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Antibodies that Attack Blood Cells at Lower Temperatures in Dogs

Cold Agglutinin Disease in Dogs

Agglutinin denotes an antibody that induces the adherence of antigens, such as red blood cells or bacteria. Cold agglutinins with low thermal capacity typically lead to direct agglutination of red blood cells at lower body temperatures within the peripheral blood vessel network, outside of the main circulatory system. Exposure to cold can trigger or intensify cold limbs or other peripheral clotting phenomena. This represents a rare type II autoimmune disorder where antibodies targeting red blood cells exhibit heightened activity at temperatures below 99°F (37.2°C).

Complement fixation and hemolysis, the release of hemoglobin into the bloodstream due to red blood cell rupture, occur as a warm-reactive process at higher body temperatures. Hence, although patients may have elevated concentrations of cold agglutinins, these antibodies may fail to cause hemolysis at the warmer temperatures found in the bloodstream.

Most cold agglutinins do not significantly shorten the lifespan of red blood cells. While high thermal amplitude cold agglutinins (rare) may induce sustained hemolysis, resulting anemia tends to be mild and stable. Exposure to cold can increase the binding of cold agglutinins and the release of hemoglobin mediated by complement within blood vessels (intravascular hemolysis).

In healthy dogs, low titers (concentration tests) of naturally-occurring cold agglutinins, usually 1:32 or less, may be present without clinical significance. The disease is genetically determined, although mean age range, breed, and sex predispositions remain unknown. The condition is more prevalent in colder climates.

Symptoms and Types

  • History of exposure to cold
  • Acrocyanosis (blueness of the skin) due to the accumulation of clumps of red blood cells in the skin’s blood vessel network
  • Erythema (redness of the skin)
  • Development of skin ulcers with secondary crusting/necrosis
  • Dry, gangrenous necrosis affecting ear tips, tail tip, nose, and feet
  • Affected areas may be painful
  • Anemia may or may not be present: characterized by pallor, weakness, rapid heartbeat (tachycardia), rapid breathing (tachypnea), jaundice, changes in skin color, mild enlargement of the spleen (splenomegaly), and soft heart murmurs


  • 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 conduct a comprehensive physical examination of your dog, considering the history of symptoms and potential triggers for the condition. Diagnosis relies on historical factors like exposure to cold, findings from the physical examination, and the demonstration of cold agglutination (red blood cell adhesion) in vitro.

Skin lesions typically manifest as vascular inflammation (erythema), acrocyanosis, and ulceration in the ear tips, tail, nose, and feet. Other conditions to consider ruling out include hepatocutaneous syndrome (skin disorder linked to liver disease), erythema multiforme (reaction to infection or medication), toxic epidermal necrolysis (skin blistering and peeling), dermatomyositis (skin rash from muscle disease), disseminated intravascular coagulation (DIC, bleeding into the skin), systemic lupus erythematosus (SLE), lymphoreticular neoplasms (cancer originating from red cell proliferation in the lymph nodes), frostbite, lead poisoning, and pemphigus (an autoimmune disorder).

Anemia diagnosis requires blood tests to differentiate warm antibody hemolytic anemia (an autoimmune condition) from other causes of red blood cell destruction or loss. Macroscopic hemagglutination (red blood cell clumping) in vitro may lead to rouleaux formation (red cell stacks resembling coin rolls), mimicking erythrocyte agglutination on a glass slide.


Hospitalization in a warm environment is essential until your dog’s condition stabilizes and the disease stops progressing. Supportive care and wound management will vary based on clinical signs. Severe necrosis of the tail tip or feet may necessitate amputation.

While spleen removal doesn’t offer significant benefits for patients with IgM-mediated hemolytic disorders, it may be beneficial for those with therapy-resistant IgG-mediated hemolytic anemia.

Living and Management

Animals that have experienced this condition are susceptible to relapse. Ensure your dog remains in a warm environment at all times to prevent recurrence. The prognosis ranges from guarded to fair, and recovery may take several weeks.

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