Immune-mediated haemolytic anaemia (IMHA) is one of the most common immune-mediated diseases of dogs and cats. While our understanding of the disease mechanism has progressed and treatment options have increased, mortality rates remain high. Consequently, specialised monitoring and nursing care of IMHA cases is essential and can be very challenging.
Definition and Pathophysiology
Haemolytic anaemia is anaemia caused by increased destruction of erythrocytes (red blood cells). IMHA, a subtype of haemolytic anaemia, is due to an immune system disorder in which antibodies are made to 'self' erythrocytes resulting in erythrocyte destruction. It is the most common reason for haemolytic anaemia. IMHA can be defined as primary or secondary. This distinction is important when forming diagnostic and treatment plans.
Primary iMHa. IMHA is classified as primary (also known as idiopathic or autoimmune) when no inciting cause can be found and it appears to occur 'spontaneously'. Genetics play an important role and certain canine breeds (Cocker Spaniels, English Springer Spaniels, Old English Sheepdogs) have a higher incidence of IMHA. Primary IMHA is commonly seen in young to middle-aged animals. The incidence may be slightly higher in female dogs. Disease and inflammation may still be important triggers in many animals with primary IMHA. The role of vaccination remains unclear: some studies have suggested that vaccination may trigger IMHA in certain patients; this is based on seeing onset of disease shortly after a booster. However, other studies do not show this link. Thus, withholding vaccination to avoid IMHA cannot be justified.
Secondary iMHa. This is associated with an identifiable underlying disease, such as neoplasia or infection, or certain drugs. Therefore, secondary IMHA occurs more frequently in an older population than primary IMHA due to the higher incidence of neoplasia in this older age group. Breed predispositions are not recognised. This is the most common form in cats, although primary IMHA is rare in this species.
In both primary and secondary IMHA, 'self' antibodies coat erythrocytes. Erythrocytes then either rupture within the blood vessels (intravascular haemolysis) or are destroyed by macrophages outside the vessels (extravascular haemolysis) in organs such as the spleen and liver. In most cases the body attempts to compensate for the resultant anaemia by producing more erythrocytes. It is therefore termed a regenerative anaemia. If the disease is severe, compensation may be inadequate and the anaemia fatal. Thromboembolic disease is another frequent cause of death in critical patients and a hypercoagulable state is recognised in over half of our canine patients.
Clinical Presentation
History and signs are variable depending on the speed of onset and severity of disease. The spectrum ranges from collapse on presentation with acute or severe disease to lethargy with chronic, mild disease. Signs attributable to anaemia may include lethargy, collapse, exercise intolerance, tachycardia, heart murmur and pale mucous membranes. Haemolysis may cause pigmented urine due to haemoglobin (haemoglobinuria) or bilirubin (bilirubinuria), jaundice and fever. Some patients have vomiting, diarrhoea or eat unusual objects (pica). An enlarged spleen is common and occasionally lymph nodes are mildly increased in size. Concurrent immune-mediated thrombocytopenia (immune destruction of the platelets) can be seen in dogs. These patients may present with signs associated with low platelet counts (petechiation, melaena, etc).
Patients with secondary IMHA may display signs relating to their underlying disease.
Diagnosis
Diagnosis is based on demonstrating anaemia together with one of the following:
Positive direct Coombs' test
True auto-agglutination
Marked spherocytosis
A Coombs' blood test detects antibodies or other components of the immune system reacting against 'self' erythrocytes. Antibodies may also cause auto-agglutination, which is the formation of clumps of erythrocytes adhering to each other. This test is easy to perform and does not require specialised equipment, simply a centrifuge, saline and a glass slide. Agglutination can be visible either grossly or microscopically on the slide. If autoagglutination is present, there is no need to perform a Coombs' test. Spherocytes are small erythrocytes lacking a central pale region. They are formed after a macrophage takes a 'bite' from erythrocytes coated with immune components and thus reflect immune-mediated destruction. They are rarely identified in cats.
IMHA is primary if there is no evidence of underlying disease or a triggering drug. Thus, in addition to the tests above, some or all of the following tests are recommended in the diagnostic work-up of IMHA: haematology; biochemistry; urinalysis; radiography; abdominal ultrasonography; bone marrow sampling; and testing for infectious disease, including feline viruses and Mycoplasma haemofelis in cats. Coagulation profiles and blood gases can assist in management of the critical patient.
Treatment and Supportive Care
The treatment goals of primary IMHA are to stop the destruction of erythrocytes, increase tissue oxygenation, prevent thromboembolism and provide supportive nursing care. The goal of treating secondary IMHA is correction of underlying disease and providing necessary supportive care until its resolution. Without removal of the inciting cause, treatment of secondary IMHA with conventional therapies is generally unsuccessful.
Immunosuppressive drugs are the mainstay of treatment to stop erythrocyte destruction. These drugs may block the immune response and reduce antibody production. The most commonly used medications are corticosteroids (prednisolone, dexamethasone). The response to corticosteroids is usually within the first week of therapy. If the disease is severe or unresponsive to corticosteroids, other immunosuppressant therapy may be used concurrently in dogs (e.g., azathioprine (Imuran®), human immunoglobulin intravenous infusion (Flebogamma®), mycophenolate mofetil (Cellcept®)). It is important to handle the oral medications with care; always use gloves and avoid splitting or crushing the tablets. If the daily dose required for a patient is lower than the tablet quantity (i.e., 15 mg required, tablet size 25 mg), the total weekly dose is calculated and a dose as close to this as possible is delivered on alternate days (i.e., 15 mg x 7 days = 105 mg, thus administer a 25 mg tablet on Monday, Wednesday, Friday and Sunday). Urine and faeces should also be handled with gloves.
Each drug has side effects which the owners need to be aware of. As corticosteroids may increase urination and thirst in dogs, water should always be available. Increased appetite is common and it is important to counsel the owners carefully to prevent excessive weight gain. Iatrogenic hyper-adrenocorticism (Cushing's disease) may occur with longer-term therapy, with signs such as panting, lethargy, coat and skin changes, and a potbellied appearance. Gastrointestinal ulcers are a potential risk and may require treatment with gastrointestinal protectants. Insulin resistance may be seen in diabetic patients. Azathioprine can be associated with bone marrow suppression, pancreatitis, hepatic toxicity and gastrointestinal toxicity. Gastrointestinal toxicity may be seen with mycophenolate mofetil. Human immunoglobulin may cause serious systemic reactions during infusion or an anaphylactic reaction during repeat administration.
Increasing tissue oxygenation can be achieved with blood or bovine haemoglobin (Oxyglobin®) transfusions if required. Providing oxygen via mask or nasal prongs is usually not helpful. With any transfusion, an adverse reaction may occur, so monitoring of vital parameters throughout the procedure is essential. Transfusion reactions to blood are either due to an incompatibility with the donor cells or proteins (immunological reaction) or due to complications associated with volume overload, anticoagulant toxicity, bacterial contamination, thromboembolism etc. (non-immunological). Signs of a reaction include vomiting, diarrhoea, agitation or depression, skin oedema, urticaria, increased respiratory and heart rate, fever and seizures. Such signs prompt rapid discontinuation of the transfusion and potentially immediate medical intervention.
Prevention of thromboembolism is challenging. Anticoagulant drugs include heparin, low-molecular weight heparins (e.g., dalteparin (Fragmin®)), warfarin and low-dose aspirin.
Fortunately, many patients with IMHA do not have severe disease and can be managed as out-patients after initial diagnostics and initiation of medication. Advanced nursing care is essential for patients with severe disease. These patients may be recumbent and require appropriate bedding. Urine output is frequently monitored. Appetite is often depressed and providing adequate nutrition is critical with prolonged hospitalisation. Enteral nutrition is ideal if the patient is not vomiting (e.g., naso-oesophageal feeding tube, gastrotomy tube). As patients are immunosuppressed, they are vulnerable to infection. Particular care is needed with catheter hygiene, and patients should not be exposed to infectious disease via other hospitalised patients or common materials and equipment. Adverse effects of the medications should be recognised. Careful monitoring of the vital parameters may provide an early warning of patient deterioration due to worsening anaemia, thromboembolism (e.g., acute dyspnoea), or organ dysfunction. This will be complemented by laboratory blood tests (packed cell volume and total protein, biochemistry, coagulation profiles) as required. Minimising stress of the patient is also important due to their fragile status. Long term, for all patients, there is a predisposition to opportunistic infections. Recurrent urinary tract infections and bacterial pyoderma are common, and intermittent urinalysis should be performed along with the routine monitoring of haematology in management of the disease.
Prognosis
The morbidity of IMHA remains high. Severe cases carry a high mortality rate, with 30-40% of patients dying during initial hospitalisation. Overall, mortality rates as high as 70% are seen in the more critical patient population within the first year following diagnosis. Less severely affected patients may have a better outcome. Treatment may eventually be discontinued in a proportion of patients.