Our published preliminary studies indicate that pulmonary hypertension occurs in nearly one-third of adults with sickle cell disease, that it is associated with increased mortality although pulmonary artery pressures are lower than in patients with primary pulmonary hypertension, and that chronic hemolysis with nitric oxide scavenging may be a part of the pathogenesis. The present proposal is based on three postulates. First, the problem of sickle cell-associated pulmonary hypertension may begin during childhood and adolescence. Second, the pathogenesis of sickle cell-associated pulmonary hypertension may not only include the effects of chronic hemolysis, but also the consequences of chronic hypoxia related to severe anemia and repeated vaso-occlusive episodes. Pulmonary hypertension is a recognized complication of conditions marked by chronic hypoxia, and we have recently found evidence that pulmonary hypertension complicates Chuvash polycythemia, a congenital disorder of oxygen sensing in which the hypoxic response is constitutively up regulated in the absence of hypoxia and in which high hemoglobin concentrations would promote nitric oxide scavenging. Third, the pathophysiology of sickle cell-associated pulmonary hypertension may be elucidated by comparing components of the hypoxic response in patients with sickle cell disease and Chuvash polycythemia according to the presence or absence of pulmonary hypertenson. Both sickle cell disease and Chuvash polycythemia may be characterized by nitric oxide scavenging and upregulated hypoxia inducible factor, leading to stimulation of pulmonary vascular proliferative pathways that eventuate in pulmonary hypertension. Comparing specific responses in both conditions may identify shared pathways that have a central role in sickle cell-related pulmonary hypertenison. New Findings to date: 1. The genetic bases of the highly variable degrees of anaemia and haemolysis in persons with Hb SS are not fully known, but several studies have indicated that G6PD deficiency is not a factor. The G6PD(202A) and G6PD(376G) alleles and alpha-thalassaemia were determined by molecular genetic testing in 261 children and adolescents with Hb SS in a multicentre study. G6PD(202A,376G) (G6PD A-) was defined as hemizygosity for both alleles in males and homozygosity in females. Among the participants 41% were receiving hydroxycarbamide. The prevalence of G6PD(202A,376G) was 13.6% in males and 3.3% in females with an overall prevalence of 8.7%. G6PD(202A,376G) was associated with a 10 g/l decrease in haemoglobin concentration (P = 0.008) but not with increased haemolysis as measured by lactate dehydrogenase, bilirubin, aspartate-aminotransferase, reticulocyte count or a haemolytic component derived from these markers (P >0.09). Similar results were found within a sub-group of children who were not receiving hydroxycarbamide. By comparison, single and double alpha-globin deletions were associated with progressively higher haemoglobin concentrations (P = 0.005 for trend), progressively lower values for haemolytic component (P = 0.007), and increased severe pain episodes (P <0.001). In conclusion, G6PD(202A,376G) may be associated with lower haemoglobin concentration in sickle cell anaemia by a mechanism other than increased haemolysis. 2. Plasma concentrations of interleukin-8, interleukin-10 and VEGF were elevated in the patients with sickle cell disease compared to controls (P or =3%. Decreasing haemoglobin concentration (P

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Arteta, Manuel; Campbell, Andrew; Nouraie, Mehdi et al. (2014) Abnormal pulmonary function and associated risk factors in children and adolescents with sickle cell anemia. J Pediatr Hematol Oncol 36:185-9
Milton, Jacqueline N; Gordeuk, Victor R; Taylor 6th, James G et al. (2014) Prediction of fetal hemoglobin in sickle cell anemia using an ensemble of genetic risk prediction models. Circ Cardiovasc Genet 7:110-5
Paul, Rabindra; Minniti, Caterina P; Nouraie, Mehdi et al. (2013) Clinical correlates of acute pulmonary events in children and adolescents with sickle cell disease. Eur J Haematol 91:62-8
Sable, Craig A; Aliyu, Zakari Y; Dham, Niti et al. (2012) Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHL(R200W) mutation (Chuvash polycythemia). Haematologica 97:193-200
Bae, Harold T; Baldwin, Clinton T; Sebastiani, Paola et al. (2012) Meta-analysis of 2040 sickle cell anemia patients: BCL11A and HBS1L-MYB are the major modifiers of HbF in African Americans. Blood 120:1961-2
Darbari, Deepika S; Onyekwere, Onyinye; Nouraie, Mehdi et al. (2012) Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia. J Pediatr 160:286-90
Nouraie, Mehdi; Cheng, Kevin; Niu, Xiaomei et al. (2011) Predictors of osteoclast activity in patients with sickle cell disease. Haematologica 96:1092-8
Gordeuk, Victor R; Minniti, Caterina P; Nouraie, Mehdi et al. (2011) Elevated tricuspid regurgitation velocity and decline in exercise capacity over 22 months of follow up in children and adolescents with sickle cell anemia. Haematologica 96:33-40
Nouraie, Mehdi; Reading, Noel S; Campbell, Andrew et al. (2010) Association of G6PD with lower haemoglobin concentration but not increased haemolysis in patients with sickle cell anaemia. Br J Haematol 150:218-25
Minniti, Caterina P; Sable, Craig; Campbell, Andrew et al. (2009) Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation. Haematologica 94:340-7

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