Updated: 5/27/2020

Autoimmune Hemolytic Anemia

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  • A 57-year-old woman recently moved from Florida to Maine over the summer. She presents in November as a new patient, looking to establish a primary care relationship. She complains that ever since the temperature dropped, she develops painful, numb, blue fingers, and toes. They return back to normal once she warms up indoors. However, this happens every time her fingers and toes are cold. Her nose sometimes turns blue too. On closer questioning, a few weeks ago, she felt fatigued and had a “long cold,” with sore throat and swollen lymph nodes. She shows a photo of her lymph nodes at the time.

  • Extrinsic hemolytic anemia caused by antibodies
    • type II hypersensitivity
  • Epidemiology
    • peak incidence in 50s-80s
Characteristics Warm Agglutinin (IgG)
Cold Aglutinin (IgM)
Temperature at which antibodies are most reactive to RBC
  • Body temperature
  • Lower temperatures (<37°F)
Chronic vs acute
  • Chronic
  • Acute
  • Complement-mediated
Associated conditions
  • SLE (most common)
  • CLL
  • Drugs (α-methyldopa and penicillin)
  • Mycoplasma pneumonia 
  • Infectious mononucleosis (EBV)
  • AIHA (most common)
  • More common in women
  • Warm weather is GGGreat
  • Cold weather is for ice cream, yuMMM
  • Symptoms
    • warm agglutinin disease
      • chronic hemolytic anemia
    • cold agglutinin disease
      • acrocyanosis (different from Raynaud)
        • painful and blue toes/fingers in the cold
        • “colder” parts of the body
      • symptoms resolve upon warming that part of the body
      • acute hemolytic anemia with the cold
  • Physical exam
    • splenomegaly
    • jaundice
  • Two types of Coombs test
    • direct (direct antiglobulin test, DAT)
      • anti-IgG (Coombs reagent) added directly to patient's RBCs
      • if RBCs coated with Ig (like in warm agglutinin disease), RBCs agglutinate
      • RBC agglutination = + DAT
      • can also use anti-C3 Coombs reagent
    • indirect
      • normal RBCs added to patient serum
      • if serum has anti-IgG, RBCs agglutinate when you add anti-IgG
      • RBC agglutination = + indirect Coombs
    • direct and indirect tells us the same thing, but indirect will tell us that there's more antibodies
Characteristics Warm Agglutinin (IgG)
Cold Aglutinin (IgM)
  • Direct Coombs test results
  • + Direct Coombs test with anti-IgG Coombs reagent 
  • + Direct Coombs test (DAT) with anti-C3 Coombs reagent
  • Indirect Coombs test results
  • + Indirect Coombs test (tests for IgG autoantibodies)
  • - Indirect Coombs test (tests for IgG autoantibodies, not performed with IgM antibodies)
  • Other tests
  • RBCs spontaneously agglutinate
    at room temperature 
  • Most accurate test
  • Cold agglutinin titer
  • Complement levels
  • Normal
  • ↓ C3 and C4
  • Peripheral blood smear
    • spherocytes (also seen in hereditary spherocytosis)
  • Urinalysis
    • hemoglobinuria
    • hemosiderinuria
Differential Diagnosis
  • Raynaud's syndrome
  • HIT
  • Hereditary spherocytosis
  • Warm agglutinin
    • from best initial therapy to further steps in treatment ladder
      • glucocorticoids
      • IVIG
      • splenectomy
      • immunosuppressants
  • Cold agglutinin
    • keep extremities warm
    • supportive therapy with folate
    • rituximab
    • plasmapheresis for those refractory to rituximab
Prognosis, Prevention, and Complications
  • Prognosis
    • mortality rate 10%
    • for most patients, prognosis is good
  • Prevention
    • for cold agglutinin disease
      • keep warm
  • Complications
    • warm agglutinin
      • lymphoproliferative disease
      • venous thromboembolism
    • cold agglutinin
      • peripheral gangrene
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