Cold Agglutinin Disease

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.

Epidemiology

  • Incidence – <1/100,000 in U.S.
  • Age – onset is >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 and lymphoproliferative disorders
    • Usually transient in children and young adults

Risk Factors

  • Lymphoproliferative disorders
    • Chronic lymphocytic leukemia (CLL)
    • Non-Hodgkin lymphomas
    • Hodgkin disease
    • Monoclonal gammopathy of undetermined significance (MGUS)
  • Primary infection
    • Mycoplasma pneumonia
    • Influenza A and B
    • Adenoviral illness
    • Mononucleosis
    • Malaria
  • Genetic
    • Mutations – Trisomy 3 and 12
  • Autoimmune disorders
    • Systemic lupus erythematosus (SLE)
    • Systemic sclerosis (scleroderma)
    • Antiphospholipid syndrome (APS)
    • Ulcerative colitis

Pathophysiology

  • Termed "cold agglutinin" because they 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

  • Hemolytic anemia is often the sole manifestation
  • Dermatologic – acrocyanosis, Raynaud phenomenon, livedo reticularis
  • Chronic cold agglutinin disease is rare
  • May present as part of a paraneoplastic syndrome

Diagnosis

Indications for Testing

  • Hemolytic anemia, particularly in presence of lymphoproliferative disorder

Laboratory Testing

  • Indications of hemolysis are positive (hyperbilirubinemia, increased LD)
  • CBC with peripheral smear – demonstrates anemia and hemolysis
  • Reticulocyte count – elevated
  • DAT 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 testing
    • 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), but usually the titers are ≥1:1000
  • Complement assessments (C3, C4, CH50)
  • Quantification of IgG, IgA and IgM
  • Once hemolysis is diagnosed, establish any associated secondary diagnosis

Differential Diagnosis

  • Hemoglobinopathies
  • Paroxysmal cold hemoglobinuria
  • Paroxysmal nocturnal hemoglobinuria – PNH
  • Thalassemias
  • Connective tissue disease
  • Antiphospholipid syndrome – APS

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
Cold Agglutinins 0050175
Method: Hemagglutination

Confirm etiology for hemolytic anemia

Low levels may be diagnostic

   
CBC with Platelet Count & Automated Differential 0040003
Method: Automated Cell Count with Flow Cell Differential

Demonstrates anemia and hemolysis

   
Reticulocytes, Percent & Number 0040022
Method: Flow Cytometry

Diagnostic if elevated

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

Determine the presence of immunoglobins and complement degradation products

   
Complement Components 3 & 4 0050149
Method: Immunoturbidimetric
   
Complement Activity Enzyme Immunoassay, Total 0050198
Method: Enzyme-Linked Immunosorbent Assay