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Acquired hemolytic anemia caused by IgM autoantibodies (called a "cold agglutinin") against red blood cells (RBCs), which characteristically react poorly with cells at 37°C but avidly at lower temperatures, usually at 0–4°C (ie, "cold" autoantibody)
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 RBCs and fixes complement
When RBCs return to warmer temperature, IgM antibody dissociates, leaving complement on the cells
Lysis of RBCs rarely occurs, but C3b present on RBCs is recognized by liver Kupffer cells, resulting in RBC sequestration and destruction in the liver (extravascular hemolysis)
In some cases, the complement-membrane-attack-complex forms, lysing the RBCs (intravascular hemolysis)
The clinical distinction between extra- and intravascular hemolysis is not always straightforward
Most cases of chronic cold agglutinin disease are 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)
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Mottled or numb fingers or toes on exposure to cold temperatures
Acrocyanosis
Episodic low back pain and dark colored urine
Hemolytic anemia is occasionally severe
Hemoglobinuria with exposure to cold
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Mild anemia, with reticulocytosis and rarely 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 is 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
Serum free hemoglobin is often elevated, and hemoglobinuria present when intravascular hemolysis is occurring
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Mild disease: Avoid exposure to cold
Rituximab is treatment of choice
Severe disease: cytotoxic agents (eg, bendamustine [plus rituximab], cyclophosphamide, fludarabine, or bortezomib) or immunosuppressive agents (eg, cyclosporine)
Splenectomy and prednisone are usually ineffective
High-dose intravenous immune globulin (IVIG) (2 g/kg)
May be difficult to find compatible blood for transfusion, if needed; RBCs should be transfused through an in-line blood warmer