Cold Agglutinin Disease

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)

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

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

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