Management of Hemolytic Anemias

Urs Giger United States

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. Removal of the triggering agent or treatment of the underlying condition can bring the IMHA under control. Thus, in cases of secondary IMHA due to infection, antiprotozoal, antirickettsial or antibiotic therapy should be instituted. Because of the potential of underlying occult infection and the predisposition to infection from immunoderegulation associated with IMHA and immunosuppressive therapy, antibiotic therapy is generally indicated. In addition, surgical correction of abscesses and other sites of infections may be considered. Non-essential drugs, particularly those that could potentially cause an immune reaction, should be withdrawn immediately. Despite these interventions, transfusion and immunosuppressive therapy are still likely required in the initial control of secondary IMHA.

In case of signs of hypoxia due to severe anemia and a dropping hematocrit, packed red blood cell transfusions are beneficial. The increased oxygen-carrying capacity provided by transfused cells may be sufficient to maintain the animal for the few days required for other treatment modalities to become effective. The notion that transfusions are especially hazardous in animals with IMHA has been overemphasized and is not supported by recent retrospective studies. As the anti-erythrocytic antibody in IMHA is not an alloantibody, the destruction of transfused cells is no higher than autologous erythrocytes. However, autoagglutination may hamper, even after RBC washing, accurate blood typing and crossmatching tests; thus, only DEA 1.1 negative blood should be transfused in dogs. If compatible blood is not available, the recently FDA-approved bovine hemoglobin solution can be administered and provides increased oxygen-carrying capacity and plasma expansion. In contrast, oxygen inhalation therapy is of little benefit, unless the animal is suffering from pulmonary disease such as pulmonary thromboemboli. Thanks to adequate transfusion support, animals with IMHA rarely die because of anemia, but because of overwhelming hemolysis and secondary complications such as thromboembolism and infection.

The main goal in the treatment of IMHA focuses on controlling the immune response by reducing phagocytosis, complement activation, and anti-erythrocytic antibody production. Glucocorticosteroids are the initial treatment of choice for 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, glucocorticosteroids may reduce the degree of antibody binding and complement activation on erythrocytes, and only after weeks, diminish the production of autoantibodies. Oral prednisone or 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 used, but is likely not more beneficial. A response reflected by a stabilized or even rising hematocrit, an appropriate reticulocytosis, less autoagglutination, and spherocytosis can be expected within days. As glucocorticosteroid therapy is associated with well-known side effects, the initial dose will then be tapered by reducing the amount by one-third every seven to ten days. Within weeks, a low dose alternative day therapy may be reached with minimal steroid side effects.

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, treatment with misoprostol (4�8 μg/kg q6h PO), a synthetic analog of prostaglandin E₁ that inhibits gastric acid secretion, cimetidine (5�10 mg/kg q6-12h PO), and sucralfate may be considered. Despite an apparent recovery as judged by reaching a normal hematocrit, particularly animals with primary IMHA may continue to have a positive Coombs� test for weeks to months and could obviously relapse. Such relapses may be controlled by the same treatment as initially used, but a more gradual tapering regime may be used which leaves the animal on an every other day prednisone therapy for months.

Other immunosuppressive therapy is warranted when prednisone fails, only controls the disease at persistently high doses, or causes unacceptable side effects. They are generally used together with prednisone but may eventually be used independently. Historically, cytotoxic drugs were the first to be added. Cyclophosphamide, an alkylating and potent myelosuppressive agent, has been advocated in cases of fulminate IMHA. However, a recent randomized limited prospective trial comparing prednisone versus a combination of prednisone and cyclophosphamide did not find any beneficial effects of cyclophosphamide in the acute management of IMHA. Retrospective studies with cyclophosphamide and/or azathioprine, an anti-metabolite, were similarly disappointing. These cytotoxic drugs inhibit lymphocytes and thereby suppress the anti-erythrocyte antibody production within weeks. These agents are, therefore, likely not effective in the acute management of IMHA, but may have a place in the long-term control of refractory and relapsing cases. A reasonable regimen for dogs might include either cyclophosphamide at 2 mg/kg every other day or azathioprine at 2 mg/kg q24h/EOD. In addition to the strong myelosuppressive effects of these cytotoxic drugs leading to reticulocytopenia, neutropenia, and thrombocytopenia, cyclophosphamide can induce a sterile hemorrhagic cystitis and secondary neoplasia. Thus, the risk versus benefit ratio should be carefully considered when using these drugs.

Recently, several other immunosuppressive agents have been used on a limited basis in conjunction with prednisone and anecdotal success has been reported in dogs and humans. As all of these agents interfere with antibody action and macrophage function, they can elicit more immediate effects. Cyclosporine, an expensive but potent immunosuppressive agent most commonly used in preventing graft rejection and graft vs. host disease in transplant patients, may be beneficial in controlling the immune response in dogs with IMHA. A dose regimen of 5-10 mg/kg q24h may be used initially, but blood concentrations should be periodically monitored to achieve an effective but safe level. Leflunamide is in a similar class of agents as cyclosporine and has been used in a few cases with anecdotal success. Danazol, an androgen derivative, at a dose of 10 mg/kg q24h may inhibit binding of antibodies and phagocytosis. However, a retrospective study in dogs with IMHA on the efficacy of danazol was disappointing; furthermore, danazol is expensive and may be hepatotoxic.

Intravenous human immunoglobulin (IVIG) may be helpful in the short-term treatment of dogs with IMHA, although its mode of action remains unresolved. IVIG can block Fc receptors on macrophages, thereby reducing Fc-mediated phagocytosis of IgG-coated erythrocytes, interfere with complement action, and suppress antibody production. Human IVIG binds to canine lymphocytes and monocytes, and inhibits erythrocyte phagocytosis. A infusion of 0.5�2 g/kg IVIG as divided dose on two consecutive days has been beneficial in some refractory cases as indicated by a rising PCV and reticulocytosis within days, but the response has often been only temporary. Anecdotally, plasmapheresis has also been used as an adjuvant therapy.

Splenectomy may be considered in IMHA patients who failed prednisone and other immunosuppressive therapy, required long-term high dose therapy to remain in remission, or who suffered intractable drug side effects. The spleen is a major site of autoantibody production as well as sequestration and destruction of erythrocytes coated with IgG, but likely does not affect the clearance of IgM-coated cells. In addition, histologic examination of the spleen may provide evidence of an underlying disease. The response to splenectomy remains to be determined in animals. There is a slight risk of developing overwhelming infections immediately post-splenectomy and systemic bacterial infections subsequently. Therefore, splenectomy should not be performed along with immunosuppressive therapy other than prednisone.

Thrombemboli and DIC are unique serious complications that greatly contribute to the morbidity and mortality of patients with IMHA. Although the pathogenesis remains unknown, venipuncture, catheters, and glucocorticosteroid therapy represent predisposing conditions. Thus far, no study has documented any successful prevention and/or management protocol for these life-threatening hemostatic problems in IMHA. Predisposing factors should, whenever possible, be limited and adequate perfusion and oxygenation of tissue should be provided with fluids and transfusions. Generally, anticoagulant therapy is instituted only after there is some evidence or suspicion of thromboemboli. Heparin at a dose of 100 IU/kg q6h SC or by continuous infusion is the most commonly used drug, and fresh frozen plasma (10 mL/kg q12h) may be administered to replenish dangerously low plasma antithrombin III concentrations. Other complications are likely related to drug therapy.

Despite appropriate implementation of the above therapeutic strategies, the mortality rate remains high; in fact, there is an impression that the fulminate form of IMHA is more frequently encountered today. Depending on the type of practice (primary to tertiary), mortality rates from 20�75% have been reported. Negative prognostic indicators are rapid drop in PCV, high serum bilirubin levels, non-regenerative anemia, intravascular hemolysis, autoagglutination, and thromboembolic complications.

Reference

1.  Giger Urs (2000), �Regenerative Anemias Caused by Blood Loss or Hemolysis,� Textbook of Veterinary Internal Medicine, S.J. Ettinger and E.C. Feldman, ed. Philadelphia, PA, Saunders.