Immune-Mediated Hemolytic Anemia, Canine

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Category: Canine

Immune-mediated hemolytic anemia, autoimmune hemolytic anemia, IMHA, AIHA

Affected Animals:
Dogs of all ages may be affected with immune-mediated hemolytic anemia. Young to middle-aged female dogs are thought to be affected more commonly with immune-mediated disease than their male counterparts. Older dogs often have underlying or concurrent problems when IMHA develops. In some dogs, IMHA can precede the identification of cancer or other serious systemic diseases. Breeds including cocker spaniels, poodles, Old English sheepdogs, Lhasa apsos, and Shih-tzus may have a higher incidence of IMHA than other breeds.

Young dogs, especially beagles, Basenjis, and English springer spaniels, may have specific red blood cell enzyme abnormalities that result in hemolytic anemia at an early age; however, this anemia is not mediated by the immune system.

Overview:
Immune-mediated hemolytic anemia, or IMHA, is a relatively common syndrome in dogs. The immune system normally helps to protect the body from outside invaders. However, it can become active against normal cells or parts of the body, or against normal cells that have been altered by exposure to infectious agents, medications, or other disease processes in the body. Although a variety of factors may be associated with the development of IMHA, in most situations it occurs without an identifiable trigger or underlying cause. This is referred to as idiopathic immune-mediated hemolytic anemia. Affected dogs show the symptoms common to anemia due to any cause—lethargy, weakness, increased respiratory rate, and pallor, or pale mucous membranes. In situations where the anemia develops rapidly, signs can be severe, with some animals actually presenting to the veterinarian in shock. In other cases, especially when the targeted red blood cells are in the bone marrow rather than in circulation in the blood vessels, the onset can be very slow and gradual.

There is no single test that is absolutely diagnostic for immune-mediated hemolytic anemia. It is usually diagnosed based on suspicion and the absence of any other specific causes for anemia. Bloodwork, x-rays, ultrasound, bone marrow examinations, and other diagnostic tests are part of the evaluation of an anemic dog. These studies are helpful in ruling out underlying or associated conditions, identifying additional abnormalities that require treatment, and in monitoring complications of the disease and its treatment.

Treatment of immune-mediated hemolytic anemia is aimed at restoring red blood cell numbers and trying to stop the ongoing destruction of additional red blood cells. Underlying causes or predisposing factors, when present, need to be addressed. If medications were being used prior to the diagnosis, they are usually stopped, in case they may have triggered hemolysis in the affected dog. Transfusions may be needed in severely ill dogs, but are generally useful only as a temporary measure unless the underlying cause of the red cell destruction is arrested. A large number of drugs have been used to suppress the immune response in dogs with IMHA. The cornerstone of treatment is prednisone. Only an attempt at treatment will provide an answer about the outcome for an individual patient with IMHA. There is an extremely wide range of severity of the condition, as well as an unpredictable response to treatment. Some animals are saved with relatively non-aggressive treatment and monitoring, while others succumb despite almost heroic efforts, either to the disease itself, complications like pulmonary blood clot formation, or side effects from the medications used to treat the disease.

Clinical Signs:
The common signs associated with anemia include lethargy and pallor. Many patients with immune-mediated hemolytic anemia have a recent history of nonspecific signs that can include anorexia and vomiting. Changes in breathing patterns are common, and can range from panting to dyspnea, especially if pulmonary thromboembolism, or blood clots to the lungs, has occurred. The presence of jaundice in an anemic animal is highly suggestive of immune-mediated hemolysis as a cause of the anemia. Dogs with IMHA may present to the veterinarian collapsed or in shock.

Symptoms:
Most anemic dogs act weak or tired. Their mucous membranes and skin may appear to be pale or jaundiced, with yellow discoloration. Many dogs with IMHA have symptoms like vomiting or loss of appetite that may precede or accompany the onset of their anemia. Respiratory symptoms are often present. Panting is the most common respiratory sign in anemia, but since some dogs with IMHA have problems with blood clots in the vessels supplying their lungs, severe respiratory difficulty may be seen. Some animals may present with very sudden onset of shock-like symptoms in severe cases of IMHA.

Description:
In immune-mediated hemolytic anemia, red blood cells are removed from circulation by interactions between components of the immune system and cells called macrophages, which essentially “eat up” the altered red blood cells. Veterinarians believe that antigens, or foreign substances, alter red blood cell membranes and stimulate formation of immune system antibodies. The antibodies in turn form an immune complex with the affected RBCs by attaching to the antigen. Circulating macrophages, or immune-system “scavenger” cells, are attracted to the immune complexes. Macrophages engulf the red blood cells with the complexes and destroy them.

This process occurs outside the blood vessels, especially in the spleen, and is termed extravascular hemolysis. Less commonly, immune complexes attach to the red blood cells in circulation, causing intravascular rupture or hemolysis. If no trigger mechanism or antigen is recognized, then the process is attributed to an exuberant or defective immune system that fails to recognize the dog’s normal red blood cells as “self.” Antibody molecules are produced against the normal or unchanged red blood cells.

Diagnosis:
Anemia is diagnosed by documenting the presence of decreased red blood cells. This is most commonly done in the hospital with measurement of a packed cell volume, or PCV. Measurement of a hematocrit is usually done in a reference laboratory. Once anemia has been documented there are many tests that are useful in further classifying the anemia.

Anemias may be classified as regenerative and nonregenerative. Regenerative anemias arise from factors that generally do not suppress the bone marrow, the normal source of red blood cells. Nonregenerative anemias occur as a result of bone marrow-suppressing events. Reticulocytes are immature, developing red blood cells. A reticulocyte count tells how many immature red blood cells are in circulation. Most dogs with immune-mediated hemolytic anemia show a regenerative response, with increased reticulocyte counts or large numbers of nucleated red blood cells in circulation. The most common causes of regenerative anemias are blood loss and hemolysis, or red blood cell breakdown. Hemolysis should be suspected if there is a regenerative anemia with no evidence of internal or external blood loss. Not all forms of immune-mediated anemia are associated with increased numbers of reticulocytes. When the immune-mediated injury is directed at cells in the marrow, the reticulocyte count is decreased. This form of immune-mediated, non-regenerative anemia, is sometimes referred to as pure red cell aplasia.

Additional red blood cell features are helpful in classifying anemia as regenerative or nonregenerative. Red blood cell size is often increased and color is often less intense than normal in regenerative anemias. Nucleated red blood cells, which are released early from the bone marrow when demand is high, are often elevated in regenerative anemia. The most specific red blood cell change in IMHA is the formation of spherocytes. A spherocyte is a round-looking red blood cell that lacks the typical zone of paleness in its center when examined on a blood smear. It is thought that spherocytes are only seen with immune-mediated injury.

Red blood cell agglutination, or clumping, may be noted when blood is collected from dogs with IMHA. The presence of agglutination is usually thought to be specific for immune-mediated anemia, but its absence does not rule it out. Agglutination may be either macroscopic, which means visible to the naked eye, or microscopic, indicating it can only be noted when drops of blood are examined under a microscope.

When IMHA is suspected, a direct antibody, or Coombs test is usually performed. This test looks for antibodies against red blood cells. Although many dogs with IMHA will have a positive Coombs test, some do not. A negative Coombs test does not rule out the possibility of IMHA. Coombs test results should always be interpreted in light of other clinical and laboratory findings.

Serum biochemical profile abnormalities are common in IMHA, but none of the commonly seen changes are specific for the diagnosis. Serum bilirubin levels are increased due to excessive red blood cell breakdown. Liver enzymes may be elevated; this occurs when anemia causes the liver to receive a decreased amount of oxygen. Protein levels are usually normal to increased in hemolytic anemia. This is a key point in distinguishing hemolysis from blood loss, since protein levels are usually decreased in whole blood loss situations.

Changes in the white blood cell and platelet counts may be seen in addition to red blood cell count abnormalities on a complete blood count. Some dogs with IMHA have marked increases in their white blood cell counts. This occurs when all cell lines within the bone marrow are excessively stimulated. Other dogs with IMHA may have decreased platelet counts, particularly if the immune-mediated injury involves platelets as well as red blood cells. This is called Evan’s syndrome, and may be associated with a worse outcome in most patients than with IMHA alone.

A complete blood count will also help reveal underlying causes for hemolytic anemia. Red blood cell parasites that can cause hemolysis may sometimes be seen on evaluation of a blood smear. Although rarely seen, Heinz body formation in dogs can occur from onion ingestion or from acetaminophen overdose. Heinz bodies are structures composed of denatured hemoglobin that can also be seen in some dogs with hemolytic anemia.

Other diagnostic tests may also help identify an underlying cause for hemolytic anemia. These tests may help differentially diagnose IMHA from non-immune-related hemolytic anemias. Chest and abdominal x-rays and abdominal ultrasound may be used to screen for evidence of cancer in older dogs with suspected IMHA. Cancer, especially lymphosarcoma, is often associated with immune-system abnormalities. Abdominal x-rays may also be useful in identifying zinc-containing foreign objects like coins, which can induce hemolytic anemia in dogs. Tests for tick-borne infectious diseases may need to be considered as well. Geography influences the incidence of such diseases; many tick-borne diseases occur more commonly in the southern and the southeastern parts of the United States. Bone marrow evaluation may be recommended if the CBC reveals unusually low platelet and white blood cell counts, or if the anemia is nonregenerative. This is done primarily to rule out the presence of diseases like leukemia within the bone marrow itself, and to further document the marrow’s ability to respond to the demand for new blood cells.

When IMHA has been tentatively diagnosed, when no likely underlying cause has been identified by additional testing, and when there is no history of recent drug or vaccine exposure that may have triggered the event, the condition is often referred to as autoimmune hemolytic anemia, or AIHA. It is assumed in these cases that for unknown reasons, the immune system targets otherwise normal red blood cells, and tries to remove them from circulation.

Prognosis:
Immune-mediated hemolytic anemia is a very serious disease. While overall about 20 to 40 percent of patients with IMHA are thought to die either from the disease itself or from its complications or treatment, this figure may be as high as 80 percent for the most severely affected dogs. Many studies have looked at possible factors that play a role in prognosis. Some factors that may be associated with greater likelihood of a poor outcome include a marked elevation of serum bilirubin, lower packed cell volumes at the time of presentation, the need for multiple transfusions, and the occurrence of pulmonary blood clots. Only an attempt at treatment will help determine the outcome in an individual dog. Those dogs that respond rapidly and favorably to treatment may do very well. Other dogs may require hospitalization for days to weeks before it becomes clear if they will survive or not.

Transmission or Cause:
Hemolytic anemia may occur secondary to an underlying trigger or cause. Such causes can include red blood cell parasites, tick-borne infectious diseases, exposure to vaccines or other biologic products, medications, bee stings, toxins like zinc or onions, and cancer. In some specific breeds, inherited red blood cell enzyme abnormalities can trigger hemolytic anemia. Although the underlying cause of anemia in these instances is hemolysis, or red blood cell breakdown, not all of these cases are due to hemolysis that is immune system-related.

There are many possible triggers for the development of immune-mediated hemolytic anemia. Sometimes IMHA is associated with exposure to certain medications that may alter the red blood cell membranes, or that serve as a stimulus for antibody production themselves. Red blood cell parasites may either attach to the red blood cell membranes or invade the red blood cells directly, triggering an immune response. Infectious diseases like ehrlichiosis may be associated with immune-mediated hemolysis. Some forms of cancer, particularly lymphosarcoma, can serve as triggers for IMHA. However, in most patients, there is no identifiable trigger or obvious underlying, associated condition. This situation is referred to as idiopathic immune-mediated hemolytic anemia. The exact cause of this syndrome and the mechanisms that perpetuate it are not completely understood. In these patients, some abnormality in the immune system allows for the destruction of otherwise normal red blood cells. Veterinarians believe that there may be a hereditary predisposition to this condition. It may occur alone or in conjunction with other immune-mediated disorders.

Treatment:
Treatment is directed toward any identified underlying causes of the hemolytic anemia and toward symptomatic illness secondary to the IMHA itself. Emergency treatment of a patient with IMHA frequently requires blood transfusion or the use of synthetic hemoglobin solutions to temporarily stabilize the patient and to permit time for other treatments to work. Packed red blood cells from a universal or cross-matched donor are used if available, but whole blood may also be used. It is possible that transfused red blood cells may also be destroyed by the patient’s immune system, so the benefit from transfusion may only be temporary.

Synthetic hemoglobin solutions have the advantage of a longer shelf life compared to blood, so they can be used in hospitals where blood donors are not available. However, their expense and their interference with the ability to monitor some biochemical parameters in patients with IMHA must be kept in mind. Plasma may also be given to patients that are thought to have serious blood clotting abnormalities secondary to their disease.

The main thrust of drug treatment in IMHA is the use of drugs to suppress the immune system. Corticosteroids like prednisone, prednisolone, and dexamethasone are most commonly used to accomplish this goal. High doses are necessary, and therefore side effects are common. Some side effects like increased thirst, increased urination, increased appetite, and panting are not very serious, but others, including the potential for gastrointestinal injury, can be severe. When immunosuppressive doses of steroids are used, most animals are placed on drugs to protect the gastrointestinal tract from ulceration.

Additional drugs to suppress or modify the immune system are commonly used to treat IMHA. It is thought that combination therapy may be more effective in some patients, and that it may limit side effects from over-reliance on a single class of drugs. These drugs have the potential to cause serious side effects, such as liver injury or bone marrow suppression, so patients must be carefully monitored. The medications may be used on a one-time only basis, or for longer periods of time during treatment. Examples of these drugs include azathioprine, cyclophosphamide, and danazol.

Some very expensive medications may also be used in the fight against IMHA. These include human intravenous immunoglobulins, and cyclosporine, a drug commonly used in transplant recipients to prevent organ rejection.

In some IMHA-patients that have failed to adequately respond to medical treatment, surgical removal of the spleen may also be considered. This invasive step is seldom performed, although there are some reports that indicate it can be associated with a high degree of success. Because many patients with IMHA are in such critical condition, the risk of general anesthesia may be too high.

Despite a relatively large number of treatment options and treatment protocols with these medications, there is no one agreed upon, universally effective treatment for IMHA. All possible treatments have potential side effects that need to be carefully monitored, and once an animal is successfully managed through an initial crisis, long-term treatment is usually necessary.

Prevention:
For most dogs with immune-mediated hemolytic anemia, there is no known means of prevention of the disease. Modified live-virus vaccinations may trigger IMHA in some dogs. Patients that are suspected of having had vaccine-related IMHA in the past probably should not be given these vaccines again.

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