What is the next step in managing a patient, likely an adult with a history of chronic blood loss or repeated transfusions, who has developed severe hyperferritinemia (ferritin level > 2000) following a 15 unit Packed Red Blood Cells (PRBC) transfusion?

Management of Transfusion-Related Iron Overload with Ferritin >2000 ng/mL

Initiate iron chelation therapy immediately, as this patient has severe transfusional iron overload that significantly increases morbidity and mortality from cardiac, hepatic, and endocrine complications. 1

Immediate Assessment Required

Before starting chelation, evaluate the following:

• Renal function: Measure serum creatinine and calculate eGFR, as chelation is contraindicated if eGFR <40 mL/min/1.73 m² 2
• Hepatic function: Obtain AST, ALT, and bilirubin levels to assess baseline liver function and rule out severe hepatic impairment 2
• Cardiac evaluation: Assess for signs of heart failure or arrhythmias, as cardiac iron deposition is the leading cause of death in transfusion-dependent patients 1
• Complete blood count: Ensure platelet count >50 x 10⁹/L, as chelation is contraindicated below this threshold 2
• Renal tubular function: Obtain serum electrolytes and urinalysis to evaluate for tubular dysfunction 2

Rationale for Chelation Therapy

Iron chelation should be initiated when ferritin exceeds 1,000 ng/mL in transfusion-dependent patients, and this patient's ferritin >2,000 ng/mL places them at high risk for organ damage. 1 The consensus guidelines from the American Journal of Hematology clearly state that secondary iron overload defined as ferritin >1,000 ng/mL significantly worsens survival, with a 30% increase in hazard for every 500 ng/mL increase above this threshold. 1

With 15 units of PRBCs transfused (approximately 3,000-3,750 mg of iron), this patient has substantial iron burden requiring immediate intervention. 3 Each unit contains 200-250 mg of iron, and cardiac abnormalities develop after >100 units while liver iron accumulation occurs after >24 units. 4

Chelation Therapy Selection

Deferasirox (oral chelation) is the preferred agent for most patients due to ease of administration and compliance. 2

Dosing Strategy:

• Standard starting dose: 20 mg/kg/day for deferasirox tablets (or 30 mg/kg/day for dispersible formulation) 2
• Dose adjustment for renal impairment (eGFR 40-60 mL/min/1.73 m²): Reduce starting dose by 50% 2
• Dose adjustment for hepatic impairment (Child-Pugh B): Reduce starting dose 2
• Avoid in severe hepatic impairment (Child-Pugh C) 2

Critical Monitoring Requirements:

First month:

• Serum creatinine and eGFR: Weekly 2
• AST, ALT, bilirubin: Every 2 weeks 2
• Serum ferritin: Monthly 1

After first month:

• Renal function: At least monthly 2
• Hepatic function: At least monthly 2
• Serum ferritin: Monthly to assess response and prevent overchelation 1, 2
• CBC: Monthly to monitor for cytopenias 2

Annually:

• Auditory testing (audiometry) 2
• Ophthalmic examination (slit lamp and dilated fundoscopy) 2

Treatment Goals and Duration

Target ferritin level: Reduce to <1,000 ng/mL, ideally maintaining between 500-1,000 ng/mL 1, 5

Duration: Continue chelation as long as transfusion therapy continues and iron overload remains clinically relevant. 1 Chelation can be withheld when ferritin declines to <1,000 ng/mL and no additional transfusions are needed. 1

Critical Safety Considerations

Overchelation Risk:

If ferritin falls below 1,000 ng/mL at 2 consecutive visits, consider dose reduction, especially if deferasirox dose >17.5 mg/kg/day. 2 If ferritin falls below 500 ng/mL, interrupt therapy immediately and continue monthly monitoring. 2

Volume Depletion:

Interrupt chelation during acute illnesses causing vomiting, diarrhea, or decreased oral intake, as volume depletion significantly increases risk of acute kidney injury and hepatic failure, particularly in pediatric patients but also relevant in adults. 2 Resume only after fluid status normalizes.

Drug Interactions:

Avoid concurrent use of NSAIDs, corticosteroids, oral bisphosphonates, or anticoagulants when possible, as these increase risk of GI ulceration and hemorrhage. 2

Special Populations Requiring Chelation

This patient should receive chelation if they meet any of these criteria:

• Transfusion burden ≥2 units/month sustained for >1 year 1, 4
• Life expectancy ≥1 year 1
• Candidate for stem cell transplant (ferritin >1,000 ng/mL at transplant increases mortality and hepatic complications) 1, 4
• Evidence of organ dysfunction from iron overload 1

Alternative Diagnostic Considerations

While initiating chelation, consider that ferritin >2,000 ng/mL can also indicate:

• Acute inflammation or infection (ferritin is an acute phase reactant) 1, 6
• Liver disease (27% of extreme hyperferritinemia cases) 6
• Hematologic malignancy (16% of cases) 6
• Hemophagocytic lymphohistiocytosis (rare but important differential) 6

However, in the context of 15 units of PRBC transfusion, transfusional iron overload is the most likely diagnosis (35% of extreme hyperferritinemia cases are due to chronic transfusion). 6

Prognosis Without Treatment

Untreated iron overload with ferritin >2,000 ng/mL leads to:

• Cardiac complications: Leading cause of death in transfusion-dependent patients 1
• Hepatic dysfunction: Observed in patients with ferritin >3,500 ng/mL 7
• Endocrine dysfunction: Including hypothyroidism and diabetes 1
• Increased mortality: Particularly in patients with serum ferritin >3,500 ng/mL (8 of 9 patients died in one study) 7

The goal of chelation therapy is to improve survival and preserve organ function, making immediate initiation critical in this clinical scenario. 1