application) The purpose of this study is to determine whether the pathologic effects of iron overload secondary to hypertransfusion are different in SCD and beta thalassemia. Iron-related organ injury and death are common in patients with beta thalassemia. Similar organ pathology and mortality have not been reported in SCD after hypertransfusion. Differences in organ and cellular iron localization, cellular processing of iron, inflammatory state, or the generation of reactive low molecular weight iron might explain the differences in disease response. Pilot data shows that the severity of iron overload is similar in hypertransfused patients with SCD and beta thalassemia, yet the rate of organ dysfunction (heart, endocrine) is much greater in beta thalassemia. The primary hypothesis of this study is that hypertransfused patients with SCD show less organ damage than patients with beta thalassemia.
The specific aims of the study are: 1) to determine the organ and cellular distribution of iron in hypertransfused patients with beta thalassemia and SCD, 2) to determine whether severe organ damage occurs less frequently in hypertransfused patients with SCD than in patients with beta thalassemia and to evaluate whether markers for early organ dysfunction can be identified and used to guide chelation therapy, 3) to determine the molecular differences in ferritin between SCD and beta thalassemia which could account for a difference in iron deposition in response to chronic RBC transfusion. Organ and cellular iron distribution will be determined 1) post-mortem by histologic and chemical analyses of tissues obtained from hypertransfused patients with SCD or beta-thalassemia matched for age, transfusion volume, sex, and 2) pre-mortem, at an earlier stage of morbidity, by quantitative and histologic analyses of liver biopsy and bone marrow aspirates. Quantitative CT will be used to compare the organ distribution of iron in the two diseases. The frequency of severe organ damage (heart disease, diabetes, spinal fracture) will be determined prospectively over 3 years in a multicenter study (200 patients) to confirm the primary hypothesis. Evidence for early organ dysfunction will be sought using sensitive markers in patients (20 patients) followed prospectively for 4 years at CHO. In summary, if this study is successful and demonstrates a strong difference in the toxicity of severe iron overload in SCD as compared to beta thalassemia, it will change the approach to chelation therapy in hypertransfused patients with SCD, lead to reduced chelator-related toxicity, and improve quality of life in these patients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZDK1-GRB-1 (J2))
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Badman, David G
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Children's Hospital & Res Ctr at Oakland
United States
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Porter, John B; Walter, Patrick B; Neumayr, Lynne D et al. (2014) Mechanisms of plasma non-transferrin bound iron generation: insights from comparing transfused diamond blackfan anaemia with sickle cell and thalassaemia patients. Br J Haematol 167:692-6
Walter, Patrick B; Porter, John; Evans, Patricia et al. (2013) Increased leucocyte apoptosis in transfused ?-thalassaemia patients. Br J Haematol 160:399-403
Buchanan, George; Vichinsky, Elliott; Krishnamurti, Lakshmanan et al. (2010) Severe sickle cell disease--pathophysiology and therapy. Biol Blood Marrow Transplant 16:S64-7
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Walter, Patrick B; Macklin, Eric A; Porter, John et al. (2008) Inflammation and oxidant-stress in beta-thalassemia patients treated with iron chelators deferasirox (ICL670) or deferoxamine: an ancillary study of the Novartis CICL670A0107 trial. Haematologica 93:817-25
Jenkins, Zandra A; Hagar, Ward; Bowlus, Christopher L et al. (2007) Iron homeostasis during transfusional iron overload in beta-thalassemia and sickle cell disease: changes in iron regulatory protein, hepcidin, and ferritin expression. Pediatr Hematol Oncol 24:237-43
Fung, Ellen B; Harmatz, Paul; Milet, Meredith et al. (2007) Morbidity and mortality in chronically transfused subjects with thalassemia and sickle cell disease: A report from the multi-center study of iron overload. Am J Hematol 82:255-65
Fung, Ellen B; Harmatz, Paul R; Lee, Phillip D K et al. (2006) Increased prevalence of iron-overload associated endocrinopathy in thalassaemia versus sickle-cell disease. Br J Haematol 135:574-82
Walter, Patrick B; Fung, Ellen B; Killilea, David W et al. (2006) Oxidative stress and inflammation in iron-overloaded patients with beta-thalassaemia or sickle cell disease. Br J Haematol 135:254-63

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