cold agglutinin disease
Summary
Cold agglutinin disease (CAD) is a type of autoimmune hemolytic anemia caused by IgM autoantibodies that bind red blood cells at cold temperatures, causing complement-mediated hemolysis and RBC agglutination. It's classically associated with Mycoplasma pneumoniae and infectious mononucleosis (EBV), as well as lymphoproliferative disorders. Patients present with acrocyanosis, hemolytic anemia, and symptoms worsened by cold exposure.
Detail
Pathophysiology: IgM autoantibodies bind RBC surface antigens (commonly anti-I antigen in Mycoplasma, anti-i in EBV) optimally at cooler peripheral body temperatures (28-31°C). IgM binding fixes complement (C3b) on RBC surfaces. As blood recirculates to warmer core temperatures, IgM dissociates but complement remains bound, marking cells for extravascular hemolysis (mainly in the liver via Kupffer cells) and sometimes intravascular hemolysis if complement cascade proceeds to membrane attack complex. This is a Coombs-positive hemolytic anemia (direct antiglobulin test positive for C3 but typically negative for IgG, distinguishing it from warm AIHA). Etiology/Associations: Secondary causes include Mycoplasma pneumoniae infection (anti-I antibodies), infectious mononucleosis/EBV (anti-i antibodies), and lymphoproliferative disorders such as Waldenström macroglobulinemia, CLL, and B-cell lymphomas (primary/idiopathic CAD, often monoclonal IgM kappa). Clinical features: Acrocyanosis and Raynaud-like symptoms of fingers, toes, ears, and nose triggered by cold exposure due to RBC agglutination causing microvascular occlusion. Hemolytic anemia with fatigue, pallor, and jaundice. Hemoglobinuria in severe intravascular hemolysis. Symptoms improve with warming. Labs: Peripheral smear shows RBC agglutination (clumping) at room temperature, which resolves with warming. Elevated reticulocyte count, indirect bilirubin, LDH; decreased haptoglobin. Direct Coombs test positive for complement (C3d) only. Cold agglutinin titer elevated. Treatment: Avoid cold exposure (mainstay for mild disease). Rituximab (anti-CD20) for symptomatic or secondary lymphoproliferative-associated disease. Complement inhibitors (e.g., sutimlimab) approved for CAD. Corticosteroids and splenectomy are generally less effective than in warm AIHA because hemolysis is complement-mediated and often hepatic rather than splenic. Differentiate from warm AIHA (IgG-mediated, associated with SLE, CLL, drugs, and extravascular hemolysis mainly via splenic macrophages, DAT positive for IgG).
Sources
- First Aid for the USMLE Step 1
- Robbins and Cotran Pathologic Basis of Disease
- UpToDate: Cold agglutinin disease
- Harrison's Principles of Internal Medicine
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