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Background Patients with sickle cell disease (SCD) experience a wide range of complications thought to be due to the systemic impact of chronically inflamed vasculature, ongoing haemolysis, multi-cellular adhesion and ischemic damage. These complications impact the health-related quality of life and the life expectancy. One of the most impactful complications is the vaso-occlusive crisis (VOC). Evidence of the relationship between VOC occurrence and the incidence of SCD-related complications is still emerging. Aims To assess the association between hospitalised VOC rates and acute and chronic complications in SCD patients. Methods This study was a retrospective observational cohort study using the French national health insurance's claims database. This database gathers information on hospital records, and primary and secondary care. Between 01-01-2012 and 12-31-2018, all patients 16 years and older suffering from SCD (through a hospital record or Long-Term Disease status with diagnostic ICD-10 codes D57.0-2) were included in the study. Participants were followed-up for at least one year and until 12-31-2018. A hospitalised VOC was defined as a hospital stay of at least one night with a primary or related diagnosis of sickle-cell anaemia with crisis (D57.0), preceded by a transit through the emergency room. The VOC annual rate was defined as the total number of VOCs during the follow-up divided by the number of follow-up years. Patients were categorised by the annual rate of VOCs they experienced into three groups: Complications [1] known to be experienced by patients with SCD and leading to a hospitalisation were identified during the follow-up using ICD-10 codes reported in the hospital discharge records. Cox proportional hazards models using age as the time scale were used to study the effect of the annualized rate of hospitalised VOCs on the risk of complications, adjusted for sex. Results A total of 17,726 patients were included in the study, of which 65.3% were female -a high proportion partly due to inclusion of women at time of pregnancy hospital stay. Ages ranged from 16 to 99 years and the average age was 35.0 years (±17.8). Overall, 90.3%, 7.4%, and 2.3% of patients experienced Over a median follow up of 7 years, the most common complications requiring a hospital admission were acute chest syndrome (ACS) (18%), sepsis (16%), acute kidney injury (12%), gallstones (10%), and eye disorder (7%). During the follow-up period, compared to Conclusions Patients frequently experiencing VOCs are at much greater risk of hospitalization for some chronic complications compared to patients rarely experiencing VOCs. The highest association were found for osteonecrosis and pulmonary hypertension or embolism. It could be an additional reason to reinforce treatment of SCD patients with recurrent VOCs. [1] ACS, Sepsis, Acute Kidney Injury, Gall stones, Eye disorder, Osteonecrosis, Liver complication, Stroke, Pulmonary embolism, Dialysis, Central nervous system, Pulmonary hypertension, Heart failure, Priapism, Kidney transplantation, Cardiomegaly Disclosures Arlet: Novartis company: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Addmedica: Research Funding. Lennon: HEVA: Ended employment in the past 24 months; IQVIA (contractor to JANSSEN Pharmaceuticals): Current Employment; WHO International Agency for Research on Cancer: Ended employment in the past 24 months. Bailey: Novartis pharmaceuticals: Current Employment. Herquelot: Pharmaceuticals and medical devices companies (BMS, MSD, Merck Sante, Janssen, Cook, Novartis, Pfizer, Takeda, ...): Other: Grants or contracts for our CRO from pharmaceutical and MD industries for research study. Lamarsalle: Pharmaceutical and medical devices comapnies (BMS, BSCI, AstraZeneca, Janssen, Merck, Novartis, Pfizer, Roche, ...): Other: Grants or contracts for our CRO from pharmaceutical and MD industries for research study. Raguideau: Pharmaceutical and medical devices companies (BMS, MSD, Merck Sante, Janssen, Cook, Novartis, Pfizer, Takeda, ...): Other: Grants or contracts for our CRO from pharmaceutical and MD industries for research study. Bartolucci: ADDMEDICA, NOVARTIS, ROCHE, GBT, Bluebird, EMMAUS, HEMANEXT, AGIOS: Consultancy; NOVARTIS, ADDMEDICA, JAZZPHARMA: Other: Lecture fees; Novartis: Other: Steering committee; ADDMEDICA, foundation Fabre, NOVARTIS, Bluebird: Consultancy, Research Funding; INNOVHEM: Other: Cofounder.

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. Hemoglobin S 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 in patients with SCD, which present as acute painful episodes called VOEs. Despite the majority of VOEs being managed at home, they remain the most common reason for emergency department (ED) visits and hospitalization among patients with SCD, with > 70% of ED visits and > 90% of hospital admissions for SCD being related to VOEs (Ballas et al. Am J Hematol 2005; Lanzkron et al. Am J Hematol 2010). One of the most severe complications of VOEs is acute chest syndrome, which is a leading cause of mortality among patients with VOEs (Vichinsky et al. N Engl J Med 2000; Bartolucci et al. eBioMedicine 2016). In the absence of targeted therapies for the management of VOEs in patients with SCD, treatment is currently limited to pain management, blood exchange transfusion (with the risk of complications), and other supportive care, representing a significant unmet medical need. Activation of the complement pathway has been described in patients with SCD at baseline, in acute pain crises, and in patients with delayed hemolytic transfusion reaction. Accumulating nonclinical data have suggested a multimodal role for complement dysregulation in the pathophysiology of SCD including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage (Roumenina et al. Am J Hematol 2020). Crovalimab is a novel, engineered, anti-complement C5 monoclonal antibody. In a Phase I/II study (Röth et al. Blood 2020) in patients with paroxysmal nocturnal hemoglobinuria, a complement-mediated disorder, crovalimab demonstrated rapid and sustained complement inhibition with promising efficacy and safety. Study Design and Methods CROSSWALK-a (NCT04912869) is a randomized, double-blind, placebo-controlled, Phase Ib study evaluating the safety of crovalimab for the management of acute uncomplicated VOEs in patients with SCD. Patients aged ≥ 12 years 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) are eligible for the study (Figure). Patients 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 up to date. Eligible patients will be randomized 2:1 to receive either a single intravenous weight-based tiered dose of crovalimab or placebo. Patients in both study arms will continue to undergo pain management and receive other supportive care for their VOE and may also continue to receive ongoing concurrent SCD-directed therapies. Patients will be followed during the hospitalization until discharge and will continue to be followed post-discharge during an observational period. The maximum total study duration for an individual patient will be 12 weeks, which includes the hospitalization and observational periods. 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. Figure 1 Figure 1. Disclosures Bartolucci: F. Hoffmann-La Roche Ltd: Consultancy; Bluebird: Consultancy, Research Funding; Emmaus: Consultancy; Hemanext: Consultancy; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; GBT: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; INNOVHEM: Other: Co-founder; Fabre Foundation: Research Funding; Addmedica: Consultancy, Other: Lecture fees, Research Funding. Ataga: Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees. Callaghan: Alnylum: Current equity holder in publicly-traded company; Roche/Genentech: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy; Pfizer: Consultancy; Global Blood Therapeutics: Consultancy, Speakers Bureau; uniQure: Consultancy; Spark: Consultancy; Biomarin: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Forma: Consultancy; Chesei: Consultancy; Agios Pharmaceuticals: Current Employment. De Franceschi: F. Hoffmann-La Roche Ltd: Consultancy. Minniti: F. Hoffmann-La Roche: Consultancy; Bluebird Bio: Other: Endpoint adjudicator; Forma: Consultancy; GBT: Consultancy; Novo Nordisk: Consultancy; CSL Behring: Other: Endpoint adjudicator; Novartis: Consultancy; Chiesi: Consultancy. Alexandrou: F. Hoffmann-La Roche Ltd: Consultancy, Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company. Imbs: F. Hoffmann-La Roche Ltd: Consultancy; Certara Inc.: Current Employment. Fox: Parexel International: Current Employment; Genentech, Inc.: Current Employment. Patel: Genentech, Inc.: Current Employment. Sostelly: F. Hoffmann-La Roche Ltd: Current Employment.

NH and EE equally contributed. ADW and PB co-signed. The expression of fetal hemoglobin (HbF) is one of the main targets of sickle cell disease treatment, as it inhibits the polymerization of hemoglobin S. The hypothesis of an inhibitory threshold of HbF per red blood cell (RBC) has been suggested, 1 although not well defined, as the overall percentage of HbF does not reflect the heterogeneous distribution of HbF per cell. Likewise, the qualitative analysis of RBCs containing HbF, called F cells, is neither reproducible nor clinically interpretable, due to low expression. 2 We have developed a technique for measuring the amount of HbF per cell, to determine thresholds of HbF expression per RBC correlated with clinical and biological effects. 2 Among genes controlling its expression, BCL11A has a major repressive effect on the expression of gamma globin/HbF during the fetal to adult hemoglobin switch. Post-transcriptional silencing of BCL11A, using lentivirus expression of a shRNA embedded in a microRNA architecture (shmiR) to re-activate γ-globin expression, is safe and demonstrates high levels of %HbF in a pilot clinical study (NCT 03282656). 3 Here, we show the quantitative measurement of HbF per RBC and reticulocyte. Methods: During patient follow-up, HbF quantification per single cell RBC was performed using a fluorescent HbF antibody. 2 Addition of an anti-CD71 fluorescent antibody allowed selection of reticulocyte sub-populations for determining their HbF content. Fold-increase in percentage of RBC versus percentage of reticulocyte were calculated. Kinetics of HbF/RBC and HbF/Reticulocyte were modeled using mixed effects polynomial linear regression to account for the correlation between repeated data over time. Results: With a median follow-up of 15 months [12-20] after gene transfer, figure 1 shows the mathematical modeling of single-RBC HbF measurement representing RBC percentage containing at least 2, 4, 6, 8 and 10 pg of HbF. Percentage of RBC above each threshold was higher compared to 14 hydroxyurea treated patients for 6 months. Figure 2 shows fold increase between reticulocytes and RBCs with same thresholds of HbF/cell. For low thresholds, RBCs were found in same percentage as reticulocytes whereas RBCs containing increasing levels of HbF were found in higher percentage than reticulocytes, until 6pg/cell showing a clear selective advantage for red cells with a threshold ≥ 6pg/cell of HbF. Figure 3 shows different kinetics of HbF increase according to two different transduction strategies with 2 enhancers in patients 2-4 compared to one enhancer in patients 6-8. Conclusion: BCL11A down-regulation in six clinical trial subjects was associated with an in vivo selection process RBCs with ≥ 6pg HbF per cell attained with different engraftment kinetics, depending on transduction processes, and ultimately stable high level and broadly distributed HbF. 1 Steinberg MH, Chui DH, Dover GJ, Sebastiani P, Alsultan A. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood. 2014 Jan 23;123(4):481-5. 2 Hebert N, Rakotoson MG, Bodivit G, et al. Individual red blood cell fetal hemoglobin quantification allows to determine protective thresholds in sickle cell disease. Am. J. Hematol. 3 Esrick EB, Lehmann LE, Biffi A, et al. Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease. N. Engl. J. Med. 2021;384(3):205-215. Figure 1 Figure 1. Disclosures Esrick: bluebird bio: Consultancy. Audureau: GBT: Honoraria. Higgins: Sebia, Inc.: Honoraria; Danaher Diagnostics: Consultancy. Williams: BioMarin: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Advisory Board; Geneception: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Emerging Therapy Solutions: Membership on an entity's Board of Directors or advisory committees, Other: Chief Scientific Chair; Beam Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Alerion Biosciences: Other: Co-founder (now licensed to Avro Bio, potential for future milestones/royalties); Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Novartis ETB115E2201 (eltrombopag in aplastic anemia). Advisory fees donated to NAPAAC.; Orchard Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Membership on a safety advisory board (SAB): SAB position ended 05/20/2021. Co-founder , Patents & Royalties: Potential for future royalty/milestone income, X-SCID. Provided GMP vector for clinical trial, Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Analysis Advisory Board, Patents & Royalties: BCH licensed certain IP relevant to hemoglobinopathies to bluebird bio. The current license includes the potential for future royalty/milestone income. Bluebird has indicated they will not pursue this as a clinical program and BCH is negotiating return of, Research Funding. Bartolucci: AGIOS: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Jazz Pharma: Other: Lecture fees; Emmaus: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding; INNOVHEM: Other: Co-founder; Hemanext: Consultancy; GBT: Consultancy; Bluebird: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; Fabre Foundation: Research Funding.

Introduction Sickle cell disease is a genetic disease with acute and chronic complications. Pediatric mortality has decreased in recent decades with the introduction of systematic antibiotic therapy, preventive management of cerebral vasculopathy and therapeutic education of families. However, in the absence of cohort follow-up at birth, life expectancy, which is a different concept from age at death, cannot be assessed. In this retrospective, monocentric study, we describe causes and circumstances of death, acute chronic complications, long-term treatments and baseline biology of these patients. It seems important to analyze the risks of morbidity and mortality in order to decide on the necessary preventive measures. Material and method: Records of patients deceased between 2000 and 2020, from the national referral center (Henri Mondor Hospital), were retrospectively reviewed. The referral center follows 3500 patients. All deaths reported to the hospital, by families, other hospitals and health professionals were retrieved from computerized records. Deaths published by the INSEE (National Institute of Statistical and Economical study) from 2000 to December 2020 were accessible and compared with our databases to identify all our deceased patients. All patients with a medical record in our center were included for the study. Patients who had never visited our center were excluded. Results: During this period 226 patients including 128 women and 138 men are recorded. Genotypes for these patients were 204(76%) SS, 41 (15%) SC, 14(5%) Sβ°thalassemia and 7 (2%) Sβ+thalassemia. The median age at death was 41 years with an IQR [32-51]. 186 (70%) patients were hospitalized, 129 (70%) of whom were admitted to intensive care. 36 (13%) patients died at home, including 15 with opioid addiction and 5 patients with psychiatric pathology, and 4 patients on dialysis. This information was not available for 44 (16%) patients. The causes of death were vaso-occlusive complications with multivisceral failure in 44 cases, 42 sepsis, among which there were 11 renal failures, 9 of which were dialyzed. 5 patients died of COVID 19. Cerebral hemorrhage and neurological accident occurred in 22 cases, 4 of which were known to have macrovasculopathy. 25 patients died of a direct complication of renal failure, of which 17 were dialysed, 8 pre-dialysed and 3 transplanted. Acute liver failure in 16 cases, 10 precapillary pulmonary hypertension, 14 DHTR, 10 end-stage heart failure were noted. Two road accidents, 2 suicides, 1 dementia are repoted. For 51 cases, there was no information on the cause or circumstance of death. The causes of death according to genotype is on Table 1. Concerning the chronic complications, 94/266 (35%) patients had significant chronic organ damage. Sixteen patients had required renal or liver transplantation in their history. End-stage organ damage was frequent, 42 had end-stage renal failure, 21 had major liver failure, of which five were transplanted and 16 were awaiting transplantation. Twenty-one patients had known heart failure, 10 of which were associated with end-stage renal disease. Ten patients were followed for significant precapillary pulmonary hypertension. Transfusion difficulties due to a history of DHTR were found for 33 patients. Fourteen patients had an opioid addiction. Nine patients were pregnant and nine had received corticosteroids. Discussion: Causes of death have changed and chronic organ failure is the leading cause of death, especially in patients with kidney, liver and heart disease. This study does not calculate life expectancy, but there was an increase in age at death of about 1/4 of the patients who were between 51 and 81 years old.The management of sickle cell disease has progressed in recent years and new therapies are being proposed. Prevention of the development of these complications is one of the new challenges, especially for renal disease, which is associated with premature mortality. DHTR and cerebral hemorrhage, Covid-19 are new entities and DHTR was probably underdiagnosed in previous publications. Pregnancy remains a period at risk, for which surveillance should be reinforced. The analysis is ongoing and correlations are currently being investigated between different parameters to find risk factors for mortality. Figure 1 Figure 1. Disclosures Habibi: Novartis: Consultancy, Honoraria; bluebird bio: Consultancy, Honoraria, Research Funding. Audard: Addmedica: Consultancy. Michel: Novartis: Consultancy; Amgen: Consultancy; Rigel: Honoraria; Alexion: Honoraria; UCB: Honoraria; Argenx: Honoraria. Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Bartolucci: INNOVHEM: Other: Co-founder; Bluebird: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; GBT: Consultancy; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; Hemanext: Consultancy; Emmaus: Consultancy; Fabre Foundation: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Addmedica: Consultancy, Other: Lecture fees, Research Funding.

In sickle cell disease (SCD), the β6 Glu→Val substitution leads to sickle hemoglobin (HbS) polymerization and red blood cell (RBC) sickling. Transplantation of autologous, genetically modified hematopoietic stem/progenitor cells (HSPCs) represents a promising therapeutic option for patients lacking a compatible donor. We previously designed a lentiviral vector (βAS3 LV) expressing a potent anti-sickling βAS3 globin and demonstrated its safety and efficacy in SCD patient cells (Weber et al., 2018). In vitro and in vivo preclinical studies demonstrated the safety and efficacy of a gene therapy (GT) protocol based on the efficient transduction of plerixafor-mobilized SCD HSPCs by βAS3 LV. Based on these results a Phase 1/2 clinical trial (NCT03964792) started in January 2020. Three homozygous SCD patients (P1, P2 and P3) were recruited. Before GT, patients suffered from severe SCD symptoms that were not controlled despite of a strict adherence to the treatment. Plerixafor-mobilized HSPCs were transduced achieving a VCN of 0.9±0.2 in liquid culture, 1.6±0.3 in BFU-E and 0.8±0.2 in CFU-GM. The patients were hypertransfused to reach HbS levels Here, for the 3 patients we report the follow-up of 18 (P1), 10 (P2) and 6 (P3) months. No drug-related severe adverse events were observed. Importantly, no sign of clonal hematopoiesis was detected by NGS sequencing performed on the graft before and after transduction. Despite of the similar VCN in the drug product, gene marking in peripheral blood mononuclear cells was variable and ranged between 0.2 and 0.6, as measured at the last follow-up (0.4 in P1, 0.6 in P2 and 0.2 in P3). These results pinpoint the difficulty to estimate the gene marking, self-renewal and engraftment potential of HSCs in the grafts. P1 and P2 clinically benefit from the GT treatment despite they presented non-severe vaso-occlusive crises (VOCs) not requiring hospitalization (two for P1 at month 6 and 14 and one in P2 at month 8 post-GT). Despite the rapid resolution of these episodes, P1 started hydroxyurea at month 10 and stopped it at month 16. P2 initiated a phlebotomy program to treat liver iron overload and decrease viscosity. Intravascular hemolysis improved in P1 and P2, as shown by a decrease in plasma hemoglobin and heme, and an increase in hemopexin (HPX). Interestingly, in P1 a mild worsening occurred at the time of VOC. In P1 and P2, total bilirubin, a marker of extravascular hemolysis, decreased post-GT. Deformability, measured using osmoscan, improved in P1 and to a lesser extent in P2; however, both still exhibited some degree of dehydration compared to normal RBCs (Fig. 1). Adhesion to thrombospondin decreased after GT with an increase during VOC in P1 or prior the VOC in P2 (Fig. 1). In both patients, markers of inflammation (e.g., C reactive protein) and reticulocyte counts decreased upon GT. An in vitro sickling assays was performed for P1 and showed significant improvement, reaching a frequency of sickling cells similar to SCD heterozygous carriers (from 88% before GT to 45% 6 months post-GT). The GT treatment was not effective in P3 due to the modest intake and rapid decline of gene modified cells. In P1 and P2, who were no longer on transfusions, HbAS3 levels correlated with the VCN (2.1 g/dl for P1 and 3.3 g/dl for P2) and the therapeutic Hb accounted for 21.5%, and 28.7% of the total hemoglobins, respectively. For P3, who remained transfusion-dependent, this frequency was Overall, these clinical data indicate a variable efficacy of the DREPAGLOBE GT treatment, which likely depends on the extent of gene marking achieved in HSCs in vivo and on the engraftment capability of genetically modified HSCs in SCD patients' bone marrow. Single-cell RNA-seq analysis of HSPCs and evaluation of the bone marrow niche in SCD patients will aid to define critical parameters for achieving successful outcomes in GT clinical trials for SCD. Figure 1 Figure 1. Disclosures Joseph: bluebird bio: Consultancy. El Nemer: Hemanext: Consultancy. Bartolucci: INNOVHEM: Other: Co-founder; AGIOS: Consultancy; GBT: Consultancy; Bluebird: Consultancy, Research Funding; Jazz Pharma: Other: Lecture fees; Fabre Foundation: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; Hemanext: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding; Emmaus: Consultancy. Cavazzana: Smart Immune: Other: co-founder.

Introduction Fetal hemoglobin (HbF) induction is a successful strategy for treating sickle cell disease. Higher levels of total HbF% are associated with better clinical outcomes, and a more uniform distribution of HbF across individual red blood cells (RBCs) is predicted to lead to better outcomes by inhibiting hemoglobin (Hb) polymerization in a higher fraction of individual RBCs. 1 Post-transcriptional silencing of BCL11A using lentivirus expression of a shRNA embedded in a microRNA architecture (shmiR) to re-activate γ-globin expression has been safe and demonstrated high levels of total HbF expression broadly distributed in red cells in a pilot clinical study (NCT 03282656). 2 We assessed the effects of BCL11A down-regulation on Hb polymer formation at the single-RBC level in 7 subjects in this trial (BCL) using novel assays of single-RBC Hb polymer content levels and single-RBC HbF. Methods Hb polymer was detected in individual RBCs using a previously published microfluidic system. 3 The system detects Hb polymer based on RBC morphology and on the principle that Hb polymer lowers RBC oxygen saturation in proportion to polymer concentration. 4,5 Single-RBC HbF mass was measured by flow cytometry using a previously published protocol. 6 These two measurements of distributions of single-RBC HbF mass and single-RBC Hb polymer were then integrated at the cell-population level to estimate the threshold of single-RBC HbF needed to inhibit formation of a detectable level of polymer as function of oxygen tension. Blood samples from BCL subjects (HbF% range 23 - 44, after stabilizing post-therapy) were compared to 14 hydroxyurea (HU) responsive patients (mean HbF% = 17, range 6 - 32), including 3 highly-responsive patients (HbF% = 25, 27, 31) as well as 4 individuals with sickle cell trait (AS). Results At 3.7% oxygen tension typical of the human microcirculation 7 and some regions of the central nervous system, 7 the typical BCL subject had detectable levels of Hb polymer in 52% (median) of RBCs vs. 66% for HU (p = 0.02) and 6% for AS (Figure 1A). At lower oxygen tensions of 1.7% typical of the bone marrow 7 or kidney medulla 7 BCL subjects had a polymerized RBC fraction of 68%, compared to 79% for HU (p Conclusions BCL11A down-regulation in seven clinical trial subjects is associated with favorable distributions of single-RBC polymer at multiple physiologic oxygen tensions compared to HU. Future study is needed to determine whether these favorable Hb polymer distributions are simply a result of higher total HbF or also due to lower single-RBC HbF thresholds for polymer inhibition. References 1. Steinberg MH, Chui DHK, Dover GJ, Sebastiani P, Alsultan A. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood. 2014;123(4):481-485. 2. Esrick EB, Lehmann LE, Biffi A, et al. Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease. N. Engl. J. Med. 2021;384(3):205-215. 3. Di Caprio G, Schonbrun E, Gonçalves BP, et al. High-throughput assessment of hemoglobin polymer in single red blood cells from sickle cell patients under controlled oxygen tension. Proc. Natl. Acad. Sci. U. S. A. 2019;116(50):25236-25242. 4. Benesch RE, Edalji R, Kwong S, Benesch R. Oxygen affinity as an index of hemoglobin S polymerization: A new micromethod. Anal. Biochem. 1978;89(1):162-173. 5. Fabry ME, Desrosiers L, Suzuka SM. Direct intracellular measurement of deoxygenated hemoglobin S solubility. Blood. 2001;98(3):883-884. 6. Hebert N, Rakotoson MG, Bodivit G, et al. Individual red blood cell fetal hemoglobin quantification allows to determine protective thresholds in sickle cell disease. Am. J. Hematol. 2020;95(11):1235-1245. 7. Keeley TP, Mann GE. Defining physiological normoxia for improved translation of cell physiology to animal models and humans. Physiol. Rev. 2019;99(1):161-234. Figure 1 Figure 1. Disclosures Esrick: bluebird bio: Consultancy. Bartolucci: INNOVHEM: Other: Co-founder; F. Hoffmann-La Roche Ltd: Consultancy; Bluebird: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; GBT: Consultancy; Emmaus: Consultancy; Hemanext: Consultancy; AGIOS: Consultancy; Jazz Pharma: Other: Lecture fees; Fabre Foundation: Research Funding; Addmedica: Consultancy, Other: Lecture fees, Research Funding. Williams: Emerging Therapy Solutions: Membership on an entity's Board of Directors or advisory committees, Other: Chief Scientific Chair; Geneception: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; BioMarin: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Advisory Board; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Novartis ETB115E2201 (eltrombopag in aplastic anemia). Advisory fees donated to NAPAAC.; Alerion Biosciences: Other: Co-founder (now licensed to Avro Bio, potential for future milestones/royalties); Beam Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Orchard Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Membership on a safety advisory board (SAB): SAB position ended 05/20/2021. Co-founder , Patents & Royalties: Potential for future royalty/milestone income, X-SCID. Provided GMP vector for clinical trial, Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Analysis Advisory Board, Patents & Royalties: BCH licensed certain IP relevant to hemoglobinopathies to bluebird bio. The current license includes the potential for future royalty/milestone income. Bluebird has indicated they will not pursue this as a clinical program and BCH is negotiating return of, Research Funding. Higgins: Danaher Diagnostics: Consultancy; Sebia, Inc.: Honoraria.

Les reactions hemolytiques dues a une allo-immunisation persistent en l’absence de connaissances sur l’ensemble des mecanismes qui sous-tendent ces reactions contre les globules rouges (GR). L’allo-immunisation se caracterise principalement par la production d’anticorps dirigees contre les GR. Les lymphocytes T CD4+ jouent egalement un role majeur dans cette production d’immunoglobulines, cependant le role des lymphocytes T CD8+, et donc l’activite cytolytique, n’est que peu documentee. Nous avons donc explore et compare les phenotypes des LT CD8+ memoire anti-Jkb entre un groupe de patients drepanocytaires polytransfuses, n’ayant jamais ete immunises malgre un regime de transfusion eleve, et un groupe de patients polytransfuses immunises contre le Jkb. Neuf peptides Jkb de 8 mers, chevauchant de 5 mers ont ete utilises pour restimuler les LT CD8+ et etudier leur lymphoproliferation, leur production de cytokines et de perforine. Le controle positif, pour chaque patient, a ete obtenu en stimulant les LT CD8+ avec un superantigene, l’enterotoxine B. Parmi les 13 patients presentant une reponse humorale anti-Jkb, 46 % d’entre eux ont une reponse T CD8+ memoire anti-Jkb. Cette reponse est fonctionnelle, les LT CD8+ proliferent et secretent des cytokines (IFNγ, TNFα, et IL2) et de la perforine en reponse aux peptides selectionnes. Nous montrons ainsi pour la premiere fois que des reponses T CD8+ perforine/cytotoxique peuvent etre presentes chez les patients allo-immunises.

Introduction Unexplained sudden death remains one of the leading causes of death in sickle cell disease (SCD) adults. Ventricular arrhythmia is a well-known risk factor for sudden death but its prevalence and determinants in the context of SCD remain understudied. Method From January 2019 to March 2021, consecutive adult patients with SCD referred to ambulatory cardiology department for possible cardiac involvement were prospectively included (Drepacoeur cohort). All patients that had 24-hour ECG monitoring (24h-holter) and thransthoracic echocardiography (TTE) on the same day were analysed. The primary end point was the occurrence of ventricular arrhythmia, defined as sustained or non-sustained ventricular tachycardia (VT), more than 500 premature ventricular contractions (PVC) on 24h-holter, or history of VT ablation. Results Overall, 90 patients were included and 54 (60%) were analysed. Mean age was 47.6 ± 11.6 years (range 21-69), 53% were male. Heart function was mainly preserved with a mean left ventricular ejection fraction (LVEF) of 57.9 ± 4.9% and a mean global longitudinal strain (GLS) of -18 ± 2.8%. Mean tricuspid regurgitation velocity was 2.6 ± 0.4 m/s. Ventricular arrhythmia was observed in 13 (24.1%) patients (4 non-sustained VT, 9 with more than 500 PVC and 1 history of VT ablation). Ventricular arrhythmia was associated with lower GLS (−15.8 ± 1.8% vs. −19 ± 2.7%, P Conclusion In SCD adults with preserved LVEF, GLS was the only independent echocardiographic predictor of ventricular arrhythmia.

Laparoscopic cholecystectomy (LC) is one of the most frequent surgeries performed in patients with sickle cell disease (SCD). LC in SCD patients is associated with a particularly high postoperative morbidity. The aim of the present study is to assess the safety and feasibility of cholecystectomy performed by mini-laparoscopy with low- and stable-pressure pneumoperitoneum (MLC + LSPP) and to compare the rate of postoperative SCD-related morbidity with standard LC. Thirty-five consecutive SCD patients admitted between November 2015 and March 2017 for cholelithiasis requiring surgery were compared with an historical cohort of 126 SCD patients who underwent LC for the same indication. Operative variables, postoperative outcomes, patient and surgeon satisfaction, and costs were evaluated. MLC + LSPP exhibited a mean operative time comparable to LC (p = 0.169). Operative blood loss was significantly reduced in the MLC + LSPP group, and the suction device was rarely used (p = 0.036). SCD-related morbidity (including acute chest syndrome) was significantly higher in the LC group compared with the MLC + LSPP group (18.3 vs. 2.9%; p = 0.029). The mean times to resume ambulation (p = 0.018) and regular diet (p = 0.045) were significantly reduced in the MLC + LSPP group. The mean incision length (all trocars combined) was 28.22 mm for MLC + LSPP and 49.64 mm for LC patients (p

Transfusion remains a key treatment of sickle cell disease complications. However, delayed hemolytic transfusion reaction, the most serious complication of transfusion, may be life-threatening if hyperhemolysis develops. This syndrome is generally underdiagnosed because its biological and clinical features resemble those of vaso-occlusive crisis, and red blood cell antibodies are frequently absent. Further transfusions may aggravate the symptoms, leading to severe multiple organ failure and death. It is therefore essential to prevent, diagnose and treat this syndrome efficiently. Prevention is based principally on the attenuation of allo-immunization through the provision of extended-matched RBCs or the use of rituximab. However, such treatment may be insufficient. Early diagnosis might make it possible to implement specific treatments in some cases, thereby avoiding the need for secondary transfusion. Diagnosis is dependent on the knowledge of the medical staff. Finally, many treatments, including steroids, immunoglobulins, erythropoietin and eculizumab, have been used to improve outcome. Improvements in our knowledge of the specific features of DHTR in SCD should facilitate management of this syndrome.

Deoxy-hemoglobin S polymerization into rigid fibers is the direct cause of the clinical sequelae observed in sickle cell disease (SCD). The rate of polymerization of sickle hemoglobin is determined primarily by intracellular hemoglobin concentration, itself dependent on the amount of sickle hemoglobin and on red blood cell (RBC) volume. Dense, dehydrated RBC (DRBC) are observed in SCD patients, and their number correlates with hemolytic parameters and complications such as renal dysfunction, leg ulcers and priapism. To identify new genes involved in RBC hydration in SCD, we performed the first genome-wide association study for DRBC in 374 sickle cell anemia (HbSS) patients. We did not find genome-wide significant results, indicating that variants that modulate DRBC have modest-to-weak effects. A secondary analysis demonstrated a nominal association (P=0.003) between DRBC in SCD patients and a variant associated with mean corpuscular hemoglobin concentration (MCHC) in non-anemic individuals. This intronic variant controls the expression of ATP2B4, the main calcium pump in erythrocytes. Our study highlights ATP2B4 as a promising target for modulation of RBC hydration in SCD patients.

Background Safety of HPV vaccines is still in question due to reports of autoimmune diseases (ADs) following HPV immunization. Objectives To assess the risk of ADs associated with HPV vaccination of female adolescents/young adults in France. Methods Systematic prospective case-referent study conducted to assess the risks associated with real-life use of HPV vaccines. Cases were female 11–25 years old with incident ADs [central demyelination/multiple sclerosis (CD/MS), connective tissue disease (CTD), Guillain-Barre syndrome (GBS), type-1 diabetes (T1D), autoimmune thyroiditis (AT), and idiopathic thrombocytopenic purpura (ITP)]. Cases were consecutively and prospectively identified at specialized centers across France (2008–2014) and individually matched by age and place of residence to referents recruited in general practice. Risk was computed using multivariate conditional logistic regression models adjusted for family history of ADs, living in France (north/south), co-medications and co-vaccinations. Results With a total of 478 definite cases matched to 1869 referents, all ADs combined were negatively associated to HPV vaccination with an adjusted odds ratio of 0.58 (95% confidence interval: 0.41–0.83). Similar results were obtained for CD/MS, AT, CT, and T1D, the last two not reaching statistical significance. No association was found for ITP and GBS. Sensitivity analyses combining definite and possible cases with secondary time window showed similar results. Conclusion Exposure to HPV vaccines was not associated with an increased risk of ADs within the time period studied. Results were robust to case definitions and time windows of exposure. Continued active surveillance is needed to confirm this finding for individual ADs.

Albuminuria is considered to be a relevant biomarker for the detection of early glomerular damage in patients with sickle cell disease (SCD). Improvements in our understanding of the pathophysiological processes and molecular mechanisms underlying albuminuria are required, because increasing numbers of patients with SCD are developing chronic kidney disease. The early recognition of sickle cell nephropathy (SCN) and studies of the natural course of this emerging renal disease are therefore crucial, together with identification of the associated clinical and biological risk factors, to make it possible to initiate kidney-protective therapy at early stages of renal impairment. The pathophysiological process underlying SCN remains hypothetical, but chronic haemolysis-related endothelial dysfunction and the relative renal hypoxia triggered by repeated vaso-occlusive crises have been identified as two potential key factors. The optimal preventive and curative management of albuminuria in the context of SCD is yet to be established, but recent studies have suggested that hydroxyurea therapy, the cornerstone of SCD treatment, could play a key role in reducing albuminuria. The place of conventional kidney-protecting measures, such as renin–angiotensin system inhibitors, in the treatment of SCD patients also remains to be determined.

Background: Cognitive impairment is a dreaded complication of sickle cell disease (SCD) that impacts quality of life, school performance and employment. In 2020, the American Society of Hematology issued a strong recommendation that clinicians supervising the care of adults with SCD conduct surveillance for cognitive impairment using simplified signaling questions (DeBaun, 2020). However, guidance on the optimal screening strategy is lacking and several available tools are biased by language and education. The Rowland Universal Dementia Assessment Scale (RUDAS) was specifically designed for cognitive screening in multicultural populations (Storey, 2004). In the general elderly population, RUDAS is less biased by education than the Montreal Cognitive Assessment (MoCA) (Naqvi, 2015). Hypothesis: In adults with SCD, performance on the RUDAS is less influenced by educational attainment when compared to the MoCA. Our primary aim was to estimate the prevalence of suspected cognitive impairment using RUDAS and MoCA in adult SCD patients. The secondary aims were to examine for the presence of educational bias and to develop mitigation strategies in case of such a bias. Methods: Study design: cross-sectional study at UMGRR clinic at Henri Mondor Hospital, Créteil (France). Inclusion criteria: out-patients ≥18 years-old; all SCD phenotypes. Exclusion criteria: inability to obtain informed consent and/or follow study instructions. Intervention: Cognitive screening was performed using the RUDAS (translated to French by Philippe Desmarais), MoCA (third alternative version) and an additional visuospatial task of copying overlapping triangles (from the French BEC96 assessment). RUDAS and MoCA scores Results: Among the first 45 consecutive adult SCD patients undergoing routine cognitive screening, the median age was 39 (range 19-67). RUDAS and MoCA scores suggestive of mild cognitive impairment were found in 33/45 (73.3%) and 29/45 (64.4%) participants, respectively. There was a strong correlation between both tests (r=0.48, p=0.001). Both RUDAS and MoCA scores increased significantly with increasing level of education (r=0.36, p=0.015 and r=0.39, p=0.007, respectively), but were not significantly influenced by the HADS score. RUDAS and MoCA test items most biased by education were visuoconstructional tasks. Tasks assessing executive functioning and language were also biased in MoCA. Substituting the 3D visuospatial task of the RUDAS by a 2D task reduced the educational bias (r=0.20, p=0.045). Adding 1 point for highest level of education £ 12 years after kindergarten did significantly mitigate the effect of education on the RUDAS but only partially for the MoCA (r=0.23, p=0.131 and r=0.30, p=0.047). Conclusions: Overall, these results suggest there is an educational bias in the neurocognitive screening of adult SCD patients using available tools such as the RUDAS and MoCA. Although RUDAS was less biased overall, visuospatial assessment remained biased. The task often considered more "culture-fair" is still subject to the impact of educational potential (Statucka, 2019). We provide different strategies to mitigate education bias when assessing with RUDAS. Thus, the RUDAS adjusted by the educational level allows to systematically identify SCD patients in need of comprehensive neurocognitive testing. Prospective validation is ongoing. Disclosures Forté: Canadian Hematology Society: Research Funding; Pfizer - Global Medical Grants: Research Funding. Soulieres:Novartis: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Kuo:Pfizer: Consultancy, Research Funding; Celgene: Consultancy; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy; Apellis: Consultancy. Bartolucci:Roche: Consultancy; Innovhem: Other; AGIOS: Consultancy; Bluebird: Consultancy; Emmaus: Consultancy; Addmedica: Research Funding; Fabre Foundation: Research Funding; Novartis: Research Funding; Bluebird: Research Funding; GBT: Consultancy; ADDMEDICA: Consultancy; HEMANEXT: Consultancy; Novartis: Consultancy.

Introduction: Sickle Cell Disease (SCD) is one of the most common genetic disease worldwide. The Acute Chest Syndrome (ACS) is a leading cause of death for SCD patients. The PRESEV1 study was set to produce a predictive score to assess the risk of an ACS development (Bartolucci et al., 2016). PRESEV2 was an international, multicenter prospective confirmatory study to validate the PRESEV score. This study aims at improving these predictions with the addition of a machine learning (ML) method. Patients and methods: Included patients follow PRESEV1 and PRESEV2 studies 'rules. The dataset thus contains 97 patients who developed an ACS episode (18.3%) against 434 patients who did not (81.7%). To compute the PRESEV score, we firstly used the method developed previously with the following variables as input: leukocytes, reticulocytes, hemoglobin levels and cervical spine pain. This method is based on a decision tree with fixed rules and is referred to as the decision tree method throughout this abstract. Secondly we used a ML method using a combined sampling method named SMOTEENN to balance the data and a C-Support Vector Classification (SVC) with fixed parameters to predict the score. This method produces a probability, with a threshold of 0.2, under which the patient is predicted to declare an ACS. We considered the dataset composed of PRESEV1 dataset and 80 percent of PRESEV2 with a randomly choice. The test dataset is thus composed of the remaining 20 percent of PRESEV2. This technique of random choice allowed us to use a 50-cross-validation and compute with Python an average score and a standard deviation (std). In order to allow comparison of the developed score with or without the addition of the ML method, rates were calculated by adding the weight of ACS representation in the dataset. Results: Among all parameters analyzed, the SVC method considered the following variables for calculation of the score: leukocytes, LDH, urea, reticulocytes and hemoglobin levels. A hundred and two adult patients with a severe VOC requiring hospitalization were included. Out of this pool of patients, 26 (25.5%) were predicted with a low risk of developing an ACS episode (SVC method). Sensibility and specificity were of 94.7% and 26.8%, respectfully. The negative predictive value (NPV) was of 95.8% and the positive predictive value (PPV) of 22.4%. Results are resumed in table 1. When compared to the PRESEV score (decision tree method), 44 patients out of 372 were identified with a low risk score (11.8%), Discussion and Conclusion: While the addition of a ML method did not allow the improvement of the sensibility or the NPV of the PRESEV score, it improved both the specificity and the PPV. The addition of artificial intelligence thus provides a better prediction with a higher percentage of "low-risk" patients. As highlighted in the international PRESEV study, this score could represent a useful tool for physicians in hospital settings, with limited beds. While the PRESEV score could allow a better management of "low risk" patients on one side, the identification of "high-risk" patients could also represent a serious advantage to physicians, as it could improve the feasibility of clinical trials for the prevention of this lethal complication in SCD patients. Disclosures Bartolucci: Innovhem: Other; Novartis: Research Funding; Roche: Consultancy; Bluebird: Consultancy; Emmaus: Consultancy; Bluebird: Research Funding; Addmedica: Research Funding; AGIOS: Consultancy; Fabre Foundation: Research Funding; Novartis: Consultancy; ADDMEDICA: Consultancy; HEMANEXT: Consultancy; GBT: Consultancy.

Introduction Sickle cell disease (SCD) is the most prevalent and severe monogenic disorder due to a mutation in the b-globin gene, responsible for the production of an abnormal hemoglobin (HbS) which polymerizes under hypoxia. Cerebral vasculopathy (CV) generally appearing during childhood, is responsible for ischemic stroke, making SCD the first etiology of stroke in children and young adults. To date, several biological and hemodynamical determinants have been identified in CV development such as severe anemia and/or high intracranial vascular flow velocities (> 200 cm/s). Chronic blood exchange transfusion decreases the risk of stroke in children having a pathological Doppler. However some patients still have a progressive impairment despite conventional treatment highlighting the need for new therapeutic strategies and a better understanding of the physiopathology. Therefore, by developing a 3D carotid model reproducing exactly vascular parameters of a SCD patient, we aim to: (i) determine the mechanisms of CV development in SCD, (ii) find new therapeutic approaches and (iii) predict the risk of progression of CV. Materials and methods Three-dimensional reconstructions of the internal carotid, middle cerebral and anterior cerebral artery from SCD patients were generated from magnetic resonance angiograms (MIMICS & 3Matics software, Materialise). We performed 3D simulations of the Navier-Stokes equations in patient specific geometries, including the state-of-the-art techniques of Computational Hemodynamics (multiscale coupling, backflow stabilization - FeLiSCe software) and other factors - such as the increase of the ejection fraction or the drop of peripheral resistances). Blood viscosity was based on a SCD cohort. Hemodynamic properties such as flow velocities (TMMV) and wall shear stress (WSS) in different areas of modelled carotid were then computed according to flow variations. Modelled carotid was obtained by 3D printing according to computer design (CATIA software). The next steps will consist in 1/importing doppler parameters from patients in a programmable pump for flow assays with blood mimicking fluid to measure TMMV and WSS at different areas in carotid, 2/incorporating resting or activated platelets in BMF to evaluate impact of high WSS on platelets degranulation, 3/developing a flow co-culture of smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs) on carotid wall. HUVECs and SMCs at different zones of the carotid undergoing high/low WSS and oscillatory flow will be analysed Preliminary results Our preliminary results suggest that the carotid inlet flow but not blood viscosity is responsible for the pathological intra cranial velocities (Figure 1A). At high carotid inlet flow, areas of high and low WSS appeared in children (Figure 1B), suggesting the existence of turbulent flow that could lead to arterial wall damages. Figure 2A shows a 3D printed carotid reproducing the exact SCD child's one. The material of artificial carotid is compatible with HUVECs culture (Figure 2B) and fluidic experiment at high inlet flow (Figure 2C). On Doppler ultrasonography, the velocities measured in different sections of carotid were comparable to patient's data and these velocities were modified according to variations of inlet flow values. Conclusions and perspectives By modification of input conditions, our 3D personalized model can predict high or low vascular velocities areas and will allow a better understanding of the pathophysiological processes involved at the interface between abnormal flow and cells on carotid wall. This innovative model could be a pertinent tool to evaluate individually effectiveness of new therapeutic strategies in SCD patients. Furthermore, this work may constitute a proof of concept that can be transposed to other diseases. Disclosures Verlhac: Addmedica, Paris: Other: Financial Support; Bluebird Bio: Consultancy. Bartolucci:AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

International audience; The prognosis of sickle cell disease (SCD) patients who need dialysis is poor, but experience with kidney transplantation is limited. This study assessed the characteristics of 36 SCD patients undergoing renal transplantation. Immediate post-surgical complications occurred in 25% of cases. Cytomegalovirus and bacterial infections were frequently observed. Twelve patients died after a median follow-up period of17-4 months. Overall patient survival was significantly lower in SCD than in the control group without significant difference for overall death-censored graft sur-vival. Our data suggest that renal transplantation should be systematically considered in SCD patients with end-stage renal disease.

Transfusion-related hemolysis is classically the result of an interaction between antibodies produced by the recipient and blood group antigens carried by the donor red blood cells. This reaction may be life threatening, especially in sickle cell patients when they develop hyperhemolysis with concomitant accelerated clearance of their own red blood cells. The complement system is a key participant in the pathophysiology of post-transfusion hemolysis. Complement can trigger the hemolytic reaction, amplify the inflammatory response and increase tissue damage. Complement is activated by the classical pathway but may also be activated by the alternative pathway in sickle cell disease. The hemolysis-derived products permanently released by sickle cell patients with chronic hemolytic anemia may affect the potency of complement activation. All the observations in sickle cell patients as well as in vitro experiments and in vivo data in animal models support the conclusion that complement is key disease driver and a promising therapeutic target in the context of transfusion-related hemolysis and hyperhemolysis.

Today, additive manufacturing (AM) is implemented in medical industry and profoundly revolutionizes this area. This approach consists of producing parts by additions of layers of successive materials and offers advantages in terms of rapidity, complexity of parts, competitive costs that can be exploited and can lead to a significant advancement in biological research. Everything becomes technically feasible and gives way to a “techno-centered” approach. Many parameters must be controlled in this field, so it is necessary to be guided for the development of such a product. This article aims to present a state of the art of existing design methodologies focused on AM to create medical devices. Finally, a development method is proposed that consists of producing vascular geometry using AM, based on patient data, designed for cell culture in vitro studies.

Epub ahead of print; Sickle cell disease (SCD) is a genetic hemoglobinopathy leading to two major clinical manifestations: severe chronic hemolytic anemia and iterative vaso-occlusive crises. SCD is also accompanied by profound muscle microvascular remodeling. The beneficial effects of endurance training on microvasculature are widely known. The aim of this study was to evaluate the effects of an endurance training program on microvasculature of skeletal muscle in SCD patients. A biopsy of the vastus lateralis muscle and submaximal incremental exercise were performed before and after the training period. Of the forty randomized SCD patients, complete data sets from 32 were obtained. The training group (n=15) followed a personalized moderate-intensity endurance training program, while the non-training (n=17) group maintained a normal lifestyle. Training consisted of three 40-minute cycle ergometer exercise sessions per week for 8 weeks. Histological analysis highlighted microvascular benefits in the training SCD patients compared to non-training patients, including increases in capillary density (CD) (P = .003), number of capillaries around a fiber (CAF) (P = .015) and functional exchange surface (LC/PF) (P < .0001). Conversely, no significant between-group difference was found in the morphology of capillaries. Indexes of physical ability also improved in the training patients. The moderate-intensity endurance exercise training program improved the muscle capillary network and partly reversed the microvascular defects commonly observed in skeletal muscle of SCD patients. This trial was registered at www.clinicaltrials.gov as #NCT02571088.

Although strenuous exercise may expose sickle cell disease (SCD) patients to risks of vaso-occlusive crisis, evidence suggests that regular endurance exercise may be beneficial. This study aimed to test (i) the safety and usefulness of a submaximal incremental exercise in evaluating physical ability of SCD patients and identify a marker for the management of endurance exercise and (ii) the feasibility of endurance exercise sessions in SCD patients.Twenty adults with SCD (12 men and 8 women) performed a submaximal incremental exercise used to determine the first lactate threshold (LT1) and stopped as soon as blood lactate concentration ([lactate]b) reached ≥4 mmol·L. Fifteen of those patients (8 men and 7 women) also performed three 30-min endurance exercise sessions at ~2.5 mmol·L of [lactate]b on separate occasions.LT1 occurred at 47 ± 3 and 33 ± 3 W for men and women, respectively, demonstrating the extreme deconditioning and, thus, low physical ability of adult SCD patients. During endurance exercise, peripheral oxygen saturation and [lactate]b most often remained stable and within acceptable ranges.The proposed strategy of submaximal incremental exercise allowed safe determination of LT1, an important parameter of patients' physical ability. The study also demonstrated the feasibility and safety of individually tailored endurance exercises at ~2.5 mmol·L of [lactate]b. These latter results suggest that endurance training programs may be considered for adult SCD patients and that the method proposed here may be helpful in that regard.

International audience; Today, additive manufacturing (AM) is implemented in medical industry and profoundly revolutionizes this area. This approach consists of producing parts by additions of layers of successive materials and offers advantages in terms of rapidity, complexity of parts, competitive costs that can be exploited and can lead to a significant advancement in biological research. Everything becomes technically feasible and gives way to a “techno-centered” approach. Many parameters must be controlled in this field, so it is necessary to be guided for the development of such a product. This article aims to present a state of the art of existing design methodologies focused on AM to create medical devices. Finally, a development method is proposed that consists of producing vascular geometry using AM, based on patient data, designed for cell culture in vitro studies.

Background: Sickle cell disease (SCD) can be complicated by moyamoya syndrome. Brain magnetic resonance angiography (MRA) is a non-invasive method to diagnose this syndrome and, steno-occlusion and moyamoya vessels (MMV) scores have been proposed to evaluate its severity. Previous studies of SCD moyamoya syndrome did not evaluate the severity according to MRA scores. The objective was to assess the characteristics of moyamoya syndrome in an adult cohort of SCD using these MRA scores. Methods: Twenty-five SCD patients with moyamoya syndrome were included using MRA with 3D time of flight technique. We evaluate steno-occlusion score for each hemisphere (range 0-10) from: steno-occlusion severity of internal carotid (ICA) (0-3), anterior cerebral (ACA) (0-3), middle cerebral (MCA) (0-2), and posterior cerebral (PCA) (0-2) arteries. MMV score for each hemisphere (range 0-5) depended from 5 MMV areas: (1) anterior communicating artery (2) basal ganglia (3) ICA/MCA (4) posterior communicating artery/PCA (5) basilar artery. Results: Eight patients (32%) showed unilateral moyamoya syndrome. ICA steno-occlusion was involved in 22 patients (88%), MCA in 23 patients (92%), ACA in 9 patients (36%), and PCA in 3 patients (12%). MMV involved ACoA area in 10 patients (40%), basal ganglia in 13 patients (52%), PCoA/PCA in 10 patients (40%), MCA/ICA in 7 patients (28%), and BA in 1 patient (4%). Steno-occlusion and MMV mean hemisphere scores were 3.4/10 (± 1.42) and 1.6/5 (± 0.71), respectively. Conclusion: Frequent unilateral moyamoya syndrome, uncommon PCA involvement and, moderate steno-occlusion and MMV scores seem to be features of SCD moyamoya syndrome. In future studies, MRA scores could be collected to assess the follow-up in these patients.

In a recent clinical trial, the metabolite l -glutamine was shown to reduce painful crises in sickle cell disease (SCD) patients. To support this observation and identify other metabolites implicated in SCD clinical heterogeneity, we profiled 129 metabolites in the plasma of 705 SCD patients. We tested correlations between metabolite levels and six SCD-related complications (painful crises, cholecystectomy, retinopathy, leg ulcer, priapism, aseptic necrosis) or estimated glomerular filtration rate (eGFR), and used Mendelian randomization (MR) to assess causality. We found a potential causal relationship between l -glutamine levels and painful crises (N = 1278, odds ratio (OR) [95% confidence interval] = 0.68 [0.52–0.89], P = 0.0048). In two smaller SCD cohorts (N = 299 and 406), the protective effect of l -glutamine was observed (OR = 0.82 [0.50–1.34]), although the MR result was not significant (P = 0.44). We identified 66 significant correlations between the levels of other metabolites and SCD-related complications or eGFR. We tested these correlations for causality using MR analyses and found no significant causal relationship. The baseline levels of quinolinic acid were associated with prospectively ascertained survival in SCD patients, and this effect was dependent on eGFR. Metabolomics provide a promising approach to prioritize small molecules that may serve as biomarkers or drug targets in SCD.

Background Echocardiography is the main non-invasive screening tool for pulmonary hypertension (PH) in sickle cell disease (SCD), but relies mostly on the tricuspid regurgitation velocity (TRV) assessment, without distinction between pre- and post-capillary patterns. Using Etendard Cohort data, the aim of this study was to refine echocardiographic assessment of PH in SCD patients. Methods The French Etendard Study is a prospective cohort initially designed to assess the prevalence of PH among 398 SCD participants. We analysed echocardiography data of the 96 Etendard patients who underwent Right Heart Catheterisation (RCH), because of a TRV ≥ 2.5 m/s, and compared them to invasive haemodynamic measurements. Results PH was found in 24/96 patients with 11 precapillary and 13 post-capillary. In addition to TRV, multivariate analysis identified indexed left atrial volume (LAVind) and lateral E’ wave velocity (E’lat) as independent echocardiographic predictors of PH (OR = 1.06 and 0.6, respectively, P 48 mL/m2 and E’lat Moreover, comparing echocardiography data of pre- and post-capillary PH patients, we observed that pulmonary acceleration time (PAcT) was different in the two groups (104 ± 22 ms vs. 160 ± 21 ms, P Conclusion Echocardiography can accurately estimates the probability of PH in SCD patients with an integrated approach using TRV, LAVind and E’lat. In addition, among patients with suspected PH, measuring PAcT as a surrogate of PVR allows a good differentiation between pre and post-capillary phenotypes.

Diagnosis of delayed hemolytic transfusion reactions (DHTR), one of the most dreaded complications of transfusion in patients with sickle cell disease (SCD), is challenging and not straightforward. Current diagnostic approaches are complex and not consensual; they are based on assessment of hemoglobin (Hb) drop and enhanced hemolysis, features also seen during classical vaso-occlusive events. In this observational study, we tested the hypothesis that the rate of decline in HbA after an index transfusion is a surrogate marker for the destruction of transfused RBC, which could be used diagnostically. We examined 421 transfusion episodes (in 128 patients of a French referral center for SCD) for which an Hb electrophoresis was obtained within 1 week following an index transfusion and repeated within 2 months (before a subsequent scheduled transfusion or during an acute complication). Chart review found DHTR to be present in 26 cases (6.2%), absent in 389 cases (92.4%), and possible in six cases (1.4%). As expected, DHTR was associated with accelerated hemolysis (increased serum bilirubin and lactic dehydrogenase concentrations) and a decline in total Hb as compared to the early post-transfusion value. However, the decline in HbA concentration appeared more effective in segregating between patients without DHTR and others. We propose a diagnostic nomogram for DHTR based on Hb A as a biologic marker of the survival of transfused RBCs. Am. J. Hematol. 91:1181-1184, 2016. © 2016 Wiley Periodicals, Inc.

Production of abnormal hemoglobin (HbS) in sickle-cell disease (SCD) results in its polymerization in deoxygenated conditions and in sickled-RBC formation. Dense RBCs (DRBCs), defined as density >1.11 and characterized by increased rigidity are absent in normal AA subjects, but present at percentages that vary of a patient to another remaining stable throughout adulthood for each patient. Polymerized HbS has reduced affinity for oxygen, demonstrated by the rightward shift of the oxygen-dissociation curve, leading to disturbances in oxygen transport. Ninety-two SCD patients' total RBCs were separated into LightDRBC (LRBC) (d 6 months on hydroxyurea. 6MWT time with SpO2

Delayed hemolytic transfusion reaction (DHTR) is one of the most feared complications of sickle-cell disease (SCD). We retrospectively analyzed the clinical and biological features, treatments and outcomes of 99 DHTRs occurring in 69 referral center patients over 12 years. The first clinical signs appeared a median of 9.4 [IQR, 3-22] days after the triggering transfusion (TT). The most frequent DHTR-related clinical manifestation was dark urine/hemoglobinuria (94%). Most patients (89%) had a painful vaso-occlusive crisis and 50% developed a secondary acute chest syndrome (ACS). The median [IQR] hemoglobin-concentration nadir was 5.5 [4.5-6.3] g/dL and LDH peak was 1335 [798-2086] IU/L. Overall mortality was 6%. None of the patients had been receiving chronic transfusions. Among these DHTRs, 61% were developed in previously immunized patients, 28% in patients with prior DHTR. Among Abs detected after the TT in 62% of the episodes, half are classically considered potentially harmful. No association could be established between clinical severity and immunohematological profile and/or the type and specificity of Abs detected after the TT. Management consisted of supportive care alone (53%) or with adjunctive measures (47%), including recombinant erythropoietin and sometimes rituximab and/or immunosuppressants. Additional transfusions were either ineffective or worsened hemolysis. In some cases, severe intravascular hemolysis can be likely responsible for the vascular reaction and high rates of ACS, pulmonary hypertension and (multi)organ failure. In conclusion, clinicians and patients must recognize early DHTR signs to avoid additional transfusions. For patients with a history of RBC immunization or DHTR, transfusion indications should be restricted. Am. J. Hematol. 91:989-994, 2016. © 2016 Wiley Periodicals, Inc.

BACKGROUND Delayed hemolytic transfusion reaction (DHTR) is a life-threatening condition in sickle cell disease (SCD) patients that is frequently complicated by hyperhemolysis. Antibodies resulting from antigen disparity between donors of European ancestry and patients of African ancestry are common, but situations involving antibodies not classically of clinical significance are also encountered. Anti-HI is generally considered to be an innocuous naturally occurring antibody. STUDY DESIGN AND METHODS We describe two cases of hyperhemolysis with anti-HI and provide details of the reported cases. RESULTS Both SCD patients were polyimmunized and belonged to blood group B. They developed anti-HI that was reactive at 37°C, after the transfusion of group O red blood cell units matched for all known and produced antibodies classically considered to be clinically significant. Both patients developed DHTR with hyperhemolysis. In the first case, a pregnant woman, a second transfusion was unavoidable and the patient died from cardiac arrest. The state of the second patient improved without the need for further transfusion. CONCLUSION Three other cases of DHTR with anti-HI have been described in the literature in SCD patients. The two additional cases reported here definitively demonstrate that anti-HI is dangerous in SCD patients. As a result, ABO-identical matching (including A1 status) must be considered in SCD patients with anti-HI.

We performed a retrospective study to assess the changes in clinical, biological and heart echocardiographic parameters in 32 sickle cell disease (SCD) patients beginning haemodialysis. Acute SCD-related complications were similar at 6 months before and 6 months after the initiation of haemodialysis. Median haemoglobin level did not change significantly, but the need for blood transfusions increased (P

Resume Introduction L’hematopoiese extra-medullaire (HE) symptomatique par compression des organes adjacents est une complication rare mais potentiellement severe des β-thalassemies. Son traitement est mal codifie. Methodes Etude descriptive retrospective monocentrique des cas d’HE symptomatiques diagnostiques entre 1997 et 2014 dans un centre de reference pour le traitement des maladies genetiques du globule rouge. Description des caracteristiques cliniques et paracliniques, des traitements entrepris et de l’evolution. Resultats Sur 182 patients β-thalassemiques suivis sur la periode d’etude, 7 cas d’HE symptomatique etaient retrouves. Il s’agissait de 5 hommes et 2 femmes d’âge moyen 37 ans. Quatre patients etaient splenectomises, 2 patients etaient sous programme transfusionnel regulier, et 4 patients avaient deja recu de l’erythropoietine recombinante. L’HE etait de siege intravertebral dorsal responsable de compression medullaire dans 5 cas, paravertebral dorsal dans un cas, et presacre dans un cas. Le taux d’hemoglobine moyen au diagnostic de l’HE etait de 7,9 g/dL. Le traitement a consiste pour 6 patients en des transfusions erythrocytaires, associees a l’hydroxyuree (HU) dans 5 cas et/ou a la radiotherapie dans 3 cas. Un patient a ete traite par chirurgie puis HU sans transfusion. Avec une duree mediane de suivi de 41 mois, l’evolution clinique etait totalement favorable chez 2 patients, avec des sequelles chez 5 patients. Conclusion Le diagnostic d’HE doit etre suspecte chez un patient β-thalassemique presentant des signes cliniques de compression d’organe et un aspect radiologique evocateur. Le traitement, dont la rapidite conditionne le pronostic, doit associer les transfusions globulaires, l’hydroxyuree, plus ou moins la radiotherapie. Le recours a la chirurgie est exceptionnel. Les sequelles sont frequentes.

Transfusion is a corner stone treatment of sickle cell disease complications. However one of the serious complications of transfusions is represented by the delayed haemolytic transfusion reaction (DHTR) with a significant mortality. It is due to a massive intravascular haemolysis of both transfused and autologous red blood cells. It occurs between 5 to 20 days after a transfusion and is accompanied by a vaso-occlusive crisis and haemoglobinuria in almost all cases. The evolution can be life-threatening because of the appearance of a severe acute chest syndrome or a multi organ failure. About half patients are transferred in Intensive Care Unit. The biological diagnosis of DHTR is made by the rapid decline, or disappearance, of Hb A in sickle cell patients who were previously transfused. This event is associated with a significant increase of lactico-dehydrogenase (LDH) and worsening of anemia due to haemolysis. Allo antibodies are not found in 30%. DHTR is under diagnosed because of the delay between the transfusion and the symptoms, which mimic sickle cell vaso occlusive crises. This can lead to further transfusions that worsen the evolution and are ineffective. Because of the severity of this manifestation many treatment have been tried to improve the outcome as steroids, immunoglobulins, rituximab or eculizumab, without consensual guidelines. Early diagnosis of DHTR should help to decide the appropriate treatment, and avoid reiteration of transfusions. Transfusion indications should be maximally restricted in patients with previous post-transfusion haemolysis.

Fetal hemoglobin induction is a key point in the management of sickle cell disease (SCD). We report the case of a kidney transplant recipient with SCD who was treated with everolimus, a mammalian target of rapamycin inhibitor. At 10 months after initiating therapy, the patient's fetal hemoglobin level was dramatically increased (from 4.8% to 15%) and there was excellent tolerance to treatment.

Introduction Vaso-Occlusive Crisis (VOC), the most common manifestation of sickle cell disease (SCD), is the first cause of death when complicated by an acute chest syndrome (ACS). We previously developed a predictive score for the occurrence of ACS in SCD patients admitted at hospital for a VOC episode (Bartolucci et al., 2016). Two hundred and fifty patients with severe VOC requiring hospitalization were included in the PRESEV I study and 19% developed a secondary ACS within days post-admission (median [IQR] : 3 [2.3]). A multivariate analysis of these data established a predictive score of secondary ACS, with a negative predictive value of 98,9% for the low-level risk. Variables for calculation of the score were: reticulocytes and leucocytes counts, hemoglobin and categorical pain score (spine -pelvis). Interestingly enough, Hydroxyurea treatment did not have any impact on the score. Our goal was to validate this score in a multicenter international study, as it could represent a useful tool for physicians, for improving VOC management, but also be of use for therapeutic trials. Herein, we present results for adults. Methods This international, multicenter, prospective, observational study was performed in thirteen centres, over two continents (Africa and Europe) and five countries (Mali, Togo, England, Belgium and France). Homozygous SCD patients, both adults and children (>2 years), were included, with severe VOC requiring admission at the emergency unit. Severe VOC was defined as pain or tenderness affecting at least one part of the body (e.g. limbs, ribs, sternum, head, spine and/or pelvis) requiring opioids (level 3) and not attributable to other causes. The primary outcome measure was the occurrence of an ACS, defined as an auscultatory abnormality (crepitation or bronchial breathing), or the association of a new radiologic infiltrate and chest pain or decreased breath sounds. Secondary outcome measures were hospital length of stay, morphine consumption, transfusion, hospitalization in intensive care unit and mortality. The following parameters were recorded: temperature, blood pressure, oxygen saturation, respiratory frequency, categorical pain score. Pulmonary auscultation was performed at least once a day by a physician, every day, for the length of stay. The auscultatory abnormality, defined as crepitation, bronchial breathing or decreased breath sounds, was confirmed by a second physician. If a patient was discharged before day 5, follow-up with a phone call and/or a visit, 3 to 7 days after discharge were performed, to prevent complications or ACS. Results Three hundred and seventy-two adult patients with a severe VOC requiring hospitalization were included. Mean age was 29 (±8) years old, sex ratio (female/male) was 1.2. A hundred and ninety-one patients came from Europe and 181 from Africa. Out of the 372 patients, 68 (18.3%) further developed a secondary ACS. Mean day of ACS episode was 3.3 (±1.37). Among the 304 patients who did not develop an ACS episode (81.7%), 41 had a low risk score of developing a secondary ACS (predictive score ≤ 5). Among the 68 patients who developed a secondary ACS, 43 had a high-risk score (≥ 11). Results are shown in table 1. Three deaths were reported, all on African continent (ACS, anemia and end-stage nephropathy). Discussion and Conclusion Our multicenter international study has allowed confirmation of the incidence of patients developing a secondary ACS during a VOC. This study confirms that the PRESEV score could indeed represent a useful tool for physicians, most especially within emergency structures, by identifying patients with a low risk of further developing an ACS with a good NPV and thus, allowing a better management of SCD patients experiencing a VOC. The PRESEV score was successfully put to practice during the Covid-19 pandemic at the referral SCD center of Henri Mondor hospital and identified "low-risk" patients, who benefited from homecare services (DREPADOM). As such, the PRESEV score could represent a significant help when one considers the shortness of bed availabilities in certain circumstances (pandemics, hospital settings in resource-limited countries, etc...). Finally, the identification of "high-risk" patients could also become useful for improving the feasibility of clinical trials for the prevention of ACS. Disclosures Arlet: Novartis: Consultancy, Honoraria. Bartolucci:Novartis: Research Funding; Emmaus: Consultancy; Addmedica: Research Funding; Fabre Foundation: Research Funding; ADDMEDICA: Consultancy; HEMANEXT: Consultancy; AGIOS: Consultancy; Roche: Consultancy; Bluebird: Consultancy; Bluebird: Research Funding; Innovhem: Other; GBT: Consultancy; Novartis: Consultancy.

INTRODUCTION Besides many problematics the Covid-19 pandemic has triggered, one issue remains the care of chronically ill patients. Regarding sickle cell disease (SCD), patients often present co-morbidities that could predispose them to poor outcome if they get infected. Vaso-occlusive crisis (VOC), a characteristic manifestation of SCD, is the first cause of patients 'hospitalizations. Here, we describe how our sickle cell referral center has managed outpatient care, with the constant preoccupation of minimizing risks for our patients and avoid them unnecessary trips to heavily burdened hospital settings. DESCRIPTION OF SETTING With the outbreak of Covid-19, our primary obsession was to provide continuous care for our patients, while ensuring their safety. All appointments were canceled when possible and patients were instructed to comply with the national lock down procedures. A hotline and helpdesk were setup as the first stage of our structure. When patients described symptoms of VOC and/or light breathing difficulties, they were enlisted for daily monitoring. This stage two consisted of calling patients daily with a specific set of questions, regarding management and improvement or deterioration of their symptoms. A dedicated team of dentists, who all volunteered and received specific training, managed both stage 1 and 2, along with nurses. SCD specialists supervised these two stages for medical decisions. All symptoms were recorded and reported. If symptoms disappeared, the patient's name was discarded from the list. If there was a worsening or no improvement of the patient's condition, he was moved to stage three by the SCD expert, with the deployment of homecare service. A whole network was then setup, with the delivery of oxygen supply at the patient's house, dispatch of a medical prescription to a neighboring pharmacy and daily visits from homecare service providers. Both opioids and parenteral treatments were prescribed and monitoring was performed daily (blood pressure, temperature, respiratory rate, pain, etc...). On the first visit, a blood sample was sent to a laboratory, to allow calculation of the PRESEV score (Bartolucci et al., 2016). This score, established by team members and colleagues, assesses the risk of acute chest syndrome (ACS). Moreover, it has just been validated by a multicenter international study (PRESEV II - under writing process). In case the PRESEV score was ≤ 5, home hospitalization was pursued. In case this score was ≥11, the patient was sent to hospital for constant monitoring and full comprehensive care. For low and intermediate scores, the patient was referred to hospital for any aggravation. The helpdesk was in constant interaction with nurses and providers of homecare services and status and evolution of the patient's global condition was reported daily for medical decisions. In addition, patients with home hospitalization care were called daily by the helpdesk, to ensure proper care and satisfaction. When home hospitalization was over, the patient automatically came back to stage two for a daily follow-up until full recovery. Early discharged patients could either re-integrate stage 2 or 3 for daily monitoring until full recovery. Out of the 305 patients included in this system, with a total of 2068 calls between March 23rd and May 29th. Seventy five were included for home hospitalization. Mean age was 36 years old [±9], sex ratio was 45/30 (female/male), mean homecare follow up was 6 days (±3), 16 patients also had Covid-19. Thirteen patients (17.3%) were hospitalized: one for an acute chest syndrome, two for a Covid-19 infection and nine for VOC management. Only one patient was in ICU due to a salmonella septicemia. No death was reported. PERSPECTIVES The Covid-19 pandemic has highlighted the need for profound reshaping of healthcare systems worldwide. In this particular context, the structure we have installed, DREPADOM, allowed follow up and monitoring of two profiles of patients: at-risk population of SCD patients and Covid-19 positive SCD patients. With the ongoing situation, our delocalized hospitalization system has proven interesting enough to enter a new phase: DREPADOM was selected as part of a public call for tenders, for financial support to make the structure permanent (DREPADOM - APRES). Disclosures Habibi: Pfizer: Consultancy; Bluebird: Consultancy; Addmedica: Consultancy; Novartis: Consultancy. Bartolucci:GBT: Consultancy; Roche: Consultancy; Emmaus: Consultancy; Innovhem: Other; Addmedica: Research Funding; HEMANEXT: Consultancy; Novartis: Consultancy; ADDMEDICA: Consultancy; Fabre Foundation: Research Funding; Novartis: Research Funding; Bluebird: Consultancy; AGIOS: Consultancy; Bluebird: Research Funding.

Objectif La perfusion par marquage de spins arteriel (ASL) est une technique d’IRM de perfusion non invasive prometteuse. Son application dans la vasculopathie cerebrale drepanocytaire reste neanmoins limite du fait de temps de transit arteriel (TTA) allonges par le developpement de nombreuses collaterales. L’ASL avec delais post-marquage multiples (ASL multi-delais) semble prometteuse dans cette indication. Notre objectif etait de valider la technique d’ASL multi-delais pour la mesure du debit sanguin cerebral chez des patients drepanocytaires avec vasculopathie cerebrale. Methodes Une sequence ASL standard a delai unique (duree du marquage = 1500 ms, delai post-marquage = 2025 ms) et une sequence ASL multi-delais (duree du marquage = 4000 ms, 7 delais post-marquage: 2000 a 5000 ms) ont ete realisees sur une IRM 3 Tesla chez 21 patients drepanocytaires avec vasculopathie cerebrale. Une IRM de perfusion T2* a ete realisee pour evaluer la severite de la vasculopathie et identifier les regions corticales avec un Tmax normal ( 4 secondes). Les valeurs de debit sanguin cerebral relatif (DSCr), de TTA et de Tmax ont ete automatiquement extraites dans 20 regions corticales. Resultats Les valeurs de DSCr mesurees en ASL standard etaient plus faibles, correspondant a 93 %, 89 % (p Conclusion L’ASL multi-delais est une technique non invasive qui ameliore l’evaluation de la perfusion cerebrale dans la vasculopathie cerebrale drepanocytaire, en particulier dans les regions corticales avec temps de transit arteriel allonge. Cette technique pourrait eviter le recours a l’injection de produit de contraste chez les patients drepanocytaires difficiles a perfuser.

Objectif La vasculopathie cerebrale drepanocytaire se caracterise par une occlusion progressive des arteres cerebrales et le developpement de collaterales pour maintenir le debit sanguin cerebral. Nous avons evalue la prevalence et la signification des hyperintensites vasculaires en 3D T1 echo de spin rapide (FSE) apres injection de chelates de gadolinium dans la vasculopathie cerebrale drepanocytaire. Methodes Nous avons inclus 19 patients drepanocytaires avec occlusion arterielle cerebrale et 50 patients drepanocytaires sans occlusion sur une angiographie par resonance magnetique a 3 Tesla. Deux neuroradiologues ont evalue la presence d’hyperintensites vasculaires dans les espaces sous-arachnoidiens sur une sequence 3D T1 FSE apres injection, en aveugle des donnees cliniques et des autres sequences IRM. La concordance entre la distribution arterielle des occlusions et celle des hyperintensites vasculaires a ete evaluee. Les valeurs de Tmax en IRM de perfusion ont ete mesurees dans les territoires arteriels cerebraux occlus. Resultats La reproductibilite inter- et intra-observateur pour la detection des hyperintensites vasculaires etaient excellentes. Les hyperintensites vasculaires etaient decelees chez 14 des 19 patients (74 %) avec occlusion et chez seulement 1 des 50 patients (2 %) sans occlusion (p Conclusion Dans la vasculopathie cerebrale drepanocytaire, les hyperintensites vasculaires en 3D T1 FSE apres injection sont associees a une hypoperfusion cerebrale marquee et constituent un signe de severite. Ce signe pourrait correspondre a des mauvaises collaterales lepto-meningees.

Summary Background Exercise could be a triggering factor for vaso-occlusive crises in patients with sickle-cell disease. We aimed to investigate whether a patient-adapted training programme of moderate endurance exercise could be safe and beneficial for patients with sickle-cell disease. Methods We did a multicentre, prospective, open-label, randomised controlled trial at four university hospitals in France. Eligible patients were older than 18 years, with an HbSS or S/β0-thalassaemia genotype, and with no severe chronic complications. All patients underwent cardiopulmonary exercise tests (CPETs) on a stationary bicycle with cardiac, pulmonary, laboratory, and muscle parameter evaluations at the start and end of the study period. We randomly assigned patients (1:1) to the training group (three 45-min exercise sessions per week, for 8 weeks) or the control group (no lifestyle changes) using a central computer-generated randomisation list. During baseline evaluation, patients and researchers were masked to group assignment; randomisation was done after completion of the baseline evaluation to minimise bias. The primary outcome was difference in power output at a blood lactate concentration of 4 mmol/L during CPET between baseline and the end of the 8-week training period. Patients were analysed on a per-protocol basis, excluding those who missed more than 20% of the training sessions or had other major protocol violations. This trial is registered with ClinicalTrials.gov, number NCT02571088, and is completed. Findings Between Sept 8, 2014, and Dec 11, 2015, 40 patients were enrolled (20 to each group). After exclusion of seven patients (one pregnancy, one appendicitis, one protocol violation, two lost to follow-up, and two incompatibilities with work schedule), 33 patients were analysed (15 in the training group, 18 in the control group). At the 8-week follow-up, the absolute change from baseline in mean power output at 4 mmol/L blood lactate was 7·2 W (SD 8·7) in trained patients (from 70·4 W [SD 16·2] at baseline to 77·6 W [15·1] at end of intervention) compared with −0·3 W (9·4) in controls (from 66·2 W [13·8] to 65·9 W [15·6]; mean difference between groups 7·3 W [95% CI 0·7–13·8], p=0·031). No adverse events requiring hospital admission occurred in the training group, whereas five occurred in the control group: four (20%) vaso-occlusive crises (one complicated by an acute chest syndrome), and one (6%) viral infection with isolated chest pain (hazard ratio 0·143 [95% CI 0·024–0·827; p=0·029). Interpretation Moderate-intensity endurance-exercise training seems to be safe for adults with sickle-cell disease without severe chronic complications and significantly improved their functional capacity, especially for exercise levels close to those needed for daily activities. Our findings support consideration of endurance-exercise training as a novel therapeutic strategy for patients with sickle-cell disease. Funding Societe Francaise de Cardiologie and Institut National du Sport, de l'Expertise et de la Performance (INSEP).

Non-typhoidal salmonellosis (NTS) often occurs in children with sickle-cell disease (SCD) and remains a significant cause of mortality in developing countries. However, there is lack of reports on the clinical presentation, outcome and complications of NTS in adults with SCD.We performed a chart review between 2006 and 2016 of adults SCD diagnosed with NTS in 3 referral centers monitoring approximately 3500 SCD adults.Twenty-three episodes of NTS were diagnosed among 22 SCD adults. Diagnosis was challenging: 65% (n = 15/23) of patients presented with vaso-occlusive crisis (VOC) and 30% had no fever. Isolated serotypes were: ser. Enteritidis (n = 8), ser. Typhimurium (n = 6), others (n = 3). We identified two patterns of infections: (1) bacteremic NTS (n = 15) with (n = 9) or without secondary foci of infections (n = 6); (2) non-bacteremic NTS with extra-intestinal foci of infection (n = 8), including primary bones/joints infections (n = 5). Half of patients with osteo-articular localization (n = 6/13) had a previous history of osteonecrosis (n = 2) or osteomyelitis (n = 4) at the same site. Morbidity was high, 6 patients (26%) were admitted to the intensive care unit, 14 patients (61%) required RBC transfusion for VOC. Half of the episodes (n = 12) required surgery (n = 10) or interventional radiology (n = 2) to control the infection. One patient presented a relapse of NTS bacteraemia one year after the first episode.Besides bloodstream infections, clinical presentation of NTS in adults with SCD is non-specific at admission. A triad including bacteraemia, secondary focis of infection and bone localizations was observed in 30% of cases.

Cette etude retrospective (2013–2018) porte sur les patients drepanocytaires ayant recu un anticorps anti-C5 (Eculizumab) inhibant les voies d’activation du complement sur avis du Centre National de Reference des Pathologies du Globule Rouge (H. Mondor), au cours – d’une hemolyse post-transfusionnelle retardee (HPTR) associant : – crise vaso-occlusive 5 a 20 jours apres une transfusion de CGR – baisse rapide de l’HbA OU urines « Porto » ou « Coca Cola » (hemoglobinurie) ou nouvel anticorps a la RAI et/ou positivation du test de Coombs direct. Seize patients repondaient a ces criteres. Ils presentaient des signes de gravite d’emblee : hemoglobine 5,7 g/dL [3,0–9,7], bilirubine totale 92 μmol/L [15–730] (N