Immune Mediated Hemolytic Anemia (IMHA)

Immune Mediated Hemolytic Anemia (IMHA)

(Formerly known as autoimmune hemolytic anemia or AIHA)

Immune-mediated hemolytic anemia is a condition where the patient's immune system begins attacking its own red blood cells. What occurs on a microscopic level is that the branch of the immune system that produces antibodies begins to direct them against the patient's own red blood cells. The red blood cells become quickly coated with tiny antibody proteins, essentially marking these red blood cells for destruction.
When the cells circulate through the spleen, liver, and bone marrow, they are plucked from circulation and destroyed, a process called extravascular hemolysis. Their iron is sent to the liver as bilirubin for recycling. The spleen enlarges as it finds itself processing far more damaged red blood cells than it normally does. The liver is overwhelmed by large amounts of iron-pigmented bilirubin and the patient becomes jaundiced.

To make matters worse, these antibodies activate a special protein system called the complement system. Complement proteins are able to simply rupture red blood cells if they are adequately coated with antibodies, a process called intravascular hemolysis. Ultimately, there aren't enough red blood cells left circulating to bring adequate oxygen to the tissues and remove waste gases. A life-threatening crisis has emerged; in fact 20% to 80% mortality (depending on the study) have been reported with this disease.

Signs You Notice

Your pet is obviously weak. He or she has no energy and has lost interest in food. Urine is dark orange or maybe even brown. The gums are pale or even yellow-tinged as are the whites of the eyes. There may be a fever. You (hopefully) brought your pet to the veterinarian's office as soon as it was clear that there was something wrong.

The Tests Show Anemia

Part of a general evaluation includes blood testing. If your pet seemed obviously pale or jaundiced (yellow-tinged), your vet may immediately run a test called a packed cell volume. This test can be run in most veterinary offices and involves spinning a small amount of blood in a small glass tube at high speed to separate the red blood cells from the serum (the blood's liquid phase). By comparing the blood tube to a chart, it will become obvious if your pet has a low red blood cell count. If your pet has hemolytic anemia, the serum may be bright orange instead of its normal off-white color.

The anemia may come up on a full blood panel submitted to a reference laboratory. These laboratories perform a test called a hematocrit, which is slightly different from a packed cell volume but essentially measures the same thing: the percentage of blood volume made up by red blood cells. This number should be 43 to 59 for dogs and 29 to 50 for cats.

Anemia is the condition where one's red blood cell count is low. Anemia can be mild or severe and can represent bleeding, red blood cell destruction (as in IMHA) or simply lack of red blood cell production. Once a patient is found to be anemic, it is important to determine why.

Icterus (Jaundice)

This is the yellow color that is taken up by a patient's tissues when the liver is overwhelmed with bilirubin, the iron that contains by-products of red blood cell destruction. Normally red blood cells are removed from the circulation when they become old and inflexible. Their iron is recycled in the liver. With so many red cells being destroyed, the liver is overwhelmed and bilirubin (a yellow pigment) spills out everywhere, coloring urine, gums, skin, and the eyes orange.

Is immune mediated red cell destruction the only cause of icterus? Absolutely not. Liver failure also leads to icterus when the diseased liver cannot process normal amounts of bilirubin. In cats especially, bacterial endotoxin (the toxic cell walls of certain types of infecting bacteria) can lead to icterus. Usually, however, a responsive anemia together with icterus suggests immune-mediated red cell destruction.

Spherocytes

Spherocytes are red blood cells produced when a red blood cell is not completely removed by the spleen. The spleen cell "bites off" only a portion of the red cell, leaving the rest to escape back to the circulation. In the adjacent graphic, the arrow points to a spherocyte. Note its uniform dense red color, as opposed to the normal red blood cells without a dense red color.
 
A normal red blood cell is concave on both sides and disc-like in shape. It is slightly paler centrally than on its rim. After a portion has been bitten off, it re-shapes into a more spherical shape with a denser red color. The presence of spherocytes indicates that red blood cells are being destroyed.

Autoagglutination

In severe cases of immune mediated hemolytic anemia, the immune destruction of red cells is so blatant that the red cells clump together (because their antibody coatings stick together) when a drop of blood is placed on a microscope slide. Imagine a drop of blood forming not a red spot but a yellow spot with a small red clump inside it. This finding is especially foreboding.

Leukemoid Reaction

Classically, in IMHA the stimulation of the bone marrow is so strong that even the white blood cells lines, which have very little to do with this disease but which also are born and incubate in the bone marrow along side the red blood cells, are stimulated. This leads to white blood cell counts that are spectacularly high.

More Tests Needed

Coomb's Test (also called a direct antibody test)

This is a test designed to identify antibodies coating red blood cell surfaces. This test is the current state of the art for the diagnosis of IMHA but, unfortunately, it is not as helpful as it might seem. It can be erroneously positive in the presence of inflammation or infectious disease (which might lead to harmless attachment of antibody to red cell surfaces) or in the event of prior blood transfusion (ultimately transfused red cells are removed from the immune system). The Coomb's test can be erroneously negative for a number of reasons as well. If the clinical picture fits with IMHA, often the Coomb's test is skipped.

 Remember, not all causes of hemolysis (red blood cell destruction) are immune-mediated. Onions in large amounts (and possibly garlic as well) will cause a toxic hemolysis. Zinc toxicity, usually from swallowing a penny minted after 1983, or from licking off a zinc oxide ointment applied to the skin, will cause hemolysis as well. In a young animal, a genetic red blood cell malformation might be suspected.

Once the diagnosis of immune mediated hemolytic anemia has been made, efforts to determine an underlying cause should be made. Radiographs of the chest and abdomen to look for tumors are a good idea especially in middle-aged or older patients. Blood tests to rule out tick-borne blood parasites such as Ehrlichia and Babesia may be in order depending on the geographic area where your pet has been living or has traveled.

Treatment And Monitoring During The Crisis

A patient with IMHA is often unstable. If the hematocrit has dropped to a dangerously low level then blood transfusion is needed. It is not unusual for a severely affected patient to require many transfusions. General supportive care is needed to maintain the patient's fluid balance and nutritional needs. Most importantly, the hemolysis must be stopped by suppressing the immune system's rampant red blood cell destruction. We will review these aspects of therapy.

Transfusion

There are several products that may be helpful in treating IMHA. If the patient is in a crisis and needs immediate therapy, artificial blood may be a good choice. Artificial blood (Oxyglobin®) is made from hemoglobin harvested from cow's blood. Because the patient does not receive actual red blood cells, the artificial blood does not further stimulate the immune system. Artificial blood does not require refrigeration and is likely sitting on the shelf ready to use at your veterinarian's office. The disadvantage of artificial blood is that it does not last in the body like a well-matched blood transfusion does. The body begins removing artificial blood immediately so that the entire transfusion is probably gone in 48 hours or so. In IMHA, this may buy some time but since IMHA tends to have a long treatment course, it is likely that the patient will be back where they started from at that point. If a compatible donor is not readily available, sometimes an artificial blood transfusion buys enough time to find a compatible donor.

Well-matched whole blood or packed red cells (a unit of whole blood with the plasma mostly removed leaving only a concentrated solution of red blood cells) may last longer. Compatible blood can last a good 3 to 4 weeks in the recipient's body. The problem, of course, with IMHA is that even the patient's own red blood cells are being destroyed so what chance do donated cells have? Cross matching of red cells is ideal but still may not lead to a good match given the hyperactivity of the patient's immune response. For this reason, it is not unusual for several transfusions to become necessarily in the treatment of this condition.

Immune Suppression

Corticosteroid hormones in very high doses are the corner stone of immune suppression. Prednisone and dexamethasone are the most popular medications selected. These hormones are directly toxic to lymphocytes, the cells that produce antibodies. If the patient's red blood cells are not coated with antibodies, they will not have been targeted for removal so stopping antibody production is a very important part of therapy. These hormones also suppress the activity of the Reticuloendothelial cells that are responsible for the removal of antibody-coated red cells.

Corticosteroids may very well be the only immune suppressive medications the patient needs. The problem is that if they are withdrawn too soon the hemolysis will begin all over again. The patient is likely to be on high doses of corticosteroids for months before the dose is tapered down and there will be regular monitoring blood tests. Expect your pet to require steroid therapy for some 6 months; many must always be on a low dose to prevent recurrence.

Corticosteroids in high doses produce excessive thirst, re-distribution of body fat, thin skin, panting, predisposition for urinary tract infection and other signs that constitute Cushing's Syndrome. This is an unfortunate consequence of long-term steroid use but in the case of IMHA, there is no way around it. It is important to remember that the undesirable steroid effects will diminish as the dosage diminishes.

More Immune Suppression

If no response at all is seen with corticosteroids, supplementation with stronger immune suppressive agents is necessary. The two most common medications used in this case are: azathioprine and cyclophosphamide. These are very serious drugs reserved for serious diseases. Please follow the links above to read more about specific side effects concerns etc.

Cyclosporine is an immune-modulator, made popular in organ transplantation technology. It has the advantage over the two above medications of not being suppressive to the bone marrow cells. It has been a promising adjunctive therapy in IMHA but has two major problems: first, it is extremely expensive and second, blood level monitoring is necessary to ensure that the dosage is appropriate. This adds dramatically to the expense of treatment but ultimately may provide the results not possible with other drugs.
 
Why Did This Happen To Your Pet?

When something as threatening as a major disease emerges, it is natural to ask why it occurred. Unfortunately, if the patient is a dog, there is a good chance that there will be no answer to this question. Depending on the study, 60% to 75% of IMHA cases do not have apparent causes.

In some cases, though, there is an underlying problem: something that triggered the reaction. A drug can induce a reaction that stimulates the immune system and ultimately mimics some sort of red blood cell membrane protein. Not only will the immune system seek the drug, but also it will seek proteins that closely resemble the drug and innocent red blood cells will be consequently destroyed. Drugs most commonly implicated include penicillins, trimethoprim-sulfa, and methimazole.

Drugs are not the only such stimuli; cancers can stimulate exactly the same reaction, especially hemangiosarcoma.
Red blood cell parasites create a similar situation except the immune system is aiming to destroy infected red blood cells. The problem is that it gets over-stimulated and begins attacking the normal cells as well.
There is some thinking that vaccination can trigger IMHA. Insect bites have also been implicated. Both have been temporally associated with the development of AIHA. The relationship between recent vaccination and IMHA development is one of the factors that has led most universities to go to an every 3 year schedule for the standard DHLPP vaccine for dogs, rather than the traditional annual schedule.

Breeds predisposed to the development of IMHA include: cocker spaniels, poodles, Old English Sheepdogs, and Irish setters.

In cats, IMHA generally has one of two origins: Feline Leukemia Virus infection or infection with a red blood cell parasite called Hemobartonella felis.

Complications of IMHA
Thromboembolic Disease

This particular complication is the leading cause of death for dogs with IMHA (between 30% to 80% of dogs that die of IMHA die due to thromboembolic disease). A thrombus is a large blood clot that occludes a blood vessel. The vessel is said to be thrombosed. Embolism refers to smaller blood clots, spitting off the surface of a larger thrombus. These mini-clots travel and occlude smaller vessels thus interfering with circulation. The inflammatory reaction that normally ensues to dissolve errant blood clots can be disastrous if the embolic events are occurring throughout the body.

Heparin, or asprin, may be used in hospitalized patients (or in patients with predisposing factors for embolism) as a preventive.

* It should be noted that 4 to 7 days are required for the bone marrow to generate a response. If hemolysis occurs suddenly there may not have been adequate time for a response. When this occurs, if there is any question about the responsive nature of the anemia, continued monitoring of the complete blood count will show a clear response in an appropriate time period.
It should also be noted that in an especially unlucky patient, the red blood cell destruction may extend to the pre-red blood cells (reticulocytes, nucleated red cells and other precursors) within the bone marrow. If these cells are also destroyed, the condition is especially dangerous and it will take weeks rather than days to begin to see a response to treatment. The lack of circulating immature red cells will lead this anemia to test as non-responsive.

Another Study

The 2005 study looking for trends, by Drs. Tristan Weinkle, Sharon Center, John Randolph, Stephen Barr, and Hollis Erb at Cornell University, reviewed 151 dogs with IMHA. They found:

 Cockers spaniels and Miniature Schnauzers were both overrepresented (i.e., felt to be predisposed). These breeds, however, showed the same mortality rate as other breeds.
 Unspayed female dogs were overrepresented.
 Neutered male dogs were more commonly affected than unneutered male dogs (begging the question of whether male hormones might have some protective effect).
 The chance of survival either long term or short term was significantly enhanced by the addition of aspirin to the treatment protocol, especially when combined with azathioprine.
 Adequate vaccination information was not obtained for enough patients to comment on association with vaccination.
 89% of affected dogs showed spherocytes on their blood smears.
 78% showed autoagglutination.
 70% of patients required at least one blood transfusion.
 Of the 151 dogs studied, 76% survived, 9% died, and 15% were euthanized. Survivors were hospitalized an average of 6 days. Non-survivors were hospitalized an average of 4 days.
 100% of dogs that died or were euthanized showed thromboembolism on necropsy (autopsy).
 Of the dogs that survived 60 days or more, 15% experienced relapse. Most dogs treated with corticosteroids, azathioprine, and ultra-low dose aspirin did not experience relapse.

Other Websites

IMHA is a very serious disease associated with a high mortality rate. Sadly, many dogs have succumbed. Several pet owners have used these sad events to create outstanding informational web sites on IMHA in tribute and to help others. I have found these sites to be especially noteworthy and recommend them highly:
www.cloudnet.com/~jdickson/
www.peppypaws.com/LillisLegacy.html