Immune-Mediated Hemolytic Anemia (IMHA) in Dogs and Cats

Wendy Brooks, DVM, DABVP

Date Published: 03/04/2003 Date Reviewed/Revised: 12/30/2020

Modified by Yuri A. Lawrence, DVM, Ph.D., Dipl.ACVIM(SAIM)

Immune-mediated hemolytic anemia (IMHA) is the condition where the body’s immune system attacks and removes its own red blood cells, thus leading to severe anemia, an unhealthy yellow coloring of the tissues called jaundice or icterus as well as an assortment of life-threatening complications may also occur. Mortality approaches 70 percent so an aggressive approach is necessary with multiple blood transfusions and immune-suppressive drugs often needed. Red blood cells are coated with Y-shaped antibodies that mark them for removal or destruction in this immune-mediated condition.

How Red Blood Cells are Normally Removed from the Body

Red blood cells have a natural life span from the time they are released from the bone marrow to the end of their oxygen-carrying days when they become too stiff to move through the body’s narrow capillaries. A red blood cell must be supple and flexible to participate in oxygen delivery and carbon dioxide removal, so when the cell is no longer functional the body destroys it and recycles its components.

When old red blood cells circulate through the spleen, liver, and bone marrow, they are plucked from circulation and destroyed in a process called extravascular hemolysis. Their iron is sent to the liver for recycling in the form of a yellow pigment called bilirubin. The proteins inside the cell are broken down into amino acids and used for any number of things (burning as fuel, building new protein etc.)

The spleen uses immunological cues on the surface of red blood cells to determine which cells should be plucked out of circulation. In this way, red cells parasitized by infectious organisms are also removed from circulation along with the geriatric red cells.

Alternatively, some old stiff red blood cells simply burst when they cannot go through narrow passages. In that case (intravascular hemolysis), the components are scavenged and recycled similarly. When the immune system marks too many cells for removal, serious problems begin.

• Too many red blood cells are removed and the patient becomes weak from lack of blood.
  

• The liver is overwhelmed by the large amounts of bilirubin it must process. The patient becomes jaundiced, or icteric, which means his tissues become yellow or orange. The extra bilirubin in the urine turns the urine orange or even brown.
  

• Hemoglobin (oxygen-carrying protein from inside the red blood cell) floats around in the bloodstream in large amounts which can damage the kidneys.
  

• All those red blood cells coated with antibodies begin to stick to each other and form small clots (embolisms). This begin to block blood vessels, compromising circulation to the organs and creating inflammation as the body tries to dissolve the clots.

This is a life-threatening cascade of events and, in fact, a 20-80 percent mortality rate (depending on the study) has been reported with this disease.

What Happens during IMHA?

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 bilirubin and the patient may become jaundiced (icteric), which means his tissues become a yellow/orange color. Making matters worse, a protein system called the complement system is activated by these anti-red cell antibodies. 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.

Clinical Findings and Test Results

There are several features to IMHA that your veterinarian will be looking for, though not every patient will show them all. To diagnose IMHA, there must be at least one sign of red cell destruction (orange urine, yellow tissues, high bilirubin blood test, for example) PLUS at least two indicators that the red cell destruction is immune-mediated and not from some other cause (such as zinc toxicity). Indicators of immune-mediated red cell destruction include a positive auto-agglutination test, positive Coombs test, or the presence of small red blood cells called "spherocytes".

Signs you Notice at Home

Your pet is often weak and may not have energy and less interest in food. The urine may be dark orange or even brown. The gums are pale or even yellow-tinged as are the whites of the eyes. There may be a fever.

Additional Helpful Tests

Coomb’s Test Called a Direct Antibody Test)

If a patient is anemic, icteric, has spherocytes (or worse, autoagglutination) on a blood smear, it is pretty obvious that there is immune-mediated hemolytic anemia. Sometimes, though, it is not so obvious and additional testing is needed. This is exactly where the Coomb's test could be used. This is a test designed to identify antibodies coating red blood cell surfaces. If there is ambiguity in the patient's presentation, the Coomb's test might be selected to confirm that the anemia is really immune-mediated and not the result of a bleed or non-immune mediated origin such as zinc toxicity, or onion/garlic toxicity.

Testing for Blood Parasites

In most canine episodes of IMHA, an underlying cause cannot be found but it is still worth looking. There are many blood parasites, especially tick-borne infections, that can initiate IMHA. The parasite attaches to the red blood cell and its structures are detected by the immune system. The immune system attacks the parasite but, unfortunately, also attacks the red blood cells as well. Parasites such as Ehrlichia, Babesia, and Anaplasma should be ruled out. If a blood parasite is confirmed, a more targeted therapy can be effected.

Treatment and Monitoring

The patient with IMHA may be unstable if the hematocrit has dropped to a dangerously low level, then blood transfusion is needed and quickly. It is not unusual for a severely affected patient to require one or more transfusions. General supportive care may also be 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, and thromboembolism must be prevented.

Transfusion Compatible blood can last a good 3 to 4 weeks in the recipient’s body.

Well-matched whole blood or packed red cells (a unit of whole blood with most of the plasma, leaving only a concentrated solution of red blood cells) may last longer. 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 necessary during treatment.

Immune Suppression

Corticosteroid hormones in high doses are the cornerstone of immune suppression. Prednisone and dexamethasone are the most popular medications selected. Remember, that the problem in IMHA is that red blood cells are being coated with antibodies which mark them for removal. Antibodies come from lymphocytes and corticosteroid hormones kill lymphocytes, thus taking out the cells that are making the offending antibodies. Even better, corticosteroid hormones also suppress the cells that are removing the antibody coated red blood cells as well. This allows the patient's red blood cells to survive and continue their job carrying oxygen and carbon dioxide.Corticosteroids may 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 weeks or months before the dose is tapered down and there will be regular monitoring blood tests. Expect your pet to require steroid therapy for some 4 months; many patients must always be on a low dose to prevent recurrence.

1. 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.

1. Additional Immune Suppression If minimal response at all is seen with corticosteroids, supplementation with stronger immune suppressive agents is necessary. The most common medication used in this case is azathioprine. This is a serious drug reserved for serious diseases. Please follow the link above to read more about specific side effects, concerns, etc.

   1. Cyclosporine is an immune-modulator, made popular by organ transplantation technology. It has the advantage over other medications of not being suppressive to the bone marrow cells. It has been a promising adjunctive medication in IMHA but may be prohibitively expensive for larger dogs.

   2. Mycophenolate mofetil is another emerging immune suppressive medication that might be prescribed. The goals of these additional medications is similar: to provide extra immune suppression and to reduce the necessary dose of steroid, thus mitigating the steroid side effects.

   3. Leflunomide is an immuno-modulator that is meant for patients with immune mediated diseases when corticosteroids either do not work or cannot be used. It is expensive (approximately $600 per month) but we may be hearing more about it in the future.

Preventing Thromboembolic Disease

While it is generally agreed that the IMHA patient needs to be anti-coagulated, a definitive drug protocol for doing so has not emerged.

Evan's Syndrome

A special disaster in IMHA is Evan's syndrome where not only are red blood cells being destroyed but platelets are also destroyed (Immune Mediated Thrombocytopenia). If a patient not only has IMHA but also has extremely low platelet numbers, this suggests that Evan's syndrome is afoot and the patient should not have treatment to prevent embolism as the platelet loss has already created an inability to clot normally. Evan's syndrome has a particularly high mortality rate.

Thromboembolic Disease

This particular complication is the leading cause of death for dogs with IMHA (between 30-80 percent of dogs that die of IMHA do so due to thromboembolic disease). A thrombus is a large blood clot that obstructs (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 obstruct 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, a natural anticoagulant, may be used as a preventive in hospitalized patients or in patients with predisposing factors for embolism.

Etiology

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 which study you read, 60-75 percent 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 it will seek proteins that closely resemble the drug and innocent red blood cells will be consequently destroyed. Drugs are not the only such stimuli; cancers can stimulate exactly the same reaction (especially hemangiosarcoma). Red blood cell parasites create a similar situation, as mentioned, 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. The possible relationship between recent vaccination and IMHA development is one of the factors which has led most veterinary universities to go to an every 3 year schedule for the standard DHPP vaccine for dogs rather than the traditional annual schedule. The role of vaccination as a trigger for this condition remains controversial as some studies show an association with recent vaccination and others show none. Vaccination involves immune stimulation, however, which may be something to avoid. Check with your veterinarian about how to proceed with future vaccinations.

In cats, IMHA generally has one of two origins: feline leukemia virus infection or infection with a red blood cell parasite called Mycoplasma hemofelis (previously known as Hemobartonella felis). The underlying cause should be sought and addressed specifically in addition to immune suppressive therapy.

Complications

Human gamma globulin transfusion is a treatment that is reserved for patients for whom more traditional methods of immune suppression have been ineffective. The gamma globulin portion of blood proteins includes circulating antibodies. These antibodies bind the reticulo-endothelial cell receptors that would normally bind antibody-coated red blood cells. This prevents the antibody-coated red blood cells from being removed from the circulation. Human gamma globulin therapy seems to improve short-term survival in a crisis but, unfortunately, its availability is limited and it is very expensive.

IMHA is a serious disease with a high mortality rate. Treatment must be aggressive and not prematurely discontinued if the patient is to survive. Transfer to a critical care or emergency facility may be necessary. Research is on-going with regard to new therapies.

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