Overview

• A rare Type II autoimmune disorder in which antierythrocyte antibodies have enhanced activity at temperatures <99°F (37.2°C) and usually <88°F (31.1°C).
• Cold agglutinins are typically IgM, although IgG and IgG-IgM mixed have been reported.
• Cold agglutinins with low thermal amplitude usually associated with direct erythrocyte agglutination at low body temperatures in the peripheral microvasculature and with acro-cyanotic disease or other peripheral vaso-occlusive phenomena, all initiated or intensified by cold exposure.
• Fixation of complement and hemolysis is a warm reactive process occurring at higher body temperatures; at those temperatures cold agglutinins have eluted off the RBC, lowering the rate of complement binding. Therefore, acute hemolytic anemias are uncommon.
• Most cold agglutinins cause little or no shortening of erythrocyte lifespan.
• High thermal amplitude cold agglutinins (rare)-may cause chronic hemolysis; the resulting anemia is often mild and stable, but exposure to cold may greatly augment binding of cold agglutinins and complement-mediated intravascular hemolysis.

Signalment

• Rare disorder in dogs and cats.
• Low titer of naturally occurring cold agglutinins (usually 1:32 or less) may be found in healthy dogs and cats; this is without clinical significance.
• Genetic basis, mean age and range, breed, and sex predilections unknown.
• More likely to occur in colder climates.

Signs

• Often a history of cold exposure.
• Acrocyanosis associated with sludging of erythrocyte agglutinates in cutaneous microvasculature.
• Erythema.
• Skin ulceration with secondary crusting.
• Dry, gangrenous necrosis of ear tips, tail tip, nose, and feet.
• Affected areas may be painful.
• Anemia may or may not be an important feature; clinical signs include pallor, weakness, tachycardia, tachypnea, icterus, pigmenturia, mild splenomegaly, and soft heart murmur.

Causes & Risk Factors

• Primary disease-idiopathic.
• Secondary disease-associated with upper respiratory infection (cats), neonatal isoerythrolysis, lead intoxication (dogs), and neoplasia.
• Cold exposure a risk factor.
• In humans, cold agglutinin disease has been described in liver transplant cases after tacrolimus administration.

Differential Diagnosis

• Diagnosis made by historical findings (cold exposure), results of physical examination, demonstrating cold agglutination in vitro.
• Skin lesions-cutaneous vasculitis, hepatocutaneous syndrome, erythema multiforme, toxic epidermic necrolysis, dermatomyositis, DIC, SLE, lymphoreticular neoplasms, frostbite, lead poisoning, and pemphigus.
• Anemia-warm antibody hemolytic anemia; other causes of anemia.
• Macroscopic hemagglutination in vitro-dysproteinemias may lead to rouleaux formation, mimicking erythrocyte agglutination on a glass slide.

CBC/Biochemistry/Urinalysis

• Autoagglutination at room temperature.
• Laboratory abnormalities secondary to hemolysis.

Other Laboratory Tests

• Cold agglutinins should be suspected when blood in heparin or EDTA on a glass slide agglutinates spontaneously at room temperature with enhancement at 39°F (3.9°C), and the erythrocytes disperse again upon warming to 99°F (37.2°C).
• If no agglutination can be induced in vitro, it is inconceivable for it to occur in vivo in extremities.
• Doubtful cases can be confirmed by Coombs' test at 39°F and 99°F.
• Coombs' test at 99°F-cold agglutinins usually not detected because they may be eluted off the erythrocytes during washing; thus test requires the use of anti–complement factor serum.
• Coombs' test at 39° F-incidence of a positive result in healthy dogs has been reported to be > 50%, which may be caused by unspecific binding of the reagent itself or by binding of naturally occurring non-pathogenic low-titer cold agglutinins.
• The globulin class can be established by immunoelectrophoresis of a concentrated eluate of the patient's erythrocytes, which may be important for prognosis and treatment.

Pathologic Findings

• Dermal necrosis.
• Ulceration with secondary features of opportunistic infections.
• Vascular thrombosis with evidence of ischemic necrosis.

Drug(s)

Contraindications/Possible Interactions

• Monitor patient for signs of infection secondary to immunosuppressive therapy.
• Do not use cold IV fluids.

See Also

Anemia, Immune-Mediated

Abbreviations

• DIC = disseminated intravascular coagulation
• EDTA = ethylene diamine tetra-acetic acid
• SLE = systemic lupus erythematosus

Author Jörg Bucheler

Consulting Editor Alan H. Rebar