What is the best treatment approach for a patient with Autoimmune Hemolytic Anemia (AIHA) and Microangiopathic Hemolytic Anemia (MAHA)?

AIHA with MAHA: Treatment Approach

Critical First Step: Identify the Underlying Cause

When AIHA and MAHA coexist, the priority is to immediately identify whether this represents a thrombotic microangiopathy (TMA) such as thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or complement-mediated hemolysis, as these require urgent specific interventions beyond standard AIHA management. 1

The combination of AIHA and MAHA is uncommon and suggests:

• Complement-mediated hemolysis (most likely if DAT shows C3d positivity) 2
• Secondary AIHA due to systemic lupus erythematosus (SLE) or other autoimmune conditions 3
• TMA syndromes requiring plasma exchange or complement inhibition 1

Immediate Management Algorithm

Step 1: Assess Severity and Initiate Emergency Measures

For severe hemolysis (Hb <8.0 g/dL) with MAHA features, immediately initiate high-dose intravenous methylprednisolone 1-2 mg/kg/day and consult hematology urgently, as delay in identification and treatment is associated with increased mortality. 1

• Administer IV methylprednisolone 1-4 mg/kg/day for life-threatening cases 3, 1
• Add IVIG 0.4-1 g/kg/day for 3-5 days (up to total dose of 2 g/kg) 3, 1
• Avoid transfusions unless life-threatening anemia is present; when unavoidable, use extended antigen-matched red cells and transfuse minimum units necessary to reach Hb 7-8 g/dL 1

Step 2: Rule Out TMA and Complement-Mediated Hemolysis

Obtain peripheral blood smear for schistocytes, LDH, haptoglobin, and ADAMTS13 activity immediately to exclude TTP, which requires urgent plasma exchange. 1

• If schistocytes are prominent and ADAMTS13 activity <10%, initiate plasma exchange for presumed TTP before results return 1
• If complement-mediated hemolysis is suspected (DAT positive for C3d only), consider eculizumab 900-1200 mg weekly as it may be life-saving 1, 2

Step 3: Evaluate for Secondary Causes

Screen for SLE with ANA, anti-dsDNA, complement levels (C3, C4), and antiphospholipid antibodies, as SLE-associated AIHA with MAHA requires combined immunosuppression and may need anticoagulation. 3

• SLE patients with AIHA should receive moderate/high-dose glucocorticoids combined with immunosuppressive agents (azathioprine, mycophenolate mofetil, or cyclosporine) 3
• If antiphospholipid antibodies are positive, combination of immunosuppression and anticoagulation may be required 3

Treatment Protocol Based on Pathophysiology

For Complement-Mediated AIHA with MAHA (DAT C3d positive)

Eculizumab is the preferred agent for complement-mediated hemolysis causing MAHA, as it directly blocks C5 and prevents membrane attack complex formation. 1, 2

• Dose: 900-1200 mg weekly initially 1
• Alternative: Sutimlimab for cold agglutinin-mediated cases 4
• Continue high-dose steroids concurrently 1

For Warm AIHA with Secondary MAHA (DAT IgG positive)

Initiate prednisone 1-2 mg/kg/day with early addition of rituximab in severe cases, as rituximab should be considered early if no prompt response to steroids is achieved. 5, 6

• Rituximab is now the preferred second-line option and should be added early in severe cases 5, 7, 6
• For refractory cases, consider plasmapheresis or immunoadsorption for acute antibody reduction 1, 7
• Cyclophosphamide may be considered for organ-threatening disease but use with caution due to gonadotoxicity 3

For Mixed AIHA (DAT IgG and C3d positive)

Treat with combined approach using high-dose steroids, IVIG, and early rituximab, while considering complement inhibition if MAHA features are prominent. 2

• This represents the most challenging scenario requiring aggressive multimodal therapy 2
• Consider eculizumab if complement-mediated hemolysis is contributing to MAHA 1, 2

Supportive Care Measures

Provide prophylactic anticoagulation for severe hemolysis, as this is an independent thrombotic risk factor, and administer erythropoietin with or without IV iron for inadequate bone marrow compensation. 1, 5

• Monitor for thrombotic complications as severe hemolysis increases thrombotic risk 1, 5
• Serial monitoring of hemoglobin, reticulocyte count, LDH, bilirubin, and urinalysis for hemoglobinuria 1

Critical Pitfalls to Avoid

• Do not withhold immunotherapy while waiting for complete workup in severe cases—treat empirically 1
• Do not rely on transfusions as primary management—they may worsen hemolysis 1
• Do not miss TTP—if ADAMTS13 is severely deficient, plasma exchange takes priority over immunosuppression alone 1
• Do not ignore complement activation—C3d positivity with MAHA suggests need for complement inhibition 1, 2
• Do not delay hematology consultation—mortality increases with delayed recognition and treatment 1

Monitoring and Follow-up

Monitor hemoglobin levels weekly until corticosteroid tapering is complete, then monthly during the first six months, followed by every 2-3 months up to 12 months. 1

• Watch for relapse at 7-9 months after cessation of immunosuppressive therapy 3
• Continue monitoring for thrombotic complications even after hemolysis resolves 1