Description

• Increased destruction of RBCs in the presence of anti-RBC autoantibodies (1)
• 3 main types defined by maximal binding temperature of the autoantibodies (1):
  • Warm-reacting [at 37°C or 98.6°F] IgG antibody: Seen in 80–90% of cases
  • Cold-reacting [<37°C or 98.6°F] IgM or IgG antibody
  • Mixed type: Both warm-reacting IgG and cold-reacting C3 antibodies

• Drug-induced: Mostly warm-reacting IgG antibodies
• System(s) affected: Hematopoietic; Lymphatic; Immunologic

Epidemiology

• Predominant age: Adults 40–50 years (2)
• Predominant sex: Female > Male
• Annual incidence of 1–3/100,000 individuals (1)

• Cold agglutinin: Primarily affects young patients (2)

Risk Factors

• Malignancy
• Autoimmune disorders
• Infection
• Medications
• Prior blood transfusion
• Prior hematopoietic cell transplant

Genetics
No known genetic or familial hereditary component (2)

Pathophysiology

• Warm autoimmune hemolytic anemia (AIHA): IgG attaches to RBCs, which are then ingested by splenic macrophages.
• Cold AIHA:
  • IgM binding to RBC surfaces activates C3b-mediated phagocytosis by liver Kupffer cells (2).
  • Rare mechanism in setting of low IgM levels: Membrane attack complex insertion causes intravascular hemolysis (2).

• Mixed-antibody AIHA: Warm IgG and cold C3 involved (2)
• Drug-induced:
  • Hapten-induced: Drug attaches to RBC to induce IgG production.
  • Immune complex: Drug–IgM immune complex binds RBC to activate complement.
  • Autoantibody: Drug induces production of anti-RBC IgG.

Etiology

• Autoantibody most common cause (1):
  • Warm antibody (48–70% of cases):
    • Primary cause: Idiopathic (most common cause)
    • Secondary causes:
      • Lymphoproliferative disorders: Chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma
      • Autoimmune disorders: Systemic lupus erythematosus (SLE)
      • Viral infections: Especially common in children
      • Chronic inflammatory disorders: Crohn disease, ulcerative colitis
  • Cold antibody:
    • Primary: Less common than secondary causes (3):
      • Defined as patient with IgM monoclonal gammopathy of undetermined significance (MGUS) or lymphoma without overt clinical significance with bone marrow infiltration
      • Usually very mild anemia
    • Cold agglutinin syndrome (CAS, 16–32% of cases):
      • Acute: Infections (mycoplasma, mononucleosis, viral)
      • Chronic: Lymphoproliferative disorders (lymphoma) (2)
      • Paroxysmal cold hemoglobinuria
  • Alloantibody (2):
    • Posttransplant
    • Pregnancy
    • Posttransfusion
• Mixed type:
  • Idiopathic
  • Secondary to lymphoproliferative or autoimmune disorders
• Drug-induced (2,4):
  • Most common drug: Fludarabine (autoantibody-induced)
  • Penicillin: Hapten-induced
  • Quinine: Immune complex
  • α-methyldopa: Autoantibody-induced
  • Also seen with cefotetan, ceftriaxone, alemtuzumab, mycophenolate, purine analogs, alkylating agents

Commonly Associated Conditions

• Evans syndrome (AIHA and idiopathic thrombocytopenic purpura)
• SLE
• Chronic lymphocytic leukemia (CLL): AIHA is the most common autoimmune condition associated with CLL; it occurs in 5–37% of patients with CLL (5).
• Diffuse lymphomas