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Anemia, Autoimmune Hemolytic

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  • Autoimmune hemolytic anemia (AIHA): increased destruction of red blood cells (RBC) 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


  • 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 (via C3b) or cell lysis (via C5 to C9 membrane attack complex).
    • 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 (NHL), Castleman disease
      • Autoimmune disorders: systemic lupus erythematosus (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

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)

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Stephens, Mark B., et al., editors. "Anemia, Autoimmune Hemolytic." 5-Minute Clinical Consult, 27th ed., Wolters Kluwer, 2019. Medicine Central, im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116024/all/Anemia__Autoimmune_Hemolytic.
Anemia, Autoimmune Hemolytic. In: Stephens MB, Golding J, Baldor RA, et al, eds. 5-Minute Clinical Consult. 27th ed. Wolters Kluwer; 2019. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116024/all/Anemia__Autoimmune_Hemolytic. Accessed April 21, 2019.
Anemia, Autoimmune Hemolytic. (2019). In Stephens, M. B., Golding, J., Baldor, R. A., & Domino, F. J. (Eds.), 5-Minute Clinical Consult. Available from https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116024/all/Anemia__Autoimmune_Hemolytic
Anemia, Autoimmune Hemolytic [Internet]. In: Stephens MB, Golding J, Baldor RA, Domino FJ, editors. 5-Minute Clinical Consult. Wolters Kluwer; 2019. [cited 2019 April 21]. Available from: https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116024/all/Anemia__Autoimmune_Hemolytic.
* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - Anemia, Autoimmune Hemolytic ID - 116024 ED - Stephens,Mark B, ED - Golding,Jeremy, ED - Baldor,Robert A, ED - Domino,Frank J, BT - 5-Minute Clinical Consult, Updating UR - https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116024/all/Anemia__Autoimmune_Hemolytic PB - Wolters Kluwer ET - 27 DB - Medicine Central DP - Unbound Medicine ER -