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Antibodies that Attack Blood Cells at Lower Temperatures in Dogs

Cold Agglutinin Disease in Dogs

The term agglutinin refers to an antibody that causes antigens, such as red blood cells or bacteria, to adhere to each each other. Cold agglutinins with low thermal capacity are usually associated with direct red blood cell agglutination (adhesion) at low body temperatures in the peripheral blood vessel network (i.e., the vessels outside of the main circulatory network). Cold limbs or other peripheral clotting phenomena are initiated or intensified by exposure to cold. This is a rare type II autoimmune disorder in which antibodies that attack red blood cells have enhanced activity at temperatures of less than 99° F (37.2° C).

Fixation of complement and hemolysis (the release of hemogloblin in the blood stream when a red blood cell breaks) is a warm-reactive process occurring at high body temperatures; therefore, patients may have very high concentrations of cold agglutinins, but these antibodies may be unable to hemolyze red blood cells (erythrocytes) at the warmer temperatures achieved in the bloodstream.

Most cold agglutinins cause little or no shortening of red blood cell life span. High thermal amplitude cold agglutinins (rare) may cause sustained hemolysis, but the resulting anemia is often mild and stable. Exposure to cold may enhance binding of cold agglutinins and complement mediated release of hemoglobin within the vessels (intravascular hemolysis).

A low titer (concentration test) of naturally-occurring cold agglutinins (usually 1:32 or less) may be found in healthy dogs, but this is without clinical significance. The disease has a genetic basis; however, mean age and range, breed, and sex predilections are unknown. The condition is more likely to occur in colder climates.

Symptoms and Types

  • History of cold exposure
  • Acrocyanosis (blueness of skin) associated with sludging of red blood cell clumps in the blood vessel network of the skin
  • Erythema (redness of the skin)
  • Skin ulceration (with secondary crusting/necrosis)
  • Dry, gangrenous necrosis of ear tips, tail tip, nose, and feet
  • Affected areas may be painful
  • Anemia may or may not be evident: associated with pallor, weakness, tachycardia (rapid heartbeat), tachypnea (rapid breathing), jaundice, change of skin color, mild splenomegaly (enlargement of the spleen), and soft heart murmur


  • Primary disease ‒ idiopathic (unknown)
  • Secondary disease in dogs ‒ neonatal destruction of red blood cells by antibodies and lead intoxication
  • Exposure to cold is a risk factor


Your veterinarian will perform a thorough physical exam on your dog, taking into account the background history of symptoms and possible incidents that might have precipitated this condition. Diagnosis is made by the historical findings, such as exposure to cold, the results of the physical examination, and demonstrating cold agglutination (adhesion of red blood cells) in vitro.

Skin lesions typically present as inflammation of the blood vessels in the skin (erythema), acrocyanosis, and ulceration of the tips of the ears and tail, nose and feet. Other associated conditions to rule out include hepatocutaneous syndrome(skin disease caused caused by liver disease); erythema multiforme (reaction to infection or medication); toxic epidermic necrolysis (blistering and peeling); dermatomyositis (skin rash caused by a muscle disease), disseminated intravascular coagulation (DIC) – bleeding into the skin; systemic lupus erythematosus (SLE); lymphoreticular neoplasms (cancer caused by proliferation of red cells in the lymphs); frostbite; lead poisoning; and pemphigus (an autoimmune disease).

A diagnosis of anemia should be demonstrated by blood tests to help distinguish warm antibody hemolytic anemia (autoimmune disease) from other causes of red blood cell destruction/loss. Macroscopic hemagglutination (clumping of red blood cells) in vitro may lead to rouleaux formation (stacks of red blood cells, as with coin rolls); mimicking erythrocyte agglutination (red blood cell clumping) on a glass slide.


A condition in which the skin becomes yellow in color as do the mucous membranes; this is due to excess amounts of bilirubin.

in vitro

The term for living organisms inside the test tube


The removal and destruction of red blood cells


A condition of dead tissue


Relating to a disease of unknown origin, which may or may not have arisen spontaneously


A condition in which the spleen becomes enlarged


The term for a quick heartbeat


A medical condition in which the patient has an abnormally fast heartbeat


Something that is related to the whole body and not just one particular part or organ


The breakdown of blood cells


A red blood cell that carries oxygen


A condition of the blood in which normal red blood cell counts or hemoglobin are lacking.


The process of removing all or part of a body part; usually refers to a limb (arm or leg) and is done for medical reasons.


a) antibodies that are created as an animal's natural response to an infection or the presence of strange micro organisms; these antibodies cause the organisms to clump together. b) any substance or antibody that causes certain organisms to clump together; usually causes the clumping of the organism that caused it to be produced in the first place.


The grouping together of certain cells, molecules, or particles into one area or clump.


A protein in the body that is designed to fight disease; antibodies are brought on by the presence of certain antigens in the system.

autoimmune disease

Any disease in which an animal's body creates antibodies that are used against itself.


Fibers that bond items together that would not normally be combined.


Redness of the skin


The process of putting something irritation onto a blemish in order to get it to go away.


The protein that moves oxygen in the blood