What is the management approach for a patient with autoimmune hemolytic anemia (AIHA)?

Management of Autoimmune Hemolytic Anemia

Initiate high-dose corticosteroids (prednisone 1-2 mg/kg/day) immediately as first-line therapy for all patients with autoimmune hemolytic anemia, which achieves clinical response in 70-80% of cases within 3 weeks. 1, 2, 3

Initial Diagnostic Confirmation

Before initiating treatment, confirm the diagnosis with specific laboratory markers:

• Hemolysis markers: Elevated reticulocytes, elevated LDH, undetectable haptoglobin, elevated indirect bilirubin, and elevated AST confirm active red cell destruction 1, 4
• Direct antiglobulin test (DAT/Coombs test): Mandatory to identify antibody type—IgG positive indicates warm AIHA (most common, 70-80% of cases), C3d only indicates cold agglutinin disease or paroxysmal cold hemoglobinuria, and both IgG and C3d positive indicates mixed AIHA 1, 4, 5
• Peripheral blood smear: Look for spherocytes (warm AIHA) or agglutination (cold AIHA), and exclude schistocytes which would suggest thrombotic microangiopathy requiring different management 1, 6
• Exclude secondary causes: Obtain ANA, anti-dsDNA, complement levels (C3, C4), hepatitis B/C, HIV serologies, and lymphoproliferative workup as 50% of cases are secondary to underlying disorders 1, 5, 7

First-Line Treatment Protocol

Corticosteroids remain the cornerstone of initial therapy:

• Dosing for severe cases (Hb <8 g/dL or symptomatic): Prednisone 1-2 mg/kg/day orally, or IV methylprednisolone 1-2 mg/kg/day for life-threatening hemolysis 1, 2, 6
• Dosing for moderate cases: Prednisone 0.5-1 mg/kg/day 2, 8
• Expected response: 80% of patients respond within 3 weeks, though adverse events including weight gain, neuropsychiatric disorders, and cardiovascular complications are common 3
• Supportive care: Add folic acid 1 mg daily to support increased erythropoiesis 2
• Monitoring: Check hemoglobin weekly until steroid tapering is complete 2

Transfusion Strategy

Use a restrictive transfusion approach with triggers between 40-50 g/L (4-5 g/dL) for hemodynamically stable patients, as this nadir range is associated with highest remission rates without increasing transfusion requirements or hospitalization length. 9

• Transfusion thresholds: Platelet transfusion if <10,000/μL or active bleeding; RBC transfusion for symptomatic anemia or Hb <40-50 g/L 1, 9
• Safety of incompatible transfusions: Least incompatible RBCs can be safely transfused when necessary—39% of transfusions in one large series used incompatible blood without decreased efficacy or hemolytic reactions 9
• Transfusion efficiency: Approximately 56% of transfusions are effective, and no hemolytic transfusion reactions were reported even with incompatible blood 9

Second-Line Therapy for Steroid-Refractory Disease

Add rituximab 375 mg/m² weekly for 4 weeks if patients fail to respond adequately to corticosteroids within 3 weeks, or for severe cases requiring rapid disease control. 1, 2, 3

• Efficacy: Rituximab achieves overall response rates of 60-80% in steroid-refractory warm AIHA and is well-tolerated 2, 3, 5
• Early escalation: Consider adding rituximab early in severe cases rather than waiting for steroid failure, as the First International Consensus Group recommends early rituximab for severe presentations 5
• Alternative immunosuppressants: For patients refractory to both steroids and rituximab, consider azathioprine, cyclophosphamide (1-2 mg/kg/day for life-threatening cases), cyclosporine, or mycophenolate mofetil 1, 2, 3

Additional Therapeutic Options

IVIG may be added in acute phases or for inadequate response to high-dose corticosteroids:

• Dosing: 0.4-1 g/kg/day for 3-5 days (total dose up to 2 g/kg) 2, 6
• Limited efficacy as monotherapy: Only 10-12% complete response rate when used alone, primarily effective in low-titer inhibitors (<5 BU) 10
• Timing consideration: Plasmapheresis immediately after IVIG will remove immunoglobulin, so avoid this sequence 10

Splenectomy should be considered for patients with inadequate response to corticosteroids, offering success rates up to 70% in idiopathic warm AIHA. 3

Special Considerations for Severe or Complex Cases

Evans Syndrome (AIHA + Thrombocytopenia + Leukopenia)

This represents multi-lineage immune destruction requiring more aggressive initial management:

• Immediate high-dose steroids: Prednisone 1-2 mg/kg/day for severe cytopenias (platelets <50,000/μL, active hemolysis) 1
• Infection prophylaxis: Required when neutrophils <1,000/μL 1
• Bleeding precautions: Implement when platelets <50,000/μL 1
• Critical pitfall: Do not assume isolated ITP—the combination of hemolysis and thrombocytopenia defines Evans syndrome, not isolated immune thrombocytopenia 1

AIHA with Microangiopathic Features (Schistocytes Present)

Urgently exclude thrombotic microangiopathy (TTP, HUS, complement-mediated hemolysis) as these require specific interventions beyond standard AIHA management:

• Urgent testing: ADAMTS13 activity to exclude TTP (requires urgent plasma exchange), complement studies (C3, C4, CH50) to exclude atypical HUS 1, 6
• Complement-mediated hemolysis: If DAT positive for C3d only, consider eculizumab 900-1200 mg weekly as it may be life-saving 6
• SLE screening: Obtain ANA, anti-dsDNA, complement levels, antiphospholipid antibodies, as SLE-associated AIHA with microangiopathy requires combined immunosuppression (moderate/high-dose glucocorticoids plus azathioprine, mycophenolate mofetil, or cyclosporine) and may need anticoagulation 6

Drug-Induced Immune Hemolytic Anemia

Immediately discontinue the causative drug, followed by supportive care and corticosteroids (prednisone 0.5-2 mg/kg/day) for moderate to severe cases. 2

• DAT pattern: Appears as warm AIHA with IgG and/or C3d positive 4
• Resolution: Some cases resolve after ceasing the instigating drug without additional therapy 4
• Critical pitfall: Avoid fluoroquinolones (e.g., ciprofloxacin) in AIHA patients as they can exacerbate hemolysis 2

Monitoring During Treatment

Track the following parameters to assess response and detect complications:

• Hemolysis markers: Hemoglobin, reticulocyte count, LDH, indirect bilirubin, haptoglobin 1, 6
• Cytopenias: Platelet count, WBC with differential 1, 6
• Infection surveillance: Monitor for fever and localizing symptoms given immunosuppression 1
• Thrombotic risk: Severe hemolysis is an independent thrombotic risk factor—consider prophylactic anticoagulation and monitor for thrombotic complications 6
• Urinalysis: Check for hemoglobinuria in severe cases 6

Critical Pitfalls to Avoid

• Do not delay corticosteroids when hemolysis and cytopenias are present—this degree of severity requires immediate treatment 1
• Do not use antiplatelet agents in AIHA as they exacerbate hemolysis 1
• Do not assume isolated ITP when both hemolysis and thrombocytopenia are present—this indicates Evans syndrome 1
• Do not miss TTP/HUS—always obtain ADAMTS13 and peripheral smear to exclude schistocytes, as these conditions require plasma exchange or complement inhibition rather than standard AIHA therapy 1, 6
• Do not withhold transfusions in critically ill patients—even incompatible RBCs are safe and effective when necessary 9

Long-Term Management

Following remission, monitor for relapse during the first year:

• Monitoring frequency: aPTT and Factor VIII:C levels can exclude recurrence of inhibitor (though this applies more to acquired hemophilia A than typical AIHA) 10
• Median time to relapse: 7-9 months (range: 1 week to 14 months) after cessation of immunosuppressive therapy 10
• Thromboprophylaxis: Following inhibitor eradication and sustained response, provide thromboprophylaxis according to standard guidelines, especially in patients with very elevated Factor VIII:C levels 10