Cold agglutination syndrome
Overview
Cold agglutination syndrome: A rare disorder where abnormal blood proteins called cold agglutinins cause red blood cells to form clumps and die. The process is triggered by exposure to cold temperatures. A small number of cold agglutinins is normal but larger numbers can cause problems such as anemia.
Symptoms
* Anemia * Pain in extremities on exposure to cold * Tissue death due to impaired blood supply * Purplish nose in response to cold * Purplish skin color on ears in response to cold
Causes
* Classic chronic CAD is idiopathic, associated with symptoms and signs in relation to cold exposure. * Rarely, the first manifestations develop when the patient is subjected to hypothermia for cardiopulmonary bypass surgery (Agarwal, 1995). * Transient acute hemolysis may occur secondary to certain infectious diseases, such as M pneumoniae infection and infectious mononucleosis (eg, EBV) infections. Other viral infections, such as influenza, HIV, CMV, rubella, varicella, and mumps, have been reported to be associated with a hemolytic anemia due to cold agglutinins. Other associated illnesses include subacute bacterial endocarditis, syphilis, and malaria. The development of a febrile illness in a patient with chronic CAD also may accelerate hemolysis. * Cold agglutinins are seen in CANOMAD syndrome (CANOMAD is an acronym for chronic ataxic neuropathy ophthalmoplegia M-protein agglutination disialosyl antibodies). CANOMAD syndrome is described by gait and upper-limb ataxia; cranial nerve involvement with external ophthalmoplegia; and the presence of cold agglutinins, IgM paraprotein, and anti-disialosyl antibodies (Delval, 2006). Both the neurologic and hematologic symptoms have been seen to respond to rituximab (Siddiqui, 2003). * Equestrian perniosis is a rare cause of persistent elevated titers of cold agglutinins (De Silva, 2000). * An idea of associated disease distribution is provided by a study of 78 patients with persistent cold agglutinins. Of these, 31 had lymphoma, 13 had Waldenström syndrome, 6 had chronic lymphocytic leukemia, and 24 had chronic idiopathic CAD (Crisp, 1982). Thus, lymphoproliferative and autoimmune diseases, myeloma, Kaposi sarcoma, and angioimmunoblastic lymphoma may occasionally be associated with the production of cold agglutinins. Nonhematologic malignancies can occasionally be associated with a high-titer cold agglutinin – induced hemolytic anemia (Wortman, 1979). * Cytogenetic studies in patients with CAD have revealed the presence of trisomy 3 and trisomy 12. Translocation (8;22) is also reported in association with CAD (Gertz, 2006; Michaux 1998; Chang, 2004). * Cold agglutinin – mediated hemolytic anemia has been described in patients after living donor liver transplant treated with tacrolimus and after bone marrow transplant with cyclosporine treatments. It is postulated that such calcineurin inhibitors, that selectively affect T-cell function and spare B-lymphocytes, may interfere with the deletion of autoreactive T-cell clones, resulting in autoimmune disease. (Kitamura, 2003; Tamura, 1994; Thomson, 1995).