Immune-mediated haemolytic anaemia (IMHA) is an autoimmune disease in which red blood cells are targeted by antibodies, leading to haemolysis. This may occur either within the vascular system, or extravascularly within the liver or spleen. In primary IMHA, no underlying cause is determined and normal red blood cells are targeted by antibodies. While primary IMHA is more common, secondary IMHA can also occur, where antibodies target red blood cells that have been altered by drugs, neoplasia, parasites or infectious diseases (McCullough 2003; Smith and Tappin, 2012).
Predispositions
IMHA is the most common reason for haemolytic anaemia in canine patients, however it is uncommon in cats (Woolcock and Scott-Moncrieff, 2019). Breeds including Springer Spaniels, Cocker Spaniels, Old English Sheepdogs, Collies and Poodles have been shown to be predisposed to IMHA (Smith and Tappin, 2012). The age of onset may range between 1–13 years, with a median age of 6 years (Smith and Tappin, 2012). Females are reportedly over represented (Garcia and South-Bodiford, 2012).
Prognosis
Various sources report that acute primary IMHA has a guarded prognosis, with Mitchell (2017) reporting numbers of dogs surviving to discharge is 50–80%. Garcia and South-Bodiford (2012) stated that between a third and two thirds of dogs with IMHA succumb to the disease, with thrombotic complications being a large factor. Jaundice, thrombocytopenia and hypoalbuminaemia may also be associated with a higher mortality rate. Piek (2011) reported around 50% of canine IMHA patients do not survive the first 2 weeks following presentation, and that this high mortality is linked with liver and kidney failure, hypercoagulability and inflammatory response. More recently, Goggs et al (2015) reported a mortality rate of 32.6% at 30 days from admission.
Clinical presentation
On clinical presentation the history and physical examination may vary depending on severity and how acutely the onset of anaemia has occurred (Tzannes, 2008; Mitchell, 2017). Piek (2011) reported that anaemia may develop rapidly, in as little as 3 days. Canine patients with IMHA typically present with an acute onset of clinical signs (Goggs and Hackner, 2019). As a result of the destruction of red blood cells (RBCs), anaemia is often marked, therefore clinical signs associated with this are often found (Garcia and South-Bodiford, 2012; Breton, 2015). Weakness, lethargy, exercise intolerance, anorexia and depression are common (Mitchell, 2017), along with vomiting and fever (Goggs and Hackner, 2019). These patients may also be collapsed, tachypnoeic and tachycardic on arrival, with bounding pulses. Pale mucous membranes are commonly revealed on clinical examination (Figure 1), as well as icterus because of the release of bilirubin, and prolonged capillary refill time. A heart murmur may also be found. Concurrent thrombocytopenia may be signalled by petechial haemorrhage, melena and/or epistaxis (Tzannes, 2008; Breton, 2015; Mitchell, 2017).
Diagnostic tests
Diagnostic testing should be used with the following goals in mind:
- To determine if the patient has IMHA
- If IMHA is indicated, then to attempt to differentiate between primary and secondary IMHA
- To identify the presence of any factors that have been found to have links with poorer outcomes, in order to estimate a prognosis (Garcia and South-Bodiford, 2012).
Diagnosis of IMHA usually involves identification of regenerative anaemia (typically with a haematocrit of less than 25%), presence of spherocytes, autoagglutination on a saline agglutination test, or a positive Coombs' test (Smith and Tappin, 2012).
The IMHA patient should undergo investigations for underlying causes or disease that may indicate secondary IMHA (Garcia and South-Bodiford, 2012; Smith and Tappin, 2012; Mitchell, 2017). This may include a complete blood count (CBC), a biochemistry profile, diagnostic imaging, and urinalysis and culture (Goggs and Hackner, 2019).
Tests for tick-borne diseases can also be undertaken as this may trigger IMHA (Garcia and South-Bodiford, 2012).
Saline agglutination test
A positive saline agglutination test is definitive for IMHA (Garcia and South-Bodiford, 2012); however, persistent agglutination may not be seen in every case, and its presence does not enable differentiation between primary and secondary IMHA (Goggs and Hackner, 2019). Macro agglutination may be visible to the naked eye (Figure 2), but saline agglutination tests should also be reviewed under the microscope to look for microagglutination and rule out rouleaux. Rouleaux is the stacking of red blood cells as opposed to agglutination, which is described to resemble a cluster of grapes (Garcia and South-Bodiford, 2012; Mitchell, 2017).
Complete blood count and blood smear evaluation
A CBC should be used to establish the presence of anaemia. Regenerative anaemia would be expected in the IMHA patient (Garcia and South-Bodiford, 2012; Smith and Tappin, 2012). Regenerative anaemia is identified by the presence of increased reticulocytes in the circulation (Garcia and South-Bodiford, 2012). Platelet numbers are also determined; if low, Evans syndrome may be present. This is a combination of IMHA with immune-mediated thrombocytopenia (Garcia and South-Bodiford, 2012; Smith and Tappin, 2012). Increased white blood cell counts are often identified. A manual blood smear should be evaluated alongside CBC results, to look for spherocytosis, and microscopic autoagglutination (Garcia and South-Bodiford, 2012).
Spherocytosis
Spherocytes are formed when phagocytosis of antibodycoated red blood cell membranes has occurred. Therefore, they provide evidence that antibodies are being directed against red blood cells. The presence of spherocytosis is not specifically indicative of IMHA; however, it is extremely suggestive (Smith and Tappin, 2012). Spherocytes can be quantified using a microscope (Piek, 2011), and are small, dense red blood cells, lacking in central pallor (Garcia and South-Bodiford, 2012; Smith and Tappin, 2012).
Coombs' test
In cases where IMHA is suspected, however not supported by a positive saline agglutination test or spherocytosis, a Coombs' test is indicated (Garcia and South-Bodiford, 2012). A Coombs' test detects anti RBC antibodies, and may identify patients with IMHA that have these antibodies in quantities too low to produce a positive agglutination test. However, a negative result cannot exclude an IMHA diagnosis (Smith and Tappin, 2012).
Coagulation testing
Coagulation testing may be indicated to rule out anaemia as a result of coagulopathy (Mitchell, 2017). Coagulation abnormalities are common in patients with IMHA and there is a risk of thrombosis (Garcia and South-Bodiford, 2012).
Biochemistry profile
Biochemistry testing may reveal various abnormalities, such as hypoalbuminaemia, hyperbilirubinaemia and increased liver enzymes including alkaline phosphatase (ALP) and alanine aminotransferase (ALT). A higher bilirubin level is associated with a poorer prognosis (Davidow and Oncken 2004; Garcia and South-Bodiford, 2012; Swann et al, 2019).
Hypoalbuminaemia, as a result of marked inflammation, is again associated with a poorer outcome (Garcia and South-Bodiford, 2012).
Lactate
Blood lactate levels are accurate indicators of tissue perfusion. Therefore, lactate levels should be monitored in any critical patient at risk of hypoperfusion (Schumacher, 2020). Breton (2015) asserted the importance of maintaining adequate perfusion in IMHA patients.
Holahan et al (2010) found that 84% of IMHA cases presented with hyperlactataemia. Blood lactate in the non-surviving patients was higher on admission than those that survived. However, patients whose hyperlactataemia normalised within 6 hours survived. Therefore, Holahan et al (2010) concluded that persistent hyperlactataemia was more likely to indicate poorer prognosis. Schumacher (2020) also recommended repeated lactate level assessment to monitor disease process in the critical patient, and stated that unsuccessful attempts to lower lactate levels may be associated with poorer outcomes.
Urinalysis
Bilirubinuria or haemoglobinuria may be present, and dogs with IMHA may also have urinary tract infections (Mitchell, 2017). Urinalysis is also recommended periodically for patients receiving glucocorticoids; a first-line treatment option for IMHA patients (Swann et al, 2019).
Diagnostic imaging
It is useful to complete imaging studies in patients with IMHA, in order to look for underlying disease that may indicate secondary IMHA. Thoracic and abdominal radiographs, as well as abdominal ultrasound, may be undertaken (Garcia and South-Bodiford, 2012; Smith and Tappin, 2012). Thoracic radiography is useful to look for neoplasia, signs of pulmonary thromboembolism (PTE), or rule out heart disease in patients with a heart murmur on presentation (Smith and Tappin, 2012). Investigations most commonly reveal splenomegaly and/or hepatomegaly in patients with IMHA, and may also show pleural and/or peritoneal effusions (Mitchell, 2017).
Treatment
Treatment goals for managing the IMHA patient involve preventing RBC haemolysis, reducing tissue hypoxia and preventing thromboembolism, as well as supportive care (Woolcock and Scott-Moncrieff, 2019).
Immunosuppressive treatment
Immunosuppressive drugs are used to prevent haemolysis, with high dose glucocorticoids being the first option used in IMHA patients (Swann et al, 2019; Woolcock and Scott-Moncrieff, 2019).
A combination of immunosuppressives is usually used, in order to reduce the side effects that may occur with single therapy (Garcia and South-Bodiford, 2012). Glucocorticoids are predominantly used, with injectable dexamethasone available if prednisolone is contraindicated as a result of vomiting or nausea. Further medications, such as azathiopine, cyclosporine, leflunomide and mycophenolate mofetil, may also be introduced (Garcia and South-Bodiford, 2012; Swann et al, 2019). Swann et al (2019) reported following a comparison of available studies, that it is yet to be established whether the introduction of a second immunosuppressive is beneficial. Consequentially, this may be an area for research in the future. Intravenous human immunoglobin (IVIG) has been used in IMHA cases to reduce immune-mediated destruction. However, this is an expensive treatment option which can be difficult to acquire (Garcia and South-Bodiford, 2012; Breton, 2015). It is not known to be more effective than other treatment options in terms of prognosis and survival of IMHA canine patients (Garcia and South-Bodiford, 2012; Swann and Skelly, 2016). Swann et al (2019) do not recommend IVIG administration in routine treatment, however this option may be used in patients not responding despite receiving two immunosuppressive treatments.
Blood transfusions
Blood transfusions may be used to support oxygen-carrying capacity in the circulation. The severity of clinical signs, as well as the packed cell volume (PCV), are used in deciding whether to transfuse. Patients with a PCV below 12%, and/or those presenting with tachycardia, tachypnoea, collapse, lethargy, weakness, poor or bounding peripheral pulses and/or pallor may require a transfusion (Smith and Tappin, 2012). Packed red blood cells are usually used in dogs with IMHA (Figure 3) as they do not often need the plasma component of whole blood, unless they exhibit significant coagulopathies (Garcia and South-Bodiford, 2012). Therefore, there is usually no added benefit to administering whole blood, unless significant thrombocytopenia is present such as in Evan's syndrome. It may also increase the risks of transfusion reaction or fluid overload (Garcia and South-Bodiford, 2012; Swann et al, 2019)
Preventing thrombosis
Thrombi formation is a major complication in canine IMHA patients, with PTE reported most frequently. Thrombi may occur in the rest of body, such as the spleen, kidneys, liver or brain (Swann and Skelly, 2016).
Anti-thrombosis medications are recommended for all IMHA canine patients by Swann et al (2019) unless severe thrombocytopenia is present, because of the substantial evidence that IMHA patients have an increased risk of thrombosis, which is a leading factor in morbidity and mortality of these patients. The medications used in IMHA treatment such as high dose glucocorticoids or IVIG may also increase the risk of thrombosis. The risk of haemorrhage when antithrombotic medications are used at recommended doses is likely to be small (Swann et al, 2019).
Treatment with heparin or low dose aspirin may be considered as a thrombosis preventative (Garcia and South-Bodiford, 2012; Swann and Skelly, 2016). Clopidogrel may also be used in some cases. The preferred choice of anticoagulant may vary between clinicians, and is likely to differ as a result of the individual patient's severity (Swann and Skelly, 2016). According to Swann et al (2019), further evidence is required to make strong recommendations regarding the choice of a particular anticoagulant. However, Swann et al (2019) suggested a preference for clopidogrel over aspirin.
Therapeutic plasma exchange
Therapeutic plasma exchange (TPE) may be used to treat canine immunological diseases, alongside medical treatment. However more research into its efficacy is required. TPE involves removing large volumes of plasma from the patient and replacing this with fresh plasma. Antibodies targeting red blood cells are removed, reducing haemolysis and assisting initial stabilisation. The costs involved, particularly in larger dogs, are likely to affect the selection of this treatment option (Francey et al, 2021). In addition, from the authors' research, only one hospital in the UK is currently able to offer this treatment.
Current research by Francey et al (2021) suggested outcomes are as good as with medical management alone, however limitations as a result of small numbers, the retrospective nature of the study, and the use of TPE in only those patients not responding to initial treatment, may support the need for further research.
Splenectomy
The clinician may consider a splenectomy, since this may help reduce destruction of RBCs. However, Breton (2015) advised that this is recommended as a last resort, as a general anaesthetic brings abundant risk factors for the patient. It is also not recommended if the patient has concurrent thrombocytopenia.
Strong evidence in human medicine, as well as limited canine studies may suggest possible success of splenectomy in management of IMHA. However, further investigation may be required (Swann and Skelly, 2016).
Studies in dogs with IMHA undergoing splenectomy have been undertaken, however because of the lack of control groups, it is difficult to ascertain the effect of splenectomy on outcome (Swann et al, 2019).
Gastroprotectants and antimicrobials
Supportive treatment including gastroprotective drugs and antimicrobials is sometimes administered to dogs with IMHA, on an individual case-to-case basis (Swann et al, 2019). Breton (2015) stated that gastroprotectants are often used because of the risk from glucocorticoids, disseminated intravascular coagulation (DIC), thrombocytopenia or ischaemic injury to the gastrointestinal mucosa in IMHA patients. Ischaemic injury to gastrointestinal mucosa in critical patients may lead to bacterial translocation, which has been associated with a higher incidence of sepsis in human patients, although requires further investigations in veterinary medicine (Krentz and Allen, 2017).
Swann et al (2019) advised gastroprotective medications should be used only if indicated by the presence of melena or other evidence of gastric ulcer, or in cases where there is a known or potential risk of gastrointestinal bleeding or ulceration. Antimicrobials should be used in dogs with a high risk of infection, and definitive diagnostics should be used to determine presence of pathogens (Swann et al, 2019).
Conclusion
Patients with IMHA may present in a critical state, with many clinical signs. They require intensive attention and comprehensive diagnostics. There are various treatment options available that the clinician may prescribe, and the RVN should be aware of what they involve, as well as possible complications. Further discussion of the impact of these is detailed in part 2, along with nursing and supportive care considerations.
KEY POINTS
- Canine patients with immune-mediated haemolytic anaemia (IMHA) may present in a critical condition and have a guarded prognosis.
- IMHA may be primary or secondary, therefore diagnostics should include investigating for any underlying cause.
- Immunosuppressive treatment is used to prevent haemolysis, with glucocorticoids being the first option.
- Blood transfusions may be used to increase oxygen carrying capacity, depending on the severity of the clinical signs and anaemia.
- Antithrombotic medications are often used in patients with IMHA because of an increased risk of thrombi formation, particularly pulmonary thromboembolism.