Immune Mediated Hemolytic Anemia in Dogs (IMHA), Autoimmune Hemolytic Anemia

Overview of Canine Immune Mediated Hemolytic Anemia in Dogs (IMHA)

Immune mediated hemolytic anemia (IMHA), also known as auto-immune mediated hemolytic anemia (AIHA, is a disease in which the body’s immune system, which is designed to attack and kill germs, attacks and kills the body’s own red blood cells. The attack begins when antibodies, which are molecules made by the immune system to target germs, instead attach to and target the animal’s own red blood cells for destruction. The red blood cells carry oxygen to the tissues, and the animal cannot survive without adequate oxygenation of the tissues.

IMHA may also be known as pure red cell aplasia (PRCA) or Evans syndrome (if it coexists with immune-mediated thrombocytopenia).

The causes of IMHA remain largely unknown. While some cases of IMHA may be associated with a triggering event (cancer, infection, and perhaps even vaccinations), these events do not explain why the immune system misdirects its arsenal of weapons against the animal it is meant to protect.

IMHA occurs more often in dogs than in cats, in middle-aged animals (3 to 8 years old), and in more females rather than males. While any breed can be affected, certain breeds develop IMHA more often than others do, such as the cocker spaniel, English Springer spaniel, miniature poodle, miniature schnauzer, Doberman pinscher, Finnish Spitz, Irish setter, Dachshund, bichon frise, collie, and Old English sheepdog.

For unknown reasons, there is an increased incidence of disease in the spring, with 40% of cases diagnosed in the months of May and June.

IMHA is a rapidly life-threatening disease. Even with appropriate treatment, this disease can be fatal.

What To Watch For

Signs of Immune Mediated Hemolytic Anemia (IMHA) in dogs may include:

• Pale gums
• Yellow tinged gums or whites of the eyes
• Discolored urine e.g. dark or dark yellow
• Tiring easily
• Progressive weakness
• Lethargy
• Loss of appetite
• Vomiting
• Tachypnea (rapid breathing)

Diagnosis of Immune Mediated Hemolytic Anemia in Dogs

Your veterinarian will recommend the following tests:

• A complete history and medical examination. Be prepared for questions about any medications your animal may have received, when the most recent vaccinations were given, and questions about the color of urine and stool.
• Complete blood count (CBC) should be performed on all dogs suspected of having anemia (decreased number of red blood cells), regardless of the cause.
• A “packed cell volume,” or PCV, is a quick and simple test for the number of red blood cells present.
• Reticulocyte counts allow the veterinarian to determine if new red cells are being made in appropriate quantities.
• A serum biochemical profile and urinalysis may be performed to give clues as to possible causes of the anemia.
• A saline agglutination test is a simple blood test that may show if the red cells are clumping together.
• A Coombs test is often indicated. A sample of your dog’s blood is incubated with special reagents to look for evidence of an immune reaction to the blood.
• Radiographs, ultrasound examinations, or blood tests for infectious diseases may be indicated in some patients. These examinations may help rule out causes of anemia other than IMHA, or may help identify triggers that preceded development of IMHA.

Treatment of Immune Mediated Hemolytic Anemia in Dogs

• Corticosteroids (such as prednisone, prednisolone, or dexamethasone) are the mainstays of treatment for IMHA. They suppress the immune system’s attack on the red cells.
• In the most severe cases, or those cases that fail to respond to corticosteroids, other immunosuppressive agents may be utilized. These include drugs such as azathioprine, cyclophosphamide, cyclosporine, danazol, or leflunomide.
• Intravenous immunoglobulins, a product made from human blood, has been used with some success in a few cases of IMHA.
• Plasmapheresis, or the process of removing antibodies from the blood, is very rarely available to veterinarians, but may be possible in some special hospitals.
• Because the spleen is responsible for removing many of the antibody targeted red cells, splenectomy (removal of the spleen) may benefit some animals after initial treatment and stabilization.
• Supportive care is essential to the successful treatment of IMHA. Such care may include transfusion, nursing, and medications.
• Transfusion of either whole blood (cells plus the liquid plasma) or of packed red blood cells (cells only after the liquid is removed) may prove life saving.
• Administration of a blood substitute (Oxyglobin®) provides the ability to carry oxygen to the tissues without administering blood itself.
• Complications of IMHA include the formation of blood clots. Heparin is a medication that helps prevent formation of these clots.
• Intravenous fluids may be indicated to prevent dehydration in some dogs.

Home Care and Prevention

It is crucial to administer all prescribed medications as directed. Even a few missed doses can have serious consequences.
Allow the dog to limit his activity. Anemic animals should not be encouraged or expected to engage in active play.
Provide adequate nutrition. Encourage the dog to eat a well-balanced dog food, but your veterinarian can suggest appropriate enticing treats for the animal that refuses food.

Because we do not understand what causes IMHA, there are no known preventive measures. If an animal’s gums are noted to be pale or white, and the animal appears weak, seek emergency veterinary assistance.

In-depth Information on Immune Mediated Hemolytic Anemia in Dogs (IMHA)

Immune mediated hemolytic anemia is exactly what the name implies. “Anemia” is a deficiency of red blood cells, and may result from many causes including bleeding, failure to produce enough new red blood cells, or destruction of existing red blood cells. “Hemolysis” refers to the lysis, or destruction, of the red blood cells (“heme” is an essential component of red blood cells that allows them to carry oxygen). The term “immune mediated” simply states that in these cases the process of red blood cell destruction is carried out by the immune system.

The immune system is a complicated network of cells and products that are secreted from cells. In a healthy animal, these cells and their products recognize germs as being foreign, and they attack and destroy those germs. The immune system is designed to recognize the animal’s own cells as being harmless, and to refrain from attacking the animal’s own healthy cells. When an animal develops immune mediated disease, the immune system destroys the animals own cells rather than just germs. Sometimes the attack on the animal’s own cells is accidental, and sometimes it is purposeful. A purposeful attack is said to be an “autoimmune” process. In those cases, the immune system thinks the animal’s own cells are foreign, and attempts to destroy them. This destructive process may be directed against many different cell types, but when the cell type under attack is the red blood cell, immune mediated hemolytic anemia is the result.

The development of immune mediated disease is complicated and poorly understood. In some cases a trigger can be identified that may have precipitated the misdirection of the immune system, but in most cases, such a trigger is never found. IMHA, like most such diseases, occurs more often in females than in males. Young adult to middle aged animals are most likely to be affected, and dogs develop the disease much more frequently than do cats. While any dog may develop IMHA, cocker spaniel, Springer spaniel, miniature poodle, Finnish spitz, Irish setter, bichon frise and Old English sheepdog are more likely than most to be affected.

Immune mediated hemolytic anemia is a rapidly life-threatening disease. With severe anemia of any cause, the tissues are unable to receive adequate oxygen. In cases of IMHA, destruction of red cells results in a sudden, and often very severe, decrease in red blood cell numbers. Although there is usually a substantial increase in the number of new red blood cells produced within the bone marrow, production of new cells cannot keep up with the rapid destruction of cells. Unless the immune system’s attack on the red cells can be curbed, the animal will die. Swift treatment may stop the attack, allowing the newly made red blood cells to replace those that were destroyed. Unfortunately, it is not always a simple matter to stop the immune attack, and there are many potential complications of IMHA. Although many animals treated for IMHA go on to live full lives, even those who receive appropriate therapy may succumb to the disease.

There are different forms or subtypes of IMHA. They are most commonly referred to as primary, secondary, intravascular and extravacular.

• Primary – primary IMHA, also known as idiopathic IMHA, results from the antibody attacking the red blood cell membrane. There is no known underlying cause or trigger for this type of IMHA. Most cases of IMHA in dogs (over 75%) are categorized as primary.
• Secondary – secondary IMHA results from the antibody attacking a membrane antigen that is exposed because of an underlying disease. There is an underlying cause for this type of IMHA. Underlying causes that can expose the membrane may include neoplasia (cancer), infections, reactions to drugs, toxins, allergic reactions to bee stings and blood transfusions. The most common cause for secondary IMHA is cancer. Possible drug triggers may include antibiotics (such as sulfonamides, cephalosporins, penicillins), vaccines and procainamide.
• Intravascular – intravascular IMHA means that they red blood cells are being destroyed in the blood vessels.
• Extravacular – extravascular IMHA means that they red blood cells are being destroyed outside of the blood vessels, most commonly destroyed by macrophages in the spleen and/or liver.

Differential Diagnoses (Other Causes of Anemia) in Dogs

It is crucial that the diagnosis of IMHA be confirmed, because there are many causes of anemia other than IMHA. Both treatment and prognosis for these other causes are often quite different that that of IMHA. Other potential cause of anemia include:

• Blood loss. Bleeding results in anemia, and the site of bleeding may not always be obvious. For example, an animal can lose a tremendous amount of blood through the gastrointestinal tract with the only evidence of bleeding being dark, tarry colored stools.
• Decreased production of red blood cells. The bone marrow is responsible for producing a continuous supply of new red blood cells. Sometimes this production of new cells falls behind, either due to disease inside the bone marrow or from other diseases with affect the signals or materials needed for production of new red cells. Examples of disease within the marrow might include cancer, toxic damage to the marrow, and infection in the marrow. Examples of other diseases that might affect the production of new red blood cells include kidney failure, iron deficiency, or chronic infections anywhere in the body.
• Hemolytic anemia is not always due to an immune system attack. Other causes of hemolytic anemia are possible.
  Infection of the red blood cells can lead to hemolytic anemia. Examples of such infections would include Babesiosis or Hemobartonellosis.
• Certain toxins can lead to hemolytic anemia. The metal zinc and certain foods (like onion and garlic) are examples of such toxins.
• The mechanical destruction of red blood cells results in hemolytic anemia. Examples would include a twisted spleen, a severe form of heartworm disease in which a clump of worms occludes the major blood vessels, or widespread formation of tiny blood clots (disseminated intravascular coagulation).
• Certain hereditary diseases result in the formation of abnormal red blood cells. These abnormal cells are more likely to be destroyed, potentially resulting in hemolytic anemia.

In-depth Information on the Diagnosis of Canine Immune Mediated Hemolytic Anemia in Dogs (IMHA)

Expect your veterinarian to obtain a complete medical history. Be prepared for questions about what symptoms you have observed and how long they have been present, any medications your animal may have received, when the most recent vaccinations were given, and questions about the color of urine and stool.

• A complete physical examination will be performed. Your veterinarian will evaluate the color of the gums and the eyes, palpate the abdomen looking for masses or swellings, and listen to the chest for heart murmurs or abnormal lung sounds.
• A complete blood count (CBC) should be performed on all dogs suspected of having anemia (decreased number of red blood cells), regardless of the cause. This will not only quantify the number of red cells present, but will allow for a visual inspection of the cells under the microscope. Certain characteristic changes are often noted in the remaining red blood cells of animals with IMHA.
• A “packed cell volume”, or PCV, is a quick and simple test for the number of red blood cells present. Your veterinarian may do this test on a daily or near daily basis both initially and as therapy progresses to evaluate the balance between production of new cells and destruction of the old.
• Reticulocyte counts allow the veterinarian to determine if new red cells are being made in appropriate quantities. The rapid production of new red cells is not only important for the animal, but helps the veterinarian rule out other causes of anemia from diagnostic consideration.
• A serum biochemical profile and urinalysis may be performed to give clues as to possible causes of the anemia.
• A saline agglutination test is a simple blood test that may show if the red cells are clumping together. In some forms of IMHA, the red cells actually stick together. If true agglutination is proven, it cements a diagnosis of IMHA.
• A Coombs test is often indicated. A sample of the dog’s blood is incubated with special reagents to look for evidence of an immune reaction to the blood. This test is very useful, but there are several causes of false positive results (for instance, prior transfusion) or of false negative results (for instance, prior corticosteroid therapy).
• Coagulation tests such as the activated partial thromboplastin time, prothrombin time, fibrinogen, platelet count and/or fibrin degradation products) may be done to determine the ability of the blood to clot. Some dogs can develop a secondary condition called disseminated intravascular coagulation (DIC), which can cause a cascade of secondary problems. For more information on DIC, go to “Disseminated Intravascular Coagulation (DIC) in Dogs.”
• Newer, specialized tests search for evidence of an immune reaction to the red blood cells in more sophisticated ways that the traditional Coombs test. Direct immunofluorescence flow cytometry is an example of such a test; while this test is less likely to give a false negative result for an animal that has IMHA, it is also more likely to give a false positive result for an animal that does not have IMHA.
• Radiographs, ultrasound examinations, or blood tests for infectious diseases may be indicated in some patients. These examinations may help rule out causes of anemia other than IMHA, or may help identify triggers that preceded development of IMHA.
• Occasionally, IMHA destroys not only the red blood cells in circulation, but also the immature red cells being produced in the bone marrow. In this case, a bone marrow aspirate may be indicated. A large needle is placed in the bone while the animal is sedated, and a small sample of marrow is removed for microscopic analysis.

In-depth Information on the Treatment of Canine Immune Mediated Hemolytic Anemia

Treatment of IMHA involves both direct attempts to halt the immune system attack on the red blood cells, and supportive care. The immune system is a complicated network of cells and cell products all designed to protect the body from foreign invaders. As with any complicated system, there are multiple places where errors can occur. When these errors result in the destruction of red blood cells (that is, IMHA), the immune system’s attack must be halted if the animal is to survive. Unfortunately, the drugs available to halt the attack are not specific, meaning that they not only diminish the attack on the red blood cells, but also interfere with appropriate immune response to germs. This puts the animal undergoing therapy for IMHA in the precarious position of needing just enough, but not too much, immune suppression.

The drugs available to suppress the immune system interfere with entire pathways of immunity, and occasionally more than one of these paths must be interrupted to stop destruction of the red blood cells. In most dogs that respond successfully to therapy, the dose of immunosuppressive drugs can be very gradually lowered. Some animals will eventually be able to discontinue medications altogether, while others will require life-long therapy. Almost all immunosuppressive therapies require some time to take effect. Until the destruction of red cells can be halted, supportive care is crucial for the animal’s survival.

Immunosuppressive Therapy

Corticosteroids (such as prednisone, prednisolone, or Dexamethasone) suppress the immune system’s attack on the red cells by several mechanisms and are the mainstays of treatment for IMHA. While the effect of corticosteroids is more rapid than that of many other immunosuppressive drugs, it is still often 3 to 4 days before a positive response may be seen. Initial dosages of corticosteroids are very high, and may be associated with unpleasant side effects such as increased thirst and appetite, along with increased urination and weight gain. The dosage will be slowly decreased over several months after the animal improves.

Adjunctive Immunosuppressive Drugs

• In the most severe cases, or those cases that fail to respond to corticosteroids, other immunosuppressive agents may be utilized. These include drugs such as azathioprine, cyclosporine, cyclophosphamide, danazol, leuflonomide, Intravenous immunoglobulins (IVIG), and Mycophenolate. The most commonly administered drugs are azathioprine and cyclosporine. Each will be discussed briefly below.
  • Azathioprine (Imuran®) is a drug that is toxic to the type of immune cell (lymphocytes) that produces antibodies. By destroying some of these cells, less antibody is produced to both red blood cells and to germs. It takes at least a week for azothiprine to become effective. It is relatively inexpensive and has a low incidence of adverse side effects. Complications can include acute liver toxicity that be life-threatening.
• Cyclosporine (Atopica®, Optimmune®) is the same drug used to prevent rejection of transplanted organs. It suppresses immunity by affecting molecules known as cytokines that are secreted from immune cells. There are few studies evaluating how effective this expensive drug is in the treatment of IMHA.
• Cyclophosphamide (Cytoxan®, Neosar®)is another drug that is toxic to lymphocytes, and it is also used to treat lymphatic cancer. In the small number of studies where it has been evaluated, the response of IMHA to cyclophosphamide has been very disappointing.
• Danazol is a synthetic molecule related to testosterone that has been used to suppress the immune attack in IMHA, although the way in which it does so is not clear. This medication is very expensive, and has not been proven effective.
• Leflunomide is one of the newer medications used to treat refractory cases of IMHA. It is being more commonly used as generic version of the drug are available making it a more affordable option. Again, there are no studies yet proving that this expensive medication is effective. Drug monitoring is recommended to ensure therapeutic concentrations in the blood.
• Intravenous immunoglobulins (IVIG), a product made from human blood, has been used with some success in a few cases of IMHA. The human antibodies (immunoglobulins) are thought to compete with the animal’s own antibody-coated red cells for the attention of other immune cells. This therapy is very expensive, and supplies of this human product to veterinarians are often limited by supply. It is most commonly used for short-term treatment in dogs with life-threatening disease. IVIG is most commonly given IV as a single dose. A recent clinical trial suggests this can be beneficial.
• Mycophenolate is a new medication being used and is similar in its affect to azathioprine but ten times as potent. It also has a more rapid onset of action.
• Gastrointestinal protectant drugs, such as Famotidine (Pepcid®), Cimetidine HCl (Tagamet®), or Ranitidine HCl (Zantac®) may be used.
• Plasmapheresis, or the process of removing antibodies from the blood, is very rarely available to veterinarians, but may be possible in some special hospitals. The animal’s blood is removed from the body, the excess antibodies are “washed” away, while the rest of the blood is returned to the animal.
• Because the spleen is responsible for removing many of the antibody-targeted red cells, splenectomy (removal of the spleen) may benefit some animals after initial treatment and stabilization. This is not an emergency therapy, but is useful in animals that continue to require high drug doses to maintain remission from disease.

Supportive Care

Supportive care is essential to the successful treatment of IMHA. Such care may include transfusion, nursing, and medications. Additional supportive therapies include:

• Transfusion of either whole blood (cells plus the liquid plasma) or of packed red blood cells (cells only after the liquid is removed) may prove life saving by allowing the transfused red blood cells to carry oxygen to the tissues. Unfortunately, animals with IMHA destroy not only their own red cells, but the transfused cells as well. In fact, the transfused cells may be destroyed even faster than the animals own cells would, and this destruction may contribute to complications of IMHA. In general, transfusion will be postponed for as long as possible in the hope that the animal will improve in response to corticosteroids. However, many dogs will die of anemia and blood transfusion may be required to support them until they can respond to the drug therapy.
• Administration of a blood substitute (Oxyglobin®) provides the ability to carry oxygen to the tissues without administering blood itself. The advantage is that there are no cells to be destroyed, but the blood substitute itself only lasts for a few days.
• Heparin is an injectable medication that helps prevent formation of blood clots. Complications of IMHA include two types of abnormal blood clotting. The first is formation of blood clots that lodge in the blood vessels of the lungs (pulmonary thromboembolism). The second involves widespread clotting (and subsequent lysis of clots) of blood inside the vessels (disseminated intravascular coagulation). Either complication may prove fatal.
• Intravenous fluids may be indicated some dogs. Intravenous catheters are required for fluid therapy, and may make formation of clots more likely. However, it is vital to maintain adequate hydration and flow of blood, so the benefits of intravenous fluid therapy may outweigh the risks in some cases.

Prognosis of Dogs with IMHA

The prognosis depends on the dog’s response to treatment and the diagnosis and treatment of any possible underlying cause for the disease. The prognosis is generally considered poor. The mortality rate is estimated to be 40 to 60% in dogs. Some dogs may relapse within the first year.

Follow-up Care for Dogs with IMHA

• Optimal treatment for your dog requires a combination of home and professional veterinary care. Follow-up can be critical, especially if your dog does not rapidly improve.
• Administer all prescribed medication(s) as directed. Alert your veterinarian if you are experiencing problems treating your dog. Even a few missed doses can have disastrous results.
• Expect to return your dog for frequent blood tests in the early days of treatment. With appropriate therapy, the red blood cell count is expected to improve. Once it increases to near normal levels, the drug dosages can be slowly decreased. Your veterinarian will need to check the red blood cell count after each adjustment to therapy.
• You should expect that dogs receiving corticosteroids will experience an increase in thirst, and with that, an increased frequency of urination. Most dogs receiving corticosteroids will also experience an increased appetite. It is important to monitor what your dog eats, and place reasonable limits on food consumption. Dogs on corticosteroids often gain large amounts of weight over a short period of time.
• Because the dog is treated with drugs to suppress the immune system, they may be prone to developing infection. If you notice lethargy, inappetence, vomiting, diarrhea, or urinary accidents in the house, these signs should be brought to your veterinarian’s attention as soon as possible.