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Transcranial Doppler (TCD) is used to detect children with sickle cell anemia (SCA) who are at risk for stroke, and transfusion programs significantly reduce stroke risk in patients with abnormal TCD. We describe the predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217 SS/Sβ0), who were early and yearly screened with TCD since 1992. Magnetic resonance imaging/magnetic resonance angiography was performed every 2 years after age 5 (or earlier in case of abnormal TCD). A transfusion program was recommended to patients with abnormal TCD and/or stenoses, hydroxyurea to symptomatic patients in absence of macrovasculopathy, and stem cell transplantation to those with human leukocyte antigen-genoidentical donor. Mean follow-up was 7.7 years (1609 patient-years). The cumulative risks by age 18 years were 1.9% (95% confidence interval [95% CI] 0.6%-5.9%) for overt stroke, 29.6% (95% CI 22.8%-38%) for abnormal TCD, which reached a plateau at age 9, whereas they were 22.6% (95% CI 15.0%-33.2%) for stenosis and 37.1% (95% CI 26.3%-50.7%) for silent stroke by age 14. Cumulating all events (stroke, abnormal TCD, stenoses, silent strokes), the cerebral risk by age 14 was 49.9% (95% CI 40.5%-59.3%); the independent predictive factors for cerebral risk were baseline reticulocytes count (hazard ratio 1.003/L × 109/L increase, 95% CI 1.000-1.006; P = .04) and lactate dehydrogenase level (hazard ratio 2.78/1 IU/mL increase, 95% CI1.33-5.81; P = .007). Thus, early TCD screening and intensification therapy allowed the reduction of stroke-risk by age 18 from the previously reported 11% to 1.9%. In contrast, the 50% cumulative cerebral risk suggests the need for more preventive intervention.

Stroke is predicted by abnormally high cerebral velocities by transcranial doppler (TCD). This study aimed at defining predictive factors for abnormally high velocities (≥ 2 m/sec) based on the Créteil pediatric sickle cell anemia (SCA) cohort composed of 373 stroke-free SCA children. α genes and β-globin haplotypes were determined. Biologic parameters were obtained at baseline. α-thalassemia was present in 155 of 325 and G6PD deficiency in 36 of 325 evaluated patients. TCD was abnormal in 62 of 373 patients. Multivariate logistic regression analysis showed that G6PD deficiency (odds ratio [OR] = 3.36, 95% confidence interval [CI] 1.10-10.33; P = .034), absence of alpha-thalassemia (OR = 6.45, 95% CI 2.21-18.87; P = .001), hemoglobin (OR per g/dL = 0.63, 95% CI 0.41-0.97; P = .038), and lactate dehydrogenase (LDH) levels (OR per IU/L = 1.001, 95% CI 1.000-1.002; P = .047) were independent risk factors for abnormally high velocities. This study confirms the protective effect of alpha-thalassemia and shows for the first time that G6PD deficiency and hemolysis independently increase the risk of cerebral vasculopathy.

Abstract 263 Early occurrence of dactylitis, severe anemia and leukocytosis have been identified as risk factors for adverse outcome in children with SCA (Miller NEJM 2000), but the impact of acute splenic sequestrations (ASS) on disease severity has not yet been reported. The goal of this study was to define the predictive factors of ASS and to evaluate if this complication was a risk factor for disease severity. Methods. SS patients of the newborn cohort, seen at our SCA Center in Créteil before 3 months of age and older than 2 years at the last visit (n=197), were included in this study. Alpha and beta genotypes, and G6PD activity were determined. Blood parameters were recorded at steady state during the second year of life. ASS was defined as an Hb-decrease of ≥20% associated with a spleen-increase ≥2cm. Vaso-occlusive crises (VOC) requiring hospitalizations and acute chest syndromes (ACS) were recorded. The yearly rates of VOC and ACS were calculated for the entire follow-up and for the period before any intensification (transfusion program, hydroxyurea or SCT). Results. Median follow-up was 7.9 yr (range 2–24), providing 1820 patient-years. Alpha-Thal was present in 70/162 (43.2%); beta-haplotypes, available in 140 patients, were Car/Car in 62 (44.3%), Ben/Ben in 35 (25%), Sen/Sen in 7 (5%), and others in 34 (25.7%). G6PD deficiency was present in 24/171 (14%). At baseline, mean (SD) blood parameters were: Hb: 8g1/dL (1.2); Ht: 24.6% (3.9); MCV: 79.2 fL(8.3); HbF: 15.7% (8.2); LDH: 919 UI/L (369) and reticulocytes: 296 (114); WBC: 14.3 (5.2), neutrophils 5.8 (3.1) × 109/L. Among the 197 SS-patients, 64 (32%) experienced their first ASS at the median age of 2.0 yr (range 0.1–12.9) and 36/64 recurred. ASS occurred before 1 yr of age in 10 (5%) and before 2 yr in 33/197 (17%). Splenectomy was performed in 24 of them at the median age of 5.1 yr (range 2.7–12.9). The KM-estimated cumulative risk of ASS occurrence at age 7 was 32% (95%CI: 25–39%). The Cox-regression analysis showed that gender, G6PD deficiency, beta haplotypes were not risk factors whereas alpha-Thal significantly increased the risk of ASS occurrence (HR: 1.9, 95% CI:1.1-3.3, p=0.021). Among blood parameters, multivariate Cox analysis retained low platelet (HR: 1.4 per 1×107/L decrease; 95%CI:1.1-1.8, p=0.014) and high reticulocyte counts (HR=2.0 per 1×107/L increase; 95%CI:1.6-2.6) as independent significant predictive factors for ASS. Comparison of patients with or without ASS history showed no significant difference in the rate of ACS but significantly higher rates of VOC during the entire follow-up (0.68±0.58 vs 0.47±0.55; p=0.014) and in the number of hospitalizations (1.64±0.83 vs 1.29±0.92; p=0.01) in patients with ASS history. Rates of VOC before intensification were 1.1±0.7 and even 2.2±2.0 in those having experienced ASS before age 1 vs 0.6±0.7 (p=0.001) in those with no ASS history. Conclusion. Results from this study in a newborn cohort show that ASS are more frequent in patients with alpha-Thal and are associated with a higher rate of VOC. Splenectomy is usually recommended in case or recurrent ASS; however, our previous results show that geno-identical SCT can cure 95%SCA children and partly restore splenic function. We suggest that this procedure be proposed to those with available donor before considering total splenectomy. Disclosures: No relevant conflicts of interest to declare.

Background Predicting the severity of sickle cell anemia (SCA) is important for providing better informed genetic counseling and for better targeting of intensive therapies. Stroke is the most severe complication in children with SCA and is predicted by abnormally high cerebral velocities by transcranial doppler (TCD). We attempted to define the risk factors associated with high velocities. Methods This study concerned the Créteil pediatric SCA cohort, composed of newborn patients, screened and followed at our Center since birth, and of patients secondarily referred to the Center because of the severity of their disease. Time-averaged mean of maximum velocities (TAMMX) higher than 200 cm/sec were considered as abnormal, resulting in initiation of a transfusion program initiated. Cerebral MRI/MRA was done after the age of 5 years or earlier in case of abnormal TCD. Alpha genes and beta-globin haplotypes were determined. Baseline biological parameters (G6PD activity; WBC, PMN, Reticulocytes, Platelets counts; Hemoglobin, Hematocrit, HbF, LDH levels; MCV; SpO2) were obtained a minimum of 3 months away from a transfusion, one month from a painful episode, after 18 months of age and, before intensive therapy. Results SS children (390; 189 F, 201 M) were annually explored by TCD (n=2286) since 1992, and followed for a total of 1962 patient-years. The follow-up before initiation of intensive therapy was 1032 patient-years. Nineteen patients experienced an overt stroke. TCD was abnormal in 65 of 390 patients (17%). MRI (n=850) was performed in 268 patients, was abnormal in 86 cases and showed silent infarcts in 67 of 249 patients (27%). Silent infarcts were seen in 33% of patients with abnormal TCD. Alpha genes study, available in 336 patients, demonstrated alpha-thalassemia in 158 patients (47%): 31 had a deletion of 2 genes (7.9%) and 127 of 1 gene (32.6%). G6PD deficiency was present in 26 of 228 evaluated patients (11%). Beta-globin haplotypes studied in 316 patients were Car/Car in 125 (40%), Ben/Ben in 76 (24%), Sen/Sen in 30 (9%) and, “other” in 85 (27%). Univariate analysis showed that the risk of abnormally high velocities was not related to sex, beta-globin haplotypes, pain and acute chest syndrom rates, WBC, PMN, platelets counts, HbF level and SpO2 but was significantly associated with the absence of alpha-thalassemia (p< 0.001), G6PD deficiency (p=0.012), low Hb and Ht levels (p< 0.001), high reticulocyte count (p=0.008), high MCV (p=0.004) and high LDH level (p 1200 UI/L [OR=4.5, 95% CI (1.5–13.5)], (p=0.007) were independent risk factors of abnormally high velocities. Conclusion This study confirms that the risk of high velocities in patients with SCA is significantly decreased by the presence of alpha-thalassemia. It shows for the first time that hemolysis is a more significant risk factor than the degree of anemia and that absence of alpha-thalassemia, G6PD deficiency and hemolysis are significant independent risk factors of cerebral vasculopathy in patients with SCA.

Treatment intensifications in SCD with HU, TP or SCT are applied in order to reduce SCD related complications but their comparative effects have still to be described. We report our experience concerning the annual check-up performed in SCD pediatric patients. Patients and Methods: Among our cohort of 397 SS/Sb0 pediatric SCD patients, 157 of them were intensified with HU (n= 86), TP (n=104) or SCT (n=36) and some of them received successively HU, TP and SCT. HU was proposed to patients > 3 years of age and having experienced more than 3 VOC/ACS/year or < 7g/dl severe anemia. TP defined as > 4 months program was applied in patients with cerebral vasculopathy defined by an history of stroke or abnormal TCD (> 200 cm/sec). TP was also proposed in patients with HU-failure and in patients with frequent VOC, less than 3 years old. SCT was proposed in patients with an indication of treatment intensification and an available HLA identical sibling donor. Annual check-up were performed in our day-care unit. We analysed 1261 check-ups performed and recorded since 1992 in 341 SS/Sb0 patients (sex: 164 F, 177 M). Median age was 8.8 ± 5.1 years. Mean number of annual check-ups per patient was 3.7 ± 2.8 (range 1 to 13): 816 were performed in non intensified patients, 196 in HU, 123 in TP and 126 in transplanted patients. Categories of age were distinguished: < 2 y of age (n=110), 2–5y (n=244), 5–10y (n=415), 10–15y (n=317) and 15–20y (n=175). Results: Respective follow-up were 4.4 y ± 3.3 in HU, 2.6 y ± 2.6 inTP and 5.8 y ± 4.7 in SCT patients. Comparison with non intensified patients showed that weight was significantly higher in SCT patients > 15 y of age (p=0.001), spleen size was significantly higher in (2–5y) young patients treated with HU (p=0.005) or TP (0.001) and in 5–10 y old patients on HU (p=0.046) but no difference was observed after the age of 10 y. O2 saturation was significantly improved after SCT (p Conclusion : Treatment intensifications (TP, HU, SC) reduced the decrease of weight observed with aging in SCD patients and significantly reduced anemia using different mechanisms. SCT was the most effective to correct anemia, supress hemolysis and decrease leucocytosis. Intensif. n Follow-up HbF% Eryht Hb MCV Retic mean (SD) No 816 11.4 (9.2) 3.1 (0.9) 8.1 (1.2) 81.4 (8.9) 268.9 (105.2) HU 196 4.4 y. (3.3) 13.9 (7.0) 2.7 (0.6) 8.5 (1.2) 97.7 (13.7) 188 (83.8) TP 126 2.6 y.(2.7) 3.3 (3.1) 3.1 (0.6) 9.1 (1.4) 86.8 (4.8) 258.2 (126.0) SCT 123 5.8 y.(4.7) 4.6 (6.4) 4.3 (0.9) 11.4 (1.6) 81.5 (8.9) 89.4 (63.4) Intensif. n Tot Bili Conj Bili LDH Ferritin Leucocytes Platelets No 816 49.8 (34.4) 5.7 (3.4) 1016 (312) 192 (322) 13.2 (9.9) 385 (124) HU 196 47.5 (34.4) 5.0 (2.2) 943 (264) 399 (582) 9.7 (3.8) 352 (133) TP 126 58.8 (39.6) 5.6 (2.2) 973 (377) 2238 (6310) 13.1 (4.7) 365 (128) SCT 123 15.6 (13.9) 2.8 (4.2) 493 (200) 1099 (1386) 6.8 (3.3) 295 (109)

Abnormal high velocities are predictive of high stroke risk which can be significantly reduced by transfusion program (Adams and al). They are related to stenosis, severe anemia or tissue hypoxia. We hypothesized that high velocities observed in patients with normal MRA and normalized on transfusion program (TP), were anemia related and could be safely decreased with hydroxyurea (HU)-therapy. Patients and Methods: since 1992, 291 pediatric SCD patients (235 SS, 40 SC, 3 Sb0, 11 Sb+) were systematically explored once a year by TCD. The newborn screened cohort (n=149) had the first TCD exploration between 12 and 18 months age. TCD was performed with a real-time imaging unit, using a 2 MHz sector transducer with color Doppler capabilities. When abnormal high velocities (defined as mean maximum velocities > 200 cm/sec in MCA, ACA or ICA) were observed, TCD was controlled and the patient treated with TP and cerebral imaging (MRI/MRA) was performed within 3 months. In patients with severe stenosis, TP was pursued or transplantation performed. In patients with normal MRA and transfusion-normalized velocities, a progressive switch towards HU therapy was applied and TCD controlled once a trimester. Results: among the stroke-free patients (n=281), abn. high velocities were detected in 25 patients (all SS:11% of incidence in SS patients). In the newborn screened population, velocities became abnormal in 10 patients at the median age of 5.7 years (range 1.4 – 12.5 y). The first MRI/MRA (n=24/25) performed in the 3 months following the detection of high velocities showed MRI/silent infarcts in 9/24 (38%): only 1/11 among the newborn screened cohort had silent infarcts in contrast with 8/13 older patients secondary referred in our center. MRA detected severe vascular abnormalities in 10 and mild in 3 patients. Mean velocities (2.69 m/sec) were significantly higher (p=0.002) in the 7 patients with abn. MRI and MRA than in the 10 patients (2.11m/sec) who had normal MRI and MRA. One stroke occurred in a very young 1.6 y old girl just before the second TCD evaluation (first abn. TCD had been observed at 1.5 y) and before the beginning of the TP. Long-term outcome: no stroke was observed following the initiation of the TP. With a median follow-up of 4.4 years (0.5 to 11.4 y.), velocities remained abnormal in 11/25 patients: 7 of them had abnormal MRA and among the 4 patients with normal MRA at first exploration MRA became abnormal in 2 cases showing that abnormal TCD can precede the occurrence of cerebral vasculopathy. TP was maintained in 7 patients and safely stopped in 4 patients transplanted with genoidentical donor. Velocities normalization (defined as < 170 cm/sec) was observed in 13/25 patients in a median delay of 0.75 years (0.25 – 2.3 years). TP was stopped in 10 patients with normal MRA and therapy was switched towards HU in 7 patients with abstention in 3. However, abnormal TCD relapsed in 4 patients who were again placed on TP. Conclusion: abnormal high velocities concerned 11% of SS patients and were predictive of MRA and MRI lesions occurrence. TP was efficient to prevent the stroke risk and normalized velocities in about 50% of patients but relapses were observed in 4/7 patients following TP stop and HU switch. Only few patients with high velocities history did not develop cerebral vasculopathy. Also, early TCD allows a selection of very high risk patients justifying the research of suitable donors.