Autoimmune Hemolytic Anemia

Johanna L. Watson • Gary P. Carlson

Definition and Etiology

Autoimmune hemolytic anemia is associated with production of autologous antibodies directed against the patient's own red cells.

Clinical Signs and Differential Diagnosis

The presenting clinical signs of autoimmune hemolytic anemia are quite variable depending on the degree of anemia and the animal's primary disease. Marked anemia (PCV < 15%) manifests signs typical of those seen in any animal with a severe hemolytic anemia (i.e., depression, pale mucous mem­branes, variable icterus, elevated heart and respiratory rate, and variable to intermittent fever). Secondary autoimmune hemolytic anemia in horses has been associated most often with some other primary problem like purpura hemorrhagica, lymphoma, other neoplasms, protein-losing enteropathy, or chronic bacterial infections.^4,5 Clinical features are typical of the primary problem, with additional findings of hemolytic anemia. In humans, exposure to a wide variety of drugs has been causally associated with development of autoimmune hemolytic anemia. There are a number of reports of an association between procaine penicillin and autoimmune hemolytic anemia in horses,^6-10 as well as a single report in a 10-year-old horse that was treated with trimethoprim- sulfamethoxazole.¹¹ This apparently occurs rarely, perhaps only in specific individuals, but drug history should be ascertained in all animals with an otherwise unexplained hemolytic anemia.

It should be noted that the anemia in cattle with anaplasmosis and babesiosis or that in horses with equine infectious anemia, piroplasmosis, or anaplasmosis is largely the result of an immune-mediated hemolytic process.

Clinical Pathology

The hemolytic process is often rapid and persistent, leading to a pronounced anemia. Hematologic features are those typically expected for a responsive hemolytic anemia. The anemia is often progressive and may become severe, even life threatening (i.e., PCV < 10%). Erythrophagocytosis and autoagglutination may be noted on blood smears. If the process has gone on for 4 days or more, hematologic evidence of active erythropoietic response may be seen in the peripheral blood of all species except the horse. This evidence of bone marrow response is a favorable prognostic indicator, even when anemia is quite advanced. A moderate neutrophilic leukocytosis is a common feature, and thrombocytopenia may be noted in some individuals if the autoimmune process is directed at platelets and megakaryocytes in addition to erythrocytes.

Diagnosis

The direct Coombs test can detect the presence of antieryth­rocyte antibodies and/or complement on the red cell membrane, whereas the indirect Coombs test detects antierythrocyte antibody in the serum. It is important to remember that the Coombs test is based on species-specific reagents. These reagents are commercially available in the United States for small animals and horses, but not all diagnostic laboratories will have suitable Coombs reagents for other species. Multivalent Coombs reagent directed against IgG, IgM, and complement is most commonly used. The Coombs test is usually conducted at body temperature (37° C) and can also be run in the cold. Cold-reacting antibodies are primarily of the IgM class. Unfortunately, false-negative results to the Coombs test are possible and possibly occur because of low concentrations of antibody, low binding to the red cell membrane, or prior treatment with corticosteroids.

Pathophysiology

Autoimmune hemolytic anemia has rarely been reported as a primary or idiopathic process in large animals, but immune- mediated anemia occurs more commonly as a secondary problem (1) in association with certain types of neoplasia; (2) with a variety of viral, bacterial, rickettsial, and protozoal infections; (3) following exposure to certain drugs; or (4) in association with other immune-mediated disorders like systemic lupus erythematosus.¹³ The initiating factors for this autoimmune disorder are not completely understood but may be related to alterations in the red cell membrane through direct or indirect injury, which elicits an abnormal response by the immune system. The red blood cell membrane is no longer recognized as self but is treated as a foreign antigen. Alternately, alterations in the immune system or stimulation by some other antigenic source may result in production of antibodies with a misdirected cross-reactivity with the patient's own normal red cells. Structural and functional changes in the red cell membrane are induced by the antigen-antibody reaction and complement fixation. The complement-fixing IgG or IgM antigen-antibody reaction may produce sufficient erythrocyte damage to result in intravascular lysis of erythrocytes, but more commonly, affected cells are removed from the circulation at a rapid rate by the reticuloendothelial system of the liver and spleen. Partial phagocytosis of affected cells may result in spherocyte formation. Although the presence of spherocytes on blood smears is a characteristic diagnostic feature in human and canine patients with autoimmune hemolytic anemia, the relatively small size of red cells of most large domestic animals may make it difficult to recognize spherocytes.

Treatment and Prognosis

The approach to treating autoimmune hemolytic anemia depends on causal factors. If the animal has a history of drug therapy, it is advisable to discontinue medication or change to another class of drug. Patients with primary or idiopathic autoimmune hemolytic anemia may be the best candidates for treatment. IMHAs that are secondary to other diseases can only be managed if the primary problem is amenable to treat­ment. Thus treatment of an IMHA in a patient with extensive Iymphoreticular neoplasia is likely to be unrewarding, and thorough diagnostic efforts should precede case selection for treatment. Although immune-mediated processes are responsible for hemolytic anemia in a number of infectious diseases, therapy must be directed at the primary agent and corticosteroids are contraindicated in these diseases. Corticosteroids can cause recrudescence of viremia in horses with EIA.

Treatment of autoimmune hemolytic anemia is directed at providing supportive care and interrupting the immune response responsible for antibody production. This is usually accom­plished with systemic glucocorticoids. For a 450-kg horse, parenteral dexamethasone is recommended at an initial dosage of 30 to 40 mg/day. This dosage is continued for 3 to 5 days and then decreased gradually over a period of 7 to 14 days, depending on response to therapy. The hematologic response to therapy should be closely monitored. If there has been no response in 5 to 7 days, the diagnosis of autoimmune hemolytic anemia should be reviewed and potential causes of bone marrow suppression should be evaluated. Once the hemolytic process is well under control, treatment can be switched to oral prednisolone, 0.5 to 1 mg/kg daily. Human patients and small animals with IMHA that is unresponsive to corticosteroids are often treated with cyclophosphamide. One case of successful management of a horse with cyclophosphamide and azathioprine when anemia failed to respond to corticosteroids has been reported.¹⁴ Supportive care consists of providing a quiet, restful environment and good nutrition, including vitamin supple­mentation. Iron- and copper-containing hematinics are generally of little benefit; neither of these elements is lost with hemolytic anemia. Blood transfusion is also of little benefit because it is often impossible to find a compatible donor, and transfused cells are rapidly removed from the circulation.