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We have studied the cellular and molecular responses to long-term hydroxyurea (HU) treatment in 29 severely affected young patients with sickle cell disease (mean age, 10.9 ± 4.1 years). Patients received HU at 20 mg/kg/d on 4 consecutive days per week initially, with a monthly escalated dose avoiding marrow-toxicity (mean steady-state dose, 34.2 ± 4.6 mg/kg/d) for 12 to 36 months (mean duration, 22 months). The studied parameters were hemoglobin F (HbF), F reticulocytes (F retics), F cells, the amount of HbF per F cell (F/F cell), polymer tendency at 40% and 70% oxygen saturation, and hemolysis. Initial HbF (Fi) was dispersed (from 0.85% to 13.9%). HbF increased in all patients but 1. HbF at maximal response (Fmax) reached a sustained level varying from a 1.5-fold to a 16-fold Fi after a variable delay (6 to 24 months). Fmax was not related to HU dosage, but ▵F (Fmax − Fi) was strongly correlated to ▵MCV (MCVmax − MCVi). HbF increase resulted from the increase of both F cells and F/F cell. In this rather short series, Fi and Fmax were not significantly associated with age, gender, or β-globin haplotype. Neither Fmax nor ▵F was related to bone marrow reserve, as measured by baseline reticulocyte or neutrophil counts. However, Fmax was highly dependent on Fi. When patients are individualized into three groups according to Fmax (group 1, Fmax >20% [12 patients]; group 2, 10% < Fmax < 20% [11 patients]; group 3, Fmax

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.

Despite systematic antibiotic therapy, severe infections (septicemia, meningitis, or osteomyelitis) are a major cause of mortality and morbidity in children with sickle cell disease (SCD). In this study, we explored the possibility that polymorphism at the human leukocyte antigen (HLA) locus might constitute an immunogenetic modifying factor to the intrinsic susceptibility to infection in patients with SCD. A cohort of 80 SCD patients living in Paris, 43 with at least one major infectious complication and 37 without infections, were typed for HLA class II loci by polymerase chain reaction-sequence-specific primers (PCR-SSP). We found that significantly more patients without infections carry the HLA class II DRB1∗15 specificity than did patients with infections (21.6% in the first group, versus 4.7% in the second group; χ 2 = 10.47, p c = 0.01), supporting a protective effect of this allele. Conversely, significantly more patients were found to carry the DQB1∗03 specificity within the group of severe infections, supporting a negative effect (34.9% versus 12.2%, χ 2 = 9.41, p c = 0.01). These findings suggest a direct involvement of HLA polymorphism in the development of major infections in SCD. Together with previous data on polymorphism of the Fc receptor and of the mannose-binding lectin, they provide evidence for a polygenic immunomodulation of the constitutively increased infectious risk in SCD.

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.