How Cold Agglutinin Disease Is Diagnosed

Cold agglutinin disease (CAD) is a rare type of anemia, a condition that happens when your body doesn’t have enough red blood cells. With CAD, red blood cells clump together in blood vessels, and proteins called antibodies — which are meant to protect you against foreign invaders — attack and destroy the red blood cells. This is triggered when your body temperature drops below your normal body temperature.

If you have symptoms that are common with CAD (like cold hands or feet, dizziness, weakness, headaches, stomach problems, or pale skin), your doctor may recommend is a blood test to see if you have anemia. After that, they may suggest other tests to figure out what’s causing it.

Physical Exam

Your doctor may check the size of your spleen, which captures and recycles dead red blood cells. If it’s larger than normal, that can be a sign that the red blood cells are dying too quickly.

Bilirubin Test

Bilirubin is a substance that’s made when red blood cells break down. A blood test can show if you have higher than normal levels of it, which can be a sign that too many red blood cells are being destroyed.
Haptoglobin Test

Hemoglobin is a protein that takes oxygen from your lungs to the rest of your body. Haptoglobin is another kind of protein that attaches itself to a type of hemoglobin that’s made when red blood cells die. Once they’re bound together, your liver flushes them out of your body. If too many red blood cells die, it can lead to low levels of haptoglobin in your blood.

Complete Blood Count (CBC)

With cold agglutinin disease, antibodies bind to red blood cells, making them clump together. This blood test can show if red blood cells are unnaturally bundled together, also known as agglutination. Doctors will also look to see if you have too few red blood cells or too many new red blood cells.

Blood Smear

In this test, lab technicians look at a sample of your blood for signs that red blood cells have been destroyed too quickly.

Coombs Test

This test can see if antibodies that destroy red blood cells are in your blood. There are two types of Coombs tests, a direct test and an indirect test. With the direct test, the red blood cells are separated out of a sample of your blood and put through a process called “washing.” The red blood cells are then mixed with a substance called Coombs reagent. If the red blood cells start to clump together, that can be a sign of cold agglutinin disease.

The indirect test is only used with pregnant women and people who are about to get a blood transfusion.


  2. National Organization for Rare Disorders: “Anemia, Hemolytic, Cold Antibody.”
  3. Office on Women’s Health: “Autoimmune Diseases.”
  4. Genetic and Rare Diseases Information Center: “Cold agglutinin disease.”
  5. Mayo Clinic: “Bilirubin Test,” “Enlarged Spleen.”
  6. Merck Manual Consumer Version: “Autoimmune Hemolytic Anemia.”
  7. University of Rochester Medical Center: “Haptoglobin.”
  8. Medline Plus: “Blood Smear.”
  9. Johns Hopkins Lupus Center: “Coombs Test.”

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