What is iron overload?

Transfusion therapy is the cornerstone of management in genetic and acquired anemias, but the body has no natural means to excrete the additional iron that this therapy confers.

Transfusion is associated with improved outcomes

Regular transfusion improved survival of transfusion-dependent thalassemia (TDT) patients.1,2

In sickle cell disease (SCD), regular transfusions reduce primary stroke risk by 92% for patients with elevated transcranial doppler (TCD) velocity,3 a protection that was not maintained when patients discontinued transfusion.4 In SCD patients with a history of stroke, regular transfusions (with iron chelation) better protect against secondary stroke risk compared with hydroxyurea (combined with phlebotomy).5 Transfusions are also indicated for a variety of acute and chronic complications of SCD (Table).6

Table: Indications for acute transfusion in sickle cell disease.6

Indications for acute transfusions

Acute exacerbation of anemia
Typically caused by Parvovirus B19 infection, splenic or hepatic sequestration, or severe vaso-occlusion; simple transfusion is necessary to increase hemoglobin concentrations to 8-9 g/dL

Acute chest syndrome
Early simple top-up transfusion is beneficial, with exchange transfusion to reduce HbS to less than 30% if deterioration of clinical condition occurs

Stroke or acute neurological deficit
Urgent transfusion to increase hemoglobin concentrations to 10 g/dL, and reduce HbS to less than 30%, which typically requires exchange transfusion

Multiorgan failure
HbS to less than 30% with hemoglobin concentration of 10 g/dL

Preoperative management
Target HbS of less than 30% before major surgery (cardiothoracic, neurosurgery), typically requiring exchange transfusion; medium-risk or low-risk surgery might need simple transfusion to increase hemoglobin concentration to 10 g/dL

Indications for regular, long-term transfusions

Primary and secondary stroke prevention
Regular transfusions, either simple or exchange, to keep HbS less than 30%

Recurrent acute chest syndrome not helped by hydroxyurea
Regular transfusions, either simple or exchange, to keep HbS less than 30%

Progressive organ failure
Including hepatic, renal, cardiac, and pulmonary failure; little evidence-based practice and transfusion strategies vary widely

Other indications
Recurrent splenic sequestration, complicated pregnancy

Controversial indications
Frequent acute pain, chronic pain, avascular joint necrosis, leg ulcers, priapism

Eighty to 90% of patients with myelodysplastic syndromes (MDS) and chronic anemia will become dependent on transfusions to manage the symptoms of anemia, improve quality of life, or survive.7

Yet transfusion can lead to iron overload

Regular transfusions lead to cumulative iron overload in TDT patients and a considerable number of thalassemia patients across the world today continue to have elevated iron levels in their livers and hearts (Figure).8

Figure: Prevalence of myocardial and liver iron overload in patients with transfusion-dependent anemias across geographic regions.8 

 

In SCD, regular transfusions lead to iron overload proportional to duration of transfusion therapy.9 Sporadically transfused SCD patients can eventually be equally iron overloaded.10

MDS patients develop iron overload as a consequence of regular transfusion therapy although they may also accumulate iron from ineffective erythropoiesis and increased intestinal iron absorption.11

Iron overload can also occur in the absence of transfusions

In patients with non-transfusion-dependent thalassemia (NTDT), iron accumulates due to increased intestinal absorption similar to patients with hereditary hemochromatosis. Iron overload in these patients is a cumulative process and can reach clinically significant levels with advancing age.12

Next: Pathophysiology

References

  1. Cao A. Quality of life and survival of patients with beta- thalassemia major. Haematologica. 2004;89(10):1157-1159.
  2. Modell B, Khan M, Darlison M, et al. Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2008;10:42.
  3. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339(1):5-11.
  4. Adams RJ, Brambilla D, Optimizing Primary Stroke Prevention in Sickle Cell Anemia Trial I. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med. 2005;353(26):2769-2778.
  5. Ware RE, Helms RW, Investigators SW. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH). Blood. 2012;119(17):3925-3932.
  6. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. The Lancet. 2010;376(9757):2018-2031.
  7. Hellström-Lindberg E. Management of anemia associated with myelodysplastic syndrome. Seminars in Hematology. 2005;42(2):S10-S13.
  8. Aydinok Y, Porter JB, Piga A, et al. Prevalence and distribution of iron overload in patients with transfusion-dependent anemias differs across geographic regions: results from the CORDELIA study. Eur J Haematol. 2015;95(3):244-253.
  9. Harmatz P, Butensky E, Quirolo K, et al. Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy. Blood. 2000;96(1):76-79.
  10. Drasar E, Vasavda N, Igbineweka N, et al. Serum ferritin and total units transfused for assessing iron overload in adults with sickle cell disease. Br J Haematol. 2012;157(5):645-647.
  11. Temraz S, Santini V, Musallam K, et al. Iron overload and chelation therapy in myelodysplastic syndromes. Crit Rev Oncol Hematol. 2014;91(1):64-73.
  12. Musallam KM, Rivella S, Vichinsky E, et al. Non-transfusion- dependent thalassemias. Haematologica. 2013;98(6):833-844.

Thalassemia

Overview of Thalassemia Find out more…

Sickle Cell Disease

Overview of Sickle Cell Disease Find out more…