Clinical, laboratory, and molecular characteristics of a cohort of children with hemoglobinopathy S/beta-thalassemia.

INTRODUCTION: Hemoglobinopathy Sß-thalassemia (HbSß-thal) has a wide range of clinical and laboratory severity. There is limited information on the natural history of HbSß-thal and its modulating factors. We described the molecular, hematological, and clinical characteristics of a cohort of children with HbSß-thal and estimated its incidence in Minas Gerais, Brazil. METHODS: Laboratory and clinical data were retrieved from medical records. Molecular analysis was performed by HBB gene sequencing, PCR-RFLP, gap-PCR, and MLPA. RESULTS: Eighty-nine children were included in the study. Fourteen alleles of ß-thal mutations were identified. The incidence of HbSß-thal in the state was 1 per 22,250 newborns. The most common ßS-haplotypes were CAR and Benin. The most frequent ßthal-haplotypes were V, II, and I. Coexistence of 3.7 kb HBA1/HBA2 deletion was present in 21.3 % of children. ß-thalassemia mutations were associated with several clinical and laboratory features. In general, the incidence of clinical events per 100 patient-years was similar for children with HbSß0-thal, IVS-I-5 G>A, and IVS-I-110 G>A. Children with HbSß+-intermediate phenotypes had a more severe laboratory and clinical profile when compared with those with HbSß+-mild ones. ßS-haplotypes and α-thalassemia did not meaningfully influence the phenotype of children with HbSß-thal. CONCLUSION: The early identification of ß-thalassemia alleles may help the clinical management of these children.

Follow-up of children with sickle cell anemia screened with transcranial Doppler and enrolled in a primary prevention program of ischemic stroke

ABSTRACT Background: Stroke is a serious complication of sickle cell anemia (SCA). The transcranial Doppler (TCD) is the risk-screening tool for ischemic strokes. The objective of the study was to describe the clinical progression of children with SCA who presented with high risk for stroke by TCD or relevant changes by magnetic resonance angiography (MRA) and underwent the regular transfusion program (RTP) and/or hydroxyurea (HU) treatment between 2007 and 2018. Method: This was a neonatal retrospective/prospective cohort study with children born between 1999 and 2014 with the homozygotic form (HbSS) or Sβ0-thalassemia who underwent TCD at least once. Results: Of the 718 children screened during this period, 675 had HbSS and 43 Sβ0-thalassemia. In 54 children (7.5%), all with HbSS, a high-risk TCD (n = 45) or, when the TCD was inconclusive, an MRA with cerebral vasculopathy (n = 9) was used for detection. Of these, 51 started the RTP and the families of three refused treatment. Of the 43 children with a highrisk TCD who initiated the RTP, 29 (67.4%) reverted to low risk. In 18 of them (62%), HU was started at the maximum tolerated dose (MTD) before transfusion discontinuation. None of these 29 patients had a stroke. Eight children (18.6%) maintained a high-risk TCD, even using the RTP/HU and two had a stroke. Conclusions: The TCD was confirmed as a viable tool for tracking patients with a risk for stroke. The RTP was effective in preventing the primary event. New strategies are necessary to prevent stroke using HU and new drugs, in addition to bone marrow transplantation.

Follow-up of children with sickle cell anemia screened with transcranial Doppler and enrolled in a primary prevention program of ischemic stroke.

BACKGROUND: Stroke is a serious complication of sickle cell anemia (SCA). The transcranial Doppler (TCD) is the risk-screening tool for ischemic strokes. The objective of the study was to describe the clinical progression of children with SCA who presented with high risk for stroke by TCD or relevant changes by magnetic resonance angiography (MRA) and underwent the regular transfusion program (RTP) and/or hydroxyurea (HU) treatment between 2007 and 2018. METHOD: This was a neonatal retrospective/prospective cohort study with children born between 1999 and 2014 with the homozygotic form (HbSS) or Sß0-thalassemia who underwent TCD at least once. RESULTS: Of the 718 children screened during this period, 675 had HbSS and 43 Sß0-thalassemia. In 54 children (7.5%), all with HbSS, a high-risk TCD (n = 45) or, when the TCD was inconclusive, an MRA with cerebral vasculopathy (n = 9) was used for detection. Of these, 51 started the RTP and the families of three refused treatment. Of the 43 children with a high-risk TCD who initiated the RTP, 29 (67.4%) reverted to low risk. In 18 of them (62%), HU was started at the maximum tolerated dose (MTD) before transfusion discontinuation. None of these 29 patients had a stroke. Eight children (18.6%) maintained a high-risk TCD, even using the RTP/HU and two had a stroke. CONCLUSIONS: The TCD was confirmed as a viable tool for tracking patients with a risk for stroke. The RTP was effective in preventing the primary event. New strategies are necessary to prevent stroke using HU and new drugs, in addition to bone marrow transplantation.

Reticulocyte count is the most important predictor of acute cerebral ischemia and high-risk transcranial Doppler in a newborn cohort of 395 children with sickle cell anemia.

Stroke is a severe clinical manifestation of sickle cell anemia (SCA). Despite the prognostic relevance of transcranial Doppler (TCD), more accurate tools to assess stroke risk in children with SCA are required. Here, we describe the effect of clinical, laboratory, and molecular features on the risk of stroke and high-risk TCD in children from the newborn cohort of Minas Gerais, Brazil. Outcomes studied were acute cerebral ischemia and high-risk TCD. Clinical and hematological data were retrieved from children's records. Genetic markers, which were known for their association with stroke risk, were genotyped by polymerase chain reaction/restriction fragment length polymorphism and sequencing. The cumulative incidence of acute cerebral ischemia by the age of 8 years was 7.4 % and that of high-risk TCD by the age of 11.5 years was 14.2 %. The final multivariate model for acute cerebral ischemia risk included high white blood cell count and reticulocyte count, acute chest syndrome rate, and the single nucleotide polymorphisms (SNPs) TEK rs489347 and TNF-α rs1800629. The model for high-risk TCD included high reticulocyte count and the SNPs TEK rs489347 and TGFBR3 rs284875. Children with risk factors should be considered for intensive risk monitoring and for intervention therapy.