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Delayed haemolytic transfusion reaction (DHTR) is a life-threatening haemolytic anaemia following red blood cell transfusion in patients with sickle cell disease, with only scarce data in children. We retrospectively analysed 41 cases of DHTR in children treated between 2006 and 2020 in a French university hospital. DHTR manifested at a median age of 10.5 years, symptoms occurred a median of 8 days after transfusion performed for an acute event (63%), before surgery (20%) or in a chronic transfusion programme (17%). In all, 93% of patients had painful crisis. Profound anaemia (median 49 g/L), low reticulocyte count (median 140 ×10

Background Sickle cell disease (SCD) children are frequent travellers to countries where yellow fever (YF) is endemic, but there are no data regarding the safety and immunogenicity of the vaccine in such children treated with hydroxyurea (HU). The main objective of this study was to compare the tolerance and immune response to YF vaccination in SCD children treated or not with HU. Method SCD children Results Among the 52 SCD children vaccinated against YF, 17 (33%) were treated with HU. Only mild adverse events, mainly fever and local reaction, were observed in the HU group with a similar frequency in the non-HU group (57 and 35%, respectively, P = 0.30). YF antibody titres were measured in 15/17 patients in the HU group and 23/35 patients in the non-HU group after a median of 6.0 months (3.5–8.5) following vaccination. The geometric mean of YF antibody titre was similar in both groups. A protective antibody level was observed in 85% of the children in the HU group vs 100% in the non-HU group (P = 0.14), suggesting a lower effectiveness of the vaccine in patients on HU similarly to what has been described in patients on immune suppressive therapy for other vaccines. Conclusion YF vaccination seems to be safe and efficient in SCD children treated with HU. Considering the potential risk of severe complications in cases of YF while travelling in Africa for those patients, the benefit-to-risk ratio argues for YF vaccination in all SCD children. Control of a protective antibody titre may also be useful to ascertain an adequate response in those treated with HU.

International audience; Delayed hemolytic transfusion reaction (DHTR) is an unpredictable severe complication of transfusion in patients with sickle cell disease (SCD). It presents clinically as a vaso-occlusive crisis (VOC), often associated with the failure of one or more organs, after the transfusion of packed red blood cells (pRBC).1,2 Hyperhemolysis is encountered in the most severe forms. Both transfused and autologous red blood cells (RBC) are lysed.The mechanisms underlying DHTR remain unclear. Alloantibodies against RBC antigens were initially thought to underlie the pathophysiology, but no such antibodies are detected in about a third of the cases.3RBC degradation products, such as hemoglobin and heme, are released into the bloodstream during intravascular hemolysis. These elements and heme-loaded membrane microvesicles have recently been implicated in inflammation and organ injury in DHTR.4 Complement is activated via the classical pathway, by alloantibodies, and/or via the alternative pathway, by free heme.5 Hemedependent complement deposits on the endothelium contribute to organ damage.6 Due to these vascular lesions, hyperhemolysis often progresses to multiple organ failure and, in some cases, death.

Spleen dysfunction and susceptibility to pneumococcal infection is a well known feature in homozygous sickle cell disease (HbSS), whilst to date splenic function in hemoglobin SC disease (HbSC) has been poorly investigated. The aim of this study was to analyze spleen function in children with HbSC disease using a high-throughput validated method (1) and to examine if the current recommendations regarding pneumococcal risk are appropriate in this population. Spleen function was evaluated using a flow cytometry quantification of red blood cells (RBCs) with Howell-Jolly bodies (HJBs), in a cross-sectional study of patients at steady state during an outpatient visit in an expert center. Quantification of HJB-RBCs was performed in children with HbSC disease aged < 10 years and compared to children with HbSS disease or healthy children of the same age groups, or splenectomized children. Additional exploratory analysis was performed according to age (under or above the age of 5 years old) and treatment group (hydroxyurea). The median (Q1-Q3) HJB-RBCs count was 16 (11-28.25) /100.000 RBCs in 40 HbSC children (Figure 1). This result was not statistically different from the control group of 22 healthy children (p=0.96) nor in subgroups < or ≥ 5 years old, indicating that children with HbSC under 10 years have a preserved splenic function. Expectedly, the HJB-RBCs counts differed significantly from splenectomized children (419 (296-489)/100.000 RBCs, n=15, p By contrast, among the 53 HbSS children, the median HJB-RBCs count was 134 (29-216) /100.000 RBCs, differing significantly from HbSC children (p The result of this study suggests that spleen function in children under 10 years old with HbSC is not altered. The routine administration of prophylactic penicillin to young children with SC disease may therefore be questioned. Similarly, fever in children with HbSC under 3 years old may not require parenteral antibiotics as it is generally currently recommended by analogy to children with HbSS. Functional or anatomical asplenia in children with HbSC is delayed compared to those with HbSS at least after the first decade of life. Future large cohort studies using similar methodology will allow better evaluation of the pneumococcal risk in adolescents and adults with Hb SC disease. Bibliography (1) El Hoss S, Dussiot M, Renaud O, Brousse V, El Nemer W. A novel non-invasive method to measure splenic filtration function in humans. Haematologica. oct 2018;103(10):e436-9. Figure 1 Figure 1. Disclosures El Nemer: Hemanext: Consultancy.

Nous rapportons le cas d’une enfant de 5 ans, initialement suivie pour anemie sideroblastique congenitale, dont les explorations vont reveler une pathologie familiale de type beta-thalassemique. Le myelogramme realise chez l’enfant met en evidence des erythroblastes matures dystrophiques avec un defaut d’hemoglobinisation et des ponctuations basophiles. Ces anomalies orientent vers une anomalie de synthese de l’heme ou des chaines de globines. Les transfusions iteratives realisees chez l’enfant ne permettent pas d’interpreter une recherche d’anomalie de l’hemoglobine. En revanche, la recherche d’anomalie de l’hemoglobine realisee chez les parents montre une augmentation du taux d’HbA2 associee a une microcytose, concluant a un trait beta-thalassemique. Sachant que les syndromes beta-thalassemiques sont des pathologies genetiques, en general recessives, la presence d’un trait beta-thalassemique chez les parents associee a la clinique de l’enfant (besoin transfusionnel mensuel) sont tres en faveur d’un syndrome beta-thalassemique chez l’enfant. Cette hypothese diagnostique sera confirmee par l’etude moleculaire des genes de globine qui va reveler une hemoglobinopathie complexe pour l’ensemble des membres de la fratrie. Les parents sont porteurs a l’etat heterozygote d’une mutation β+thalassemique que l’enfant atteint presente a l’etat homozygote permettant de porter le diagnostic de syndrome beta-thalassemique. De plus, une triplication des genes α-globine est presente respectivement a l’etat heterozygote chez la mere et a l’etat homozygote chez le pere et l’enfant. La triplication des genes α-globine est un facteur connu d’aggravation des beta-thalassemies et ce cas clinique, avec le continuum clinico-biologique observe, illustre parfaitement les intrications entre genes α et β globine.

This study&rsquo, s objective was to assess, on a national scale, residual risks of death, major disease-related events, and quality of care during the first five years in children diagnosed at birth with sickle cell disease (SCD). Data were retrospectively collected from medical files of all children with SCD born between 2006&ndash, 2010 in France. Out of 1792 eligible subjects, 1620 patients (71.8% SS or S/beta&deg, thalassemia -SB&deg, ) had available follow-up data, across 69 centers. Overall probability of survival by five years was 98.9%, with 12/18 deaths related to SCD. Probability of overt stroke by five years in SS/SB&deg, patients was 1.1%, while transcranial Doppler (TCD) was performed in 81% before three years of age. A total of 26 patients had meningitis/septicemia (pneumococcal in eight cases). Prophylactic penicillin was started at a median age of 2.2 months and 87% of children had received appropriate conjugate pneumococcal vaccination at one year. By five years, the probability of survival without SCD-related events was 10.7% for SS/SB&deg, patients. In contrast, hydroxyurea was prescribed in 13.7% and bone marrow transplant performed in nine patients only. In this study, residual risks of severe complications were low, probably resulting from a good national TCD, vaccination, and healthcare system coverage. Nonetheless, burden of disease remained high, stressing the need for disease-modifying or curative therapy.

Summary We conducted a retrospective study on newborns with sickle-cell disease (SCD), born 1995–2009, followed in a multicentre hospital-based network. We assessed patient outcomes, medical care and compliance with the national guidelines published in December 2005. Data from 1033 patients (742 SS/Sβ°-thalassaemia) with 6776 patient-years of follow-up were analysed (mean age 7·1 ± 3·9 years). SCD-related deaths (n = 13) occurred only in SS-genotype patients at a median age of 23·1 months, mainly due to acute anaemia (n = 5, including 2 acute splenic sequestrations) and infection (n = 3). Treatment non-compliance was associated with a 10-fold higher risk of SCD-related death (P = 0·01). Therapeutic intensification was provided for all stroke patients (n = 12), almost all patients with abnormal transcranial Doppler (TCD) (n = 76) or with >1 acute chest syndrome/lifetime (n = 64) and/or ≥3 severe vaso-occlusive crises/year (n = 100). Only 2/3 of patients with baseline haemoglobin

BACKGROUND Chronic exchange transfusion is effective for primary and secondary prevention of stroke in children with sickle cell anemia (SCA). Erythrocytapheresis is recognized to be the most efficient approach; however, it is not widely implemented and is not suitable for all patients. The aim of our study was to compare automated exchange transfusion (AET) with our manual method of exchange transfusion and, in particular, to evaluate the efficacy, safety, and cost of our manual method. STUDY DESIGN AND METHODS Thirty-nine SCA children with stroke and/or abnormal findings on transcranial Doppler were included in the study. We retrospectively analyzed 1353 exchange sessions, including 333 sessions of AET and 1020 sessions of manual exchange transfusion (MET). RESULTS Both methods were well tolerated. The median decrease in hemoglobin (Hb)S per session was 21.5% with AET and 18.8% with our manual method (p

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

Children with sickle cell anemia (SCA) may be at risk of cerebral vasculopathy and strokes, which can be prevented by chronic transfusion programs. Repeated transfusions of packed red blood cells (PRBCs) is currently the simplest and most used technique for chronic transfusion programs. However, iron overload is one of the major side effects of this therapy. More developed methods exist, notably the apheresis of RBC (erythrapheresis), which is currently the safest and most efficient method. However, it is costly, complicated, and cannot be implemented everywhere, nor is it suitable for all patients. Manual exchange transfusions combine one or more manual phlebotomies with a PRBC transfusion. At the Reference Center of Sickle Cell Disease, we set up a continuous method of manual exchange transfusion that is feasible for all hospital settings, demands no specific equipment, and is widely applicable. In terms of HbS decrease, stroke prevention, and iron overload prevention, this method showed comparable efficiency to erythrapheresis. In cases where erythrapheresis is not available, this method can be a good alternative for patients and care centers.

Background: Delayed hemolytic transfusion reaction (DHTR) is an unpredictable and severe complication of transfusion, especially in Sickle Cell Disease (SCD) patients (Habibi Am J Hematol 2016). The clinical presentation is a vaso occlusive crisis (VOC), often associated with one or more organ failures, after packed red blood cell transfusion (pRBC). The hypothesis of complement activation through the classical pathway by alloantibodies and/or the alternative pathway by free heme (released by hemolysis) suggests that an inhibitor of complement activation may be a treatment option for DHTR. Methods: This retrospective study focuses on the SCD patients who received anti-C5 monoclonal antibody during DHTR treatment after consulting with our French SCD referral center between 2013 and 2018. DHTR diagnosis associated VOC signs occurring 5 to 20 days after pRBC transfusion, with no other cause for intravascular hemolysis, and one or more of the following: - rapid decrease in, or unexpectedly low, hemoglobin A (HbA) concentration - hemoglobinuria defined by dark urines - direct antiglobulin test (DAT) positivity or new antibody formation. The treatment efficacy was evaluated through patients' clinical and biological data. Findings: Sixteen patients received anti-C5 for a DHTR defined by a VOC 5 to 20 days after a transfusion and the following criteria: 12 had low HbA or rapid decrease of HbA, 10 had hemoglobinuria, and 10 had positive DAT or antibody formation. One patient received anti-C5 for hyperhemolysis without being able to discriminate DHTR from hemolysis under Extracorporeal Membrane Oxygenation and was excluded from the analysis. The 16 patients included in the analysis had severe DHTR at diagnosis, with one or more organ failures (N=7), median hemoglobin concentration 57 g/L [30-97], LDH 2807 UI/L [510-12500], total bilirubin 92 mmol/L [15-730]. Two additional patients had organ failures during the follow-up. Lowest hemoglobin concentration was 32 g/L [19-58] and highest LDH 4238 UI/L [510-24000]. One to 3 anti-C5 doses were given at 1 week intervals, associated with symptomatic treatment (hydration, oxygen, analgesia; N=16), erythropoietin (N=15), pRBC transfusions (N=12), immunoglobulins (N=8), plasma exchange (N=4), steroids (N=1). The outcome was favorable for 13 patients. The number of pRBC transfused were limited as much as possible. Three patients died. All three had acute liver failure that required emergency liver transplant. Two patients improved after anti-C5 and could be grafted, but died of infectious complications unrelated to anti-C5: Klebsiella pneumoniae pulmonary infection 11 days after transplant for one, and digestive and urinary infection 47 days after transplant for the other. For the third patient, no compatible organ could be found. Conclusion: In association with other therapies (EPO, plasma exchange, limiting pRBC transfusions), anti-C5 can be a treatment option for severe DHTR despite its high cost, in the absence of effective alternatives. Disclosures Michel: Amgen: Consultancy; Rigel: Consultancy; Novartis: Consultancy. Bartolucci: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; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Anti-C5 is currently used to treat paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).

Objective To examine morbidity among children with sickle-cell disease (SCD) during and after travel to a tropical area. Design Observational study. Setting Tertiary care children; Robert Debre Hospital, Paris, France. Population Children with SCD younger than 18 years old and managed in the SCD referral centre at the Robert Debre Hospital who travelled to a tropical or subtropical area between 1 June 2009 and 31 December 2009. Main outcome To assess morbidity, we used the number of clinical events requiring medical consultation during the trip as the primary outcome and the number of hospitalisations required after returning as the secondary outcome. Results Thirty-nine children were included. The median age was 7.8 years (4.3–11.7 years). All of the children and their parents attended a pretravel visit focusing on the prevention of travel-related diseases. Twelve children (30%) consulted a physician while they were abroad. Thirteen children (33%) were hospitalised, and 23 children (59%) consulted a physician while they were abroad or within 3 months after returning to France. Considering the 3 months before and after travel, the number of children hospitalised after travel (n=12, 30.7%) was significantly higher than the number hospitalised before (n=4, 10.2%; p=0.01). One child was hospitalised for multifocal osteoarthritis as a complication of Salmonella enterica septicaemia of gastrointestinal origin. Conclusions Travels to tropical areas are associated with high morbidity in children with SCD. Salmonella infection is a particularly significant threat, and empirical antibiotic therapy should be prescribed routinely for traveller9s diarrhoea in this population.

Children with sickle cell disease (SCD) have a significant vascular morbidity, especially cerebral macrovasculopathy (CV), detectable by transcranial Doppler. This study aimed to identify risk factors for CV using longitudinal biological and clinical data in a SCD newborn cohort followed at the Robert Debre Reference centre (n = 375 SS/Sβ(0) ). Median follow-up was 6·8 years (2677 patient-years). Among the 59 children presenting with CV, seven had a stroke. Overall, the incidence of CV was 2·20/100 patient-years [95% confidence interval (95% CI): 1·64-2·76] and the incidence of stroke was 0·26/100 patient-years (95% CI: 0·07-0·46). The cumulative risk of CV by age 14 years was 26·0% (95% CI: 20·0-33·3%). Risk factors for CV were assessed by a Cox model encompassing linear multivariate modelling of longitudinal quantitative variables. Years per upper-airway obstruction [Hazard ratio (HR) = 1·47; 95% CI: 1·05-2·06] or bronchial obstruction (HR = 1·76; 95% CI: 1·49-2·08) and reticulocyte count (HR = 1·82 per 50 × 10(9) /l increase; 95% CI: 1·10-3·01) were independent risk factors whereas fetal haemoglobin level (HR = 0·68 per 5% increase; 95% CI: 0·48-0·96) was protective. Alpha-thalassaemia was not protective in multivariate analysis (ancillary analysis n = 209). Specific treatment for upper or lower-airway obstruction and indirect targeting of fetal haemoglobin and reticulocyte count by hydroxycarbamide could potentially reduce the risk of CV.

Chronic exchange transfusion is effective for primary and secondary prevention of stroke in children with sickle cell anemia (SCA). Erythrocytapheresis is recognized to be the most efficient approach; however, it is not widely implemented and is not suitable for all patients. The aim of our study was to compare automated exchange transfusion (AET) with our manual method of exchange transfusion and, in particular, to evaluate the efficacy, safety, and cost of our manual method.Thirty-nine SCA children with stroke and/or abnormal findings on transcranial Doppler were included in the study. We retrospectively analyzed 1353 exchange sessions, including 333 sessions of AET and 1020 sessions of manual exchange transfusion (MET).Both methods were well tolerated. The median decrease in hemoglobin (Hb)S per session was 21.5% with AET and 18.8% with our manual method (p 0.0001) with no major increase in red blood cell consumption. Iron overload was well controlled, even with the manual method, with a median (interquartile range) ferritin level of 312 (152-994) µg/L after 24 months of transfusions. The main differences in annual cost relate to equipment costs, which were 74 times higher with the automated method.Our study shows that continuous MET has comparable efficacy to the automated method in terms of stroke prevention, decrease in HbS, and iron overload prevention. It is feasible in all hospital settings and is often combined with AET successively over time.

Cerebral vasculopathy is a serious complication of sickle cell anemia. Overt strokes are largely due to intracranial arteriopathy, detected by routine transcranial Doppler and largely prevented through chronic transfusions. As extracranial internal carotid artery arteriopathy was considered rare, it has not been routinely assessed in sickle cell anemia. Recent cases of overt strokes associated with stenosis/occlusion of the extracranial portion of the internal carotid artery prompted us to include extracranial internal carotid artery assessment to our transcranial Doppler sonography protocol.The aim of the study was to perform a cross-sectional study in children with sickle cell anemia to evaluate Doppler flow patterns of the extracranial internal carotid arteries and to assess potential associated factors.Between June 2011 and April 2012, 435 consecutive stroke-free children with sickle cell anemia (200/235 M/F, median age: 7.9 years) were assessed for extracranial internal carotid artery using a 2-MHz transcranial Doppler sonography probe via a submandibular window during routine transcranial Doppler sonography visits. The course of both extracranial internal carotid artery was assessed by color Doppler mapping, and the highest flow velocity was recorded after insonation of the entire length of the artery and analyzed. Intra- and extracranial MR angiographies were available in 104/435 subjects for comparison.Mean (SD) extracranial internal carotid artery time-averaged mean of maximum velocity was 96 (40) cm/s. Extracranial internal carotid artery tortuosities were echo-detected in 25% cases and were more frequent in boys (33% vs.18%; P 0.001). Velocity ≥160 cm/s in at least one extracranial internal carotid artery was found in 45 out of 435 patients with sickle cell anemia (10.3%) and was highly predictive of MR angiography stenosis. Simultaneous abnormal intracranial velocity (≥200 cm/s) was recorded in 5/45 patients, while 40 patients had isolated extracranial internal carotid artery velocity ≥160 cm/s. Low hemoglobin (odds ratio: 1.9/g/dL, 95% confidence interval (CI): 1.3-2.9; P = 0.001) and tortuosities (odds ratio: 19.2, 95% CI: 7.1-52.6; P 0.001) were significant and independent associated factors for isolated extracranial internal carotid artery velocities ≥160 cm/s.Adding extracranial internal carotid artery evaluation via the submandibular window to transcranial Doppler sonograpy allowed us to detect 10.3% patients at risk for extracranial internal carotid arteriopathy. Further studies are needed to evaluate the prognosis of these anomalies.

In patients with sickle cell anaemia (SCA), concomitant glucose-6-phosphate dehydrogenase (G6PD) deficiency is usually described as having no effect and only occasionally as increasing severity. We analysed sequential clinical and biological data for the first 42 months of life in SCA patients diagnosed by neonatal screening, including 27 G6PD-deficient patients, who were matched on sex, age and parents' geographic origin to 81 randomly selected patients with normal G6PD activity. In the G6PD-deficient group, steady-state haemoglobin was lower (-6·2 g/l, 95% confidence interval (CI), [-10·1; -2·3]) and reticulocyte count higher (247 × 10(9) /l, 95%CI, [97; 397]). The acute anaemic event rate was 3 times higher in the G6PD-deficient group (P

This retrospective study assessed the long-term effect of transfusional exchange therapy on MRA/MRI abnormalities in 24 homozygous sickle-cell anemia (HbSS) children presenting with abnormal brain MRA. The median time elapsed from baseline to last available MRA was 29 months. Follow-up MRAs showed improvement, stabilization or worsening of cerebrovascular lesions in 11, 6 and 7 patients respectively. Complete normalization of MRA was observed in 6 patients within a mean time of 1.4 years, but stenosis recurred at the same location in the 4 patients in whom transfusion therapy was discontinued. Baseline severe stenosis/occlusion of large cerebral arteries and occurrence of moyamoya syndrome were significantly associated with an absence of improvement of the cerebral vasculopathy. These data emphasize the heterogeneity of the course of cerebrovasculopathy in SS children receiving chronic transfusion. Further studies are needed to determine whether different therapeutic approaches have to be considered according to these different evolutive patterns in SS children.

Children with sickle cell disease have a significant vascular morbidity, specifically cerebral vasculopathy (CV) that can be detected by transcranial Doppler. The aim of this study was to identify CV risk factors using longitudinal biological and clinical data including upper and lower respiratory tract evaluation in the newborn cohort of Robert Debre Pediatric Sickle Cell Referral Center. 375 patients with sickle cell anemia with a total of 2677 patient-years and a 7 years median follow-up were evaluated. Among the 59 children presenting CV, seven had a stroke. Overall, the incidence rate of CV was 2.20/100 patient-years (95% CI 1.64-2.76) and the incidence rate of stroke was 0.26/100 patient-years (95% CI 0.07-0.46). The cumulative risk of CV by the age of 11.3 years was 26.0% (95% CI 20.0%-33.3%). CV risk factors were assessed by a Cox model encompassing linear multivariable modelling of longitudinal quantitative variables. The final model retained four variables. Years with upper airways obstruction (HR=1.47, 95%CI 1.05-2.06), bronchial obstruction (HR=1.76, 95%CI 1.49-2.08), fetal hemoglobin level (HR=0.68 per 5% increase 95%CI 0.48-0.96) and reticulocyte count (HR=1.82 per 50000/mm3 increase 95%CI 1.10-3.01) were independent risk factors. An ancillary analysis performed for the 209 patients with α-thalassemia data (29 patients with CV and 180 without) found that α-thalassemia was protective in bivariate analysis but was not retained in multivariable analysis. The final Cox multivariable analysis for CV in this subgroup retained three variables. Years with upper airways obstruction and bronchial obstruction were significant risk factors for CV (with respectively HR=1.57 IC95% [1.05-2.32] and HR=1.73 IC95% [1.37-2.17]) whereas fetal hemoglobin was protective (HR=0.54 per 5% increase IC95% [0.31-0.94]). Reticulocyte count was no more retained as risk factor for CV after introducing α-thalassemia in the final multivariable model. Early evaluation and specific treatment for symptoms of asthma or nocturnal respiratory abnormalities could potentially reduce the risk of CV and stroke. They are currently under evaluation in a multicenter clinical trial with systematic nocturnal polysomnography. Disclosures No relevant conflicts of interest to declare.

To the Editor .— We read with great interest the report from Hill et al,1 who showed evidence of a significant increase of cerebral blood flow velocity (CBFV) in children recruited from adenotonsillectomy waiting lists because of a history of snoring compared with controls. These features had major implications in the management of children with sickle cell disease (SCD) by underlining a relationship …

Children with sickle cell disease (SCD) have a significant vascular morbidity responsible of pain and stroke. They are at high risk of cerebral vasculopathy (CV) that can be detected in these children by transcranial Doppler. The aim of this study was to identify risk factors for CV using longitudinal data in the 375 newborn cohort of Robert Debre Pediatric Sickle Cell Referral Center. Among the 59 children presented CV, seven had a stroke. There was a total of 2677 patient-years of follow up. Overall, the incidence rate of CV was 2.20/100 patient-years (95% CI 1.64-2.76) and the incidence rate of stroke was 0.26/100 patient-years (95% CI 0.07-0.46). The cumulative risk of CV by age 14 years was 26.0% (95% CI 20.0%-33.3%).To take into account longitudinal data, risk factors of CV were assessed by a survival Cox model built in two steps. The final Cox multivariable analyze for CV retained five variables. Upper airways obstruction (HR 1.41 95%CI 1.00-1.98), bronchial obstruction (HR 2.13 95%CI 1.77-2.57), acute anemic event (HR 1.15 95%CI 1.01-1.32) and reticulocyte count (HR 1.41 per 20000/mm3 increase 95%CI 1.16-1.71) were independent risk factors whereas hydroxycarbamide therapy (HR 0.03 95%CI 0.01-0.35) was protective. Evaluation and specific treatment for symptoms of asthma or sleep apnea or nocturnal respiratory abnormalities could potentially reduce the risk of CV and stroke after treatment. Our findings suggest that hydroxycarbamide could protect from CV. Disclosures: No relevant conflicts of interest to declare.

Abstract 88 Background. Strokes are a well-known complication of sickle-cell anemia (SCA), and are largely due to intracranial arteriopathy, detected by routine transcranial Doppler (TCD). Adams et al. showed in the STOP I trial (N Engl J Med, 1998) the efficiency of transfusion programs for primary stroke prevention in patients identified by TCD as being at risk of stroke. We recently reported in the CHIC newborn cohort (Bernaudin et al., Blood, 2011) that early TCD imaging (TCDI) screening significantly reduces the risk of stroke by age 18 from the previously reported 11% to only 1.9%, but has not allowed adequate prevention of silent infarcts, with a risk of 37.1% by age 14, suggesting that TCDI does not distinguish all SCA-patients at risk of silent infarcts. Extracranial internal carotid artery (eICA) vasculopathy is considered rare and has not been routinely assessed; however, several recent cases of stroke with extracranial arteriopathy prompted the inclusion of eICA evaluation in routine screening. The aim of the study was to establish the ranges of eICA velocities in SCA-patients, to determine the cut-off limits of velocities predictive of eICA stenoses by extracranial MRA, to evaluate the prevalence of abnormal eICA velocities and to determine their association with intracranial stenoses and/or silent infarcts by MRI. Methods. Since June-2011, all stroke-free SCA patients from the CHIC and Debre cohorts who had routine yearly TCDI for intracranial arteries were also systematically assessed for eICA using submandibular windows (Gorman et al., Neurology 2009) and the same 2Mhz TCDI transducer probe. Time-averaged mean of maximum velocities (TAMMV) were obtained for intra and extracranial cerebral arteries. By color Doppler mapping, the course of eICA was considered as straight, or as tortuous if the artery changed direction with an angle > 120° between adjacent segments. Extracranial cervical MRA was added to routine intracranial MRI/MRA, performed every 2 years or as soon as abnormal velocities were found. Results. Between June 2011 and January 2012, 435 consecutive SCA-children from the two cohorts (202M, 233F) were assessed by Doppler at the median age of 8.5 years (range: 1.3–18.7). MRI/intra and extracranial MRA was performed in 104 patients. At time of Doppler assessment, mean±SD hemoglobin was 9.1±1.6 g/dl. eICA velocities were significantly correlated with middle cerebral arteries (MCA) velocities (r=0.234, p Conclusion. This study shows for the first time that in cohorts previously assessed early by TCDI for intracranial arteries, about 10% stroke-free patients have eICA vasculopathy. Moreover, we show that intra and/or extracranial stenoses are significant risk factors for silent infarcts. These data may explain why silent infarcts still occurred in patients early assessed by TCDI exploring only intracranial arteries. Thus, extracranial Doppler assessment should be routinely done with TCD to evaluate the full extent of cerebral vasculopathy in SCA. Disclosures: No relevant conflicts of interest to declare.