Management of Immune-Mediated Hemolytic Anemia in Dogs

Chapter 60


Management of Immune-Mediated Hemolytic Anemia in Dogs




Immune-mediated hemolytic anemia (IMHA) is one of the most devastating and rapidly fatal diseases of domestic dogs worldwide. Interestingly, there are no reports of IMHA occurring in nondomestic dogs. Despite a large amount of research conducted over the past 20 years, the mortality rate for IMHA in dogs remains high, with mortality estimates ranging from 30% to 70% within 1 to 2 months of diagnosis (Scott-Moncrieff, 2001). Diagnosis of IMHA in dogs is relatively straightforward. The major diagnostic criterion for IMHA is the presence of strongly regenerative anemia with evidence of spherocytosis or autoagglutination. Other common abnormalities in dogs with IMHA include hyperbilirubinemia, leukocytosis, thrombocytopenia, and elevated liver enzymes. Mortality in dogs with IMHA is generally the result of euthanasia due to severe and persistent erythrocyte destruction or to rapid onset of widespread, severe thromboembolic disease (McManus and Craig, 2001).



Pathogenesis


The primary cause of erythrocyte destruction in dogs with IMHA is the presence of high concentrations of antierythrocyte autoantibodies. These autoantibodies bind to the surface of erythrocytes and target them for destruction by macrophages in the spleen (extravascular hemolysis) or by complement-mediated lysis in the bloodstream (intravascular hemolysis). Although autoantibodies produced by B cells are the immediate cause of erythrocyte destruction in IMHA, from the standpoint of therapy IMHA is primarily a CD4 T cell–driven disorder. Several erythrocyte antigens recognized by T cells from IMHA patients have been identified previously (Day, 1999).



Triggers for Development of IMHA


At present there is no convincing explanation as to what triggers the spontaneous production of high concentrations of antierythrocyte antibodies in dogs with IMHA. The disease has a genetic susceptibility component, as evidenced by the high prevalence of IMHA in certain breeds of dogs such as cocker spaniels. A number of potential initiating factors have been implicated, although not proven, including previous infection, tissue injury, recent vaccination, and drug therapy (Duval and Giger, 1996). In many respects IMHA in dogs differs greatly from the disease in most other species. For one thing, IMHA in dogs appears to exhibit a slight predilection for certain seasons, with the highest number of cases reported in the spring and early summer. In addition, disease onset is also extremely rapid in dogs, with otherwise previously healthy-appearing animals succumbing within a few days of diagnosis. It is difficult to detect circulating antierythrocyte antibodies in the serum of affected dogs even though erythrocyte surface–bound immunoglobulin G (IgG) can be readily detected in the same animals using flow cytometry (Morley et al, 2008). The most puzzling aspect of all may be the strong association between IMHA and the extremely high risk of developing widespread and often fatal thromboembolic disease.


In the vast majority of cases, IMHA develops spontaneously, with no known inciting cause. The diagnosis of primary IMHA is based on exclusion of other obvious causes for development of antierythrocyte antibodies, such as infection with erythroparasites or hemoplasmas or certain species of rickettsia. Secondary IMHA is diagnosed in animals in which potential inciting causes for development of antierythrocyte antibodies can be identified, primarily neoplasia or infection with erythroparasites.



Immunologic Abnormalities


The presence of immunoglobulin molecules bound to the surface of erythrocytes is the primary immunologic abnormality in dogs with IMHA. When evaluated using flow cytometry, most animals were found to have either IgG only or IgG plus IgM antibodies bound to erythrocytes, whereas it was distinctly rare to find animals with only IgM antibodies bound to their erythrocytes (Morley et al, 2008). Surface-bound antibodies on erythrocytes target the cells for rapid destruction in the spleen via macrophage engulfment, whereas intravascular hemolysis may occur when IgM antibodies activate complement. However, dogs with IMHA also have a number of other immunologic abnormalities. For example, dogs with active IMHA have increased serum concentrations of proinflammatory cytokines, especially monocyte chemoattractant protein-1 (MCP-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (Kjelgaard-Hansen et al, 2011). Platelet activation is also a common finding in dogs with IMHA, with up to 75% of these dogs having activated platelets in circulation (Weiss and Brazzell, 2006). The authors have also found that antierythrocyte antibodies are commonly detected in dogs with thrombocytopenia, suggesting that cross-reactive antigens may be present in dogs with immune-platelet destruction. T cells reactive to peptides derived from erythrocyte antigens such as glycophorin have also been detected in dogs with IMHA, suggesting that autoimmune recognition of self-antigens by T cells may be a key immunologic abnormality in IMHA.



Thromboembolism


One of the most perplexing aspects of IMHA in dogs is the high prevalence of thromboembolic disease. Although the prevalence of thromboembolism is estimated at 30% to 50% clinically, careful necropsy studies suggest that the prevalence of thromboembolism in IMHA may actually be much higher. In addition, while pulmonary symptoms are often the first sign of thromboembolism in IMHA, emboli are actually quite widespread throughout the body in nearly all dogs with IMHA-associated thromboembolic disease, including emboli in the brain, heart, liver, spleen, and kidneys.


Thromboembolism is generally thought to result from endothelial injury, low blood flow, and/or hypercoagulability. While the cause of thromboembolism in IMHA is not currently known, several hypotheses have been proposed and others recently discounted. For one, endothelial injury due to antiendothelial antibodies or complement deposition does not appear to be an important inciting factor for thromboembolism in dogs with IMHA (Wells et al, 2009). Moreover, since dogs with IMHA primarily develop emboli in the venous circulation, low blood flow in arteries also does not appear to be an important factor. However, coagulation abnormalities are quite common in dogs with IMHA and are thought to reflect a fundamental interruption in normal coagulation pathways. For example, a prospective study of 20 dogs with IMHA found disseminated intravascular coagulation was present at the time of diagnosis in more than half the animals (Scott-Moncrieff et al, 2001). What is not clear at present is whether coagulopathies represent the primary hemostatic abnormality in dogs with IMHA or are instead simply a manifestation of a more fundamental problem.


Studies to determine whether dogs with early-onset IMHA are hypercoagulable have not yet been reported. It is known that dogs with IMHA have increased numbers of activated platelets, as assessed by up-regulation of P-selectin expression. Activated platelets are much more likely to spontaneously form thrombi, and platelet activation may be driven by increased concentrations of proinflammatory cytokines in dogs with IMHA, as reported recently (Kjelgaard-Hansen et al, 2011).


The role of lupus anticoagulant activity or antiphospholipid antibodies in triggering spontaneous clot formation in dogs with IMHA has also recently been investigated because these syndromes in humans are associated with widespread spontaneous formation of venous thromboemboli. However, at present there is little evidence of increased lupus anticoagulant activity or antiphospholipid antibodies in dogs with IMHA. Thus it remains an open question as to the primary underlying abnormality that drives the high prevalence of thromboembolic disease in dogs with IMHA.



Prognostic Factors


Given the high morbidity and mortality associated with IMHA in dogs, it is not surprising that there have been multiple attempts to identify clinical factors that are associated with a poor prognosis. Interestingly, factors specifically associated with positive outcomes have not yet been identified. At present, the clinical parameters most consistently associated with poor prognosis in dogs with IMHA include hyperbilirubinemia, thrombocytopenia, and leukocytosis, especially with increased band neutrophils. Other factors that have been identified in at least one study each as negative prognostic factors include petechiation, azotemia, and hypoalbuminemia. Somewhat counterintuitively, the degree of anemia, the magnitude of the reticulocyte response, and the degree of spherocytosis were not associated with outcomes in dogs with IMHA.


There have also been attempts to identify biomarkers that accurately predict treatment outcomes in animals monitored in a critical care setting. The acute-phase proteins α-1-acid glycoprotein and C-reactive protein were both found to be significantly elevated early in dogs with IMHA, but neither was able to predict survival. It was also reported recently that higher serum lactate concentrations at diagnosis correlated with increased mortality in IMHA, although serial lactate measurements were not performed (Holahan et al, 2010). In general it is believed that the change in serum lactate concentration over time is more predictive of outcome than a single baseline value measurement. In a recent study in which serum cytokines were evaluated in dogs with IMHA, the cytokines interleukin-15 (IL-15), IL-18, GM-CSF, and MCP-1 were associated with poor outcomes (Kjelgaard-Hansen et al, 2011). We also found increased serum MCP-1 concentrations were associated with a higher risk of death in dogs with IMHA (Duffy et al, 2010).

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Management of Immune-Mediated Hemolytic Anemia in Dogs

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