What are the risks associated with iron transfusions?

Risks of Iron Transfusions

Red blood cell transfusions carry significant risks including iron overload leading to cardiac disease and death, increased mortality and thrombosis, infections, and transfusion reactions—with iron overload being the leading cause of death in chronically transfused patients.

Iron Overload: The Primary Long-Term Risk

Mechanism and Accumulation

• Each unit of packed red blood cells contains approximately 200-250 mg of elemental iron that accumulates in the body with no active physiological excretion mechanism 1, 2
• When iron levels exceed transferrin's binding capacity, non-transferrin bound iron (NTBI) is released into circulation, entering cardiac myocytes through L-type calcium channels and causing direct organ damage 2, 3
• Iron catalyzes production of highly reactive oxygen species (ROS) leading to widespread injury to the liver, heart, and endocrine organs 3, 4

Organ-Specific Toxicity

• Cardiac complications: Iron overload is the leading cause of death in transfusion-dependent patients, with heart disease accounting for approximately 70% of deaths in conditions like β-thalassemia 5, 2
• Hepatic damage: Liver disease with fibrosis and cirrhosis occurs from iron deposition; even small amounts of iron amplify toxic effects of alcohol and viruses, rapidly accelerating fibrotic response 5
• Endocrine dysfunction: Hypothyroidism and diabetes cause considerable morbidity and mortality in chronically transfused patients 5

Impact on Survival

• In myelodysplastic syndromes (MDS), developing secondary iron overload significantly worsens survival, with a 30% increase in hazard for every 500 ng/mL increase in serum ferritin above threshold 5
• Elevated pretransplantation serum ferritin is associated with lower overall and disease-free survival in patients undergoing allogeneic stem cell transplantation, attributable to increased treatment-related mortality and risk of veno-occlusive disease 5

Acute Transfusion Risks

Mortality and Morbidity

• Red blood cell transfusion in cancer patients is associated with increased risks of arterial and venous thrombosis as well as increased mortality risk 5
• In surgical cancer patients, transfusion is independently associated with increased risk of mortality, morbidity, and cancer recurrence 5
• Acute transfusion in critically ill patients results in increased mortality, prolonged hospital stays, and elevated risk of nosocomial infection, with effects more profound with increasing age of stored blood 3

Infection Risk

• Transfusion-related immunosuppression increases risk of infections 5
• Risk of transmitting unknown or emerging pathogens remains before development and implementation of effective tests 5

Other Acute Complications

• Volume overload: Particularly problematic in patients with cardiac or renal dysfunction 5
• Transfusion-related acute lung injury (TRALI): A serious complication requiring vigilance 5
• Storage lesion: Stored allogeneic blood elicits prothrombotic and inflammatory responses 5
• Severe infusion reactions: More common with intravenous iron preparations (relative risk 2.47) 6

Critical Pitfalls to Avoid

Misconception About Iron Availability

• A common clinical error is assuming packed red cells reverse iron deficiency immediately 5
• The average lifespan of a transfused red cell is 100-110 days, meaning iron from transfused cells is not immediately available for erythropoiesis 5, 1
• In anemia of inflammation, iron takes even longer to be recycled due to sequestration in macrophages 5

Monitoring Failures

• Patients receiving chronic transfusion therapy should be screened and monitored for iron overload, yet this is not always done routinely 4, 7
• Serial serum ferritin levels exceeding 1000 ng/mL with total infused red blood cell volume ≥120 mL/kg body weight require chelation therapy 7
• Serum ferritin trends over time are more reliable than single measurements, as ferritin is influenced by infection, inflammation, and alcohol abuse 5

Risk Mitigation Strategies

Restrictive Transfusion Thresholds

• Maintain hemoglobin transfusion threshold around 7-8 g/dL in stable, non-cardiac inpatients rather than liberal thresholds 5
• Restrictive approaches (Hb <7 g/dL) show significant reductions in total and in-hospital mortality, rebleeding, acute coronary syndrome, edema, and bacterial infections compared to liberal strategies 5
• Transfuse only the minimum number of RBC units required to relieve severe anemia symptoms 5

Iron Chelation Therapy

• Patients with MDS and regular transfusion need should be considered for chelation therapy to preserve quality of life, organ function, and possibly improve survival 5
• Initiate chelation when serum ferritin reaches ≥1000 ng/mL or after ≥20 red blood cell transfusions 8, 7
• Available chelators include deferoxamine, deferiprone, and deferasirox, each with different efficacy profiles for organ-specific iron removal 8, 9

Cardiac Risk Management

• Chronic anemia increases cardiac output to compensate for impaired tissue oxygenation, leading to dilated left ventricle and gradual deterioration of contractile reserve, making the ventricle more susceptible to iron overload effects 5
• Cardiac T2* MRI showing T2* <20 ms suggests cardiac iron accumulation, with T2* <6 ms conferring 47% risk of heart failure within 1 year 8
• Favorably impacting iron accumulation decreases cardiac risks by suppressing gut iron absorption and decreasing chronic cardiac workload 5