Cold Agglutinin Disease

Cold agglutinin disease is a form of autoimmune hemolytic anemia caused by cold-reacting antibodies and classified as either primary (idiopathic) or secondary (due to an underlying disease). Laboratory testing generally includes CBC and an antiglobulin test (direct Coombs) to determine the presence of immunoglobulins and complement degradation products.  

Diagnosis

Indications for Testing

Hemolytic anemia, particularly in presence of lymphoproliferative disorder

Laboratory Testing

  • Establish hemolysis
    • CBC with peripheral smear – demonstrates anemia and hemolytic anemia
    • Reticulocyte count – usually elevated
    • Positive indicators of hemolysis – hyperbilirubinemia, increased lactate dehydrogenase
  • Direct Coombs
    • Establish presence of immunoglobins and complement degradation products on red blood cell (RBC) surfaces
    • Positive test alone does not establish autoimmune hemolytic anemia – 0.007-0.01% of unaffected population is positive
  • Serum cold agglutinin titer at 4°C – typically ≥1:64
    • 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
  • Once hemolysis diagnosed, evaluate for associated secondary diagnosis
    • Complement assessments – C3, C4, CH50
    • Quantification of IgG, IgA, IgM
    • Other testing based on clinical presentation

Differential Diagnosis

Background

Epidemiology

  • Incidence – <1/100,000 in U.S.
  • Age – most common ≥60 years
  • Sex
    • M<F, 0.55:1 
    • 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 (tends to be polyclonal) or lymphoproliferative disorder (tends to be monoclonal)
    • Usually transient in children and young adults

Risk Factors

Pathophysiology

  • Accounts for ~25% of autoimmune hemolytic anemias (Berentsen, 2015)
  • Termed "cold agglutinin" because the antibodies cause affected human red blood cells (RBCs) to agglutinate at 4ºC
  • Cold-reacting autoantibodies are usually IgM, occasionally IgG, and rarely IgA
    • Polyclonal – presence of kappa and lambda light chains
    • Monoclonal – single type of light chain, usually kappa
  • Immunoglobulin-mediated deposition of complement on RBC membranes leads to complement-mediated hemolysis

Clinical Presentation

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

ARUP Laboratory Tests

Primary Tests

Determine presence of immunoglobins and complement degradation products

Evaluate for cold agglutinin disease

Evaluate complement system

Initial screening for functional ability of complement system; tests for defects in classical complement pathway

Use for individuals with recurring infections and/or symptoms of autoimmune and antigen complex diseases

Initial test in workup of immunoglobulin disorders

In adults and older children with suspected hypogammaglobulinemia, order in conjunction with serum protein electrophoresis and immunofixation to rule out plasma cell dyscrasia

Related Tests

Evaluate for evidence of hemolysis or anemia

Assess erythropoiesis in hematologic conditions

Evaluate for possible hemolysis

Evaluate for possible hemolysis

Medical Experts

Contributor

Couturier

Marc Roger Couturier, PhD, D(ABMM)
Associate Professor of Clinical Pathology, University of Utah
Medical Director, Parasitology/Fecal Testing, Infectious Disease Antigen Testing, Bacteriology, and Molecular Amplified Detection, ARUP Laboratories
Contributor

Delgado

Julio Delgado, MD, MS
Executive Vice President, ARUP Laboratories
Division Chief of Clinical Pathology, University of Utah and ARUP Laboratories
Professor of Clinical Pathology, University of Utah
Medical Director, Protein Immunology and Immunologic Flow Laboratories, ARUP Laboratories
Contributor

Genzen

Jonathan R. Genzen, MD, PhD
Associate Professor of Clinical Pathology, University of Utah
Chief Operations Officer, Medical Director of Automated Core Laboratory, ARUP Laboratories
Contributor

References

Additional Resources