Immune-mediated hemolytic anemia (IMHA) arises when an immune response targets directly or indirectly erythrocytes and hemolytic anemia ensues. In primary IMHA no inciting cause can be identified, hence the term idiopathic IMHA or autoimmune hemolytic anemia (AIHA). In contrast, secondary IMHA is associated with an underlying condition or triggered by an identifiable agent. The various breed and family predilections (about 1/3 of all cases of IMHA are seen in American Cocker Spaniels) suggest strongly the involvement of genetic factors leading to a predisposition to IMHA. There is ample evidence for infectious agents to be associated with IMHA, including parasitic (babesiosis, leishmaniasis, ehrlichiosis, and dirofilariasis), fungal, and bacterial (leptospirosis, chronic abscesses, discospondylitis, pyometra, colitis, and pyelonephritis). The relationship between infection and autoimmunity may be explained by molecular mimicry. Furthermore, several drugs and toxins (e.g., sulfonamides, bee sting) and neoplastic disease processes have been associated with IMHA.

In dogs idiopathic IMHA (AIHA) has been considered the most common cause of hemolytic anemias for decades, and many anemic dogs are presumptively managed for AIHA. Nevertheless, an extensive search for an underlying disorder or trigger is always warranted. This presentation will discuss some of the challenges and controversies in the management of IMHA in dogs. Because of a paucity of evidence on treatment of canine IMHA, some food-for-thought rather than a definitive treatment regime for IMHA will be provided.

A diagnosis of IMHA must demonstrate accelerated immune destruction of erythrocytes. Evidence of a hemolytic anemia is suggested clinically by icterus and a regenerative anemia with hyperbilirubinuria, and hemoglobinemia and hemoglobinuria refers to an intravascular process. However, the erythroid response in the bone marrow may be blunted by the immune process or the underlying disease thereby leading to non-regenerative anemias. Besides documenting a hemolytic anemia, one or more of the following three hallmarks must be present to support a diagnosis of immune-mediated hemolysis: persistent agglutination, marked spherocytosis and a positive direct Coombs test result.

Because the severity of IMHA ranges from indolent to life-threatening disease, therapy has to be tailored for each patient and depends in part on whether the IMHA is primary or secondary in nature. Removal of the triggering agent or treatment of the underlying condition can bring the IMHA rapidly under control.

Restoration and maintenance of tissue perfusion with crystalloid fluids is important even when it results in further lowering of the hematocrit. When severe anemia and a dropping hematocrit result in signs of tissue hypoxia, packed cell transfusions appear beneficial. The increased oxygen-carrying capacity provided by the transfused red blood cells may be sufficient to maintain the animal's hematocrit for a few days while other treatment modalities have time to become effective. The notion that transfusions pose an increased hazard to animals with IMHA has been overemphasized and is not supported by recent retrospective clinical studies. However, the common occurrence of autoagglutination may make blood typing and crossmatching of the patient impossible. In these cases DEA 1.1 negative blood should be transfused.

If compatible blood is not available, the bovine hemoglobin solution Oxyglobin may be administered and provides increased oxygen-carrying capacity and plasma expansion. In contrast to blood and Oxyglobin, oxygen inhalation therapy is of little benefit, unless the animal is suffering form pulmonary disease such as pulmonary thromboemboli. Thanks to adequate transfusion support, animals with IMHA rarely die because of anemia, but because of secondary complications such as thromboemboli and infections.

The insufficient understanding of the pathogenesis, the generally guarded prognosis, the lack of good therapeutic trials, the serious drug side effects, and the high costs of intensive care greatly hamper the successful management of dogs with IMHA. The main goal of immunosuppressive therapy is to reduce phagocytosis, complement activation, and anti-erythrocytic antibody production. Glucocorticosteroids are the initial treatment of choice for canine and human IMHA. They interfere with both the expression and function of macrophage Fc receptors and thereby immediately impair the clearance of antibody-coated erythrocytes by the macrophage system. In addition glucocorticoids may reduce the degree of antibody binding and complement activation on erythrocytes, and only after weeks, diminish the production of autoantibodies. Thus, oral prednisone at a dose of 1-2 mg/kg twice daily is the mainstay treatment. Alternatively, oral or parenteral dexamethasone at an equipotent dose of 0.2-0.4 mg/kg twice daily can be used, but is likely not more beneficial.

Additional immunosuppressive therapy is warranted when prednisone fails, only controls the disease at persistently high doses, or when corticosteroids cause intolerable side effects. They are generally used together with prednisone, but may eventually be used independently. Historically, cytotoxic drugs such as cyclophosphamide were added, however a small randomized study and several retrospective surveys failed to show any beneficial effects, but may be associated with greater morbidity and mortality in the acute management of IMHA. Retrospective studies and anecdotal reports with azathioprine, cyclosporine, danazol, mycophenolate, leflunomide and human intravenous immunoglobulin indicate some efficacy and may be associated with fewer side effects, but controlled prospective clinical trials that document their efficacy and safety are lacking.

Response to therapy may be indicated by a hematocrit that rises or stabilizes, an appropriate reticulocytosis, diminished autoagglutination, and fewer spherocytes; this response can be expected to be seen within days. The subsiding of autoagglutination would allow the performance of a Coombs' test and thereby permit the direct documentation of anti-erythrocytic antibodies. As glucocorticosteroid therapy is associated with well-known side effects, the initial dose will be tapered by reducing the amount by one-third every 7-14 days. In secondary IMHA with appropriate control of the underlying disease, the tapering can be accomplished more rapidly. Because of the potential of gastrointestinal ulceration by steroids, gastrointestinal protectants such as sucralfate may be considered. Because dogs with IMHA suffer from an immune deregulation which may have been triggered by an infections and are treated with immunosuppressive agents, these patients are prone to experience infections; it is, therefore, prudent to administer preventative as well as therapeutic antibiotics to these dogs with IMHA on immunosuppressive therapy.

Thromboemboli and DIC are unique serious complications that greatly contribute to the morbidity and mortality of dogs with IMHA. Although the pathogenesis remains unknown, venopuncture, catheters, and glucocorticosteroids as well as other immunosuppressive agents may be contributing factors. Thus far, no study has documented any successful prevention and/or management protocol for these life-threatening hemostatic problems in canine IMHA. Predisposing factors should, whenever possible, be limited, and adequate perfusion and tissue oxygenation should be provided with fluids and transfusions or Oxyglobin. Generally, anticoagulation therapy is instituted after there is some evidence or suspicion of thromboemboli. Heparin is the most commonly used drug and is used at a dose of 50-250U/kg sc every 6 hours or by continuous infusion. The replacement of coagulation factors and antithrombin III has not been proven to be beneficial. Other antithrombotic agents such as aspirin, low molecular weight heparin and novel antithrombotic agents have been used occasionally, but their efficacy and safety remain unproven.

References

1.  Giger, U: Regenerative Anemias Caused by Blood Loss or Hemolysis. In Textbook of Veterinary Internal Medicine, SJ Ettinger and EC Feldman (eds) 6th edition. WB Saunders, Philadelphia, PA, pp 1886-1807, 2005.