IMHA: Diagnosing and treating a complex disease

Differentiating IMHA from other causes of hemolytic anemia is challenging, but a careful diagnostic process will help you determine whether your veterinary patients will require long-term immunosuppressive therapy.
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Dec 01, 2008


Kip Carter
Autoimmune hemolytic anemia, or immune-mediated hemolytic anemia (IMHA), is a complex disease in which hemolysis occurs because of antierythrocyte antibody production. This article explores the pathophysiology of primary and secondary IMHA and diagnostic and treatment options, as well as prognosis in dogs and cats. Our review of the recent literature regarding IMHA in veterinary patients reveals a focus on individual cases and a lack of controlled clinical studies, which makes a detailed review of IMHA triggers and treatment options difficult.

HEMOLYTIC ANEMIA VS. IMHA

Many causes of anemia exist in dogs and cats, so a clear distinction should be drawn between hemolytic anemia and IMHA.

Hemolytic anemia

Hemolytic anemias are conditions in which red blood cells (RBCs) are destroyed at an accelerated rate and a normal regenerative response is seen in the bone marrow. In these non-immune-mediated conditions, RBCs can be destroyed as a result of inherited membrane and enzyme defects, increased fragility from oxidative damage, or metabolic causes such as hypophosphatemia or water intoxication.1 Traditional immune-mediated mechanisms (immunoglobulins, complement) do not mediate lysis in hemolytic anemia. Instead, destruction occurs because of factors such as increased osmotic fragility, decreased RBC function in an alkalemic environment, or increased clearance from oxidative damage.1 Unlike the treatment of immune-mediated anemia, immunosuppression is generally not used to treat hemolytic anemias. Thus, it is imperative to investigate whether an anemia has an underlying cause before assuming it is immune-mediated.


Table 1: Selected Causes of Canine and Feline Non-immune-mediated Hemolytic Anemia
Below we discuss some of the common causes of hemolytic anemia. A more exhaustive list can be found in Table 1.

Zinc and copper toxicosis. One of the most common causes of hemolytic anemia in dogs is zinc toxicosis from the ingestion of zinc-containing objects. High zinc concentrations can be found in pennies minted since 1983, board game pieces, zippers, zinc oxide ointment, and various other sources. Zinc toxicosis can cause a severe intravascular hemolysis that is associated with small amounts of Heinz body and spherocyte formation. Hemolysis from zinc toxicosis can be easily mistaken for IMHA if a survey abdominal radiographic examination is not performed. Treatment consists of removing the foreign object and providing supportive care. Copper toxicosis can also result in a marked intravascular hemolysis and methemoglobinemia.1

Heinz body anemia. Heinz bodies are dark-staining refractile material that indicate irreversibly denatured and precipitated hemoglobin in RBCs and can occur from oxidative damage in animals that have ingested onions or received drugs such as methylene blue, dl-methionine, or vitamin K3.1 In some cases of hemolytic anemia, eccentrocytes—cells in which the damaged hemoglobin is clustered together and shifted to one side of the RBC membrane, leaving a clear crescent-shaped region—are also present. Eccentrocytes and cells containing Heinz bodies have less deformability and more rigidity, making them more likely to be lysed or removed from the circulation by the spleen.

Feline RBCs are especially sensitive to oxidative damage because of a high number of sulfhydryl groups in their hemogloblin. In addition, feline spleens, because of their nonsinusal conformation, are less effective at removing Heinz bodies than are canine sinusal spleens. Thus, Heinz body anemia is more commonly seen in cats and can be present during toxicosis as well as in a variety of other diseases such as hyperthyroidism, diabetes mellitus, and lymphoma.1

Hypophosphatemia. Hypophosphatemia can also cause hemolytic anemia in patients being treated for diabetes mellitus, hepatic lipidosis, starvation, and other conditions.1 In these cases, it is thought that an abrupt drop in plasma phosphate concentrations can cause a concurrent depletion of RBC adenosine triphosphate, diphosphoglycerate, and reduced glutathione. These depletions lead to less deformability, more osmotic fragility, and more susceptibility to oxidative injury in erythrocytes. A rapid drop in packed cell volume and a mild Heinz body anemia can be seen in animals with hypophosphatemia. Treatment consists of phosphate supplementation (intravenous in cases of severe depletion, oral in mild cases).1