell related pain in children with SCD. Aims: The aim of this systematic review is to evaluate the evidence on the efficacy of non-pharmacological interventions in reducing the frequency and intensity of sickle cell related pain in children with SCD. Methods: We performed a literature search through October 2021 using the terms 'sickle cell', 'pain', 'psychotherapy', 'analgesic', and 'health service'. We included randomized controlled trials and quasi-experimental studies that investigated the efficacy of non-pharmacological interventions on (1) pain frequency and intensity, and (2) analgesic and health service use in children with SCD. Results: Eleven articles including 441 participants were included. Nine studies performed in the outpatient clinic investigated the efficacy of cognitive behavioral therapy, biofeedback, and massage. Two studies performed during hospital admission included virtual reality and yoga. Five studies reported significant reductions in the frequency and/or intensity of pain. One study reported a significantly reduced analgesic use. The remaining six studies did not report a reduction in pain related outcomes.

The evidence for non-pharmacological interventions to reduce pain in children with SCD seems promising, but due to heterogeneity of the included/published studies no firm conclusions can be drawn.

To target SCD related pain in children, a multidisciplinary approach focusing on the physical, psychological and social aspects seems most appropriate, but the clinical implementation of non-pharmacological interventions first needs further exploration. Methods: A team of expert biocurators is involved in the collection, validation and annotation of information with weekly updates on scientific literature collected from PubMed, while the curation strategy also involves the incorporation of new and updated information from existing public databases. ITHANET also accepts contributions to its content with acknowledgement of unpublished data in a specifically designed section.

The ITHANET Portal offers a wide range of curated databases, as follows:

1. IthaGenes is a database that organises genes and variations affecting haemoglobinopathies and integrates the NCBI sequence viewer for detailed graphical representation of each variation. 2. IthaMaps is a database that stores epidemiological information as documented in published literature and illustrates this information on a dynamic global to regional map for a total of over 196 countries. 3. IthaChrom provides digitised reports of standard diagnostic high-performance liquid chromatography analyses as a reference tool for haemoglobinopathy diagnosis, allowing database searches of key data. 4. IthaPhen is a database that demonstrates the correlations between genotype and phenotype and is a unique and powerful tool for clinicians and molecular geneticists

The ITHANET Portal has a high-profile international governance structure and is already the most comprehensive knowledgebase on haemoglobinopathies. As an official partner of the Human Variome Project's Global Globin Network, ITHANET has been selected for data storing, curation and sharing within and between countries, as well as for the development of a thalassaemia-specific genotype-phenotype database. Aims: SCAN (Sickle Cell Anemia Narrations) is a project aimed to collect narratives of patients with sickle cell disease (SCD) and their family members, to gain insight on living with SCD. Italian SCD population is multicultural, melting endemic patients of Caucasian descent and subjects of African descent as first or second-generation Italian citizen.

The research was carried in Italy between January-September 2021 and involved two patients' associations and seven comprehensive sickle cell centers. Illness plots for patients with SCD and family members, together with a sociodemographic survey, were collected online through the project's website. In-depth interviews were also conducted. Narratives were analyzed through narrative-based medicine classifications, NVivo software, and interpretative coding. Results: Twenty-two patients with SCD (53% Caucasian, 33% African, 14% other) and ten family members participated in the survey. The patient's care pathway in 44% of the cases was described as difficult at the beginning but in the present was considered satisfactory. Misdiagnose of SCD was reported in 33% of patients' narratives, and their caregivers remarked the overall lack of empathy in communication of the diagnosis. Transitional care was described as positive in 17% of the cases. Although in 41% of the cases family members were described by patients as supportive, in the other cases difficult family situations were reported. Caregivers confirmed the difficulties encountered in managing the care pathway and the lack of coordination between comprehensive SCD centers and general practitioners. Lack of knowledge about SCD, even among health professionals, was remarked by 56% of the respondents. Weakness (53%), and pain in the limbs and hips (41%) impact patients' quality of life. Acceptance of SCD was the main coping element (79%). Patients' absence from job showed an average of 39 days per year due to the illness related to SCD. When stimulated about future expectations, patients indicated less pain (30%) and more efficient cures (20%) as still unmet needs. Conclusion: SCAN is the first project on narratives from patients with SCD. Our findings highlight the SCD disease burden for both patients and caregivers. We also identify the need to increase disease awareness and to activate/improve services such as psychological/anthropologic support and transitional care.

Background: Countries around the world were dealing with an increase in demand for COVID-19 healthcare, which was exacerbated by fear, confusion, and mobility restrictions, all of which impacted the provision of health care for all conditions. Patients with severe diseases, such as hemoglobinopathies, seem to pose additional challenges. Aim-Methods: An anonymous questionnaire was developed and given to 130 patients from four Thalassemia and Sickle Cell Disease Units of the National Health System of Greece Hospitals using stratified random sampling technique. To perform statistical analysis on the questionnaires, the MedCalc 2018 application was used.

Results: There were 130 participants (51 % women, 49 % males) with transfusion-dependent thalassemia (84%), transfused sickle cell disease (15%), and other conditions (1%). During the pandemic, patients' main concern was a lack of blood for transfusions (64 percent). The consistency of scheduled transfusions was not impaired (72 %) during the lock-down, while they were occasionally delayed (21 %) or did not appear at all (7 %). Similarly, when it came to systemic iron chelation therapy, 82 % were consistent, whereas 6 % stopped taking the drug on a regular basis because of worry of not having enough. The pandemic and lockdown had an impact on the annual follow-up of basic disease comorbidities, with 42% postponing the standard cardiac evaluation, 30% postponing magnetic resonance imaging of the liver-heart, and 23% cancelling major assessments or treatments such as biopsies or in vitro fertilisation (IVF) therapeutic interventions. Finally, 6% of scheduled surgeries had to be rescheduled. Conclusion: Patients with hemoglobinopathies received their scheduled transfusions without delay during the pandemic. A small percentage of patients modified their home medications because they were concerned about not being adequate during the pandemic. The significant consequence of the pandemic on our patients was the postponement of scheduled assessments and medical procedures required for chronic complications of their underlying condition.

Background: Sickle Cell Disease (SCD) comprises a group of red blood cell (RBC) disorders, with a diagnosed global population of ~20 million 1 . It is a chronic disease characterised by morphological RBC abnormalities in low oxygen due to β-globin mutation, causing vascular obstruction and complications including pain crisis and stroke 2-4 . The pandemic has seen patients with SCD face a higher risk of severe forms of COVID-19 infection and mortality 5 . Despite the approval of COVID-19 vaccinations, there is limited understanding of their impact in SCD. Evidence suggests that this has led to poor vaccine uptake due to patients feeling uncertain of their safety, potentially putting patients with SCD at risk, in addition to negatively impacting quality of life. Aims: To improve understanding of the real-world impacts of COVID-19 vaccination on both patient-reported outcomes and automatically recorded biometric datapoints in real-time, specifically in the context of Sickle Cell Disease, in order to support the improvement of patient confidence and vaccine uptake, thereby reducing COVID-19 risk. Methods: An FDA approved, CE marked smartwatch was provided to a 37 year old male with diagnosed HbSC following informed consent. This device was worn day and night over a 15-month period, automatically recording key biometrics including sleep quality, heart rate, and activity levels. This was supplemented by manual patient self-recording of SpO 2 levels and ECG traces through the device, as well as self-reported pain scores (0-10, low-high), psychological scores (0-10, lowhigh), and symptoms entered via a patient-reported outcomes (PRO) portal. Metrics were compared as a 7-day pre-vaccination average, day of vaccination snapshot, and post-vaccination 2-day and 5-day average, in order to track any changes in patient wellbeing across the period following vaccination with reference to their baseline. Results: Live monitoring of day-by-day indicators of patient health revealed that, following an initial spike post-COVID-19 vaccination, physiological and psychological wellbeing metrics, as well as real-time biometrics such as sleep quality and activity levels, returned to pre-vaccination levels within 5 days.

While pain scores remained statistically significantly high following influenza vaccination, this had returned to pre-vaccination levels over the 5-days following COVID-19 vaccine (Dose 1). Notably, while no significant difference was seen after 2-days of the second dose, pain scores had dropped significantly lower than even pre-vaccination levels post-Dose 2 in regards to the 5-day average. No significant changes were seen following the combined COVID-19 booster and flu vaccinations.

Our data identifies trends in the temporary impact of COVID-19 vaccination upon both PROs and real-time biometric datapoints. However, PROs highlighted a lesser impact in comparison with more traditional influenza vaccination. Furthermore, these impacts were seen to resolve within 5 days following vaccination, with post-vaccination SpO 2 , activity levels, sleep quality, and PRO averages returning to pre-vaccination levels following this initial spike. No ECG abnormalities were recorded pre-or post-vaccination.

In conclusion, this work indicates a visible but short-term impact of COVID-19 vaccination upon a patient with SCD, suggesting no heightened risk with COVID-19 vaccination in a previously poorly explored disease. | 2022; 6:S1

inclusion. Following the meeting, a summary and any material used was circulated to the whole group. Results: 13 meetings January-November 2021 (Initially weekly, however we changed to monthly over the summer as demand dropped off). Subjects covered include: COVID-19 & dealing with anxiety, stress, Low mood/dealing with sadness, Vaccine safety, fatigue, returning to school, Paintalking to people about your diagnosis.Attendance was variablewith the maximum being 6 young people. A short survey was circulated to try and identify what was working, what needed to change and to have input from the YP on content. As a result of this feedback, we moved to a different day of the week and a later session time. Summary: small numbers YP would regularly attend, parents commented they looked forward to this group, which we took to be a sign of success.

Other attendees, joined sporadically on 1 or more occasions. We found the YP to be engaged. Most were happy to say hello and introduce themselves on camera but would then prefer the camera off. We didn't have anyone comment on difficulties with access, many used their smartphone devices. Session preapration was time consuming, but as we progressed, we became more efficient at re-using material and needing less 'team brief' time as we understood how the sessions ran. It is an expensive service, professional time wise. However, we haven't compared to using a clinic environment or education room on site, which would take more organising and possibly less availability. There are no transport cost or travel time, so equitable for all Conclusion: This has been a valuable service for a small cohort 

The Hemoglobinopathy VCEP focuses on the review and annotation of variants located in the globin gene clusters, namely α-globin locus (NG_000006), which includes genes HBA1, HBA2 and HBZ, and β-globin locus (NG_000007) which includes genes HBB, HBD, HBG1, HBG2 and HBE and the regulatory element LCRB. Using a consensus approach and guidance by the ClinGen Sequence Variant Interpretation Working Group, the Hemoglobinopathy VCEP has prepared a pre-final version of the specified ACMG/AMP criteria for hemoglobinopathies. Results: The Hemoglobinopathy VCEP developed disease-specific rules for sequence variant classification based on evidence criteria that assess variant frequency, variant types and disease causality, protein domains and mutational hotspots implicated in disease, clinical manifestations, segregation, in silico predictions and functional evidence. Conclusions: For the first time, the Hemoglobinopathy VCEP will provide a standardised classification of the pathogenicity of variants related to hemoglobinopathies. The Hemoglobinopathy VCEP specifications were approved by ClinGen in April 2021 (Step 2 approval), which initiated the process of further validation and adaptation with known globin gene variants in a pilot study (toward Step 3 approval). | 2022; 6:S1 Sickle cell disease (SCD) is a common genetic condition defined by abnormalities in hemoglobin, an oxygen carrying protein in red blood cells. About 5% of the world's population carries genes for hemoglobin disorders, with the highest prevalence in countries in Subsaharan Africa (SSA). SCD causes significant morbidity, mortality, and economic burden in the countries and populations affected. Various countries have established national guidelines for SCD management, which serve to standardize care and improve patient outcomes. Ten such guidelines were identified for compilation and analysis in this paper as of summer 2021. Qualitative analysis of the guidelines has identified the priorities of each government and medical institutions' stance on best practices across high-, middle-, and low-income countries. The analysis identified that care for acute complications of SCD is more frequently endorsed in the guidelines of low-and-middle income countries (LMIC), which also have higher disease burden, over high-income countries (HIC). Chronic preventative care for SCD disease, which is shown to be an evidence-based effective approach to improve patient outcomes, is more frequently recommended in guidelines of HIC over LMIC. Furthermore, national newborn screening guidelines are scarce in the countries with high prevalence rates and adolescent mortality. While most countries recommend screening programs, LMIC have limited recommendations for newborn preventative measures. Incorporation and prioritization of preventive care guidelines in LMIC may serve as a path to inform sustainable nationwide interventions to improve patient outcomes for SCD. Implementation of these guidelines would contribute to preventing acute complications and improving morbidity and mortality for individuals with SCD. In addition, prioritization and inclusion of preventive and chronic care measures in healthcare services may mitigate the economic burden of SCD in LMIC.

Ferriprox® (deferiprone) tablets, Prescribing Information

VOCS) IN PATIENTS (PTS) WITH SICKLE CELL DISEASE (SCD) TREATED WITH CRIZANLIZUMAB FOR 12 MONTHS: RESULTS FROM A REAL-WORLD, MANAGED ACCESS PROGRAM (MAP)

Department of pediatrics: Immunology, Hematology and Stem cell transplantation

KNOWLEDGE AND RESOURCE AVAILABILITY FOR CARE OF SICKLE CELL DISEASE AT HEALTH FACILITIES

Bull World Health Organ

A Cross-sectional Survey

Sampling Techniques

World Health Organisation, Agenda item 11.4. 59th World Health Assembly

Government medical college, nagpur, INDIA References 1. Hockham et al, The spatial epidemiology of sickle-cell anemia in india

Develepment and validation of pediatric severity index for sickle cell patients

P110 CLINICAL CHARACTERISTICS OF COVID-19 IN SICKLE CELL DISEASE (SCD) PATIENTS

TWO PHASE 3, RANDOMIZED, DOUBLE-BLIND

M 9 1 Division of Hematology

Division of Hematology

P114 NEWBORN SCREENING FOR HAEMOGLOBINOPATHIES

White Paper: Pathways to Progress in Newborn Screening for Sickle Cell Disease in Sub-Saharan Africa

Inherited haemoglobin disorders: An increasing global health problem

World distribution, population genetics, and health burden of the hemoglobinopathies

Neonatal screening & Natural history of sickle cell disease

Age at Diagnosis of Sickle Cell Anaemia in

Abnormal haemoglobins in the Sudan savanna of Nigeria I. Prevalence of haemoglobins and relationships between sickle cell trait, malaria and survival

Newborn screening for sickle cell disease in a Nigerian hospital

Sickle Cell Disease Screening in Northern Nigeria: The Co-Existence of Β-Thalassemia Inheritance

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P117 THE INTERNATIONAL HAEMOGLOBINOPATHY RESEARCH NETWORK (INHERENT): AN INTERNATIONAL INITIATIVE TO STUDY THE ROLE OF GENETIC MODIFIERS IN HAEMOGLOBINOPATHIES

CHILDREN WITH SICKLE CELL DISEASE: DATA FROM A NATURAL HISTORY COHORT

References 1. Ballas et al

THE PREVENTION OF VASO-OCCLUSIVE EPISODES (VOES) IN PATIENTS (PTS) WITH SICKLE CELL DISEASE (SCD)

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P128 ITHANET: AN INFORMATION AND DATABASE COMMUNITY PORTAL FOR HAEMOGLOBINOPATHIES

ITHANET: Information and database community portal for haemoglobinopathies bioRxiv

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Increasing the involvement of diverse populations in genomics-based health care-lessons from haemoglobinopathies

P129 NARRATING SICKLE CELL DISEASE: THE EXPERIENCES OF PATIENTS AND CARGIVERS

Clinic of Pediatric Hematology Oncology, Department of Child and Maternal Health

Quality of life in adults with sickle cell disease: an integrative review of the literature Rev Bras Enferm

Life for patients with myelofibrosis: the physical, emotional and financial impact, collected using narrative medicine-Results from the Italian 'Back to Life' project

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P130 PROVIDING ADEQUATE HEALTHCARE TO PEOPLE WITH HEMOGLOBINOPATHIES DURING THE PANDEMIC

Theodoros Aforozis

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A 14

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Background: COVID19 pandemic has put an incomparable pressure on all health services -including those offered to hemoglobinopathy patients. Sickle cell disease management, although not routinely requiring inpatient facilities, is dependent upon hospital based services on a great extent. Aims: Aim of the present study was to evaluate the impact of COVID19 pandemic on medical management of sickle cell disease patients followed at a single pediatric center in Northern Greece. Methods: Patient records were reviewed in order to assess changes reflecting limited access to specialized care, i.e. number of disease related complications, number of hospital routine visits and number of disease related hospitalizations, during the 18month pandemic in Greece. Results: The study included 23 patients, 17 female (74%) and 6 male (26%). Age range was 2 to 19 years. Eighteen (18) patients (78.3%) were double heterozygotes for sickle cell and beta thalassemia, 4 (17.4%) were sickle cell homozygotes and 1 patient (4.3%) was double heterozygote for sickle cell disease and hemoglobinopathy D. Out of 23 patients, 4 were on regular blood transfusions due disease related issues (primary prophylaxis for cerebrovascular disease or hypersplenism in 2 cases, severe anemia or repeated pain crises in 2 other cases). No significant difference was recorded in number of hospital visits during the 18month period before and during the pandemic (5.45 visits/year and 6 visits/year, respectively -p = 0.49), reflecting a stable course for patients not receiving regular transfusions and an unaffected by blood shortage or limited hospital access course for regularly transfused patients. To that end, no significant changes were recorded in non-COVID related hospitalizations between the two groups (0.57/year before the pandemic and 0.39/year during the pandemic, p = 0.32). In addition, no difference was found between the reported number of pain crises (0.63 episodes per year vs 0.63 episodes per year, p = 1.0). An otherwise unremarkable overall clinical and laboratory course was reported for all patients during the two time periods compared. No changes in regular monitoring was noted and no changes in drug prescription or drug availability for patients on hydroxyurea was recorded. Summary-Conclusions: Although sickle cell patients require close monitoring, mostly dependent upon hospital based services, the COVID19 pandemic does not seem to have limited access to recommended care in this patient group. Background: People living with Sickle Cell Disease (SCD) often suffer excruciating painful episodes, which can be triggered by infection, extreme weather conditions or stress, and lead to frequent hospital admissions ( 1,2 ). Having the requisite knowledge about the disease and adequate health literacy may be beneficial for early recognition of symptoms, avoidance of triggers of these painful episodes and overall management of the condition ( 3 ). This is a pilot study in preparation for a larger study to examine relationships between health literacy, disease knowledge and health outcomes in young persons with SCD. Aim: This pilot study aimed to test the use of a French version of The Health Literacy Measure for Adolescents (HELMA) questionnaire and a sickle cell disease-specific knowledge questionnaire to assess the health literacy and disease knowledge levels of young people with SCD in a clinical setting in West Africa. Methods: Young patients (aged 15 to 24 years) attending a routine Hematology clinic of The University Hospital (CNHU) in Benin and who could speak French were invited to participate in a questionnaire study. An SCD knowledge questionnaire was developed by administering a survey to 7 medical doctors to gather questions they considered relevant for young patients living with SCD. These responses formed the basis of the questionnaire with 18 questions. Of these, 17 questions were given a score of 1 point while 1 question was given a score of 6 points giving a total of 23 points, with a score greater than 16 indicating high knowledge. The HELMA questionnaire was translated into French. It consists of 44 items transferred to a score from 0 to 100. A score of over 66 is considered an adequate health literacy level. Results: A total of 27 patients were recruited for the study (17 males, 63%). The mean age of the patients was 20 years (range: 15-24 years). Most of the patients in this sample (n=17, 63%) were attending secondary schools, 33% (n=9) were in tertiary institutions while 4% (n=1) had completed primary education. The average time used to complete the SCD questionnaire was 6 minutes (range: 4-8 minutes) while most of the patients completed the health literacy questionnaire after 30 minutes (range: 25-35 minutes). Few patients (n=3; 11%) scored less than 16 points on the SCD knowledge questionnaire indicating a high SCD knowledge in this group, while most of the patients (n=20, 73%) had a score of less than 66 on the HELMA questionnaire indicating inadequate health literacy levels. Summary/Conclusions: This study suggests that it may be challenging to use the HELMA in a clinical setting due to the long duration needed for the administration. A shorter version of the HELMA for use in a clinical setting might be helpful. However, the sickle cell disease-specific questionnaire is suitable to assess patients' knowledge about their condition in a clinical setting.

Background: Despite a reduction in morbidity and mortality associated with the use of disease modifying therapies, sickle cell disease (SCD) remains associated with high healthcare resource utilization (HRU), primarily attributed to vaso-occlusive crisis (VOC). (1, 2) There are limited national estimates on HRU, cost of medical care, and treatment expenditures for patients with SCD in Lebanon. A better understanding of these estimates may provide new perspectives to improve access to high-quality cost-effective health care services. Aims: We aimed to evaluate patterns of HRU and related cost in a cohort of patients with SCD receiving care in a Comprehensive SCD referral center at NINI hospital in North Lebanon. Methods: A retrospective non-interventional observational study was conducted among 136 patients (54.4% females) with confirmed diagnosis of SCD in North Lebanon. Data on HRU including emergency department (ED) visits, ambulatory visits and hospitalizations collected in a patient health information (PHI)-anonymized format during the period 01 May2018 -30 Apr 2020 were obtained from patients' paper and electronic medical files, as well as hospital and ED files. Uncomplicated VOCs were defined as pain crises, whereas complicated VOCs were defined as acute chest syndrome, acute splenic sequestration, acute hepatic sequestration or priapism. The annual rate of HRU visits was calculated as a ratio of the total number of visits to the total number of years of follow-up across all patients. The average annual cost was similarly calculated as the ratio of total cost of these visits to the total number of years of follow-up, based on available data. Results: In the present study, the median age of patients at the time of study was 10.8 years (IQR 5.3 to 19.6 years). Majority of patients were diagnosed with SS (72.1%) and Sβ0 (21.3%) genotype across all age groups. Pain crisis (90.4%), fever (43.4%), acute chest syndrome (33.1%), and acute splenic sequestration (22.8%) were the most common SCD-related complications. The annual rate of HRU visits (per patient) was 5.7. Uncomplicated VOCs led to majority of hospitalizations, ICU and ED visits in adult patients (age >16 years). The average annual costs of HRU were 8,270,920 Lebanese pounds (LBP) amounting to 5,514 USD (per patient per year) of which 92.1% was for hospitalizations, 4% for ED visits and 3.9% for ambulatory visits. Annual costs for ED, ICU and hospitalizations were highest for uncomplicated VOC. Costs related to medications, diagnostics, non-hematologist medical consults, uncompensated care and lost productivity are not included in this analysis. Analgesics, folic acid and hydroxyurea were the most frequently administered medications across all age groups with 84% of patients being treated with hydroxyurea.Conclusion: This real world study reveals that SCD and its related complications resulted in significant acute HRU. VOCs remain the primary factor for resource use, ICU admission and costs with the largest proportion of annual cost being attributed to hospitalizations. Despite the high HRU rate in this relatively young SCD cohort, the cost of HRU in a comprehensive setting with effective outpatient management as that in North Lebanon appears affordable for the health care system. However when additional SCD related and non SCD related costs of care are included, the economic burden of SCD care is likely to be significantly higher than the figures reported. As a centre of excellence for the care of people with Sickle Cell, HPS has been forward-thinking in its endeavour to find ways to provide integrated person-centred care since it was founded in 1997. This includes working alongside other healthcare professionals as part of a multi-disciplinary team on ward rounds and specialist clinics. A twice-weekly annual review clinic is held at Guy's Hospital for people with Sickle Cell in line with national guidelines. Aims: This poster presents the findings from a recent evaluation of the long-standing integrated psychology input at the Sickle Cell annual review clinic. The aim is to explore the outcomes of the annual review clinic for people with sickle cell and consider the benefits and limitations of this holistic model of care. Methods: This evaluation explores whether a need for further support was identified during the annual review appointment and what kind of support was offered. This could include a referral for psychological therapy in the service, a briefer intervention offered during or post the review or being signposted or referred to alternative sources of support. Clinical risk is also examined. Results: The analysis is currently still in progress. Summary/Conclusion: Although the analysis is still ongoing, the benefits of an increased presence of psychology in traditionally medical-only clinics will be discussed and the implications of a 'catch-all' approach will be explored; that many patients may have been seen for appropriate psychological support who might otherwise have not known it was available, or may have been reluctant to reach out for support. This will highlight the importance of holistic care when striving for excellence in person-centred Sickle Cell provision. In the Thames Valley we look after approx 200 YP with haemoglobinopathy disorders, a third between the ages of 13 & 18 years. A low prevalence area, a very wide geographical spread, making access to specialist services challenging. Access to technology and virtual connections, and a newly appointed psychologist led us to look at provision of an online wellbeing support group for teenagers. Aims: To invite teenagers between 13-18 years to a weekly 'drop in' group, where they would be able to access strategies and resources to support with varying aspects of well-being, as well as the opportunity to ask questions, in a safe supportive environment. Method: The group initially ran on a weekly basis for one hour at the end of the school day, led by 2 specialist nurses and a clinical psychologist. We covered subjects such as: stress, anxiety, low mood, fatigue, as well as more media related content like vaccinations and navigating social media. We used the Zoom platform, but then moved to Microsoft Teams, as this was the Trust's preferred platform. Our YP and their parents were contacted and asked if they would like to join and then they would be sent an invite via email. A reminder was also sent the day before the next meeting. Parents would be included in any email communication and resources; however, they were not encouraged to join the meeting. Meeting etiquette and ground rules were explained at the beginning of the meeting and with each new attendee, in order to establish trust and Background: The chronic transfusion regimen consists of procedures that take time and that significantly impact the quality of life of patients with thalassemia or sickle cell disease; sometimes these procedures are carried out in uncomfortable environments where the patient tries with his own means to get distracted or "estranged". Therefore, the need to pay attention not only to the strictly physical needs but also to the psychological, emotional and social needs of patients emerges with the aim of recovering valuable time "monopolized" by therapy by enriching the therapeutic path with activities capable of involving more the person. Aims: From this need and the opportunities offered by the digital technologies available today, the AREAL project was born, developed by the Italian startup Softcare Studios in partnership with the pharma company Novartis. AREAL consists of a gaming experience enjoyed in virtual reality thanks to the use of suitable VR viewers, designed in collaboration with medical staff to enhance the time spent in the hospital during the transfusion routine of young adult and adult patients. Methods: AREAL consists of three gaming activities developed to immerse the patient in a sensorially stimulating scenario different from the hospital one in which the user is forced to spend his time, and designed to stimulate cognitive skills (memory, reflexes, attention, auditory processing and visual, logic and association, spatial navigation), providing added value to the patient's engagement / entertainment and compensating for the near physical immobility required during the transfusion / medical procedure (Figure 1 ). AREAL also integrates elements of patient education in therapy and recommended lifestyle habits to promote their well-being, and is equipped with a social functionality thanks to which patients can play together with other patients in the same hospital or between hospitals. different, laying the foundations for building a delocalized patient community. Results: AREAL is currently in use in 3 pilot hospital centers in Italy, Padova, Genova, Napoli, where, over a period of 4 months, evidence will be collected on its impact on the therapeutic experience of patients, usability will be assessed and the integration in the staff work routine will be refined. doctor, with the ultimate goal of extending the concept of "care" not only to clinical but also emotional and psychological aspects during all the time spent in the hospital. Those affected by sickle cell disease have an increased susceptibility to infection by encapsulated bacteria and hepatitis B virus due to reduced splenic function and increased likelihood of receiving blood transfusions. Sickle cell disease patients are also more likely to suffer from complications, such as vaso-occlusive crises or acute chest syndrome, following infection with influenza or COVID-19. Standards for Clinical Care of Adults with Sickle Cell Disease in the UK (2018) outline that that those with sickle cell disease are recommended to be vaccinated against invasive pneumococcal disease, Haemophilus influenza type B, Neisseria meningitis types ACWY and type B, hepatitis B, and influenza. These patients are also recommended to have their hepatitis B immunity reviewed annually and to receive a hepatitis B vaccination booster if hepatitis B surface antibody (HBsAb) levels are less than 100mIU/ml. According to the Standards, hospital staff is advised to remind and check with the patients' primary care teams whether these vaccinations have been administered. In this audit, we examined the records of 64 patients with sickle cell disease who receive regular care at the Cambridge University Hospitals NHS Foundation Trust. We collected data on the uptake of the pneumococcal conjugate vaccine (PCV13), pneumococcal polysaccharide vaccine (PPV23 or Pneumovax) within 5 for the second dose of the COVID-19 vaccine. 43.8% had their HbsAB reviewed and 20.0% received a HepB booster following HBsAb levels of less than 100mIU/ml. The uptake levels for the recommended vaccinations are lower than expected in our hospital trust. The COVID-19 pandemic has highlighted the effect of health inequalities and the uptake of the vaccination programme by patients of different ethnicities. During our patient support group, patients identified the Tuskegee syphilis experiment as one of the reasons why there is still distrust of the medical profession by those with Afro-Caribbean heritage. Beyond directed patient education, more communication is needed with the primary care teams to raise awareness of which vaccinations are required for sickle cell patients. Certain vaccinations, such as MenACWY and MenB were only introduced in 2015, meaning that some general practitioners may be still unaware of their necessity in adults with sickle cell disease. Racism impacts all aspects of patient care, not least for those with Sickle Cell Disease (SCD). Minimal research exists in this area, despite being long identified as a compelling issue for patients [ 1 ] , and highlighted as a "Top 10" Priority in a workshop during ASCAT 2019. In response, we conducted a series of workshops to explore how race and racism impacts the quality of care in the SCD community and to identify actionable areas of change. This comprised three 90 minute sessions held over Zoom in May, June and July 2021. Attendees included people living with SCD, doctors, nurses, medical students, and members of the local community. Outcomes broadly centred around the themes of medical education; public education; and ways of better supporting the SCD patient community. However, we were struck by a rich discussion on how the name 'Sickle Cell Disease' may, in itself, influence the mindset of caregivers and perpetuate stigma in both clinical and social settings. The term 'Sickle Cell Anaemia' traditionally refers to HbSS only, though OMIM uses it to cover all genotypes [ 2 ] . Meanwhile the ICD-10 classification code D57 refers to 'Sickle Cell Disorders', with sub-categories using 'Disease' and divided by genotype [ 3 ] .From the workshops, the patient group shared a strong consensus view that Sickle Cell Disorder, rather than 'Disease', would be preferable as a more neutral term of reference.

To verify the results of the workshop in an independent sample, a questionnaire was circulated to a small SCD patient support group (12 individuals) to assess their preference for one or other label. 9/12 (75%) preferred 'Disorder', one preferred 'Disease' and two expressed no preference. Which label was used by patients themselves, their families and friends, and their medical teams was important to patients, with 67% expressing a wish that this issue be pursued further. Interestingly, the acceptability of Disorder/Disease showed some variation by the patient's country of birth. These findings point towards a pressing need for increased sensitivity around the language used to talk about illness, particularly where the condition has been historically stigmatised.