Cold and Warm Autoimmune Hemolytic Anemia: Diagnostic and Treatment Approach
Distinguishing Cold from Warm AIHA
The critical first step is performing a monospecific direct antiglobulin test (DAT/Coombs), which definitively distinguishes these entities: cold agglutinin disease shows C3d positivity (with or without IgM), while warm AIHA shows IgG positivity. 1, 2
Key Diagnostic Features
Cold Agglutinin Disease (CAD):
- DAT positive for C3d complement only 3, 4
- IgM autoantibodies active at temperatures below 37°C 5, 3
- Cold agglutinin titer ≥1:64 at 4°C (typically 1:1024 or higher in clinically significant disease) 3, 4
- Symptoms triggered by cold exposure: Raynaud phenomenon, acrocyanosis, cold urticaria 5, 6
- Blood samples must be maintained at 37°C during collection to prevent in vitro agglutination and obtain accurate results 5
Warm AIHA:
- DAT positive for IgG (with or without C3) 1, 2
- Autoantibodies active at physiologic temperature (37°C) 1
- Symptoms not specifically cold-triggered 2
Essential Workup for Both Types
- Complete blood count with reticulocyte count 5, 1
- Hemolysis markers: elevated LDH, low haptoglobin, elevated indirect bilirubin 5
- Serum protein electrophoresis and immunofixation to detect monoclonal IgM (CAD) 7
- Screen for secondary causes: lymphoproliferative disorders (especially Waldenström macroglobulinemia in CAD), infections (HBV, HCV, HIV), autoimmune conditions 7, 5, 1
- Bone marrow biopsy with immunophenotyping if lymphoproliferative disorder suspected 7
Treatment Algorithms
Cold Agglutinin Disease
First-Line Treatment:
Rituximab-based regimens are the primary treatment for CAD, NOT corticosteroids. 5, 2, 3
- Rituximab monotherapy: 375 mg/m² weekly × 4 weeks (response rate 45-60%) 2, 3
- Rituximab + bendamustine: Superior efficacy for higher tumor burden 7, 5, 2
- Rituximab + fludarabine: 75% response rate versus 50% with rituximab alone 5, 3
Critical Management Points:
- Avoid cold exposure as primary supportive measure 5, 6
- Corticosteroids are NOT effective in CAD and should not be used 3, 8
- Warm all blood products to 37°C before transfusion 5
- For high IgM levels (>5000 mg/dL): consider plasmapheresis before rituximab to prevent IgM flare 7, 5
- Alternative: bortezomib induction before rituximab to rapidly reduce IgM without hyperviscosity risk 5
Severe/Life-Threatening Disease:
- Plasmapheresis for immediate relief 7, 5
- Complement inhibitors (eculizumab, sutimlimab) for acute severe hemolysis 2, 3
Warm AIHA
First-Line Treatment:
Corticosteroids remain first-line therapy: prednisone 1 mg/kg/day (typically 60 mg daily). 5, 1
Second-Line Treatment:
Add rituximab early in severe cases or if no prompt response to steroids within 2-3 weeks. 1, 2
- Rituximab: 375 mg/m² weekly × 4 weeks 1, 2
- Splenectomy is traditional second-line but rituximab now preferred 1, 2
Critical Pitfalls to Avoid
Do not use cold agglutinin titers alone to guide management—clinical symptoms and hemolysis markers are more reliable 5
Do not treat CAD with corticosteroids—they are ineffective and delay appropriate therapy 3, 8
Do not ignore the need to rule out Waldenström macroglobulinemia in CAD patients—90% have MYD88L265P mutation and require specific lymphoma-directed therapy if symptomatic 7
Do not transfuse cold blood products in CAD—all blood must be warmed to 37°C 5
Do not perform extensive phenotyping without warming samples in CAD—cold agglutinins interfere with accurate testing 5, 4
Do not use rituximab in high IgM levels without considering plasmapheresis first—50% experience IgM flare that can worsen hyperviscosity 7, 5
Indications for Treatment Initiation
Treatment is indicated for: 7
- Hemoglobin ≤10 g/dL with symptoms
- Symptomatic anemia affecting quality of life
- Hyperviscosity syndrome (CAD)
- Cold-induced symptoms significantly impairing function (CAD)
- Underlying lymphoproliferative disorder requiring therapy