Description

• Autoimmune hemolytic anemia (AIHA): increased destruction of red blood cells (RBCs) mediated by autoantibodies against RBC surface antigens (1,2)
• Classified into three main groups (1,2)
  • Warm AIHA (antibodies optimally bind at 37°C): mainly IgG mediated; triggers are either idiopathic or secondary to an underlying process.
  • Cold AIHA/cold agglutinin syndrome (antibodies optimally bind at 4–18°C): mainly IgM mediated; includes paroxysmal cold hemoglobinuria (PCH)
  • Mixed AIHA (antibodies bind from 4°C to 37°C): a range of autoantibody thermal amplitudes that has features of both warm and cold AIHA
• Drug-induced AIHA: related to drug exposure; similar to warm AIHA and mainly IgG mediated

Epidemiology

Incidence

• Adults: 10 to 30 cases per million, female > male (1,2,3)
  • Warm AIHA (75%): median onset 40 to 60 years
  • Cold AIHA (15%): median onset >65 years
  • Mixed AIHA: rare
• Pediatric: 4 cases per million (4)
  • ~20% copresent with immune thrombocytopenia (combination referred to as Evans syndrome).

Etiology and Pathophysiology

• Mechanisms of RBC destruction (1,2,3)
  • IgG, IgM, or IgA isotypes target RBC antigens, causing either direct opsonization and/or triggering of complement fixation.
  • Antibody-triggered complement fixation can lead to cell death either by opsonization or cell lysis.
  • Less common: antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer lymphocytes
• Extravascular hemolysis (1,2)
  • Macrophage-mediated phagocytosis or lymphocyte-mediated ADCC
  • Mediator: opsonization of RBCs by autoantibody binding and/or antibody-induced complement fixation, mainly in spleen
• Intravascular hemolysis (1,3)
  • Direct destruction of circulating RBCs within bloodstream
  • Mediator: membrane attack complex insertion triggered by complement fixation (as a result of autoantibody–RBC binding)
  • Not as common as extravascular hemolysis because of protective proteins (cell surface complement inhibitors CD55 and CD59)
• Pathogenicity of autoantibodies depends on circulating antibody titer, antibody class, avidity for RBC antigens, and ability to fix complement (2,3).
• Symptoms depend on rate of hemolysis, reticuloendothelial system’s ability to break down blood products, and bone marrow’s ability to respond to the demand of brisk erythropoiesis (1,2,3).
• Warm AIHA (1,2)
  • Pathophysiology: autoantibody formation (typically IgG targeting Rh peptide or RBC band 3 on RBCs) leading to extravascular hemolysis
  • Causes (idiopathic in 50% of cases):
    • Acquired lymphoproliferative disorders: chronic lymphocytic leukemia (CLL), non-Hodgkin lymphomas (NHLs), Castleman disease
    • Autoimmune disorders: SLE, rheumatoid arthritis (RA), ulcerative colitis (UC)
    • Immune checkpoint inhibitors (e.g., pembrolizumab and nivolumab)
    • Viral: Epstein-Barr virus (EBV) or influenza
    • Bacterial: brucellosis
    • Solid organ or hematopoietic stem cell transplantation
• Cold AIHA (1,3)
  • Pathophysiology: autoantibody formation (typically IgM targeting I-i peptide on RBCs) leading primarily to intravascular hemolysis
    • IgM binds RBCs at low temperatures (e.g., acral areas) and can trigger permanent complement fixation even if IgM later detaches at warmer temperatures.
  • Intravascular hemolysis possible in states of CD55/CD59 deficiency; also common in PCH
  • Causes (if not idiopathic):
    • Infections (commonly Mycoplasma or EBV)
    • Lymphoproliferative disorders and dyscrasias
  • PCH:
    • Rare subtype historically linked to tertiary syphilis in adults or varicella/measles immunization in children
    • Mediator: Donath-Landsteiner antibodies against P antigen, forming an anti–P-P complex which triggers complement deposition
    • Primarily intravascular hemolysis
• Mixed AIHA (2)
  • Mediated by antibodies (often IgM targeting I-i peptide) with wide range of binding temperatures
• Drug-induced AIHA (1)
  • Pathophysiology: RBC opsonization by antidrug antibodies or immune complexes; rarely, de novo anti-RBC antibody production
  • Specific drug-induced causes:
    • Antimicrobials: ribavirin, cephalosporins, penicillin, piperacillin, quinine
    • Antineoplastics: fludarabine, cladribine, oxaliplatin, alkylating agents
    • Others: methyldopa, interferon, NSAIDs (particularly diclofenac), sulfa drugs, procainamide, aripiprazole

Genetics
No genetic component in majority of cases

Risk Factors

• Malignancy, solid organ or hematopoietic stem cell transplantation, lymphoproliferative disorders, infection, autoimmune disorders
  • 20% of idiopathic AIHA cases may ultimately represent prodrome of lymphoproliferative disorder.
• Pediatric: underlying congenital abnormalities (e.g., common variable immunodeficiency [CVID] or autoimmune lymphoproliferative syndrome)
• Causative drugs (as above): immune checkpoint inhibitors, antimicrobials, antineoplastics, NSAIDs

Commonly Associated Conditions

• Autoimmune diseases (e.g., SLE, RA, or UC) (1,2)
• Lymphoproliferative disorders (especially CLL), plasma cell dyscrasias, or other immune system abnormalities such as CVID (1,2)
• EBV or Mycoplasma infections for cold AIHA (1,3)