Immune-Mediated Hemolytic Anemia (IMHA) in Dogs

By Lisa Gorman, DVM, DACVIM
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Immune-mediated hemolytic anemia (IMHA) is a common immune-mediated disease in dogs and an important cause of severe anemia. IMHA occurs when autoantibodies are formed against red blood cells, leading to their destruction by phagocytic cells in the liver and spleen (extravascular hemolysis), or by complement proteins within blood vessels (intravascular hemolysis). This results in a rapid onset of potentially life-threatening hemolytic anemia.

Figure 1: Severe icterus and pallor of mucous membranes in a dog with IMHA

Although IMHA can occur in any dog, one large study noted that purebred dogs represented 89% of all cases, with Cocker and Springer Spaniels being overrepresented.¹ Clinical signs of IMHA are often non-specific, including lethargy, inappetence, and weakness. Owners may notice jaundice, particularly of the gums, sclera, pinnae, or poorly haired areas of the body such as the ventral abdomen. In cases of intravascular hemolysis, owners may notice discoloration of the urine secondary to hemoglobinuria. Physical exam may reveal an enlarged spleen and liver, which can occur secondary to both extravascular hemolysis and extramedullary hematopoiesis. Fever is frequently present due to the severe systemic inflammatory response, and compensatory responses to anemia such as tachycardia and tachypnea are common.

IMHA should be considered as a differential diagnosis in any dog with an acute onset of anemia that has evidence of hemolysis. An immune-mediated pathogenesis is supported by the presence of significant spherocytosis, a positive saline agglutination test, or a positive Coomb’s test. Any of these factors combined with evidence of hemolysis, such as hyperbilirubinemia, ghost cells, hemoglobinemia or hemoglobinuria is considered strong evidence for IMHA. Although most dogs with IMHA have a strongly regenerative anemia, approximately 30% will not have evidence of regeneration at the time of diagnosis.² In the majority of these dogs, this is due to the anemia being “pre-regenerative,” meaning the bone marrow has not had adequate time to mount a regenerative response.

Although most cases of IMHA are considered primary as they have no established underlying cause, some dogs with IMHA may develop the disorder secondary to another disease process. While many vector-borne diseases have been implicated in the development of IMHA, only Babesosis has strong evidence of truly causing IMHA in dogs. Other vector-borne pathogens, including Leishmania, Bartonella, and heartworm, have been associated with Coomb’s positive anemia, while others such as Anaplasma have been noted concurrently in patients with IMHA. The causal relationship of these infectious agents with IMHA has not been established, but treatment of infectious comorbidities is still an important part of therapy.² In areas like New England where tickborne infections are common, treatment with doxycycline while awaiting results of tick testing is a common and prudent practice. Although Babesia is a relatively uncommon infection, testing should be strongly considered in any dog with IMHA, particularly in overrepresented breeds such as pit bull terriers. There have been anecdotal associations of several types of cancer with IMHA, so imaging of IMHA patients with abdominal ultrasound and thoracic radiographs is often performed. An abdominal radiograph to rule out zinc foreign bodies such as coins that could lead to hemolysis is also an important diagnostic step. Unlike immune-mediated thrombocytopenia (ITP), there is not strong evidence of medications acting as triggers for IMHA, although drug-induced IMHA may still be possible. Similarly, no definitive link between vaccination and IMHA has been established.²

IMHA is treated with immunosuppressive medications, anti-thrombotic medications, and supportive therapy including blood transfusions. Multiple blood transfusions are often needed to stabilize the patient while waiting for immunosuppressive medications to take effect. Steroids are the mainstay of treatment for IMHA, with recommended starting doses of prednisone of 2 mg/kg/day, or 40-60 mg/m² for dogs >25 kg. Secondary immunosuppressive drugs such as cyclosporine and mycophenolate are frequently used, although there is no strong evidence of a beneficial effect with any of these medications. It is generally not recommended to use more than two immunosuppressive medications together due to the significantly increased risk of infectious complications. Since cyclophosphamide has been shown to potentially worsen outcomes in IMHA patients, this medication is not recommended.³

In cases of severe or refractory disease, more aggressive treatments may be considered. Human intravenous immunoglobulin (hIVIG) has been used as a salvage treatment for IMHA, although a survival benefit has not been established. Splenectomy has also been used in cases of refractory IMHA, and has been shown in some studies to result in reduced medication and transfusion requirements.³ Therapeutic plasma exchange is a newer therapy to remove autoantibodies in IMHA patients, and shows promise in stabilization of severe or refractory cases of IMHA.

Anti-thrombotic medications are an important part of therapy for IMHA, as thromboembolism is a leading cause of death in these patients. Because venous clots (particularly pulmonary thromboembolism) are most common in IMHA patients, anti-coagulant medications such as heparin may have better efficacy than anti-platelet agents like clopidogrel or aspirin.³ However, since heparin should ideally be adjusted in each individual patient based on measurement of anti-factor Xa levels, this is not a practical option for most patients. Rivaroxaban is a newer oral factor Xa inhibitor that is used in human medicine to prevent venous thrombosis without requiring monitoring of anti-Xa levels. Although rivaroxaban has not yet been widely used in canine IMHA patients, one small study did show it was well-tolerated and not associated with bleeding complications in this patient population.⁴ This medication is currently prohibitively expensive for many veterinary patients, but may become a better option in the future if generic versions become available.

Because of the current practical limitations associated with anti-coagulant medications in veterinary patients, most dogs with IMHA are given clopidogrel or aspirin to try to prevent thromboembolism. Clopidogrel (1.1-4 mg/kg once daily) is the preferred choice over aspirin, both because of unpredictable platelet inhibition for low doses of aspirin, and a higher likelihood of inducing gastrointestinal bleeding if aspirin is used.³ A recent study showed that in healthy dogs, clopidogrel alone is not associated with development of GI bleeding, and its use in addition to prednisone does not increase GI bleeding risk compared to prednisone alone.⁵ However, administration of aspirin alone was associated with GI bleeding in healthy patients. Furthermore, dogs that received aspirin and prednisone together had more severe lesions on endoscopy after 2 weeks of treatment than dogs receiving prednisone alone.⁶ Generic clopidogrel is widely available and inexpensive, making it simple to use for most owners.

The prognosis for patients with IMHA is guarded, with mortality rates of 50% and relapse rates of 6-13% commonly reported.⁷ Patients are at greatest risk during the acute phase of treatment, when immunosuppressive medications have not yet reached full effect and the risk for thromboembolic disease is highest. However, patients that make it through this period may have prolonged survival with appropriate continued therapy and monitoring. In general, the dose of prednisone should be reduced every 3 weeks as long as the hematocrit remains stable above 30%, and evidence for ongoing hemolysis (such as spherocytosis) is minimal. It is recommended to continue anti-thrombotic medication until prednisone has been discontinued, since use of steroids is associated with increased risk of thrombosis. If secondary immunosuppressive drugs such as cyclosporine or mycophenolate are used, they are typically tapered or discontinued only after patients have been successfully weaned off of prednisone. Due to the slow nature of the taper recommended for IMHA, owners should be prepared that patients will be on immunosuppressive medications for at least 3-6 months.³

IMHA is a serious disease, with death frequently occurring from thromboembolic disease or severe anemia. However, patients treated appropriately and aggressively that make it through the initial period of hospitalization may have prolonged survival with a good quality of life.

Figure 2: Severe icterus of the sclera in a dog with IMHA

References

1. Predicting outcome in dogs with primary immune-mediated hemolytic anemia: results of a multicenter case registry. Goggs, R. et al. J Vet Intern Med 2015; 29: 1603-1610.
2. ACVIM consensus statement on the diagnosis of immune-mediated hemolytic anemia in dogs and cats. Garden, O.A. et al. J Vet Intern Med 2019; 33: 313-334.
3. ACVIM consensus statement on the treatment of immune-mediated hemolytic anemia in dogs. Swann, J.W. et al. J Vet Intern Med 2019; 33: 1141-1172.
4. Evaluation of the safety and tolerability of rivaroxaban in dogs with presumed primary immune-mediated hemolytic anemia. Morassi, A. et al. J Vet Emerg Crit Care 2016; 26: 488-494.
5. Clinical, clinicopathologic, and gastrointestinal changes from administration of clopidogrel, prednisone, or combination in healthy dogs: a double-blind randomized trial. Whittemore, J.C. et al. J Vet Intern Med 2019; 33: 2618-2627.
6. Clinical, clinicopathologic, and gastrointestinal changes from aspirin, prednisone, or combination treatment in healthy research dogs: a double-blind randomized trial. Whittemore, J.C. et al. J Vet Intern Med 2019; 33: 1977-1987.
7. Systematic review of evidence relating to the treatment of immune-mediated hemolytic anemia in dogs. Swann, J.W. and Skelly, B.J. J Vet Intern Med 2013; 27: 1-9.