Cold Agglutinin Syndrome

A disorder that is idiopathic or secondary to a malignancy, resulting in immune-hemolytic anemia with exacerbation upon exposure to cold.

Cold Agglutinin Disease; Cold Hemagglutinin Disease.

First described in 1903 by Karl Landsteiner, an Austrian pathologist and immunologist, who is considered the father of modern transfusion medicine, since he also discovered the ABO system, for which he was awarded the Nobel Prize in 1930.

It has been estimated that approximately 5 to 20% of all autoimmune hemolytic anemias are caused by cold agglutinins (approximately 1:300,000). No ethnic predilection has been reported, however, females are affected slightly more often than males (1.5:1). All age groups can be affected, although it most often occurs in patients in the seventh decade of life or older and rarely in children. Even in otherwise healthy persons, low cold agglutinin titers (1:64 or less) are common. Significantly higher titers may be associated with infections by Mycoplasma pneumoniae, cytomegalovirus, human immunodeficiency virus, influenza virus, Epstein-Barr virus, mumps virus, with malaria, listeriosis, and trypanosomiasis, but these increased levels are transient and the development of cold agglutinin syndrome is relatively uncommon, at least in the classic chronic form.

Trisomy 3 has been found in some patients with this disorder. However, cold agglutinin syndrome is acquired and not inherited.

Cold agglutinin syndrome as a secondary disease usually is associated with a hematologic malignancy (e.g., Waldenström macroglobulinemia [production of monoclonal IgM paraprotein], multiple myeloma, lymphomas, Kaposi sarcoma) and infections. Activated B lymphocytes produce pathogenic antibodies (most commonly monoclonal IgM, rarely IgA or IgG, directed against the I antigen of the erythrocyte membrane in adults; rarely the antibodies are targeted against the fetal i antigen). When the blood cools below the “thermal threshold” (approximately 32°C, i.e., in acral areas), these autoantibodies cause red cell agglutination, slugging, and complement binding in peripheral vessels. Upon returning to the central circulation (warmer areas), the IgM antibodies dissociate, leaving complement on the cell surface. In severe cases, the red cell-antibody complexes activate the complement system, which may result in intravascular hemolysis. Sequestration of opsonized red cells occurs, mainly by the Kupffer cells in the liver.

Based on the clinical picture with exacerbation on exposure to cold (finger pain and paresthesias). Anemia, spherocytosis, reticulocytosis, and in vitro agglutination of blood that resolves upon rewarming are characteristic.

Usually mild chronic anemia is present. Red blood cell agglutination may result in a Raynaud-like phenomenon upon exposure to cold (acrocyanosis, livedo reticularis). Purpura, acral gangrene, and immune complex nephritis are rare complications, but have been described. Hemolysis may lead to worsening of anemia, hemoglobinuria, and renal failure, mild hepatomegaly, jaundice, and/or splenomegaly. The presence of circulating inhibitors of specific coagulation factors has been reported and must be considered because they may be associated with hemorrhage.

Prevention of hemagglutination by keeping the patient warm is paramount. Check for anemia, which most often is mild. Rule out hematologic diseases or active infections. Cyclophosphamide, steroids, interferon, and plasmapheresis have all been used to reduce the severity of the disease. Cross-matching must be performed carefully at 37°C to minimize the effects of cold agglutinins.

Exposure to a cold environment in the perioperative period may precipitate an attack. In the event of hemolysis, circulating complement may hemolyze transfused red cells. Preoperative plasmapheresis may be effective in preventing an attack by reducing the IgM load. Temperature regulation, with special attention being paid to maintain peripheral temperature, is the most important task. With regard to cardiopulmonary bypass, severe-to-moderate hypothermic cardiopulmonary bypass and cold cardioplegia should be avoided. Careful evaluation of arterial flow and collateral flow prior to insertion of an arterial catheter is recommended in the presence of Raynaud phenomenon or acral lesions. Strict asepsis is mandatory for any invasive procedure.

High-dose steroid regimens have been used with variable success. Steroid stress dose supplements should be used in case of prolonged preoperative treatment.

Cold Hypersensitivity Syndrome: A familial form of urticaria with systemic reactions that occurs as a result of cold exposure.