Cold Agglutinin Disease

Diagnosis

Indications for Testing

• Hemolytic anemia, particularly in presence of lymphoproliferative disorder

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

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

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

• Lymphoproliferative disorders
  • Chronic lymphocytic leukemia
  • Non-Hodgkin lymphoma
  • Hodgkin lymphoma
  • Monoclonal gammopathy of undetermined significance
• Primary infection
  • Mycoplasma pneumoniae
  • Influenza A and B
  • Adenoviral illness
  • Mononucleosis
  • Malaria
• Genetic
  • Mutations – trisomy 3 and 12
• Autoimmune disorders
  • Systemic lupus erythematosus
  • Systemic sclerosis (scleroderma)
  • Antiphospholipid syndrome
  • Ulcerative colitis

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
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