Updates in Immune-Mediated Hemolytic Anemia (IMHA) in Dogs and Cats

By Tara Ghormley, DVM, DACVIM

What Is IMHA and Who Is at Risk? 

Immune-mediated hemolytic anemia (IMHA) is one of the most life-threatening hematologic diseases we encounter in veterinary practice. It is thought to arise from a genetic predisposition combined with environmental triggers. Certain breeds are more commonly affected, including Cocker Spaniels, Bichon Frise, Miniature Pinschers, Miniature Schnauzers, English Springer Spaniels, Rough-coated Collies, and Finnish Spitz. Although most cases occur in dogs, cats can also develop IMHA, though less commonly. A seasonal pattern may also exist.

How Patients Present 

Dogs 

Clinical signs are often vague and can appear suddenly. Symptoms may include inappetence and lethargy, pale or icteric mucous membranes, tachycardia and tachypnea, and fever. Patients may have a heart murmur, splenomegaly, or hepatomegaly. Common laboratory abnormalities include hemoglobinemia and/or hemoglobinuria, an inflammatory leukogram, thrombocytopenia and hyperbilirubinemia.

Cats 

Cats may show subtler changes including pale gums, icterus, heart murmurs and occasionally lymphadenopathy. Unlike dogs, they may lack a red blood cell regenerative response early on and often do not show neutrophilia. Instead, some develop lymphocytosis. They may also have concurrent problems such as DIC, hyperglobulinemia, or hepatic hypoxic damage.

Pathophysiology 

At its core, IMHA represents a failure of self-tolerance. The immune system inappropriately targets red blood cells (RBCs), leading to their destruction. Antibody-mediated destruction occurs when IgG and IgM bind to RBC membranes. IgG-coated cells are removed by splenic macrophages, which results in extravascular hemolysis. IgM is more likely to activate complement, causing direct RBC lysis and intravascular hemolysis. In some patients, antibodies target precursor cells, leading to precursor-targeted immune-mediated anemia (PIMA) or even pure red cell aplasia (PRCA). These forms are typically non-regenerative or minimally regenerative and carry a different prognosis.

Complications can occur secondary to inappropriate immune system activation. IMHA triggers widespread activation of tissue factor, fibrinogen, platelets, and endothelium, while suppressing natural anticoagulant pathways. This explains the high risk of thromboembolic complications.

Trigger Factors

IMHA can result from a specific trigger to the immune system or without a known inciting factor. These are termed associative (secondary) and non-associative (primary) disease.

A variety of conditions may precipitate associative IMHA:

Infectious diseases in dogs include Babesia spp. (especially B. gibsoni), Anaplasma, Ehrlichia, Leishmania, and Dirofilaria. Mycoplasma haemofelis is the most common infectious cause of IMHA in cats. Babesia felis, FeLV, FIV, FIP, and bacterial infections (soft tissue or urinary) are also possible triggers in cats, but less well documented.

Paraneoplastic syndromes can be seen in dogs, although there are limited studies on specific forms of neoplasia. In cats, evidence for a neoplastic trigger is lacking.

Sulfonamides and other medications are reported triggers. Anecdotally, vaccines have been considered a cause of IMHA. In one canine study, about 8% of IMHA cases had received a vaccine within the preceding 30 days. This may suggest a temporal relationship, although definitive causation has not yet been proven. In cats, no clear association with vaccination has been demonstrated.

Diagnosis

 A diagnosis of IMHA requires evidence of immune-mediated destruction plus evidence of hemolysis. These include the presence of spherocytes (dogs only; ideally ≥5 per 100× field), persistent saline agglutination after washing red cells, and a positive direct antiglobulin test (Coombs/DAT) or flow cytometry. The last two tests must be performed before immunosuppression or transfusion to avoid false negative and positive results.

Laboratory findings that indicate hemolysis include hyperbilirubinemia in the absence of cholestasis, bilirubinuria (normal up to 1+ in dogs but always abnormal in cats), hemoglobinemia or hemoglobinuria, and the presence of RBC ghosts on blood smear.

Once an autoimmune hemolytic process is diagnosed, testing to classify primary or secondary disease is required. These diagnostics may include urine culture, fecal floatation, thoracic radiographs, abdominal ultrasound, and infectious disease testing. For cats, FIV/FeLV testing is essential and Mycoplasma spp. PCR is recommended. Diagnostics should be tailored to the individual patient’s risk for a secondary trigger.

Treatment

When suspicion is high for IMHA, immunosuppression should begin after samples are collected. Treatment often lasts 3–6 months for steroids, and up to 4–8 months for combination regimens.

Glucocorticoids are the mainstay of treatment, with prednisone or prednisolone at 2–3 mg/kg/day in dogs. Due to significant steroid side effects in larger dogs, the dose should be based on body surface area, at 50–60 mg/m² /day. Cats may need up to 2 mg/kg every 12 hours. Dexamethasone sodium phosphate (0.2–0.4 mg/kg/day) is used if oral therapy is not tolerated or the patient is hospitalized and not eating. Once-daily dosing in dogs may reduce side effects compared to split dosing.

Adding a Second Agent

Indications to add a second medication to the glucocorticoid include severe disease, lack of stabilization in the first week, or intolerable steroid side effects. Options include:

• Azathioprine, starting at 2 mg/kg PO q24h. There is a risk of myelosuppression, hepatopathy, and pancreatitis. Azathioprine should never be used in cats.

• Cyclosporine at 5 mg/kg PO q12h. Therapeutic monitoring of drug levels is sometimes performed but not required. Side effects include GI upset (especially diarrhea), gingival hyperplasia, and rare hepatotoxicity. Cyclosporine must be a modified form (veterinary brand name Atopica, human brand name Neoral). Generic modified cyclosporine has been shown to reach adequate blood levels at high doses used for immune mediated diseases. Cyclosporine may be used in cats.

• Mycophenolate mofetil, dosed at 8–10 mg/kg PO q12h. GI upset is common. Mycophenolate is safe for cats.

• Leflunomide at 2–4 mg/kg/day, which inhibits pyrimidine synthesis. There is limited data for efficacy in IMHA and it may cause GI upset or hepatotoxicity.

Other Therapies

Additional therapies are often required. Blood products are almost always needed and packed red blood cells are preferred. Blood typing and cross-matching is not required for dogs without a history of transfusion but should always be performed in cats. To guide transfusion volume, the target PCV is 20% or higher.

Because thromboembolism is a leading cause of death, anticoagulation should be started unless platelet count <30,000/uL. Options include unfractionated heparin (150–200 U/kg SC q6h, adjust with anti-Xa assays), low molecular weight heparin (e.g., enoxaparin 0.8–1 mg/kg SC q6h), rivaroxaban (0.9 mg/kg PO q24h), and clopidogrel (1–4 mg/kg/day). Aspirin is less predictable and carries a higher risk of ulceration.

There are additional treatment options that can be considered for patients who do not respond to immunosuppression. IV immunoglobulin (IVIg) temporarily blocks antibody activity. It is costly and may not outperform traditional therapy. Therapeutic plasma exchange has been used in refractory cases, although there is limited veterinary data.

Splenectomy has been reported as an option in refractory cases.

Supportive Care

Many patients are inappetent and should receive supportive care while in hospital and recovering at home. These include antiemetics, appetite stimulants, and sometimes feeding tubes. GI protectants (proton pump inhibitors such as omeprazole or pantoprazole) are often added to counter steroid-related gastritis.

Relapse and Long-Term Management 

Relapses occur in 11–15% of cases. If the PCV drops, other causes such as GI bleeding, infection, or neoplasia must be ruled out. In some dogs, relapses may be linked to estrus, making spaying advisable.

• If a relapse occurs during tapering, the drug dose should be increased to the last effective level, followed by a slower taper.

• Some patients require years or even lifelong therapy which should be at the lowest effective doses of immunosuppressants.

• Caution is needed with medications and possibly vaccines in recovered patients, as they may act as triggers.

Prognosis

Prognosis in IMHA is variable. Mortality ranges widely, with a 60-day survival rate of about 60%. Most deaths result from thromboembolic complications rather than anemia itself.

Poor prognostic indicators include:

• Severe thrombocytopenia

• Bilirubin >5 mg/dL

• Hypoalbuminemia

• High ALT, low PCV, or lack of regenerative response

The CHAOS score (Canine Hemolytic Anemia Objective Score) helps stratify prognosis. A score ≥3 is associated with death within 30 days of admission. Interestingly, cats may have a better prognosis than dogs, though data are limited.

Key Takeaways

• IMHA is driven by immune-mediated destruction of red blood cells, often with genetic predisposition and environmental triggers.

• Diagnosis requires proof of both immune-mediated destruction and hemolysis.

• Prednisone/prednisolone is the first-line therapy although second-line immunosuppressants may be needed.

• Thromboprophylaxis is critical since thromboembolism is the leading cause of death.

• Relapses occur in 10–15% of patients; some need lifelong treatment.

Prognosis is guarded, with survival rates around 60% at 60 days in dogs. Cats may fare somewhat better.