12 Autoimmune Hemolytic Anemia
- Warm antibody-induced AIHA is mediated by IgG (±IgA) against RBC & manifest w/ phagocytic destruction
- Cold agglutinin disease (CAD) is IgM-mediated w/ complement activation; RBC agglutination & spherocytes on blood film
- Multiple drugs cause immune hemolytic anemia; clinical lab support may not be available; discontinue offending drug
- Symptoms from AIHA are indistinguishable from other hemolysis causes; direct antiglobulin test (DAT) is primary diagnostic tool
- DAT may be negative in AIHA; consider IgA-mediated or drug-induced mechanisms if clinical suspicion high
- Warm-antibody AIHA treated w/ glucocorticoids, rituximab, & immunosuppressive meds ± splenectomy
- Avoidance of cold environments may prevent CAD complications; rituximab, sutimlimab, chemotherapy control chronic hemolysis
- Severe AIHA may be lethal/life-threatening; transfusion may be necessary; involve transfusion medicine & blood bank to minimize serologic incompatibility delays
12.1 Pathophysiology & Presentation
Hemolysis: ↑↑ RBC destruction → ↓ survival - Compensated: ↑ EPO, marrow response → normal Hgb - Uncompensated: marrow fails → anemia develops
Autoimmune hemolytic anemia (AIHA): autoantibodies → RBC antigens - Mechanism: splenic macrophage phagocytosis or complement-mediated lysis
Clinical presentation - Fatigue, malaise, pallor, jaundice, dark urine (cola-colored) - ± splenomegaly - Free Hgb sequelae: erectile dysfunction, chest pain, pulmonary HTN, leg ulcers, ↑ VTE
12.2 Diagnosis
12.2.1 Direct Antiglobulin Test (DAT/Coombs)
DAT: detects IgG, IgA, IgM, C3 on RBCs - Mechanism: RBCs + Coombs reagent (anti-globulin) → agglutination if antibody bound - Polyspecific: broad-spectrum detects all; monoclonal panels ID specific antibody/complement
Interpretation - DAT+ (IgG ± C3): consistent w/ AIHA (false+ possible, clinical context key) - DAT−: occurs in 5–10% AIHA; consider IgA-mediated or drug-induced mechanisms
Limitations: temp-dependent, may miss IgA, rare antibodies, low-abundance cases
12.2.2 DAT Patterns & Differential
| Reaction pattern | Differential diagnosis |
|---|---|
| IgG alone | Warm AIHA (primary) |
| IgG + complement | Warm or warm-IgM AIHA |
| Complement alone | Warm AIHA or CAD |
| IgG + C3 | Warm AIHA, CAD, or IgG-type |
| Cold agglutinin | Cold agglutinin disease |
| Panreactive | Warm, warm-IgM, CAD, or drug-induced AIHA |
Further testing: antibody elution (specificity via RBC panels), plasma absorption w/ elution gradients for low-abundance antibodies
12.3 AIHA Types & Mechanisms
12.3.1 Classification
| Type | Presentation | Key Features |
|---|---|---|
| Warm AIHA (37°C) | Primary (50–60%) or 2° to SLE, lymphoma, CLL, drugs | IgG ± IgA; splenic destruction |
| Cold agglutinin disease (4–37°C) | Acute post-infectious or chronic lymphoproliferative | IgM; C1q fixation → C3 binding; hepatic sequestration |
| Mixed | IgG + cold IgM/IgG | Warm + cold components |
| Donath–Landsteiner | Rare, post-infectious | IgG biphasic hemolysin |
| Drug-induced | Adsorption, immune complex, or true autoantibody | DAT pattern varies by mechanism |
12.3.2 Warm AIHA
Epidemiology: most common AIHA type; 50–60% idiopathic, rest 2° (SLE, lymphoma, CLL, drugs)
Pathophysiology - IgG (± IgA) polyclonal autoantibodies against RBC antigens (glycophorin A, band 3) - Splenic macrophage-mediated phagocytosis or membrane priming - ± IgA complement activation
12.3.3 Cold Agglutinin Disease (CAD)
Pathophysiology: IgM cold-reactive antibodies → C1q fixation → C3d/C3 coating → hepatic C3 receptors → splenic/hepatic destruction
Clinical features - Hemolytic anemia, jaundice, ± splenomegaly (less common than warm) - Cold exposure worsens hemolysis
Serology: DAT+ complement (C3) ± IgM; cold agglutinin titer >1:16 typical - Titer & thermal amplitude (highest temp detecting RBCs) predict severity
Etiology: primary or 2° (post-infectious, lymphoproliferative)
12.3.4 Drug-Induced Hemolytic Anemia
Mechanisms
- Drug adsorption: drug → RBC membrane → immune response; DAT IgG (±C3). Examples: penicillin, quinidine
- Immune complex: Ag-Ab complex → RBC → complement; DAT complement ± IgG. Examples: sulfonamides, quinidine
- True autoantibody: triggers autoimmunity; indistinguishable from idiopathic AIHA
Management: discontinue offending drug (lab support may be unavailable)
12.4 Treatment
12.4.1 Warm AIHA
1st-line: Glucocorticoids - Prednisone or methylprednisolone 1–2 mg/kg/day × 7–14 days, then taper - Mechanisms: ↓ splenic macrophage function, ↑ RBC survival, immunosuppression - Response: 70–80%; median onset 7–10 days
2nd-line - Rituximab: anti-CD20; 375 mg/m² IV q wk × 4. Lower response than steroids; steroid-sparing option - Splenectomy: removes primary destruction site; 50–70% response if strong splenic sequestration on scan. Laparoscopic preferred - Immunosuppressants: azathioprine, mycophenolate, cyclophosphamide for steroid-refractory cases or taper failure
12.4.2 Cold Agglutinin Disease (CAD)
Avoid cold exposure (primary prevention)
Treatment - Rituximab: first-line for chronic hemolysis; 375 mg/m² IV q wk × 4 - Sutimlimab: C1s inhibitor; newer agent for refractory CAD - Chemotherapy: if 2° to lymphoproliferative disorder - Avoid transfusion if possible (may worsen agglutination)
12.5 Special Situations
12.5.1 Transfusion in AIHA
Key principles - Severe AIHA may require transfusion despite serologic incompatibility (life-threatening hemolysis) - Coordinate w/ blood bank & transfusion medicine to minimize delays - CAD: avoid cold-stored RBCs; use warm blood if possible
12.5.2 Drug-Induced AIHA
Key steps - Obtain detailed drug history - Discontinue suspected agent (critical; lab support may be unavailable) - Monitor Hgb recovery post-discontinuation - Common culprits: penicillin, quinidine, sulfonamides, methyldopa, NSAIDs
- DAT−: 5–10% AIHA still negative; consider IgA-mediated or drug-induced if high clinical suspicion
- Warm vs CAD: warm AIHA steroids-responsive; CAD steroid-refractory → avoid cold, rituximab/sutimlimab
- Drug-induced: detailed drug Hx essential; drug d/c critical; lab support may be unavailable
- Severe AIHA: life-threatening; transfuse w/ coordination to minimize incompatibility delays