Transfusional iron overload

In the beginning of the eighties, the clinical application of DFO expanded to a new type of patient, namely those on maintenance dialysis. As we will see in Chapter 12, some patients suffered from aluminium overload, mostly due to the use of aluminium salts as phosphate binders, while others had obvious transfusional iron overload in the pre-erythropoietin era. DFO was therefore used either to remove aluminium, excess iron or both. Nephrologists established that DFO therapy did not increase the overall incidence of bacterial infections but that it slightly increased the risk of bacteraemia caused by Y. enterocolitica or Y. pseudotuberculosis, as had been previously observed in thalassaemic patients (Boelaert et ah, 1987 Tielemans et ah,... 

Listeria monocytogenes Transfusional iron overload (e.g. dialysis) I.2a... 

Roberts DJ, Rees D, Howard J, Hyde C, Brunskill S. Des-ferrioxamine mesylate for managing transfusional iron overload in people with transfusion-dependent thalas-saemia. Cochrane Database Syst Rev 2005. 

Araujo A, Kosaryan M, MacDowell A, et al, A novel delivery system for continuous desferrioxamine infusion in transfusional iron overload, BrJ Haematol 1996 93 835-837. 

Ferrioxamines, typical constituents of culture broths of Actinomycetes, occm as both hnear and cychc compounds containing l-amino-5-hydroxyaminopentane (A-hydroxycadaverine) and succinic acid as building blocks (Figure 1(c)). A cyclic trimer of succinyl-(A-hydroxycadaverine), is named ferrioxamine E. In some cases the pentane moiety is replaced by a butane carbon skeleton (putrescine). The most prominent representative of this siderophore family, desferrioxamine B (Figure 1), has become the drug of choice for the treatment of transfusional iron overload (Section 6.2). The crystal structure of ferric ferrioxamine B has been published recently. Certain derivatives of the ferrioxamines display antibiotic activity and therefore have been designated as ferrimycins. ... 

Treatment of chronic iron overload, e.g. haemochro-matosis, patients who are transfusion-dependent due to chronic haemolytic anaemias, thalassaemia and refractory anaemias with transfusional iron overload (siderosis). The goal of therapy is the reduction and maintenance of body iron stores at normal or near-normal levels to avoid the tissue damage associated with iron overload. 

Nausea, occasionally with vomiting, occurred in six out of 20 children taking deferiprone (21). In another study, in 38 patients with transfusional iron overload, three withdrew because of severe nausea and another three had mild gastrointestinal complaints (17). The daily doses were 3-6 g (50-100 mg/kg). 

In 38 patients with transfusional iron overload, deferiprone had to be withdrawn in one case because of a rash (17). Another patient developed a systemic vasculitis with arthritis, palpable purpura of the legs, erythema of the palms and soles, and desquamation over the distal phalanges. This patient had also had agranulocytosis in association with deferiprone (22). 

Kersten MJ, Lange R, Smeets ME, Vreugdenhil G, Roozendaal KJ, Lameijer W, Goudsmit R. Long-term treatment of transfusional iron overload with the oral iron chelator deferiprone (LI) a Dutch multicenter trial. Ann Hematol 1996 73(5) 247-52. 

Jensen PD, Heickendorff L, Pedersen B, Bendix-Hansen K, Jensen FT, Christensen T, Boesen AM, Ellegaard J. The effect of iron chelation on haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol 1996 94(2) 288-99. 

Marcus RE, Huehns ER. Transfusional iron overload. Chn Lab Haematol 1985 7(3) 195-212. 

This study is mentioned just to illustrate the potential seriousness of the clinical condition of provoked iron overload. A similar illustration comes from the life-threatening situations associated with transfusional iron overload seen in fi-thalassemia major patients [14]. A more dramatic illustration of the incompatibility of life with iron overload stems from the studies of rare cases of neonatal hemochromatosis. In a review of 25 published cases, survival ranged from minutes after birth to 9 days, with a mean of 2.7 days [15]. 

Ladis V, Berdousi H, Gotsis E, Kattamis A. Deferasirox administration for the treatment of non-transfusional iron overload in patients with thalassaemia intermedia. Br J Haematol 2010 151 504-8. 

In a review of the current outlook of transfusional iron overload in Latin America, an expert panel formulated a number of recommendations [5 ], which are relevant to the safe and rational use of iron chelators, including... 

Excessive iron intake by diet or dietary supplements (> 1000 mg/day) and particularly in the event of a disorder of iron resorption regulation may cause accumulation of haemosiderin in the hver and other unwanted effects. This phenomenon is known as haemosiderosis and can lead to severe hver damage. The disorder of iron resorption known as hereditary haemochromatosis is a genetic disease. Transfusional iron overload can be the result of repeated blood transfusion. 

Hoffbrand AV, Taher A, CappelHni MD. How I treat transfusional iron overload. Blood November 1,2012 120(18) 3657-69. 

MarseUa M, Borgna-Pignatti C. Transfusional iron overload and iron chelation therapy in thalassemia major and sickle cell disease. Hematol... 

Cancado R, Olivato MC, Bruniera P, Szarf G, de Moraes Bastos R, Rezende Melo M, et al. Two-year analysis of efficacy and safety of deferasirox treatment for transfusional iron overload in sickle cell anemia patients. Acta Haematol 2012 128(2) 113-8. 

Aydinok Y, Unal S, Oymak Y, Verqin C, Turker ZD, YUdiz D, et al. Observational study comparing long-term safety and efficacy of deferasirox with desferrioxamine therapy in chelation-naive children with transfusional iron overload. Eur J Haematol May 2012 88(5) 431-8. 

Abnormally high iron levels in particular biological compartments can have a profound effect on a number of disease processes. Thus, iron-mediated diseases can be separated into two fundamental categories, systemic and focal iron overload disorders. The systemic disorders are typified by hemochromatosis and transfusional iron overload associated with either hemolytic anemias, such as thalassemia and sickle cell anemia, or bone marrow deficiency, for example, myelodysplasia. Disorders with focal iron sequestration include ischemia-reperfusion injury (5, 6), Parkinson s disease, Alzheimer s disease, and Friedreich s ataxia, to name a few (7, 8, 9,10, 11,12). 

Cooley s anemia (P-thalassemia major), with chronic transfusional iron overload, probably best illustrates the hurdles which must be overcome in chelator design. The lifelong treatment necessary in this disorder dictates that both the long-term toxicity of the drug and the efficiency wiA which the ligand... 

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