Soumit K. Basu, MD, PhD, and Michael Linenberger, MD

2010-04-27

Drs. Basu and Linenberger indicated no relevant conflicts of interest.

Li H, Rybicki AC, Suzuka SM, et al. Transferrin therapy ameliorates disease in b-thalassemic mice. Nat Med. 2010;16:177-82.

The pathophysiology of β-thalassemia involves both ineffective erythropoiesis and hemolysis. Reduced or absent β-globin synthesis leads to excess free α-globin chains, increased apoptosis of erythroid precursors, and markedly shortened erythrocyte survival due to membrane precipitates of denatured α-globin. Clinical features, which vary depending on the degree of α:β globin imbalance, include microcytic anemia, extramedullary hematopoiesis, hepatosplenomegaly, and iron overload related to dysregulated iron absorption and recycling and chronic transfusions. In addition to the deleterious effects of parenchymal cell iron deposition, alterations in iron trafficking and distribution may contribute to ineffective erythropoiesis through inadequate delivery of transferrin-bound iron to the massively expanded erythron and generation of non-transferrin-bound labile plasma iron (LPI), which can mediate free radical tissue damage.

Previous work by Yelena Ginzburg and colleagues at the New York Blood Center using the Hbb^th1/th1 mouse model of β-thalassemia intermedia demonstrated that iron dextran treatment significantly improved reticulocyte production, red cell numbers, and hemoglobin levels by stimulating extramedullary, but not intramedullary, erythropoiesis.¹ Suspecting there was a relative lack of transferrin-bound iron delivery to the marrow, Li et al. in the Ginzburg laboratory investigated the effects of human transferrin therapy in Hbb^th1/th1 mice. Wild-type (WT) and β-thalassemic mice were given daily intraperitoneal human apotransferrin or holotransferrin for 60 days. β-thalassemic mice receiving transferring demonstrated significant amelioration of anemia, normalization of erythrocyte lifespan, marked lowering of serum erythropoietin levels, increased proportion of mature erythroid precursors with fewer apoptotic cells, and decreased circulating reticulocytes compared to untreated animals. In addition, serum LPI levels normalized, intraerythrocytic α-globin precipitation decreased, extramedullary hematopoiesis was suppressed, and spleen size regressed to near normal. Notably, red cell numbers increased by roughly 50 percent, but mean cell volume (MCV) and mean cell hemoglobin (MCH) decreased further below the low baseline values. Hepcidin levels, which are inappropriately low in β-thalassemic patients and Hbb^th1/th1 mice, increased significantly with a corresponding reduction in hepatic Kupffer cell ferroportin expression. No differences were noted between mice receiving apotransferrin versus holotransferrin. WT mice exhibited no transferrin-related toxicities; however, like treated Hbbth1/th1 mice, red cell numbers increased, and MCV and MCH decreased significantly.

The mechanisms responsible for the impressive beneficial effects of transferring injections in this mouse model were not fully defined. The decreases in MCV and MCH in both WT and thalassemic mice suggest that excess apotransferrin actually resulted in less iron per transferrin molecule delivered to individual erythroid precursors. This would presumably down-modulate heme and globin production² and reduce α-globin excess, α-chain precipitates, and cell death. The increase in hepcidin, which could limit toxicity due to macrophage iron release, might be modulated by regulatory factors associated with apoptotic erythroid precursors^3,4; however, this too remains speculative. Short-term apotransferrin administration was safe in one human trial.⁵ Therefore, pilot studies in patients with intermediate/severe β-thalassemia are feasible. Recapitulating these results would be a major advancement if transfusions can be avoided and complications from extramedullary hematopoiesis and secondary iron overload can be mitigated. By extension, this principle of “iron redirection” to the erythron may prove useful in other diseases exhibiting ineffective erythropoiesis and iron overload.

1. Ginzburg YZ, Rybicki AC, Suzuka SM, et al. Exogenous iron increases hemoglobin in beta-thalassemic mice. Exp Hematol. 2009;37:172-83.
2. Chen JJ. Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias. Blood. 2007;109:2693-99.
3. Tanno T, Bhanu NV, Oneal PA, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13:1096-1101.
4. Tanno T, Porayette P, Sripichai O, et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood. 2009;114:181-86.
5. Parkkinen J, Sahlstedt L, von Bonsdorff L, et al. Effect of repeated apotransferrin administrations on serum iron parameters in patients undergoing myeloablative conditioning and allogeneic stem cell transplantation. Br J Haematol. 2006;135:228-34.

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