A practical approach to managing immune-mediated hemolytic anemia

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Immune-mediated hemolytic anemia (IMHA) is seen in both dogs and cats and has the potential for high mortality. Because treatment requires prolonged administration of immunosuppressive medications, obtaining an accurate diagnosis is essential. Christopher Byers, DVM, DACVECC, DACVIM (SAIM), CVJ, founder of CriticalCareDVM.com, discussed a practical approach to the diagnosis and management of immune mediated hemolytic anemia in dogs and cats, during a session at the 2023 Fetch Coastal conference in Atlantic City, New Jersey.¹

The Diagnostic Challenge

“What I want you to do is make an accurate diagnosis,” said Byers. “Proving each component of the name of the disease is required.” There must be evidence of anemia that is caused by hemolysis and is immune-mediated. Each of these components requires different information to prove. Diagnosing anemia is the easiest part and can be done with a complete blood count (CBC) or even simply a packed cell volume (PCV) test and total solids.

Proving the condition is immune-mediated and includes hemolysis is more challenging. Evidence of immune-mediated destruction includes a positive saline slide agglutination test (SAT), direct Coomb’s test, spherocytosis (in dogs), and flow cytometry. Byers noted that with the SAT, “what is unquestionably important, regardless of the number of [saline] drops, is that we wash the red blood cells.” Evidence of hemolysis includes hyperbilirubinemia and bilirubinuria in the absence of hepatobiliary disease, hemoglobinemia and hemoglobinuria, spherocytosis (in dogs), and the presence of ghost cells.

“Even with unlimited financial resources, making a definitive diagnosis can be pretty challenging,” shared Byers. There are 3 categories of diagnosis listed in the American College of Veterinary Internal Medicine (ACVIM) Consensus statement on diagnosing IMHA²:

1. A definitive diagnosis requires 2 or more signs of immune-mediated destruction or a positive SAT that persists with washing and 1 or more sign of hemolysis.
2. A supportive diagnosis requires 1 sign of immune-mediated destruction and at least 1 sign of hemolysis.
3. A suspicious diagnosis is made when there is 1 sign of immune-mediated destruction with no evidence of hemolysis and other causes of anemia have been ruled out.

Nonassociative vs associative disease

Even after a definitive, supportive, or suspicious diagnosis of IMHA is reached, further diagnostics are needed to determine if the disease is nonassociative (formerly known as primary) or associative (formerly known as secondary). Underlying causes of IMHA can include infectious diseases, neoplasia, inflammatory diseases, vaccinations, and some drugs.

Byers noted that “this is a scenario where dogs and cats are very different. Dogs have nonassociative disease until proven otherwise.” It is still important to do the diagnostic investigation though, as patients with associative disease will have a better prognosis if the underlying condition is identified and addressed. On the other hand, cats most often have associative IMHA. According to Byers, “realistically, cats [with IMHA] have an infectious disease or neoplasia until proven otherwise.”

Obtaining a thorough history is essential. “Any time we are concerned about an immune-mediated process, I want to know about travel history, flea and tick preventives, and any recent exposure to vaccinations or antimicrobials,” said Byers. A basic diagnostic workup starts with a thorough history, physical examination, CBC, chemistry panel, and urinalysis. Hematologic testing is required to make the diagnosis of IMHA, as discussed above.

Additional diagnostics to look for an associative condition include imaging of the thorax and abdomen, infectious disease screening (which varies by geographic area), and bone marrow sampling. Byers encourages general practitioners to perform bone marrow sampling in primary care, especially if the patient lacks a regenerative response within 5-7 days of diagnosis or has bi- or pancytopenia. He recommended obtaining samples for both cytology and histopathology.

Immunosuppressive therapy

The core of treatment for IMHA is immunosuppression with corticosteroids. The 2019 ACVIM Consensus on the treatment of IMHA recommends prednisone at 2-3 mg/kg/day for patients less than 25 kg and 50-60 mg/m2/day for patients over 25 kg.3 An equivalent dose of dexamethasone can be used for patients that are not eating. Based on personal experience, Byers recommended a slightly lower dose for dogs (1-2 mg/kg/day for patients less than 25 kg and 40 mg/m2/day for larger patients) and a higher dose for cats (2-4 mg/kg/day). Byers reminded clinicians to prepare owners for the expected adverse effects of corticosteroids.

Adding an additional immunosuppressant agent from the beginning is strongly recommended.³ If a secondary agent is not started immediately, it should be started with a PCV that drops more than 5% in a 24-hour period, a PCV that does not improve within 1 week, and a patient not tolerating corticosteroids.

Secondary agents include cyclosporine (at higher doses than what is used for atopy), mycophenolate, azathioprine (in dogs only), and leflunomide. Byers noted there is no data that shows superiority of one agent to another and the choice of second agents is often clinical preference, though cost may play into the decision as well. The use of 3 or more immunomodulating agents is not recommended because of an increased risk of sepsis.³ Intravenous immunoglobulin therapy may be considered for patients that have not responded to traditional treatment, though there is little data available to support its use.

The ACVIM Consensus suggests that immunomodulating agents can be weaned once the patient is clinically well with a stable PCV above 30% for at least 2 weeks. Dosage reductions should be made in small increments (less than 25%) one drug at a time. Byers prefers to wait for patients to be stable for at least 3-4 weeks before beginning weaning. He recommended utilizing technician appointments to help with the monitoring for dosage adjustments, checking a PCV 1 week after any dosage decrease.

Additional therapy

Some patients will need packed RBC transfusions early in the course of the disease. For Byers, the decision to transfuse is based on the clinical signs of the patient, not a particular PCV or laboratory value. Plasmapheresis is becoming increasingly available in some areas but is cost-prohibitive for many owners. Splenectomy is only indicated in cases of extravascular hemolysis.

“The number one killer of dogs with IMHA other than euthanasia is thromboembolic disease,” shared Byers. Thromboprophylaxis is recommended for dogs with IMHA, which can be anticoagulants such as heparin or antiplatelet drugs such as clopidogrel. This is not a concern in feline patients.

Take Home Points

Obtaining a diagnosis of IMHA can be challenging and requires proof of anemia, immune-mediated destruction, and hemolysis. Underlying causes for the disease should be investigated, though the disease is most commonly nonassociative in dogs and associative in cats. Treatment relies on immunosuppressive therapy with corticosteroids. Secondary agents are strongly recommended. In dogs, thromboembolic disease is a common cause of death, so antithrombotic agents are recommended. The prognosis is variable but those that survive the first 2 weeks after diagnosis have a better long-term prognosis.

Kate Boatright, VMD, a 2013 graduate of the University of Pennsylvania, is a practicing veterinarian and freelance speaker and author in western Pennsylvania. She is passionate about mentorship, education, and addressing common sources of stress for veterinary teams and recent graduates. Outside of clinical practice, Boatright is actively involved in organized veterinary medicine at the local, state, and national levels.

References

1. Byers C. Immune-mediated hemolytic anemia–diagnosis and management. Presented at Fetch Coastal 2023: Atlantic City, NJ. October 9, 2023.
2. Garden OA, Kidd L, Mexas AM, et al. ACVIM consensus statement on the diagnosis of immune-mediated hemolytic anemia in dogs and cats. J Vet Int Med 2019;33(2):313-334. https://doi.org/10.1111/jvim.15441
3. Swann JW, Garden OA, Fellman CL, et al. ACVIM consensus statement on the treatment of immune-mediated hemolytic anemia in dogs. J Vet Int Med 2019;33(3):1141-1172. https://doi.org/10.1111/jvim.15463