Cold Agglutinin Disease

Diagnosis

Indications for Testing

Laboratory Testing

  • CBC with peripheral smear – demonstrates anemia and hemolytic anemia
  • Reticulocyte count – elevated is classic
  • Positive indications of hemolysis – hyperbilirubinemia, increased lactate dehydrogenase
  • Once hemolysis diagnosed – establish any associated secondary diagnosis
  • Direct Coombs
    • Specific for C3d and IgG – usually positive
    • Establishes the presence of immunoglobins and complement degradation products on RBC surface
    • Positive test alone does not establish autoimmune hemolytic anemia – 0.007-0.01% of normal population is positive
  • Serum cold agglutinin titer at 4°C – typically ≥64
    • Low levels may also be found in healthy adults and those with peripheral vascular disease or nonlymphoid neoplasm
    • Clinical hemolysis may occur with low titers (1:64) – usually titers ≥1:1,000
  • Complement assessments – C3, C4, CH50
  • Quantification of IgG, IgA, IgM

Differential Diagnosis

Clinical Background

Cold agglutinin disease is a form of autoimmune hemolytic anemia caused by cold-reacting antibodies and is classified as either primary (idiopathic) or secondary (due to an underlying disease).

Epidemiology

  • Incidence – <1/100,000 in U.S.
  • Age – onset >60 years; most common ≥70 years
  • Sex – M:F, equal 
    • Some report a slight female predominance in older populations

Classification

  • Primary cold agglutinin disease
    • Usually associated with monoclonal cold-reacting autoantibodies
  • Secondary cold agglutinin disease
    • May be associated with either monoclonal or polyclonal cold-reacting autoantibodies
    • Predominantly caused by infection or lymphoproliferative disorders
    • Usually transient in children and young adults

Risk Factors

Pathophysiology

  • Termed "cold agglutinin" because the antibodies cause affected human red blood cells to agglutinate at 4ºC
  • Cold-reacting autoantibodies are usually IgM, occasionally IgG, and rarely IgA
    • May be polyclonal with the presence of kappa and lambda light chains
    • May also be monoclonal with a single type of light chain – usually kappa
  • Immunoglobulin-mediated deposition of complement on red blood cell membranes

Clinical Presentation

  • Fatigue and malaise due to hemolytic anemia – often the sole manifestation
  • Dermatologic – acrocyanosis, Raynaud phenomenon, livedo reticularis
  • Chronic cold agglutinin disease – rare
  • May present as part of a paraneoplastic syndrome

Treatment

  • Cold avoidance
  • Treat underlying disease if present
  • Recent success with rituximab

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Evaluate for evidence of hemolysis or anemia

   
Reticulocytes, Percent & Number 0040022
Method: Flow Cytometry

Evaluate for increased red cell production

   
Direct Coombs (Anti-Human Globulin) with Reflex to Direct Antiglobulin-Mono 0014008
Method: Hemagglutination

Determine presence of immunoglobins and complement degradation products

   
Cold Agglutinins 0050175
Method: Semi-Quantitative Hemagglutination
Evaluate for etiology of hemolytic anemia    
Complement Components 3 and 4 0050149
Method: Quantitative Immunoturbidimetry

Rule out complement deficiency

   
Complement Activity Enzyme Immunoassay, Total 0050198
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Rule out complement deficiency

   
Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630
Method: Quantitative Nephelometry

Initial test in the workup of immunoglobulin disorders

In adults and older children with suspected hypogammaglobulinemia, order in conjunction with serum protein electrophoresis and immunofixation

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Bilirubin, Direct, Serum or Plasma 0020033
Method: Quantitative Spectrophotometry

Determine presence of hemolysis

Lactate Dehydrogenase, Serum or Plasma 0020006
Method: Quantitative Enzymatic

Determine presence of hemolysis