• Bacterial Infections such as mycoplasma, Legionnaires' disease, syphilis, listeriosis, or E. Coli
• Viral infections such Epstein-Barr virus, cytomegalovirus, mumps, varicella, rubella, adenovirus, HIV, influenza, or hepatitis C
• Parasitic infections such as malaria or trypanosomiasis
• Other autoimmune diseases such as systemic lupus erythematosus
• Certain types of cancers such as lymphoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, multiple myeloma, and Kaposi sarcoma

Symptoms of cold agglutinin disease (CAD) are often triggered or made worse by cold temperatures or a viral infection. Therefore, symptoms generally are worse during winter months. Symptoms may arise suddenly or gradually.

Most people with CAD have symptoms of hemolytic anemia (destruction of red blood cells, causing low levels of red blood cells). However, the number of symptoms and severity of symptoms may depend on how severe the anemia is. Signs and symptoms of hemolytic anemia may include:

• Tiredness (fatigue).
• Dizziness.
• Headaches.
• Cold hands and feet.
• Pale skin.
• Dark urine.
• Jaundice.
• Chest pain.
• Pain in the back or legs.
• Vomiting or diarrhea.
• Heart problems such as an irregular heartbeat (arrhythmia), a heart murmur, an enlarged heart, or heart failure. These may occur because the heart has to work harder to make sure the body gets enough healthy red blood cells.

Many people with CAD also experience pain and bluish coloring of the hands and feet (acrocyanosis) or Raynaud's disease. These symptoms result from slow or poor circulation and can range from mild to disabling.

Other signs and symptoms of CAD may include enlargement of the spleen (splenomegaly) and mottled discoloration of the skin (livedo reticularis).

In people with secondary CAD (associated with another underlying condition), there may be additional signs and symptoms depending on the condition present. For example:

• Mycoplasma pneumoniae infection (the most common cause of secondary CAD) may cause respiratory symptoms.
• Various infections or cancers may cause enlarged or swollen lymph nodes.

A diagnosis of cold agglutinin disease may be made after several types of tests are performed by a health care provider. In some cases, the diagnosis is first suspected by chance if a routine complete blood count (CBC) detects abnormal clumping (agglutination) of the red blood cells. In most cases, the diagnosis is based on evidence of hemolytic anemia (from symptoms and/or blood tests). A person may also be physically examined for spleen or liver enlargement. An antiglobulin test (called the Coombs test) may be performed to determine the presence of a specific type of antibody. In people with cold agglutinin disease, the Coomb's test is almost always positive for immunoglobulin M (IgM).