Updated: 8/19/2018

Autoimmune Hemolytic Anemia

Review Topic
  • 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 sample
      • anti-IgG (Coombs reagent) is added to mixture
      • if mixture has RBCs coated with Ig, RBCs agglutinate
      • 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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Questions (3)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2

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