What is the recommended evaluation and treatment for a patient with drug‑induced hemolysis, including G6PD‑deficiency and immune‑mediated causes?

Management of Drug-Induced Hemolysis

Immediately discontinue the offending drug, obtain a comprehensive hemolysis workup including G6PD testing, and initiate corticosteroids for immune-mediated hemolysis while providing supportive care with transfusion only when hemoglobin drops below 7-8 g/dL with symptoms. 1

Initial Diagnostic Evaluation

When drug-induced hemolysis is suspected, perform the following workup:

Essential Laboratory Tests

• CBC with peripheral smear looking specifically for anemia, macrocytosis, and schistocytes 1
• Hemolysis markers: LDH, haptoglobin, indirect and direct bilirubin, reticulocyte count, free hemoglobin 1
• Direct antiglobulin test (Coombs) to identify immune-mediated hemolysis 1
• G6PD enzyme activity (quantitative assay preferred) 1, 2
• DIC panel including PT/INR to rule out thrombotic microangiopathy 1
• Methemoglobin level if oxidant drug exposure suspected 1

Critical Timing Considerations for G6PD Testing

• Do not test during acute hemolysis as reticulocytes have falsely elevated G6PD levels that mask deficiency 2, 3
• Wait 50-120 days after RBC transfusion before testing, as donor cells cause false-negative results 3
• Repeat testing after 3 months if initial test during crisis was normal but clinical suspicion remains high 4, 3

Medication History Review

Specifically inquire about recent exposure to high-risk oxidant drugs: 1, 2

• Absolutely contraindicated in G6PD deficiency: dapsone, methylene blue, primaquine, rasburicase 2, 4
• Common culprits for immune hemolysis: cephalosporins, penicillins, NSAIDs, quinine/quinidine, fludarabine, ciprofloxacin, rifampin, interferon 1

Management Algorithm by Severity

Grade 1 (Mild): Hemoglobin >10 g/dL, asymptomatic

For immune-mediated hemolysis:

• Continue close clinical and laboratory monitoring 1
• Discontinue offending drug immediately 5
• No corticosteroids required 1

For G6PD-related hemolysis:

• Discontinue oxidant drug immediately 2, 5
• Provide aggressive IV hydration to prevent hemoglobin-induced kidney injury 2
• Monitor for progression 2

Grade 2 (Moderate): Hemoglobin 8-10 g/dL or symptomatic

For immune-mediated hemolysis:

• Permanently discontinue the offending drug 1
• Initiate prednisone 0.5-1 mg/kg/day 1
• Strongly consider hematology consultation 1

For G6PD-related hemolysis:

• Discontinue oxidant drug 2, 5
• Aggressive IV hydration 2
• Monitor continuously for acute kidney injury from hemoglobinuria 2

Grade 3 (Severe): Hemoglobin <8 g/dL with symptoms

For immune-mediated hemolysis:

• Permanently discontinue the offending drug 1
• Admit patient or strongly consider admission 1
• Consult hematology immediately 1
• Administer prednisone 1-2 mg/kg/day (oral or IV depending on severity) 1
• Transfuse RBCs only to hemoglobin 7-8 g/dL (minimum necessary to relieve symptoms) 1
• Add folic acid 1 mg daily 1, 4
• Notify blood bank that patient has possible drug-induced hemolysis 1

For G6PD-related hemolysis:

• Admit patient 2
• Aggressive IV hydration and renal monitoring 2
• Supportive transfusion if hemoglobin <7-8 g/dL with symptoms 4

Grade 4 (Life-Threatening): Hemodynamic instability, severe anemia

For immune-mediated hemolysis:

• Admit to hospital immediately 1
• Permanently discontinue the offending drug 1
• Consult hematology urgently 1
• Administer IV prednisone 1-2 mg/kg/day 1
• If no improvement or worsening on corticosteroids, escalate to additional immunosuppression: rituximab, IVIG, cyclosporine A, or mycophenolate mofetil 1
• Transfuse RBCs per guidelines after discussion with blood bank 1
• Add folic acid 1 mg daily 1

For G6PD Mediterranean variant with severe hemolysis:

• Admit to ICU 2
• Aggressive IV hydration to maintain renal perfusion 2
• Continuous monitoring for acute kidney injury 2
• Consider exchange transfusion for life-threatening cases 3

Special Considerations for G6PD Deficiency

Variant-Specific Risk Stratification

• Mediterranean variant (G6PD-B⁻): causes life-threatening hemolysis requiring absolute avoidance of all oxidant drugs 2, 3
• African variant (GdA⁻): produces milder, self-limited hemolysis; found in 10-15% of Black individuals 2, 3
• Quantitative G6PD activity <30%: all oxidant drugs absolutely contraindicated 3
• Activity 30-70%: modified primaquine regimens possible with close monitoring (not applicable to other oxidants) 2, 3

Management of Methemoglobinemia in G6PD Deficiency

If methemoglobinemia develops from oxidant drug exposure:

• Do NOT use methylene blue (contraindicated in G6PD deficiency) 2, 3
• Use high-dose ascorbic acid 0.5-10 g as alternative treatment 3
• Consider exchange transfusion for severe cases 3
• Monitor for rebound methemoglobinemia requiring repeat dosing every 6-8 hours for 2-3 days 3

Patient Education for G6PD Deficiency

Educate patients to recognize early hemolysis signs: 2

• Dark urine (hemoglobinuria)
• Sudden fatigue or pallor
• Jaundice
• Abdominal or back pain

Critical Pitfalls to Avoid

• Never transfuse more than necessary: target hemoglobin 7-8 g/dL in stable patients, not "normal" levels 1
• Never test G6PD during acute hemolysis: reticulocytes cause falsely normal results 2, 4, 3
• Never use qualitative G6PD tests for medication decisions: quantitative assays are essential for risk stratification 2, 3
• Never give methylene blue to G6PD-deficient patients: it worsens both hemolysis and methemoglobinemia 2, 3
• Never restart the offending drug: permanent discontinuation is required for grade 2 or higher immune-mediated hemolysis 1

Screening Recommendations

Screen for G6PD deficiency before initiating oxidant drugs in patients of Mediterranean, African, Indian, or Southeast Asian descent 2, 3

Screen first-degree relatives of G6PD-deficient patients 3