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Cold Agglutinins

Cold agglutinins are antibodies, usually of the immunoglobulin M (lgM) type, that cause red blood cells (RBCs) to aggregate at low temperatures. They may occur in small amounts in healthy people. Transient elevations of these fectious diseases, notably primary atypical pneumonia. This test reliably detects such pneumonia within 1 to 2 weeks after onset.

Patients with high cold agglutinin titers, such as those with primary atypical pneumonia, may develop acute transient hemolytic anemia after repeated exposure to cold; patients with persistently high titers may develop chronic hemolytic anemioa after repeated exposure to cold ; patients with persistently high titers may develop chronic hemolytic anemia.


  • To help confirm primary atypical pneumonia
  • To provide additional diagnostic evidence for cold agglutinin disease associated with many viral infections and lymphoreticular cancer
  • To detect cold agglutinins in patients with suspected cold agglutinin disease

Patient preparation

  • Explain to the patient that this test detects antibotics in the blood that attacks RBCs after exposure to low temperatures.
  • If appropriate, inform him that the test will be repeated to monitor his responce to therapy.
  • Advise him that he needn't restrict food or fluids.
  • Tell him that the test requires a blood sample and who will perform the venipuncture and when.
  • Reassure him that although he may experience transient discomfort from the needle puncture and the tourniquet, collecting the blood sample usually takes less than 3 minutes.
  • If the patients is receiving antimicrobial drugs, note this on the laboratory slip becouse the use of such drugs may interface with the development of cold agglutinins.

Procedure and posttest care

  • Perform a venipuncture, and collect the sample in a 7-ml red-top tube that has been prewanned to 98.6° F (37° C).
  • If cold agglutinin disease is suspected, keep the patient warm. If the patient is exposed to low temperatures, agglutination may occur within peripheral vessels, possibly leading to frostbite, anemia, Raynaud's phenomenon and, rarely, focal gangrene.
  • Watch for signs of vascular abnormalities, such as mottled skin, purpura, jaundice, pallor, pain in or swelling of extremities, and cramping of fingers and toes. Hemoglobinuria may result from severe intravascular hemolysis on exposure to severe cold.
  • If a hematoma develops at the venipuncture site, apply warm soaks.
  • Handle the sample gently to prevent hemolysis, and send it to the laboratory immediately.
  • Don't refrigerate the sample; cold agglutinins will coat the RBCs, leaving none in the serum for testing.

Reference values

Cold agglutinin screening results are reported as negative or positive. A positive result, indicating the presence of cold agglutinin, is titered. A normal titer is less than 1:64.

Abnormal findings

High titers may occur as primary phe­nomena or secondary to infections or lymphoreticular cancer. They may be present in infectious mononucleosis, cytomegalovirus infection, hemolytic anemia, multiple myeloma, scleroderma, malaria, cirrhosis, congenital syphilis, peripheral vascular disease, pulmonary embolism, trypanosomiasis, tonsillitis, staphylococcemia, scarlatina, influenza and, occasionally, pregnancy. Chronically elevated titers are most commonly associated with pneumonia and lymphoreticular cancer; an acute transient elevation commonly accompanies many viral infections.

Extremely high titers (> 1:2,000) can occur with idiopathic cold agglutinin disease that precedes development of lymphoma. Patients with titers this high are susceptible to intravascular agglutination, which causes significant clinical problems.

Interfering factors
  • Hemolysis due to rough handling of the sample (possible false-low titer)
  • Refrigeration of the sample before serum is separated from RBCs (possible false-low titer)
  • Antimicrobial drugs

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