Chapter 13: AIHA

Classification of Immune Hemolytic Anemias

• Four major AIHA subtypes
  • Warm-reacting AIHA
  • Cold agglutinin disease (CAD)
  • Paroxysmal cold hemoglobinuria (PCH)
  • Mixed-type AIHA
• Other immune hemolytic entities
  • Drug-induced immune hemolytic anemia (DIIHA)
  • Alloantibody-mediated hemolysis (hemolytic disease of the fetus/newborn, hemolytic transfusion reaction)

Epidemiology & Incidence

• Primary (idiopathic) AIHA is rare: $\approx 1/75{,}000\text{–}1/80{,}000$ persons/yr.
• Pediatric median age $3.8\,\text{yr}$; infants/toddlers typically post-infectious.
• Adolescents: higher rate of secondary disease.
• Sex ratio variably reported; no race predilection.

Natural History & Prognosis

• Warm IgG AIHA in young children: acute onset ➜ intermittent remissions/relapses; potential chronification.
• Cold-reactive PCH: abrupt but self-limited episodes, usually needing short supportive care only.
• Mortality improved to $\approx 4\%$ (vs. historical $11\text{–}18\%$) due to modern supportive & immunosuppressive therapy.
• Prognostic factors
  • Mixed IgG/C3 DAT ➜ higher chronicity risk.
  • Chronic course more likely with positive family history/immune disorders.
  • Post-infectious cases: best outcomes (>90 % CR).

Pathophysiologic Overview

• IgG-coated RBCs cleared mainly by splenic macrophages via FcγRI, FcγRIIIA, FcγRIIA.
• IgM antibodies activate classical complement ➜ C3b deposition ➜ hepatic clearance or intravascular lysis.
• Rare IgA autoantibodies also described.

Clinical Manifestations

• Common: pallor, fatigue, jaundice, scleral icterus, dark urine (up to 80 %).
• Hemoglobinuria typical of cold IgM hemolysis; unusual in pure warm IgG.
• Cardiovascular compensation usually adequate; CHF rare.
• PE: tachycardia, flow murmur, possible gallop if severe; tender splenomegaly ± hepatomegaly.
• Intravascular hemolysis ➜ hemoglobinemia, hemoglobinuria, hemosiderinuria, flank pain, fever.
• Extravascular hemolysis ➜ hyperbilirubinemia without hemoglobinuria.

Routine Laboratory Evaluation

• Hemoglobin often $4\text{–}7\;\mathrm{g/dL}$ at presentation.
• Reticulocytosis expected; >!1/3 may show transient reticulocytopenia (autoantibody vs progenitors).
• Leukocytosis/neutrophilia common; severe thrombocytopenia suggests Evans syndrome.
• Peripheral smear
  • Warm IgG: numerous spherocytes, polychromasia, occasional erythrophagocytosis.
  • Cold IgM: RBC agglutination, few spherocytes.
• Chemistry: ↑ LDH, ↑ AST, normal ALT/GGT, ↑ unconjugated bilirubin, ↓ haptoglobin (watch neonatal, inflammatory confounders).
• Urine: hemoglobinuria (heme+ dipstick, few RBCs), hemosiderin.

Serologic Evaluation (DAT / Coombs)

• Detects IgG and/or C3 on RBC surface.
• Procedure: wash EDTA RBCs, add polyspecific AHG ➜ monospecific anti-IgG / anti-C3 if positive.
• Grading 1–4 +.
• Typical patterns
  • Warm AIHA: IgG ± C3 at $37^\circ\mathrm{C}$.
  • Cold CAD: C3 only (IgM detached).
  • PCH: C3 only; biphasic Donath-Landsteiner IgG.
• DAT-negative AIHA (5–10 %): low-density IgG (<150/RBC), low-affinity Ab, IgA/IgM coating; use ELISA, gel card, flow, anti-IgA/IgM reagents.

Differential Diagnosis

• Hereditary spherocytosis (Eosin-5-maleimide flow test, negative DAT).
• Microangiopathic HAs (TTP, HUS): schistocytes + thrombocytopenia.
• PNH (CD55/CD59 flow).
• Burns, clostridial sepsis, Wilson disease, CDA-II.
• Drug-induced immune HA, delayed transfusion reactions.

Characteristics of Autoantibodies (Warm vs Cold)

• Warm (mostly IgG1/IgG3): react $37^\circ\mathrm{C}$, panagglutinin or Rh-specific; DAT IgG±C3; splenic destruction.
• Warm IgA (≤14 %), warm high-affinity IgM (rare, severe, DAT C3 only).
• Cold CAD: monoclonal/polyclonal IgM anti-I/i, high titer ≥$256$, reacts $4^\circ!–30^\circ\mathrm{C}$; hepatic ± intravascular clearance.
• PCH: biphasic IgG anti-P; Donath-Landsteiner test positive; intravascular lysis.

Diagnostic Tests for Cold Antibodies

• Cold agglutinin titer at $4^\circ\mathrm{C}$.
• Donath-Landsteiner test: patient serum + P+ RBCs incubated cold then $37^\circ\mathrm{C}$ ➜ hemolysis pattern (Table 13-2).

Treatment Principles

General/Acute

• Hospitalize; evaluate transfusion need.
• Transfuse if Hb <$6\;\mathrm{g/dL}$ or symptomatic/rapid drop.
• Exclude alloantibodies via auto/allo-adsorption; provide “least-incompatible” units, warmed if cold antibody.

First-Line for Warm AIHA

• Corticosteroids:
  • IV methylpred $1\text{–}2\,\mathrm{mg/kg}\,q6h$ ×1-3 d ➜ PO prednisone $1\text{–}2\,\mathrm{mg/kg/day}$ (children) or $1\,\mathrm{mg/kg}$ (adolescents).
  • Taper 10–20 % every 1–2 wk; therapy 3–12 mo.
  • Response ≈80 %.
• IVIG: $0.4\text{–}2\,\mathrm{g/kg/day}$ ×2-5 d; ~40 % response; consider steroid-refractory.
• Therapeutic plasma exchange: category III; consider severe IgM hemolysis.

Second-Line / Chronic

• Rituximab $375\,\mathrm{mg/m^2}$ weekly ×4; >90 % pediatric response, median 12 d to Hb rise; monitor IgG, HBV reactivation.
• Splenectomy: ~63 % remission; vaccinate (S. pneumoniae, N. meningitidis, H. influenzae), lifelong infection prophylaxis; long-term TE/pulmonary HTN risk.
• Immunosuppressants
  • Cyclosporine, azathioprine/6-MP, MMF, cyclophosphamide (standard or high-dose), campath-1H.
  • Danazol (androgen) – limited pediatric use.
• Refractory: high-dose cyclophosphamide without stem rescue; HSCT (rare, for life-threatening disease).

Cold AIHA (CAD/PCH)

• Avoid cold; use blood warmers.
• Supportive transfusion; IgM antibodies do NOT hinder compatibility tests.
• Plasmapheresis effective for high-titer IgM (adult CAD).
• PCH: self-limited; steroids unnecessary once diagnosis secure.

Pathogenesis of Autoantibody Formation

• Loss of self-tolerance: molecular mimicry, inefficient antigen presentation, defective deletion/anergy, HLA-B8/B27 associations.
• Polyclonal, antigen-driven B-cell expansion (somatic mutation signatures in Ig genes).
• Regulatory T-cell (CD4⁺CD25⁺, IL-10 secreting) defects demonstrated; murine depletion models induce AI