Pathophysiology
Cold agglutinins, or cold autoantibodies, occur naturally in nearly all individuals. These natural cold autoantibodies occur at low titers, less than 1:64 measured at 4 °C, and have no activity at higher temperatures. Pathologic cold agglutinins occur at titers over 1:1000 and react at 28-31 °C and sometimes at 37 °C. Cold agglutinin disease usually results from the production of a specific IgM antibody directed against the I/i antigens (precursors of the ABH and Lewis blood group substances) on red blood cells (RBCs). Cold agglutinins commonly have variable heavy-chain regions encoded by VH, with a distinct idiotype identified by the 9G4 rat murine monoclonal antibody. Diagnosis
Classification
AIHA can be classified as warm autoimmune hemolytic anemia  or cold autoimmune hemolytic anemia, which includes cold agglutinin disease and paroxysmal cold hemoglobinuria. These classifications are based on the characteristics of the autoantibodies involved in the pathogenesis of the disease. Each has a different underlying cause, management, and prognosis, making classification important when treating a patient with AIHA. Autoimmune hemolytic anemiaWarm-antibody typePrimary
Secondary  (lymphoproliferative disorders, autoimmune disorders) : 259 Cold-antibody type (anemia)Primary cold agglutinin disease
Secondary cold agglutinin syndromeAssociated with malignant disease
Acute, transient, infection-associated  (acute cold antibody mediated AIHA complicating Mycoplasma pneumoniae or viral infections )
Chronic (lymphoproliferative disorders) : 259 Paroxysmal cold hemoglobinuria: 259 Idiopathic
SecondaryAcute, transient (Infections other than syphilis): 259 
Chronic (syphilis): 259 Mixed cold- and warm-antibody typeIdiopathic
Secondary (lymphoproliferative disorders, autoimmune disorders) Drug-induced immune hemolytic anemia : 259 Autoimmune type
Drug absorption type
Neoantigen type

Treatment
Cold agglutinin disease may be managed successfully using protective measures (clothing) alone in most cases. Special protective clothing is sometimes necessary in extreme cases.
Trisomy and translocation: Cytogenetic studies in patients with cold agglutinin disease have revealed the presence of trisomy 3 and trisomy 12. Translocation (8;22) has also been reported in association with cold agglutinin disease. Transplantation: Cold agglutinin–mediated hemolytic anemia has been described in patients after living-donor liver transplantation treated with tacrolimus and after bone marrow transplantation with cyclosporine treatments. It is postulated that such calcineurin inhibitors, which selectively affect T-cell function and spare B-lymphocytes, may interfere with the deletion of autoreactive T-cell clones, resulting in autoimmune disease. Systemic sclerosis: Cold agglutinin disease has been described in patients with sclerodermic features, with the degree of anemia being associated with increasing disease activity of the patients systemic sclerosis. This may suggest a close association between systemic rheumatic disease and autoimmune hematologic abnormalities. Hyperreactive malarial splenomegaly: Hyperreactive malarial splenomegaly (HMS) is an immunopathologic complication of recurrent malarial infection. Patients with HMS develop splenomegaly, acquired clinical immunity to malaria, high serum concentrations of anti-Plasmodium antibodies, and high titers of IgM, with a complement-fixing IgM that acts as a cold agglutinin. DPT vaccination: Diphtheria-pertussis-tetanus (DPT) vaccination has been implicated in the development of autoimmune hemolytic anemia caused by IgM autoantibody with a high thermal range. A total of 6 cases have been reported; 2 followed the initial vaccination and 4 followed the second or third vaccinations. Other: Equestrian perniosis is a rare cause of persistent elevated titers of cold agglutinins. Also rarely, the first manifestations of cold agglutinin disease can develop when a patient is subjected to hypothermia for cardiopulmonary bypass surgery.