Controversies in managing IMHA (Proceedings)

The diagnostic challenges of immune-mediated hemolytic anemia (IMHA) were covered in a previous presentation. The controversies in managing IMHA are being discussed in this lecture and illustrated by case presentations. Issues as transfusion support, selection of immunosuppression and anti-thrombotic therapy will be highlighted although there is limited published evidence.

What fluids, blood transfusions, oxygen and/or oxyglobin?

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 lead to signs of tissue hypoxia, packed red blood 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 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.  Additional blood types are being recognized which may be also important and become responsible for transfusion reactions.

If compatible blood is not available, the bovine hemoglobin solution Oxyglobin – if still available - may be administered and provides increased oxygen-carrying capacity and plasma expansion.  The original FDA study documented the beneficial effects of Oxyglobin, whereas more recent retrospective studies refer to undesirable side effects and do not allow any conclusions.  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.  Furthermore, adequate hydration will reduce, while catherization may increase the thrombotic tendency.  Thanks to adequate transfusion support, animals with IMHA rarely die because of anemia, but because of secondary complications such as thromboemboli and infections.

Which immunosuppressive therapy?

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.  Glucocorticoids 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, but only after weeks, diminish the production of autoantibodies.  Thus, oral prednisolone at a dose of 1-2 mg/kg twice daily is the mainstay treatment.  Alternatively, oral or parenteral dexamethasone at an equipotent dose of 0.6 mg/kg daily can be applied, but is likely not more beneficial.  It should be noted that the markers of immune destruction such as autoagglutination, sherocytosis and positive direct Coombs' test results will only slowly disappear following treatment.

Additional immunosuppressive therapy is warranted when prednisone fails, only controls the disease at persistently high doses, or when it causes unacceptable side effects.  They are generally used together with prednisolone, but may eventually be used independently.  Historically, cytotoxic drugs such as cyclophosphamide were added, however, a randomized study and several retrospective surveys failed to show any beneficial effects.  In fact, cyclophosphamide may be associated with greater morbidity and mortality in the acute management of IMHA.  Retrospective studies and anecdotal reports with azathioprine, cyclosporine, danazol, mycophenylate, 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 are lacking.  While cyclosporine, mycopheylate and human immunoglobulin can act rapidly, azathioprine takes weeks to be potentially working and should only be used for the chronic management of IMHA.  Recently various serious side effects have been noted with generic azathioprine products.  Liposomal clodronate (dichloromethylene diphosphonate) has been used to deplete macrophages and block clearance of opsonized cells in mouse models of autoimmune disease and may be a promising option in dogs; studies are in progress.

It should be noted that an apparent therapeutic response to immunosuppressive therapy is insufficient evidence for the diagnosis of IMHA.  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 to weeks.  The subsiding of autoagglutination would allow the performance of a direct 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 and moving toward an every other day therapy.  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 glucocorticosteroids, gastrointestinal protectants such as sucralfate may be considered.  Because dogs with IMHA suffer from an immune deregulation which may have been triggered by an infection 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.

How to recognize and treat or prevent thromboembolic complications?

Thromboemboli and DIC are unique serious complications that greatly contribute to the morbidity and mortality of dogs with IMHA.  Although the pathogenesis remains unknown, venipuncture, catheters, confinement, and glucocorticosteroids as well as other immunosuppressive agents may be contributing factors.  Thus far, only one limited heparin study utilizing high doss and close dose adjustments has shown successful prevention of 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.  Unfractionated Heparin (dose of 50-300U/kg subcutaneously every 6 hours or by continuous intravenous infusion) or Low Molecular Weight Heparin (LMWH; Dalteperin 150 IU/kg sc every 12 hours) are the most commonly used drugs.  The replacement of coagulation factors and antithrombin III has not been proven to be beneficial.  Antiplatelet agents may also be used and for instance an ultralow dose of aspirin (0.5mg kg once daily) has been advocated by a couple of groups, but other studies question its efficacy.  Other antithrombotic agents such as modern antithrombotic agents have been used occasionally, but their efficacy and safety remain also unproven.

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. Prednisolone or dexamethasone are the first-line immunosuppressive drugs. Alternatives in case of resistance or unacceptable side effects may include cyclosporine and human intravenous immunoglobulin. The mortality remains high despite aggressive therapy and transfusion support.  The major complications caused by thromboembolism are difficult to predict, treat and prevent.

Specific references are available from author upon request. Also see Giger U: Blood Loss and Hemolytic Anemias, in Textbook of Veterinary Internal Medicine, Eds. Ettinger S.J. and Feldman E.C., Philadelphia, PA, Saunders, 2005.