The Pulmonary Hypertension and the Hypoxic Response in Sickle Cell Disease (PUSH) study has concluded enrollment and follow up. Data analysis on existing data and specimens continues to generate new information and new research manuscripts. The following information has been adapted from publications during 2011-2012. 1. Elevated tricuspid regurgitation velocity and decline in exercise capacity over 22 months of follow up in children and adolescents with sickle cell anemia While in adults with sickle cell disease an elevation of tricuspid regurgitation velocity is associated with increased mortality, the importance of this finding in children has not been established. We conducted a prospective, longitudinal, multi-center study of 160 individuals aged 3-20 years with hemoglobin SS, performing baseline and follow-up determinations of clinical markers, six-minute walk distance less than tricuspid regurgitation velocity and E/Etdi ratio by echocardiography. At baseline, 14.1% had tricuspid regurgitation velocity of 2.60 m/sec or over, which suggests elevated systolic pulmonary artery pressure, and 7.7% had increased E/Etdi, which suggests elevated left ventricular filling pressure. Over a median of 22 months, baseline elevation in tricuspid regurgitation velocity was associated with an estimated 4.4-fold increase in the odds of a 10% or more decline in age-standardized six-minute-walk distance (P = 0.015). During this interval, baseline values above the median for a hemolytic component derived from four markers of hemolysis were associated with a 9.0-fold increase in the odds of the new onset of elevated tricuspid regurgitation velocity (P = 0.008) and baseline E/Etdi elevation was associated with an estimated 6.1-fold increase in the odds (P = 0.039). In pathway analysis, higher baseline hemolytic component and E/Etdi predicted elevated tricuspid regurgitation velocity at both baseline and follow up, and these elevations in turn predicted decline in six-minute-walk distance. 2. Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia We sought to identify factors associated with frequent severe vaso-occlusive pain crises in a contemporary pediatric cohort of patients with sickle cell anemia (SCA) enrolled in a prospective study of pulmonary hypertension and the hypoxic response in sickle cell disease. We evaluated the clinical and laboratory characteristics of children with SCA who had 3 severe pain crises requiring health care in the preceding year were compared with those of subjects with <3 such episodes. We found that seventy-five children (20%) reported 3 severe pain episodes in the preceding year, and 232 (61%) had none. Frequent pain episodes were associated with older age (OR, 1.2;95% CI, 1.1-1.3;P <.0001), -thalassemia trait (OR 3.5;1.6-6.7;P = .002), higher median hemoglobin (OR 1.7;95% CI: 1.2-2.4;P <.003), and lower lactate dehydrogenase concentration (OR 1.82;95% CI: 1.07-3.11;P = .027). Children with high pain frequency also had an increased iron burden (serum ferritin, 480 vs 198 g/L;P = .006) and higher median tricuspid regurgitation jet velocity (2.41 vs 2.31 m/s;P = .001). In our cohort of children with SCA, increasing age was associated with higher frequency of severe pain episodes as were -thalassemia, iron overload, higher hemoglobin and lower lactate dehydrogenase concentration, and higher tricuspid regurgitation velocity. 3. Genomic regulation of fetal hemoglobin expression Fetal hemoglobin (HbF) protects against many but not all of the hematologic and clinical complications of sickle cell anemia.
Our aim was to perform a meta-analysis of genome-wide association studies (GWAS) to find genetic loci with modest effect sizes that were associated with HbF when a larger sample size was examined. In the CSSCD cohort, the most significant SNPs in BCL11A (rs766432) and the HMIP region (rs9494145) explained 11.1% and 3.2% of the phenotypic variability in HbF, respectively, and together explain only 14.7% of the variability. Twelve additional SNPs reached statistical significance of 10−5 or less, although none reached genome-wide significance. HbF is regulated as a complex trait and the missing heritability not detected by GWAS has various explanations. 4. Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to Chuvash polycythemia Patients with Chuvash polycythemia, (homozygosity for the R200W mutation in the von Hippel Lindau gene (VHL)), have elevated levels of hypoxia inducible factors HIF-1 and HIF-2, often become iron-deficient secondary to phlebotomy, and have elevated estimated pulmonary artery pressure by echocardiography. We performed a comprehensive assessment of cardiovascular physiology and to identify risk factors for elevation of tricuspid regurgitation velocity in children and adults with Chuvash polycythemia. The age-adjusted mean SE tricuspid regurgitation velocity was higher in VHL(R200W) homozygotes than controls with normal VHL alleles (2.50.03 vs. 2.30.05 m/sec, P=0.005). The age-adjusted left ventricular diastolic diameter (4.80.05 vs. 4.50.09 cm, P=0.005) and left atrial diameter (3.40.04 vs. 3.20.08 cm, P=0.011) were also greater in the VHL(R200W) homozygotes, consistent with increased blood volume, but the elevation in tricuspid regurgitation velocity persisted after adjustment for these variables. Among VHL(R200W) homozygotes, phlebotomy therapy was associated with lower serum ferritin concentration, and low ferritin independently predicted higher tricuspid regurgitation velocity (standardized beta=0.29;P=0.009). Children and adults with Chuvash polycythemia have higher estimated right ventricular systolic pressure, even after adjustment for echocardiography estimates of blood volume. Lower ferritin concentration, which is associated with phlebotomy, independently predicts higher tricuspid regurgitation velocity. 5. Predictors of osteoclast activity in patients with sickle cell disease Bone changes are common in sickle cell disease, but the pathogenesis is not fully understood. Tartrate-resistant acid phosphatase (TRACP) type 5b is produced by bone-resorbing osteoclasts. In other forms of hemolytic anemia, increased iron stores are associated with osteoporosis. We hypothesized that transfusional iron overload would be associated with increased osteoclast activity in patients with sickle cell disease. Tartrate-resistant acid phosphatase 5b concentrations were higher in 58 adults with sickle cell disease than in 22 controls (medians of 4.4 versus 2.4 U/L, respectively;P=0.0001). Among the patients with sickle cell disease, tartrate-resistant acid phosphatase 5b independently correlated with blood urea nitrogen (standardized beta=0.40, P=0.003), interleukin-8 (standardized beta=0.30, P=0.020), and chemokine C-C motif ligand 5 (standardized beta=−0.28, P=0.031) concentrations. There were strong correlations among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity (r>0.35, P<0.001). Patients with sickle cell disease have increased osteoclast activity as reflected by serum tartrate-resistant acid phosphatase 5b concentrations. Our results may support a potential role of inflammation rather than increased iron stores in stimulating osteoclast activity in sickle cell disease. The positive relationships among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity raise the possibility of a common pathway in the pulmonary and bone complications of sickle cell disease.
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