Iron Overload In Transfusion-Dependent Survivors Of Hemoglobin Bart’s Hydrops Fetalis

Homozygous α0-thalassemia (hemoglobin Bart’s hydrops fetalis) results from deletion of all duplicated α-globin genes on chromosome 16p. The absent production of α-globins leads to significant fetal anemia and hypoxia, and subsequently hydrops fetalis. Without intrauterine transfusion, almost all affected patients die in-utero or shortly after birth.1 Similar to patients with transfusion-dependent beta-thalassemia (TDT-β), survivors of hemoglobin Bart’s hydrops fetalis require lifelong regular transfusions.1 Without effective iron-chelation therapy, frequent transfusions of iron-rich erythrocytes ultimately results in saturation of transferrin and generation of toxic non-transferrin bound iron (NTBI). NTBI is then deposited in organs, mainly the liver, heart, and endocrine system with eventual organ dysfunction.2 In chronically transfused patients with TDT-β, iron loading is predominantly derived from blood transfusions.3 By contrast, dysregulation of hepcidin, the main regulator of iron homeostasis, drives the iron overload in patients with iron loading anemias (e.g., non-transfusion-dependent thalassemia [NTDT]).4–5

We have recently reported that the underlying disease process in homozygous α0-thalassemia differs from that of TDT-β.6 The production of non-functional hemoglo-bin-H (HbH) and the resulting tissue hypoxia play a central role in the pathophysiology of homozygous α0-thalassemia. When regularly transfused using TDT-β protocols, patients with homozygous α0-thalassemia still show features of hypoxia and erythropoietin-driven increased erythropoietic activity, including marked reticulocytosis and increased soluble transferrin receptor, while erythropoiesis is generally suppressed in adequately transfused β-thalassemia patients.3 A more aggressive transfusion regimen aimed at achieving optimal “functional” hemoglobin concentration and improved tissue oxygenation resulted in decreased serum erythropoietin levels and reduced erythropoietic activity in patients with homozygous α0-thalassemia.6 On the backdrop of these pathophysiologic differences as outlined in our previous report, we hereby present our data on iron overload in patients with homozygous α0-thalassemia. We show that the pattern of iron overload in these patients also differs from their TDT-β counterparts, suggesting that both transfusional iron loading and increased intestinal absorption of iron contribute to siderosis in these patients.

Following Institutional Review Board approval, we retrospectively collected longitudinal data on a birth cohort of 9 patients with homozygous α0-thalassemia and 14 other patients with TDT-β followed at the Hospital for Sick Children and McMaster Children’s Hospital. None of the patients had been splenectomized. All homozygous α0-thalassemia patients received intrauterine transfusions followed by regular chronic transfusions after birth. Up until 2014, seven of these patients (all born before 2009) were on a transfusion program targeting a pre-transfusion total hemoglobin of >90 g/L, similar to TDT-β protocols. The transfusion regimen was later intensified in four of these patients targeting a pre-transfusion “functional” hemoglobin (non-HbH) of >100 g/L with a goal to suppress the markedly increased erythropoiesis and improve tissue oxygenation.6 Of the three who were not aggressively transfused, one received hematopoietic stem cell transplant at age 5 years and no longer required transfusions, one had transferred to another institution for adult care, and one remained on conventional transfusion regimen. Two additional patients were born after 2014 and have been on the aggressive transfusion regimen since birth.

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