Parental and other factors associated with hydroxyurea use for pediatric sickle cell disease.

BACKGROUND: Hydroxyurea (HU) is highly effective treatment for sickle cell disease (SCD). While pediatric use of HU is accepted clinical practice, barriers to use may impede its potential benefit. PROCEDURE: A survey of parents of children ages 5-17 years with SCD was performed across five institutions to assess factors associated with HU use. RESULTS: Of the 173 parent responses, 65 (38%) had children currently taking HU. Among parents of children not taking HU, the most commonly cited reasons were that their hematology provider had not offered it, their child was not sufficiently symptomatic and concerns about potential side effects. Even parents of HU users reported widespread concern about effectiveness, long-term safety, and off-label use. In bivariate analyses, children's ages, parental demographics such as education level, or travel time to their hematology provider were not correlated with HU use. Bivariate analysis and multivariate logistic regression revealed three significant factors associated with current HU use: better parental knowledge about its major therapeutic effects (P < 0.001), sickle genotype (P = 0.005), and institution of clinical care (P = 0.04). CONCLUSIONS: Pervasive concerns about HU safety exist, even among parents of current users. Varying knowledge among parents appears to be independent of their demographics, and is associated with HU use. Inter-institutional variability in parental knowledge and drug uptake highlights potentially potent site-specific influences on likelihood of HU use. Overall, these survey data underscore the need for strategies to bolster parental understanding about benefits of HU and address concerns about its safety.

Variation in Gamma-Globin Expression before and after Induction with Hydroxyurea Associated with BCL11A, KLF1 and TAL1.

The molecular mechanisms governing γ-globin expression in a subset of fetal hemoglobin (α2γ2: HbF) expressing red blood cells (F-cells) and the mechanisms underlying the variability of response to hydroxyurea induced γ-globin expression in the treatment of sickle cell disease are not completely understood. Here we analyzed intra-person clonal populations of basophilic erythroblasts (baso-Es) derived from bone marrow common myeloid progenitors in serum free cultures and report the level of fetal hemoglobin production in F-cells negatively correlates with expression of BCL11A, KLF1 and TAL1. We then examined the effects of hydroxyurea on these three transcription factors and conclude that a successful induction of γ-globin includes a reduction in BCL11A, KLF1 and TAL1 expression. These data suggests that expression changes in this transcription factor network modulate γ-globin expression in F-cells during steady state erythropoiesis and after induction with hydroxyurea.

Transcranial Doppler Changes in Children With Sickle Cell Disease on Transfusion Therapy.

Transcranial Doppler (TCD) is an effective method for screening patients with sickle cell disease (SCD) at risk for first stroke. Its usefulness in monitoring children with SCD receiving transfusions has not been established. The authors studied 17 children with SCD evaluated with TCDs and magnetic resonance angiograms (MRAs) while receiving transfusion therapy. Patients with normalized TCDs had normal MRAs that remained normal on transfusions. Patients with persistently abnormal TCDs had abnormal MRAs. In these children, TCD velocities decreased but rarely reverted to normal. Patients with low TCD velocities (<70 cm/s) had corresponding vasculopathy on MRA. Low velocities may be a risk factor for stroke and should be followed. Overall, there was good correlation between TCD velocity changes and MRA analysis.

Multiagent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP).

Patients with severe immune thrombocytopenic purpura (ITP) may require an acute increase in the platelet count for surgery or ongoing hemorrhage as well as long-term maintenance treatment. Certain of these patients may be refractory to steroids, intravenous anti-D, intravenous immunoglobulin (IVIG), and splenectomy. Therefore, acute platelet increases were studied in 35 patients completely unresponsive to IVIG or high-dose steroid treatment. Because of their lack of response to either or both single agents, these patients were administered a 3- or 4-drug combination including IVIG 1 g/kg, intravenous methylprednisolone 30 mg/kg, Vinca alkaloids (VCR 0.03 mg/kg), and/or intravenous anti-D (50-75 microg/kg). Subsequent maintenance therapy with the oral combination of danazol (10-15 mg/kg) and azathioprine (2 mg/kg) was given to 18 of the 35 patients. Seventy-one percent of the patients responded to the intravenous combination treatment with acute platelet increases of at least 20 x 10(9)/L to a level greater than 30 x 10(9)/L. Two thirds of the patients given maintenance therapy achieved stable platelet counts greater than 50 x 10(9)/L without other treatments. One patient developed an ileus, but otherwise there was little toxicity of combination treatment. Combination chemotherapy is a useful approach for patients with ITP refractory to conventional treatments both for acute induction and for long-term maintenance therapy.

Hydroxyurea therapy lowers TCD velocities in children with sickle cell disease.

INTRODUCTION: Hydroxyurea (HU) improves hematologic parameters and decreases adverse events in patients with sickle cell disease (SCD). HU has been proposed as an alternative to chronic transfusions for secondary stroke prevention. Transcranial doppler (TCD) is an accepted method of stroke risk stratification in patients with SCD. We sought to determine if HU affects TCD velocities in children with SCD. METHODS: A cohort of 24 children with HbSS with a baseline TCDi prior to HU and a follow-up after at least 6 months of therapy was analyzed. Twenty-four age-matched children with HbSS formed the control group. Differences in hematologic parameters before and after HU therapy were evaluated. RESULTS: TCDi velocities decreased in the HU-treated patients. The adjusted mean change in TCDi velocities was -13.0 cm/sec (95% CI -20.19, -5.92) in the HU-treated group and +4.72 cm/sec (95% CI -3.24, 12.69) in the controls. Changes in TCDi between the two groups were statistically significant (P < 0.001). Changes in hematologic parameters were not predictive of changes in TCDi velocities in the treated patients. Four out of five patients with TCDi velocities >170 cm/sec had normalization of TCDi velocities on HU. Mean change was -34.75 cm/sec in this subgroup. No patients experienced cerebrovascular accidents (CVA) while on HU. CONCLUSIONS: HU-treated patients experienced statistically significant decreases in TCDi velocities compared to age-matched controls. Changes in hematologic parameters were not predictive of changes in TCDi velocities in the treated group. The decrease in TCDi velocities is not a consequence of changes in hematologic values in patients treated with HU.

Pseudotumor cerebri in children with sickle cell disease: a case series.

Headache is a frequent symptom in sickle cell disease (SCD) that usually is attributable to anemia or cerebrovascular disease. We report 3 pediatric patients with SCD (1 patient with SCD-SC and 2 patients with SCD-SS) who presented with headache and were diagnosed with pseudotumor cerebri (PC). All 3 patients had elevated opening pressures during a lumbar puncture with normal cerebrospinal fluid studies. Magnetic resonance imaging revealed no evidence of hydrocephalus or arteriopathy in all 3 cases. Magnetic resonance venograms performed in 2 of the patients at diagnosis revealed no evidence of cerebral sinus thrombosis. Each patient received a thorough ophthalmologic examination. A diagnostic funduscopic examination revealed bilateral papilledema without signs of retinopathy in all 3 patients. There were no clinically significant changes in visual acuity or abnormalities of color vision in any patient. Goldmann or Humphrey visual-field assessment was abnormal only in patient 1, who demonstrated bilaterally enlarged blind spots at diagnosis and later developed reduced sensitivity in the inferomedial quadrant of the left eye in an arcuate pattern (which later resolved). The diagnosis of PC was made in all 3 patients, and acetazolamide treatment was started. Two of the patients' symptoms resolved completely with medical treatment, whereas the third patient's symptoms improved. None of these patients had permanent visual-field deficits as a result of their syndrome. PC has been reported in several other types of anemia including SCD-SC, but these cases are the first reported in conjunction with pediatric SCD. Early recognition of the signs and symptoms of PC in patients with SCD who present with headache can expedite proper diagnosis and treatment and prevent long-term ophthalmologic sequelae.

Transcranial Doppler changes in children with sickle cell disease on transfusion therapy.

Transcranial Doppler (TCD) is an effective method for screening patients with sickle cell disease (SCD) at risk for first stroke. Its usefulness in monitoring children with SCD receiving transfusions has not been established. The authors studied 17 children with SCD evaluated with TCDs and magnetic resonance angiograms (MRAs) while receiving transfusion therapy. Patients with normalized TCDs had normal MRAs that remained normal on transfusions. Patients with persistently abnormal TCDs had abnormal MRAs. In these children, TCD velocities decreased but rarely reverted to normal. Patients with low TCD velocities (<70 cm/s) had corresponding vasculopathy on MRA. Low velocities may be a risk factor for stroke and should be followed. Overall, there was good correlation between TCD velocity changes and MRA analysis.

Stroke risk in siblings with sickle cell anemia.

Cerebrovascular disease is a common cause of morbidity in sickle cell anemia (HbSS): approximately 10% of patients have a clinical stroke before 20 years of age, and another 22% have silent infarction on magnetic resonance imaging. The phenotypic variation among patients with HbSS suggests a role for modifier genes and/or environmental influences. To assess the familial component of clinical stroke in HbSS, we estimated the prevalence of clinical stroke among all patients and among HbSS sibling pairs at 9 pediatric centers. The sample included 3425 patients with sickle cell disease who were younger than 21 years, including 2353 patients with HbSS. The stroke prevalence was 4.9% for all genotypes; 7.1% for patients with HbSS; 1.1% for patients with HbSbeta(o) thalassemia; 0.6% for patients with Sbeta(+) thalassemia; and 0% for patients with HbSC. In 207 sibships, more than 1 child had HbSS. There were 42 sibships in which at least 1 sibling had a stroke, and in 10 of the 42, 2 siblings had a stroke. A permutation test indicated that the number of families in which 2 children had strokes was larger than the number expected if strokes were randomly distributed among children in sibships (P =.0012). There was no difference in stroke prevalence based on sex, nor was the mean age at stroke presentation significantly different between singletons and sibships with stroke. We conclude that there is a familial predisposition to stroke in HbSS. Attempts to identify genetic modifiers should be initiated with family-based studies.