13-19: Cold Agglutinin Disease

ESSENTIALS OF DIAGNOSIS

GENERAL CONSIDERATIONS

Cold agglutinin disease is an acquired hemolytic anemia due to an IgM autoantibody (called a “cold agglutinin”) usually directed against the I/i antigen on RBCs. These IgM autoantibodies characteristically will react poorly with cells at 37°C but avidly at lower temperatures, usually at 0–4°C (ie, “cold” autoantibody). Since the blood temperature (even in the most peripheral parts of the body) rarely goes lower than 20°C, only cold autoantibodies reactive at relatively higher temperatures will produce clinical effects. Hemolysis results indirectly from attachment of IgM, which in the cooler parts of the circulation (fingers, nose, ears) binds and fixes complement. When the RBC returns to a warmer temperature, the IgM antibody dissociates, leaving complement on the cell. Complement lysis of RBCs rarely occurs. Rather, C3b, present on the RBCs, is recognized by Kupffer cells (which have receptors for C3b), and RBC sequestration and destruction in the liver ensues (extravascular hemolysis). However, in some cases, the complement membrane attack complex forms, lysing the RBCs (intravascular hemolysis). The clinical distinction between extra- and intra-vascular hemolysis is not always straightforward.

Most cases of chronic cold agglutinin disease are idiopathic. Others occur in association with Waldenström macroglobulinemia, lymphoma, or CLL, in which a monoclonal IgM paraprotein is produced. Acute postinfectious cold agglutinin disease occurs following mycoplasma pneumonia or viral infection (infectious mononucleosis, measles, mumps, or cytomegalovirus [CMV] with autoantibody directed against antigen i rather than I).

CLINICAL FINDINGS

A. Symptoms and Signs

In chronic cold agglutinin disease, symptoms related to RBC agglutination occur on exposure to cold, and patients may complain of mottled or numb fingers or toes, acrocyanosis, episodic low back pain, and dark-colored urine. Hemolytic anemia is occasionally severe, but episodic hemoglobinuria may occur on exposure to cold. The hemolytic anemia in acute postinfectious syndromes is rarely severe.

B. Laboratory Findings

Mild anemia is present with reticulocytosis and rarely spherocytes. The blood smear made at room temperature shows agglutinated RBCs (there is no agglutination on a blood smear made at body temperature). The direct antiglobulin (Coombs) test will be 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. There is indirect hyperbilirubinemia and the haptoglobin is low during periods of hemolysis. Serum free hemoglobin is often elevated, and hemoglobinuria is present when intravascular hemolysis is occurring.

TREATMENT

Treatment is largely symptomatic, based on avoiding exposure to cold. Splenectomy and prednisone are usually ineffective (except when associated with a lymphoproliferative disorder) since hemolysis takes place in the liver and blood stream. Rituximab is ...