Cold agglutinin disease is a subcategory of autoimmune hemolytic anemias and is caused by antibodies (mostly IgM type, sometimes IgG or IgA) directed towards the red blood cells. This disease is primary or secondary to an infection, malignancy or connective tissue disease.
The disease usually affects women and may become apparent in the 5th- 7th decade of life  .
Other symptoms are triggered by exposure to cold and consist of livedo reticularis and acrocyanosis (that does not go through the three phases of the Raynaud phenomenon) or Raynaud syndrome   . Obstruction of circulation by agglutinated red blood cells may occur, leading to cutaneous necrosis.
Hemoglobinuria is due to hemolysis but is less important than the one seen in paroxysmal nocturnal hemoglobinuria open link. Patients may also exhibit dizziness, tinnitus, vision abnormalities, amenorrhea and pain in the extremities after cold exposure.
The clinician might notice a low degree splenomegaly, lymphadenopathy, jaundice and signs of an underlying disease: pneumonia, mononucleosis, lymphoma or leukemia, lupus erythematous. Severe anemia might precipitate heart failure. Hepatomegaly may be present if the underlying disease is an immunoproliferative disease but it is not a consequence of cold agglutinin disease per se.
Workup normally starts with a standard complete blood count, which reveals anemia and red blood cell agglutination. The mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) are falsely elevated. This type of anemia is regenerative, therefore reticulocyte count is high. If reticulocytes are found to be low, decreased bone marrow erythropoiesis should be suspected and demonstrated by needle aspiration. This can be due to infection or lymphoproliferative disease. Hemolysis causes hyperbilirubinemia and elevated lactate dehydrogenase. As with other hemolytic anemias, spherocytes may be present.
The next step is to perform a Coombs reaction, that determines if the red blood cells are coated with immunoglobulin, complement or both in vivo. If positive, and in cold agglutinin disease this test is usually positive for IgM, it should be followed by the determination of the titer of antibodies and their thermal activity .
Titers higher than 1:512 are considered to be clinically significant, while titers greater than 1:64 are considered abnormal. If high titers are found, blood should also be tested after being warmed to 37 degrees Celsius.  . When bovine serum albumin is added during cold agglutinin titer and thermal amplitude testing, the results provide a better correlation with the clinical condition. 
Another useful test is protein electrophoresis or immunoelectrophoresis to determine if dysproteinemia is present.
Given the fact that cold agglutinin disease is often secondary to other diseases, certain entities should be tested for: influenza, infectious mononucleosis, AIDS, hepatitis, malaria, cytomegalovirus infection, systemic lupus erythematosus , scleroderma, rheumatoid arthritis , sarcomas , carcinomas , melanomas, and immunoproliferative diseases. If the latter is suspected, bone marrow evaluation and lymph node biopsies should be performed.