Cold agglutinin disease


Cold Agglutinin Disease, a rare blood disorder, is a type of Autoimmune Hemolytic Anemia. Cold agglutinin antibodies are made in your bone marrow and high levels can occur when your immune system malfunctions. The body mistakenly perceives, as foreign, the very antibodies that it produces and sets up an autoimmune response thereby prematurely killing the red blood cells (hemolysis). The antibodies called cold agglutinins, are activated by cold temperatures and react by causing a sticking together or clumping of the red blood cells to which they are attached. The temperature, at which the agglutination (clumping) takes place, varies from patient to patient. A thermal study may be done to determine the level.


Most cold agglutinins only react at temperatures lower than body temperature and affect the cooler parts of the body that can be exposed to the cold, such as the fingers, nose and ears by causing reduced blood flow. Occasionally, peripheral gangrene and, rarely, fatalities, have occurred after inadvertent prolonged exposure to cold temperatures. Usually, however, the affected RBCs in cold agglutinin disease merely stimulate complement production. Residual complement can result in a process leading to hemolysis. However, with the depletion of complement, hemolysis becomes self-limited. Likewise, temporary increases in complement due to febrile illnesses can increase hemolysis. In laboratory tests, cold agglutinins often interfere with laboratory assays, particularly red blood cell indices and blood typing procedures. Cold agglutinins that react at body temperatures can cause Blood Bank crossmatching problems, moderate to severe hemolysis and lead to anemia.


Cold agglutinin disease may be primary (idiopathic) or secondary, caused by infection, systemic autoimmunity, or neoplasm. Primary (idiopathic) cold agglutinin disease is associated with monoclonal autoantibodies. Secondary cold agglutinin disease can be associated with either monoclonal or polyclonal autoantibodies. * Primary (idiopathic) cold agglutinin disease, monoclonal - Usually chronic, occurring in adults * Secondary cold agglutinin disease, monoclonal - Usually chronic, occurring in adults (Cases of cold agglutinin disease in children with B-cell lymphoproliferative diseases [eg, acute lymphoblastic leukemia] induced by an associated infection have been reported.) o B-cell neoplasms - Waldenström macroglobulinemia, lymphoma, chronic lymphoid leukemia, myeloma o Nonhematologic neoplasms * Secondary cold agglutinin disease, polyclonal - Usually acute, transient, and postinfectious, occurring in children and young adults o Mycoplasma infections -Mycoplasma pneumoniae o Viral infections - Infectious mononucleosis due to Epstein-Barr virus (EBV) or cytomegalovirus (CMV) o Viral infections, other - Mumps, varicella, rubella, adenovirus, human immunodeficiency virus (HIV), influenza, hepatitis C o Bacterial infections - Legionnaire disease, syphilis, listeriosis, Escherichia coli o Parasitic infections - Malaria, trypanosomiasis


Diagnosis * Indications for testing – hemolytic anemia, particularly in presence of lymphoproliferative disorder * Laboratory testing o Indications of hemolysis are positive (hyperbilirubinemia, increased LDH) o CBC with peripheral smear – demonstrates anemia and hemolysis o DAT specific for C3d and IgG o Serum cold agglutinin testing + Low levels may also be found in healthy adults, peripheral vascular disease, nonlymphoid neoplasm + Clinical hemolysis may occur with low titers (1:64), but usually the titers are ?1:1000 o Complement assessments (C3, C4, CH50) o Quantification of IgG, IgA and IgM