Immune mediated haematological diseases are commonly identified in dogs and to a lesser extent in cats. Immune mediated destruction of mature erythrocytes (i.e., immune mediated haemolytic anaemia [IMHA]) and platelets (i.e., immune mediated thrombocytopaenia) are most commonly encountered. This lecture will focus on treatment strategies for IMHA, with discussion of newer developments that may help with these cases.
Pathophysiology of IMHA
An understanding of the basic mechanisms underpinning immune-mediated diseases is helpful to understand the principles behind case management.1,2 Under normal circumstances, the immune system is adept at recognizing and removing foreign entities (e.g., bacteria). In the case of bacteria, molecular characteristics on their cell surface termed pathogen associated molecular patterns (PAMPs) like lipopolysaccharide interact with specialized receptors on immune system cells (pattern recognition receptors or PRRs). The engagement of PAMPs with PRRs kick starts intracellular signaling pathways within immune system cells leading to the transcription of genes involved in the adaptive immune response. The adaptive immune system is the specialized portion of the immune system based on the presence of ‘immunological memory’ mediated through a complex variety of cellular (white blood cell mediated) and humoral (antibody based) mechanisms. The endpoint of the interaction between the innate and adaptive immune responses is the elimination of foreign pathogens with the potential for established long-term protection through acquisition of immunological memory. In the context of immune-mediated disorders, specifically when considering auto-immune conditions, there may be inappropriate engagement of PRRs with self-antigens that have been falsely identified as being foreign. This might include red blood cell or platelet surface antigens leading to their elimination, much in the same way the immune system will target invading pathogens. The factors necessary for autoimmunity to occur are complex and multifactorial, including genetic predisposition, age, breed, neuter status,3 environmental triggers, the role of infection, as well as drug reactions. Clinically it can prove challenging to identify whether animals with immune-mediated disorders have primary (‘autoimmune’) diseases or whether their immune-mediated disorder has developed secondary to another comorbidity (e.g., infection, neoplasia).
In cases of IMHA, immune mediated targeting and destruction of red blood cells occurs.4,5 The destruction may occur within the vasculature affecting circulating erythrocytes (intravascular IMHA) or in organs of the haematopoietic system like the spleen (extravascular haemolysis). Middle aged to older dogs are commonly affected, with a possible predilection for females, with certain breeds of being over represented (e.g., Cocker Spaniels, Maltese Terriers, Dobermans). Clinical signs commonly seen in dogs with IMHA including tachypnoea and tachycardia are typically related to issues with impaired oxygen delivery to tissues due to anaemia (i.e., reduced haemoglobin mass impairing oxygen carrying capacity) rather than an inability to oxygenate normally (i.e., lungs are usually normal). Additional symptoms relating to the haemolytic process may be noted by owners, including very dark (‘port wine’) urine due to haemoglobinuria, pallor with icterus, and lethargy. Some pathophysiological differences likely occur between intravascular and extravascular forms of IMHA. Intravascular IMHA appears to be largely mediated by IgM antibodies, with affected dogs usually being severely affected, associated with their massive acute red cell destruction, and more likely to have haemoglobinuria. Extravascular haemolysis results in haemolysis of red cells in the erythrophagocytic system (e.g., spleen) and tends to be IgG mediated. A diagnosis of IMHA is ideally made by identifying regenerative anaemia (often a robust regenerative response characterized by marked reticulocytosis) with at least two of spherocytosis, autoagglutination, or positive Coomb’s test. The Coomb’s test, also known as the direct antibody test, effectively enables visual recognition of antibodies mediated towards red cells in the laboratory setting. In addition, it is typical for dogs with IMHA to have leukocytosis (neutrophilia with left shift), normal or slightly elevated total proteins, and hyperbilirubinaemia (which can be very high in some dogs). If a dog does not perfectly fit these signs, an immune-mediated condition could still be present, but directed at red cell precursors. The American College of Veterinary Internal Medicine has recently published a consensus statement on the diagnosis of IMHA in dogs.5
A diagnostic work up focused on identifying any potential triggers for immune-mediated disease is recommended in case of suspected IMHA. Large disease categories to consider include underlying infectious disease (especially vector borne diseases), neoplasia, and drug/toxin exposure. Consequently, comprehensive blood work (CBC and serum chemistry), urinalysis +/- urine culture, vector borne testing for disease endemic to your area (e.g., babesia), thoracic radiographs, and abdominal ultrasound are all reasonable recommendations for these patients. In individual patients aspirating abnormal tissues (e.g., enlarged peripheral lymph nodes, abdominal organs with abnormal ultrasonographic appearance) may also help confirm underlying disease processes (e.g., lymphoma). Understandably not all budgets can stretch to as comprehensive a work up as this and some variation on these plans may be necessary. Another important rule out for dogs with haemolysis is the potential for zinc toxicity that may occur following ingestion of zinc containing metallic objects (e.g., pennies, zippers). For cats, retroviral testing should be performed in any cat with suspected IMHA with a particular concern for FeLV in affected individuals.
Treatment of IMHA
Immunosuppressive Drugs
Immunosuppressive drugs are the core therapeutic strategy for dogs with IMHA. The current evidence base demonstrates that corticosteroids (dexamethasone, prednisone) are the only consistently effective immunosuppressive agent for this disease. Clinical remission is considered when the haematocrit stabilizes and the dog is no longer transfusion dependent. With corticosteroids, this usually takes 5–7 days. No convincing evidence exists that additional agents necessarily speed up the recovery process4 but additional benefits of dual therapy may exist. Long-term administration of corticosteroids are renowned for inducing a variety of unpleasant side effects (e.g., panting, polyuria, polyphagia). Once remission has been achieved, co-administration of other immunosuppressive drugs may enable faster weaning of the steroid component, without adversely increasing the risk of relapse. It is generally advisable and necessary to immunosuppress pets with IMHA for a protracted period of time (6 months or more) with cautious dose reduction in this time period.
Cyclosporine functions as an immunosuppressive by inhibition of T lymphocyte function. Cyclosporine has theoretical advantages over steroids for IMHA since it is considered to induce immunosuppression faster than steroids. There is no convincing evidence it more reliably achieves remission for IMHA than steroids alone however. It is recommended that cyclosporine therapeutic monitoring be used to tailor dosing in individual patients. Another important pharmacological feature of cyclosporine is that it is metabolized by the cytochrome P450 system. Consequently, concurrent administration of drugs also metabolized by P450 enzymes (e.g., ketoconazole) could help to reduce the dosage and, therefore, cost of cyclosporine. Azathioprine is also commonly employed as a second line immunosuppressive agent in dogs. It is a thiopurine analog and interferes with purine metabolism within cells inhibiting normal synthesis of DNA, RNA, and proteins.1 Its onset of action is considered to be quite slow taking at least 7 days to achieve immunosuppression. Consequently, it may be less helpful in acute IMHA but can be helpful in the long-term for its glucocorticoid sparing effects. Mycophenolate works similarly to azathioprine but has a reported faster onset of action.1 It is a prodrug of mycophenolic acid, which inhibits the inosine monophosphate dehydrogenase enzyme needed for purine synthesis. Disruption of purine synthesis leads to both inhibition of T lymphocytes, B lymphocytes, and antibody production. Oral and intravenous formulations exist but oral administration is much more common. A practical limitation is the gastrointestinal intolerance of some dogs to mycophenolate. Myelosuppression could theoretically also occur. There is again no convincing evidence that mycophenolate with steroids confers any advantage over steroids alone for IMHA. Other miscellaneous medications have also been considered as adjunctive immunosuppressive agents, including danazol and leflunomide.1 In many circumstances, personal clinician preference may dictate their ‘go to’ second line immunosuppressive agent or patient factors (e.g., drug cost for size of patient) will influence the drugs used.
Human intravenous immunoglobulin (HIVIG) is another therapeutic option that has been used in dogs with IMHA. The mechanism of action for HIVIG likely involves saturation of Fc receptors on macrophages with the antibodies contained in this product. The saturated Fc receptors will then not interact with the antibody coated red cells or platelets, preventing their clearance from the body by phagocytosis. A prospective study performed in dogs with IMHA found no advantage of glucocorticoid and HIVIG administration with respect to achievement of clinical remission or length of hospitalization compared to glucocorticoid monotherapy.6 In contrast, HIVIG does appear to expedite time to clinical remission in dogs with ITP also treated with glucocorticoids, yet did not prove superior to glucocorticoid and vincristine.7 Safety concerns also exist in using allogenic protein sources in dogs, although overall tolerability appears to be good based on the current veterinary evidence base. It is also a costly product and this will play a role in the likelihood of recommending its usage in veterinary patients.
Extracorporeal Options
An emerging alternative therapeutic strategy for IMHA is plasmapheresis or therapeutic plasma exchange (TPE).8-10 This technique involves separation of plasma and red cells, removal of this plasma that contains immunoglobins, and replacement with donated plasma from healthy dogs. Some clinicians replace only with plasma, while others will use a combination of synthetic colloid with plasma. The rationale for TPE is that efficient removal of immunoglobulins will limit the number available to target red blood cells. The author has seen this technique used in dogs that appear refractory to conventional therapy. Some dogs have responded very well to this therapy and this therapy may become a more important and available treatment option in the future.
Ancillary Supportive Strategies
Non-immunological management of IMHA cases may involve red blood cell transfusion. There has historically been concern that providing red cells to an actively haemolysing animals may add ‘fuel to the fire.’ There is no compelling evidence that this is true, while severe anaemia is life threatening in affected patients. Provision of extra red cells/haemoglobin to improve oxygen delivery to their tissues is helpful, even if it is a short-lived therapeutic measure. Some dogs with IMHA are transfusion dependent, meaning several transfusions are needed to support them before their immunosuppression is optimized and their haematocrit stabilizes. Interestingly it is uncommon for dogs with IMHA to be hypovolaemic, with normovolaemia (or even hypervolaemia) being more common. Consequently, replacement fluids (e.g., lactated Ringer’s solution, colloids) are unlikely to be helpful in ameliorating their clinical signs associated with anaemia. In a similar vein, while oxygen administration (e.g., flow by) will not be harmful in the short-term, abnormal breathing patterns early in the disease course in these pets are typically due to their anaemia. Later on, new onset respiratory effort and tachypnoea in a dog with IMHA could be indicative of other complications (e.g., pulmonary thromboembolism).
Antithrombotic Strategies
Thromboembolic complications of IMHA are important causes of morbidity and mortality in dogs with IMHA. Multiple factors are likely present in these dogs to explain their prothrombotic tendency. Previous work has demonstrated improved outcome for dogs receiving antithrombotic medications.11 The best drugs to use to lower the risk of thromboembolic complications are open to debate. Currently a combination therapy of a drug to inhibit platelet function (clopidogrel or low dose aspirin) with a drug to slow down the clotting cascade (e.g., heparin, rivaroxaban) is usually recommended. Challenges exist with administering oral medications in sick dogs in the acute setting, however, with further issues relating to optimal at-home therapy (e.g., drug choice, duration of treatment) after discharge from the hospital. Newer anticoagulant medications (e.g., rivaroxaban) are growing in popularity since they are once daily oral medications, although our clinical experience of these medications is in our infancy. The greatest risk of thromboembolism is present in the first two weeks of therapy and the ideal duration of antithrombotic prescription in these dogs is not known. There is evidence that inflammation is closely associated with thromboembolic risk, so weaning antithrombotic medications when inflammation wanes in affected dogs is a reasonable strategy. It is also important to consider treating underlying disease processes when present (e.g., antimicrobials for infectious diseases). Recently, the American College of Veterinary Emergency and Critical Care have published evidence-based guidelines on the use of antithrombotics in small animals.12
References
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