IMHA treatment's first goal to improve oxygen delivery to cells

Q: Please review the management of immune-mediated hemolytic anemia.

A: Dr. Douglass K. Macintire at the 2006 American College of Veterinary Internal Medicine Forum in Louisville, Ky., gave a lecture on new therapies for immune-mediated hemolytic anemia (IMHA). Some relevant points from this lecture are outlined in this article.

IMHA is caused by the production of antibodies against red blood cells, resulting in the premature destruction of erythrocytes, which leads to clinically significant hemolytic anemia. Clinical signs include lethargy, weakness, anorexia, pale mucus membranes, icterus, pyrexia, vomiting, systolic murmur, tachycardia, hepatomegaly, splenomegaly and mild lymphadenopathy. The diagnosis is usually made by finding a positive Coombs' test, autoagglutination when blood is mixed with an equal volume of saline, and the presence of spherocytes on the blood smear. Other causes of hemolytic anemia—such as hematogenous parasites, toxins, metabolic derangements (hypophosphatemia, hypotonicity or severe acidosis), mechanical damage to red blood cells and genetic defects—should be ruled out with history and diagnostic testing.

Current treatment protocols are based mostly on subjective information and are modified as new information is obtained from research findings and retrospective studies. This discussion will summarize some of the newer ideas in treatment of this acute, life-threatening disease.

Treatment goals

The first goal of IMHA treatment is to improve oxygen delivery to cells to prevent the terrible consequences of multiple organ dysfunctions. In anemic animals, the best way to improve oxygen delivery to cells is to increase the hemoglobin concentration of the blood. In the past, veterinarians have avoided blood transfusions so they wouldn't "add fuel to the fire." Now realized is that poor oxygenation can result in liver failure, coagulation activation, release of inflammatory cytokines, endothelial damage, myocardial depression and initiation of the systemic inflammatory response syndrome.

Rather than let an animal remain severely anemic (PCV <12%) for prolonged periods, most veterinarians prefer to maintain the hemoglobin between 7-10 g/dl and the hematocrit between 20-30 percent. This goal can be achieved through the administration of purified bovine hemoglobin (Oxyglobin®), packed red cells or stored whole blood. Some veterinarians prefer to use Oxyglobin initially in dogs with severe autoagglutination in the hope that a blood transfusion will be better tolerated after several days of immunosuppressive therapy. The dose of Oxyglobin is 15 ml/kg over three hours given twice daily. Once autoagglutination begins to resolve, a transfusion of packed red cells can be given at a dosage of 10-15 ml/kg over four hours. Whole blood can be used instead of packed red cells, but it is more likely to cause volume overload because it contains plasma as well as red blood cells. Dogs with hemolytic anemia have normal plasma protein levels despite reduced red cell mass. It is not necessary to crossmatch a dog that has never been transfused, since dogs do not have naturally occurring antibodies against red blood cell antigens. If the dog has been previously transfused more than five days earlier, blood must be crossmatched before transfusion to avoid serious reactions.

The second goal of IMHA treatment is to provide adequate perfusion in order to promote tissue oxygenation, avoid capillary stasis that predisposes to thrombosis, and provide for diuresis of hemoglobin from lysed cells. In the past, veterinarians avoided intravenous catheters in animals with IMHA because of concern that they might predispose the animal to thrombosis. Many animals with IMHA have nausea, anorexia and vomiting, leading to the potential for dehydration and electrolyte and acid-base abnormalities. In the past, veterinarians also worried that intravenous fluids would dilute the hematocrit even lower. This is not a concern if hemoglobin levels are maintained with Oxyglobin or transfusions. Animals that have autoagglutination, dehydration, capillary stasis and poor perfusion are at risk for thrombosis and should receive intravenous fluids. Once dehydration is corrected, fluids should be administered at 1- to 1.5-times maintenance rate until the animal is eating and drinking, and autoagglutination is no longer present.

The third goal of IMHA treatment is immunosuppression. Glucocorticoids remain the mainstay of treatment despite the common side effects of polyuria, polydipsia, polyphagia, weight gain, hair loss, panting and urinary incontinence. Initial treatment begins with prednisone (2.2 mg/kg PO q 2 h) until the hematocrit reaches 25-30 percent. The dose is gradually tapered by approximately 25 percent (q 2-3 weeks) until a dose of 0.5 mg/kg PO q 48 hrs is reached. Some dogs must remain on low-dose prednisone for life to avoid relapses. In dogs that are vomiting, injectable dexamethasone (0.3 mg/kg IV q 12 h) can be used. The dose is much lower than the prednisone dosage because dexamethasone is seven to 10 times more potent.

In severe cases (autoagglutination, hemolytic crisis with rapid decline in hematocrit, and/or intravascular hemolysis), azathioprine (2.2 mg/kg PO q 24 h) is added to suppress T-cell function as well as to decrease immunoglobulin production. Side effects of azathioprine include bone marrow suppression, gastrointestinal upset, hepatotoxicity and possible exacerbation of pancreatitis. In most cases, it is well tolerated by dogs but should not be used in cats. Retrospective studies of dogs with IMHA have shown the longest survival times in dogs receiving the combination of prednisone and azathioprine.

Cyclosporine was originally used in humans to prevent rejection of organ transplants. It suppresses interleukin-2 and other cytokines, thereby blocking the proliferation of activated T-cells. It is now available as a veterinary product (Atopica, Neoral) and has been used for immune-mediated diseases such as perianal fistulas, histiocytosis and inflammatory bowel disease. Although it is expensive, it may be effective in refractory cases of IMHA, especially those that are nonregenerative. It is given at a dose of 5-10 mg/kg divided BID to achieve plasma trough levels >200 mg/ml. Large-breed dogs can be dosed concurrently with ketoconazole (10 mg/kg daily) to allow reduction of the cyclosporine dose through inhibition of hepatic microenzymes, making treatment more economical.

Cyclophosphamide seems to be falling out of favor as an adjunctive treatment for IMHA, as recent retrospective studies have shown no benefit over prednisone alone. Furthermore, the potential side effects are serious and include marked myelosuppression, gastrointestinal signs and hemorrhagic cystitis. Cyclophosphamide can be given orally at a dosage of 1-2 mg/kg (50 mg/m2 ) for four days a week. Alternatively, it can be given as a weekly injection of 100-200 mg/m2 IV.

Human intravenous immunoglobulin (IVIG) has shown some benefit in IMHA animals that are refractory to conventional treatment. It is given at a dose of 0.5-1.5 g/kg IV over 12 hours. It binds the Fc receptors on mononuclear phagocytes and down-regulates immunoglobulin production. It has both immediate and long-term effects, but is very expensive.

Mycophenolate mofetil (MMF, CellCept, Roche Labs) is a novel immunosuppressive drug used in people to prevent transplant rejection. Because of its relative specificity for lymphocytes, myelosuppression is not a common side effect. The drug has been used in people to treat psoriasis, vasculitis, systemic lupus, nephrotic syndrome and uveitis. In dogs, limited use has shown a beneficial response in those with IMHA, myasthenia gravis and glomerulonephritis. It is given in conjunction with prednisone (2.2 mg/kg q 12-24 h) at a dosage of 12-17 mg/kg PO SID or divided BID.

Another drug that may show promise in dogs with IMHA is leflunomide (Arava, Aventis Pharmaceuticals, Kansas City, Mo.). At a dosage of 4 mg/kg PO daily with a trough concentration of 20 mcg/ml, leflunomide showed beneficial results in a limited number of dogs with IMHA, systemic histiocytosis and immune-mediated thrombocytopenia. The drug is very expensive, but was effective in reducing or negating the need for glucocorticoids.

Because the spleen is the major site of RBC removal in dogs with IMHA, splenectomy has been recommended in dogs refractory to immunosuppressive therapy. Results are often discouraging because the dogs are poor surgical candidates when splenectomy is considered as a last resort therapy. However, a recent preliminary study has shown improved survival in dogs receiving early splenectomy in conjunction with prednisone and azathioprine therapy. Splenectomy is not recommended if there is any suspicion of hemoparasites.

The fourth goal of therapy is to prevent serious side effects of IMHA. The most life-threatening consequence of IMHA is pulmonary thromboembolism (PTE). Various doses of heparin have been advocated to prevent this life-threatening complication in dogs with IMHA. Recent evidence reveals that doses lower than 300 U/kg SC q 6 h are usually ineffective in achieving desired target levels of heparin. Subtherapeutic doses of heparin may actually exacerbate the tendency toward thrombosis. Most success has been in administering heparin as a constant-rate infusion at a dose of 18 U/kg per hour following an IV bolus of 80 U/kg IV. The activated partial thromboplastin time (APTT) should be monitored twice daily and the infusion adjusted to keep its activity at 1.5 to 2 times baseline. Low molecular weight heparins have increased bioavailability, a longer half life, and are safer than unfractionated heparin; but low molecular weight heparins are more expensive. Unfortunately, preliminary trials have not been encouraging.

The best preventive against PTE, disseminated intravascular coagulation, hypercoagulable state and tendency toward thrombosis in dogs with IMHA appears to be ultra-low-dose aspirin (0.5 mg/kg PO q 24 h). Dogs that received prednisone, azathioprine and ultra-low-dose aspirin had the longest survival times.

Other supportive care includes gastrointestinal protectants (sucralfate and an H2 blocker) during the initial high doses of glucocorticoids. Doxycycline (5 mg/kg q 12 h for 14-21 days) is often administered if there is thrombocytopenia or any suspicion of tick-borne disease.

Dogs should not be vaccinated again or receive any penicillin, sulfa or cephalosporin drugs. All dogs previously diagnosed with IMHA will relapse, so extended initial drug therapy for IMHA, not using certain drugs and not vaccinating are ways to decrease the likelihood of an IMHA relapse.

Johnny D. Hoskins

Dr. Hoskins is owner of DocuTech Services. He is a diplomate of the American College of Veterinary Internal Medicine with specialities in small animal pediatrics. He can be reached at (225) 955-3252, fax: (214) 242-2200 or e-mail: jdhoskins@mindspring.com.