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