Causes of Cold Agglutinin Disease
Cold agglutinin disease is caused by a clonal B-cell lymphoproliferative disorder that produces monoclonal IgM autoantibodies, and can be classified as either primary (idiopathic) or secondary to underlying conditions such as lymphomas, infections, or autoimmune diseases. 1, 2
Primary Cold Agglutinin Disease
Primary CAD represents an indolent clonal B-cell lymphoproliferative disorder where monoclonal B-lymphocytes in the bone marrow produce pathogenic cold agglutinins. 3, 4
- A monoclonal CD20+ B-lymphocyte population is demonstrable in the bone marrow of 90% of patients with primary CAD, with lymphoplasmacytic lymphoma being a frequent histologic finding. 4
- The clonal B cells produce monoclonal IgM autoantibodies, most commonly of the IgMκ class, with heavy chain variable regions encoded by the V(H)4-34 gene segment. 3, 4
- Recent molecular studies have identified mutations in CARD11 and KMT2D genes in a high proportion of patients with CAD, establishing it as a distinct lymphoproliferative entity rather than purely autoimmune. 5
- Primary CAD accounts for approximately 50% of all cold agglutinin disease cases and occurs in the absence of any identifiable underlying condition. 2
Secondary Cold Agglutinin Syndrome (CAS)
Secondary CAS develops in association with underlying diseases that must be actively investigated and treated. 1, 6
Lymphoproliferative Disorders
- Waldenström's macroglobulinemia is a key association, where cold agglutinin disease can be a presenting manifestation requiring evaluation for organomegaly, hyperviscosity, and neuropathy. 7
- Chronic lymphocytic leukemia (CLL) can present with CAS even in early phases without lymphocytosis or lymphadenopathy, potentially being misinterpreted as primary CAD. 5
- Diffuse large B-cell lymphoma and other low-grade lymphomas are recognized causes of secondary CAS. 8
- The American Society of Hematology recommends ruling out underlying lymphoproliferative disorders as secondary causes requiring specific treatment. 1
Infectious Causes
- Mycoplasma pneumoniae and other atypical infections can trigger transient cold agglutinin production. 1
- Viral infections including hepatitis C should be screened, particularly when cryoglobulinemia is suspected. 7
Autoimmune Conditions
- Systemic autoimmune diseases can be associated with secondary cold agglutinin syndrome and should be evaluated when AIHA is diagnosed. 1, 2
Pathophysiologic Mechanism
Regardless of primary or secondary etiology, the disease mechanism involves:
- IgM autoantibodies bind to red blood cell surface antigens (typically the "I" antigen) at temperatures below 37°C. 6, 9
- This binding triggers complement classical pathway activation, resulting in C3b opsonization of erythrocytes. 3
- Extravascular hemolysis occurs predominantly in the liver (not the spleen as in warm AIHA), producing chronic anemia with elevated LDH, low haptoglobin, elevated indirect bilirubin, and reticulocytosis. 1, 3
- The direct antiglobulin test (Coombs) is positive for C3 complement with or without IgM. 1, 2
Critical Diagnostic Pitfall
Early-phase CLL with small clonal populations (as low as 6.8% bone marrow infiltration) can present as apparent "primary" CAD without lymphocytosis or lymphadenopathy, emphasizing the need for thorough bone marrow evaluation and molecular testing when CAD is diagnosed. 5 The presence of CARD11 and KMT2D mutations with IGHV4-34 overrepresentation suggests underlying CLL even in the absence of typical CLL features. 5