Clinical Importance of Treating Iron Overload in Sickle Cell Disease

Summary

Hypothesis: The investigators suspect that significant degrees of iron overload in subjects with SCD result in decreased red cell survival, abnormal endothelial function and markedly dysregulated autonomic function. Furthermore, the investigators anticipate that the magnitude of these effects is proportional not only to the magnitude of total body iron stores but also to the duration of exposure to the high iron levels in tissues. Primary objective To determine if red cell survival as assessed by 51Cr red cell survival analysis, hemoglobin level, reticulocyte count, lactic acid dehydrogenase, and plasma hemoglobin in sickle cell patients is related to the degree of iron overload. Secondary objective(s) 1. Determine if the magnitude of endothelial-dependant vasodilation is related to The degree of iron overload. 2. Determine if the degree of change in cardiac beat to beat variability in response to hypoxic exposure or to cold exposure ("cold-face-test") is related the magnitude of iron overload. The primary measure of iron overload will be MRI determination of liver iron concentration.

Timeline

Start

2009-04

Primary completion

2010-10

Completion

2010-12

Publications

• Background Cappellini MD, Cohen A, Piga A, Bejaoui M, Perrotta S, Agaoglu L, Aydinok Y, Kattamis A, Kilinc Y, Porter J, Capra M, Galanello R, Fattoum S, Drelichman G, Magnano C, Verissimo M, Athanassiou-Metaxa M, Giardina P, Kourakli-Symeonidis A, Janka-Schaub G, Coates T, Vermylen C, Olivieri N, Thuret I, Opitz H, Ressayre-Djaffer C, Marks P, Alberti D. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood. 2006 May 1;107(9):3455-62. doi: 10.1182/blood-2005-08-3430. Epub 2005 Dec 13.
• Background Vichinsky E, Onyekwere O, Porter J, Swerdlow P, Eckman J, Lane P, Files B, Hassell K, Kelly P, Wilson F, Bernaudin F, Forni GL, Okpala I, Ressayre-Djaffer C, Alberti D, Holland J, Marks P, Fung E, Fischer R, Mueller BU, Coates T; Deferasirox in Sickle Cell Investigators. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol. 2007 Feb;136(3):501-8. doi: 10.1111/j.1365-2141.2006.06455.x.
• Background Natta C, Creque L, Navarro C. Compartmentalization of iron in sickle cell anemia--an autopsy study. Am J Clin Pathol. 1985 Jan;83(1):76-8. doi: 10.1093/ajcp/83.1.76.
• Background Koduri PR. Iron in sickle cell disease: a review why less is better. Am J Hematol. 2003 May;73(1):59-63. doi: 10.1002/ajh.10313.
• Background Castro O, Poillon WN, Finke H, Massac E. Improvement of sickle cell anemia by iron-limited erythropoiesis. Am J Hematol. 1994 Oct;47(2):74-81. doi: 10.1002/ajh.2830470203.
• Background Romero Mestre JC, Hernandez A, Agramonte O, Hernandez P. Cardiovascular autonomic dysfunction in sickle cell anemia: a possible risk factor for sudden death? Clin Auton Res. 1997 Jun;7(3):121-5. doi: 10.1007/BF02308838.
• Background Wood JC, Ghugre N. Magnetic resonance imaging assessment of excess iron in thalassemia, sickle cell disease and other iron overload diseases. Hemoglobin. 2008;32(1-2):85-96. doi: 10.1080/03630260701699912.
• Background Cheung YF, Chan GC, Ha SY. Arterial stiffness and endothelial function in patients with beta-thalassemia major. Circulation. 2002 Nov 12;106(20):2561-6. doi: 10.1161/01.cir.0000037225.92759.a7.
• Background Sangkatumvong S, Khoo MC, Coates TD. Abnormal cardiac autonomic control in sickle cell disease following transient hypoxia. Annu Int Conf IEEE Eng Med Biol Soc. 2008;2008:1996-9. doi: 10.1109/IEMBS.2008.4649581.

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