Cold Agglutinin Disease

Key Features

• Acquired hemolytic anemia caused by IgM autoantibodies against RBCs, which characteristically react poorly with cells at 37°C but avidly at lower temperatures, usually at 0–4°C

• Because blood temperature rarely falls below 20°C, only cold autoantibodies active at relatively higher temperatures than this produce clinical effects

• In cooler parts of the circulation (fingers, nose, ears), IgM binds to RBC and fixes complement

  • When RBC returns to warmer temperature, IgM antibody dissociates, leaving complement on the cell

  • Lysis of red blood cells rarely occurs, but C3b present on RBCs is recognized by Kupffer cells in the liver, resulting in RBC sequestration and destruction in the liver (extravascular hemolysis)

  • In some cases, the complement-membrane-attack-complex forms, lysing the red blood cells (intravascular hemolysis)

• Most cases of chronic cold agglutinin disease idiopathic; other cases occur in association with Waldenström macroglobulinemia, lymphoma, or chronic lymphocytic leukemia

• Acute postinfectious cold agglutinin disease occurs following mycoplasmal pneumonia or viral infection (infectious mononucleosis, measles, mumps, or cytomegalovirus)

Clinical Findings

• Mottled or numb fingers or toes on exposure to cold

• Acrocyanosis

• Episodic low back pain and dark colored urine

• Hemolytic anemia is occasionally severe

• Hemoglobinuria with exposure to cold

Diagnosis

• Mild anemia, with reticulocytosis and spherocytes

• Blood smear made at room temperature shows aggluntinated RBCs (there is no agglutination on a blood smear made at body temperature)

• Direct antiglobulin (Coombs) test positive for complement only

• Serum cold agglutinin titer will semi-quantitate the autoantibody

• A monoclonal IgM is often found on serum protein electrophoresis and confirmed by serum immunoelectrophoresis

• The serum indirect bilirubin is elevated and serum haptoglobin low during periods of hemolysis

Treatment

• Mild disease: Avoid exposure to cold

• Rituximab is treatment of choice

  • 375 mg/m² intravenously weekly for 4 weeks

  • Relapses may be effectively re-treated

• Severe disease: cytotoxic agents (eg, bendamustine (plus rituximab), cyclophosphamide, fludarabine, or bortezomib) or immunosuppressive agents (eg, cyclosporine)

• Splenectomy and prednisone usually ineffective

• High-dose intravenous immune globulin (IVIG) (2 g/kg)

  • May be effective but only temporarily

  • Rarely used because of high cost and short duration of benefit