Iron homeostasis
Introduction
Transfusions are often lifesaving but they also carry risks for transfusion-related complications, including iron accumulation. Although transfusion of a RBC unit is a safe, often life-saving therapy, a substantial percentage (10-25%) of the transfused RBC are degraded within 24hrs after the transfusion. This loss of donor RBC is the result of the detrimental changes that occur in the RBC during cold storage, and as each RBC unit contains 250 mg of iron, this means a patient receives 25 to 62.5 mg of iron that needs to be recycled in the first 24 hrs after transfusion. Since the human body has no regulatory mechanism to excrete the excess iron delivered to the body by transfusion, chronic blood transfusions result in high circulating iron levels and tissue iron overload. Also, many patients who receive RBCs have ineffective erythropoiesis that is associated with higher iron uptake from the diet and iron redistribution from the reticuloendothelial system to the parenchymal cells and as such contributes to toxic body iron overload. If untreated this transfusion related iron overload leads to irreversible organ injury and causes considerable morbidity, such as heart failure, liver cirrhosis, growth retardation, and diabetes, ultimately resulting in death. The underlying mechanism(s) leading to tissue toxicity of iron overload are still mostly unknown.
On the other hand, in some circumstances, iron intake is inadequate to compensate for physiological or pathological losses, leading to depletion of body iron stores. For instance, by withdrawing blood from blood donors, vast amounts of iron are being transferred from donor to patient. As a result, donors may be deprived of iron due to frequent donations, ultimately leading to iron deficiency and anemia and causing whole blood donor deferral.
Our research focusses on the understanding of (cell specific) pathways leading to iron overload toxicity after RBC transfusions, and the identification of novel genetic variants for the prediction of iron deficiency and/or anemia in donors.
Research lines
- Patients that receive chronic red blood cell transfusions are at risk of iron overload leading to tissue damage and organ failure. Within this research line we will focus on specific receptors that are involved in cellular import and export of iron. Insights from this research line will provide a better understanding of the processes leading to iron overload and toxicity after transfusion and allow the development of targeted intervention and treatment strategies to prevent and/or treat this iron overload in transfusion-dependent patients.
- In transfusion dependent patients, the underlying pathology affects the kinetics of iron uptake and export on systemic and cellular level. As a consequence, in underlying diseases with increased levels of ineffective erythropoiesis (i.e. β-thalassemia, inherited and acquired sideroblastic anemias and some forms of hereditary hemolytic anemias), iron is redistributed and stored mostly in parenchymal cells, where it is considered more toxic compared to iron storage in reticuloendothelial system cells (RES cells, i.e. macrophages). Within this research line we will focus on the cellular pathways that determine, and potentially protect from, this sensitivity of a cell to iron-induced cell damage. Results from this research will open up possibilities to specifically target, redistribute or inhibit transfusion-induced iron toxicity in chronically transfused patients.
- A close link exists between iron homeostasis and the immune system, both in immune cell maturation as well as functionality. Within this research line we aim to investigate the effect of iron overload on the functionality of the immune system in patients with ineffective erythropoiesis reflected by relatively low hepcidin levels (i.e. patients suffering from β-thalassemia, or hereditary hemochromatosis), compared to patients with no increased erythroid demand reflected by relatively normal/high hepcidin levels (i.e. patients with bone marrow failure). Results from this research will provide new insights in functional immunological consequences of iron overload and possibilities in identifying early biomarkers of iron overload with clinical significance.
Iron Expert Center
The research line on iron homeostasis is part of the Iron Expert Center, which transitioned recently from Radboudumc to Sanquin. Together with prof. Dorine Swinkels, appointed at Sanquin Blood Bank, the Iron Expert Center focuses on research (Sanquin Research), assays for patient diagnostics and CRO (contract research organization) activities (Sanquin Diagnostic Services), all centered around knowledge about iron homeostasis in donors, transfusion-dependent patients and hematopoiesis.
Key publication
Neri S, Swinkels DW, Matlung HL, van Bruggen R. Novel concepts in red blood cell clearance. Curr Opin Hematol. 2021 Nov 1;28(6):438-444.
Funding:
Sanquin Product & process development fund
