What is the management of Autoimmune Hemolytic Anemia (AIHA)?

Management of Autoimmune Hemolytic Anemia (AIHA)

Corticosteroids are the first-line treatment for warm AIHA, with prednisone at 1-2 mg/kg/day recommended as initial therapy, followed by rituximab for refractory cases. 1, 2

Classification and Causes of AIHA

AIHA is classified based on the thermal reactivity of the autoantibody:

1. Warm AIHA (wAIHA):

   • Most common type (70-80% of cases)
   • IgG antibodies active at body temperature
   • DAT positive for IgG, C3d, or both 3
   • Causes:
     • Primary/idiopathic (50%)
     • Secondary to:
       • Lymphoproliferative disorders (CLL, lymphoma)
       • Autoimmune diseases (SLE)
       • Medications
       • Infections

2. Cold AIHA:

   • IgM antibodies active at low temperatures
   • DAT positive for C3d only 3
   • Subtypes:
     • Cold agglutinin disease (CAD) - monoclonal
     • Cold agglutinin syndrome (CAS) - polyclonal, often post-infection

3. Mixed AIHA: Both warm and cold antibodies present

4. Drug-induced AIHA: Various mechanisms including drug-dependent antibodies

Diagnostic Workup

• Complete blood count showing anemia
• Reticulocyte count (usually elevated)
• Peripheral blood smear (spherocytes, polychromasia)
• Direct antiglobulin test (DAT/Coombs test) - critical for diagnosis
• Hemolysis markers: elevated LDH, indirect bilirubin, low haptoglobin
• Evaluation for underlying causes:
  • Autoimmune serology (ANA, etc.)
  • Screening for lymphoproliferative disorders
  • Infection workup
  • Medication review 1

Treatment Algorithm for AIHA

1. Warm AIHA Management

First-line therapy:

• Prednisone 1-2 mg/kg/day (typically 60-100 mg daily for adults) 1, 2
• Continue until hemoglobin stabilizes (usually 1-3 weeks)
• Then taper slowly over 3-6 months
• Response rate: 70-85% 2

For inadequate response after 3 weeks or relapse:

• Rituximab (375 mg/m² weekly for 4 weeks) 2
• Response rate: 80-90%
• Consider earlier use in severe cases

Third-line options:

• Splenectomy (effective in approximately 2/3 of cases) 2
• Immunosuppressive agents:
  • Azathioprine (1-2 mg/kg/day)
  • Mycophenolate mofetil
  • Cyclophosphamide
  • Cyclosporine

For severe, life-threatening anemia:

• Intravenous immunoglobulin (IVIG) 1 g/kg for 2 days
• Plasma exchange in emergency situations

2. Cold AIHA Management

First-line therapy:

• Rituximab (375 mg/m² weekly for 4 weeks) 2
• Avoid cold exposure
• Corticosteroids generally ineffective

For refractory cases:

• Rituximab + bendamustine combination
• Complement inhibitors for severe cases

3. Mixed AIHA

• Combination of approaches for both warm and cold AIHA

Special Considerations

Transfusion Support

• Reserve for hemodynamically unstable patients or those with severe anemia
• Use the least incompatible units available
• Warm blood products for cold AIHA 4
• Pre-medication with antihistamines and steroids may help

Monitoring Response

• Weekly CBC during initial treatment
• Monitor hemolysis markers (LDH, bilirubin, haptoglobin)
• Adjust therapy based on response

Treatment of Underlying Conditions

• Address any identified secondary causes
• Specific treatment for lymphoproliferative disorders if present
• Discontinue any implicated medications

Emerging Therapies

• Complement inhibitors (eculizumab, sutimlimab)
• Proteasome inhibitors (bortezomib)
• FcRn antagonists
• Spleen tyrosine kinase inhibitors 5

Pitfalls and Caveats

1. Don't delay treatment while waiting for complete diagnostic workup in severe cases
2. Avoid rapid steroid taper, which often leads to relapse
3. Monitor for steroid complications including hyperglycemia, hypertension, osteoporosis
4. Consider prophylaxis against Pneumocystis jirovecii pneumonia for patients on prolonged immunosuppression
5. Be cautious with transfusions - they can exacerbate hemolysis and make cross-matching difficult

AIHA management requires prompt recognition, appropriate classification, and a staged treatment approach. While corticosteroids remain the cornerstone of initial therapy for warm AIHA, rituximab has emerged as an effective option for refractory cases and as first-line therapy for cold AIHA.