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
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