Veterinary Issues: Immune Mediated Hemolytic Anemia First printed in the Australian Shepherd Journal by Margaret Muns DVM Animal blood is made up of three major components. Red blood cells carry oxygen to the cells of the body. White blood cells help the body defend itself against infectious disease. Both cells are suspended in the fluid plasma. Because of its vital role in the body, blood is often affected by disease. If a disease process leads to a loss of red blood cells, then a state called “anemia” exists. One or the most important causes of anemia in dogs occurs when the immune system turns on the animal’s own red blood cells. The resulting Immune Mediated Hemolytic Anemia can be severe, difficult to treat, and often life threatening. Cause Immune Mediated Hemolytic Anemia (IMHA) occurs when a dog’s immune system triggers abnormally and directs antibodies against its own red blood cells (RBC). In normal dogs, the immune system produces anti-RBC antibodies as the red cells reach the end of their normal lifespan. These “marked” cells are then removed by the spleen. At the same time, the bone marrow produces new RBC to keep the total numbers stable. If an event occurs that triggers an abnormal immune response, this tightly controlled system can break down. Instead of targeting only old cells, the immune system directs antibodies against the dog’s entire RBC population. As a result, there is widespread destruction of red cells, leading to severe anemia. In most affected dogs, the bone marrow activates to produce more RBC in an attempt to fight back (regenerative anemia). However, in some patients, antibodies are also directed against the immature red cells in the marrow. As a result, the body cannot respond to the anemia (non-regenerative anemia). Immune Mediated destruction of RBC can be triggered in two different ways. Primary IMHA occurs when the immune system triggers without an identifiable underlying cause. The exact cause is unknown, but it is thought that a major factor is a breakdown of the normal processes responsible for controlling RBC destruction. Currently, researchers feel that the breakdown may be the result of a yet unidentifiable infection in genetically susceptible dogs. Once the breakdown occurs, the immune system begins to recognize the body’s own RBC as being foreign. As a result, anti-RBC antibodies are produced. These “auto-antibodies” attach to the proteins in the red blood cell’s outer membrane. Depending on which antibodies attach where, the red cell may rupture while still in the bloodstream (intravascular hemolysis). Alternately, the red cell may survive the initial insult, only to be removed later by the spleen (extravascular hemolysis). Secondary IMHA occurs when antibody becomes attached to the RBC membrane in response to an underlying cause. Common underlying conditions associated with secondary IMHA include cancer and chronic inflammatory disease. Exposure to various drugs and infectious agents has also been implicated in causing secondary IMHA. The role of vaccinations in causing secondary IMHA has recently become a hot point of debate in the lay literature. A direct link between vaccinations was assumed because of a few cases in which IMHA began within a short period after immunization. This appeared to be substantiated by a study published in 1996, which reported that vaccination produced an increased risk of IMHA in the 30 days following immunization. However, subsequent studies have failed to validate the assumptions of the 1996 study. Therefore, the current view is that there is no statistically significant association between vaccination and IMHA. Regardless of the exact underlying cause, the mechanisms responsible for producing secondary IMHA are the same. The antibody may be directed against drugs or viruses that attach to the red cell’s membrane. Alternately, antibody may be produced against normal RBC membrane components that are similar to the foreign substances associated with the underlying cause. Lastly, the underlying cause may expose RBC components that are normally hidden from the immune system, leading to subsequent production of anti-RBC antibody. Diagnosis The majority of symptoms associated with canine IMHA are a reflection of the anemic state and the body’s attempts at compensation. Common symptoms include weakness, lethargy, and pale gums. The dog’s respiratory and heart rates will be increased to compensate for the loss of oxygen-carrying capacity. The thinner blood will also lead to turbulence as it passes over the heart valves. The result is an audible heart murmur when a stethoscope is applied to the chest. Lastly, jaundice may also be present if the liver’s ability to remove the by-products of RBC destruction is overwhelmed. All of the above symptoms can be seen in varying degrees, depending on the severity of the disease and how quickly it develops. Dogs with slowly developing IMHA can appear to be remarkably normal—despite being severely anemic—because their bodies have been able to compensate. These dogs typically are not jaundiced because the liver can cope with the slower release of RBC breakdown products. On the other hand, dogs with severe, acute IMHA may become profoundly weak and depressed. Some dogs may even collapse suddenly, with little sign of prior illness. Diagnostic testing also reflects the degree of anemia and the body’s response (or lack thereof). Standard tests may also reflect changes associated with whatever underlying disease may be present. The closest thing to a definitive test for IMHA is the Direct Antiglobulin Test (DAT, or Coombs Test). This test is designed to detect the presence of antibody on an affected dog’s RBC. So a positive test supports the diagnosis of IMHA, while a negative test indicates a non-immune mediated reason for the dog’s anemia. Unfortunately, the DAT test also has its limitations. First, it cannot tell the difference between primary and secondary IMHA. Second, numerous studies have suggested that the accuracy of the DAT test is less than ideal. In fact, both false negative and false positive tests occur with a significant frequency. However, most experts still advise clinicians to run a DAT test as part of the workup for any dog suspected of having IMHA. Treatment The precise treatment plan for dogs with IMHA depends on how severe the disease is and how rapidly it starts. Treatment for canine IMHA can be difficult, frustrating, and expensive. Contributing to the difficulty is the fact that experts differ on the best way to treat affected dogs. As a result, most treatment plans are devised using a combination or knowledge, experience, and clinical judgment. Regardless of which plan is chosen, the main objective in treating IMHA is suppressing the abnormal immune response. High dose cortisone therapy is the easiest way to accomplish this goal. Therefore, it is often the first line of treatment for IMHA. Cortisone blocks the destruction of antibody-coated RBC. It also acts secondarily to decrease the production of anti-RBC antibodies. A response should be seen within a week if cortisone therapy is going to work by itself. However, the full therapeutic benefit may not be seen until 2-4 weeks after treatment is begun. Once the dog’s condition is stable, treatment is slowly tapered over a 3-6 month period. Slow tapering is mandatory. Rapid drug withdrawal often leads to a relapse, which is much harder to control. Cortisone therapy can be totally stopped only if a dog has remained stable (with no relapses) for 6 months. Dogs that relapse will need cortisone therapy for life. The side effects associated with high dose cortisone therapy can be debilitating and severe. However, there is no choice in the matter because of life threatening IMHA. Dogs (and owners) who cannot tolerate the side effects of cortisone therapy will need other immune suppressive therapy. Azathioprine is the drug most often for this purpose. It is also the drug of choice for dogs who fail to respond to cortisone alone. The exact timing of Azathioprine use is a controversial subject. Some specialists advocate starting it when treatment is begun, because the drug can take weeks to reach therapeutic levels. Others advise clinicians to wait and see if cortisone alone will work. Azathioprine is not a benign drug either. It can cause severe bone marrow suppression and liver damage. Also, the cost of the drug plus required monitoring can add significant cost to treatment. Therefore, the decision to add Azathioprine depends on the judgment of the individual veterinarian. Once added, Azathioprine is continued with cortisone until the dog has been stable for four weeks. Only then can the cortisone be slowly tapered off. Azathioprine is then continued for another 4-8 weeks, before it can be slowly withdrawn. Other Treatment Options Severely affected dogs may require treatment with more than cortisone and Azathioprine. Cyclophosphamide is sometimes used as a rescue therapy for dogs with severe IMHA. But the severe side effects often associated with the drug can be difficult for the dog to tolerate. Cyclosporine is a powerful immune suppressive agent that is usually well tolerated. It also does not cause bone marrow suppression. Cyclosporine probably would be the drug of choice for canine IMHA except for the high cost of the drug and the required therapeutic monitoring. Dogs with severe IMHA-induced anemia do not have enough RBC to deliver oxygen to their tissues. So the animal’s cells are literally starved of oxygen (tissue hypoxia). This can lead to catastrophic organ damage. Whole blood transfusion can help correct tissue hypoxia, but it is not the ideal method to use. First, the transfused blood contains proteins that could intensify the immune mediated reaction (like adding fuel to the fire). Second, the lifespan of transfused RBC is very short. Still, in critical situations blood transfusion has the potential to be lifesaving. Oxyglobin® is another product that can be used to increase oxygen carrying capacity. It is not a blood product. Rather it is a solution of bovine polymerized hemoglobin. Hemoglobin is found inside the RBC of normal animals. It is the substance that binds with oxygen so that the RBC can deliver it to the cells. When infused into an animal, Oxyglobin® can provide a temporary (several days) boost in oxygen carrying capacity. It is an easy product to use in general practice because typing and cross matching are not required. It can also be stored on the shelf for up to two years at room temperature without losing efficacy. Aggressive supportive care is also indicated for canine IMHA patients. Dogs with secondary IMHA will require additional therapies to deal with the associated underlying cause. All affected dogs are at risk for developing blood clots because of immune mediated interference with normal clotting functions. Therefore, anti-clotting therapies may be needed (heparin or low dose aspirin). Surgical removal of the spleen (splenectomy) may be needed for dogs who either don’t respond to therapy or cannot tolerate it. Prognosis Generally, canine IMHA is a serious disease with a high mortality rate. Most fatalities occur because of severe anemia, blood clots, and relapses or from the side effects of immune suppressive therapy. Dogs fortunate enough to survive can develop other immune mediated disease later in life. Vaccination should probably still be avoided in recovering dogs, even though a definitive association has not been proven. Instead, vaccine titers should be used to monitor immunity. References 1. Day, MJ. “Immune Mediated Hemolytic Anemia: Pathophysiology,Clinical Presentation and Diagnosis.” In: IMHA: New Perspectives on a Challenging Disease. Biopure Corp, 2002. Pages 2-6 2. Scott-Moncrieff, JC. “Immune Mediated Hemolytic Anemia: Treatment.” In: IMHA: New Perspectives on a Challenging Disease. Biopure Corp, 2002. Pages 7-11. 3. Mackin, A. “Immune-Mediated Hemolytic Anemia: Pathophysiology and Diagnosis.” ACVIM Meeting, 2002. Downloaded from www.vin.com/Members/Proceedings/Proceedings 4. Mackin ,A “Immune-Mediated Blood Disorders: Chronic Therapeutic Management.” ACVIM Meeting 2002. Downloaded from www.vin.com/Members/Proceedings/Proceedings 5. Mackin, A. “Immune-Mediated Blood Disorders: Emergency Management.” ACVIM Meeting 2002. Downloaded from www.vin.com/Members/Proceedings/Proceedings