Cold Agglutinin Disease

Indications for Testing

Hemolytic anemia, particularly in presence of lymphoproliferative disorder

Laboratory Testing

Indications of hemolysis are positive (hyperbilirubinemia, increased lactate dehydrogenase)
CBC with peripheral smear – demonstrates anemia and hemolytic anemia
Reticulocyte count – elevated is classic
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), but usually the titers are ≥1:1,000
Complement assessments (C3, C4, CH50)
Quantification of IgG, IgA and IgM
Once hemolysis is diagnosed, establish any associated secondary diagnosis

Differential Diagnosis

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 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 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
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 4º C
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