What Is Cold Agglutinin Disease?

Reviewed by Kumar Shital, DO on February 21, 2021

Cold weather is more than a nuisance if you have a rare blood disorder called cold agglutinin disease (CAD). It can make you dangerously sick.

Cold agglutinins are a part of your immune system called antibodies. (CAD is also called cold antibody disease.) These proteins are supposed to find and kill germs that don’t belong in your body, like bacteria and viruses. But when you have an autoimmune illness, this system instead turns against your body’s normal cells.

CAD is a form of a disease called autoimmune hemolytic anemia. It makes your body’s natural defense system attack and destroy healthy red blood cells. With CAD, this happens when the temperature of your blood drops below normal body temperature.

Only about 16 per million people have CAD.

How Damage Is Done

With cold agglutinin disease, the problem antibodies attack healthy red blood cells when you’re in cold temperatures, below about 50 degrees. Blood in your fingers, toes, nose, and ears can quickly drop below normal body temperature.


The cold agglutinins attach themselves to red blood cells and pull them together into clumps. That attracts other proteins in your immune system that break down the cell walls and destroy the cells. As your blood circulates back to warmer areas, the antibodies let go of the red blood cells. But the damage is done, and the antibodies attack more cells.

Eventually, your body can’t make new red blood cells fast enough to replace the ones being destroyed, and you become anemic. That’s when your blood isn’t able to carry enough oxygen for your organs to work like they should.

What Causes CAD?

Cold agglutinin disease can be either primary or secondary. Primary CAD is when it happens on its own, without being related to another illness. Like many other autoimmune illnesses, scientists don’t know why certain people get it or what triggers it. It typically affects people over 60 and seems to happen slightly more often in women than men.

Secondary CAD is caused by another medical condition and can show up in people of all ages. It’s usually linked to three kinds of disease:

  • Infection, most often “walking” pneumonia (mycoplasma) and mononucleosis (Epstein-Barr virus). It’s also linked to viruses like the mumps, rubella, chickenpox, cytomegalovirus, the flu and HIV; bacteria including Legionnaires' disease, syphilis, listeriosis, and E. coli; and certain parasite infections, including malaria.
  • Blood cancers, including lymphoma, chronic lymphocytic leukemia and myeloma
  • Autoimmune disorders
WebMD Medical Reference



Genetic and Rare Diseases Information Center: “Cold agglutinin disease.”

National Organization for Rare Disorders: “Anemia, Hemolytic, Cold Antibody.”

Merck Manual: “Autoimmune Hemolytic Anemia.”

Medscape: “Cold Agglutinin Disease.”

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