IMMUNE MEDIATED HEMOLYTIC ANEMIA (IMHA)

IMMUNE MEDIATED HEMOLYTIC ANEMIA or “IMHA”
(FORMERLY KNOWN AS AUTOIMMUNE HEMOLYTIC ANEMIA or “AIHA”)

Immune-mediated hemolytic anemia (“IMHA”) is the condition where the body’s immune system attacks and removes its own red blood cells leading to severe anemia, an unhealthy yellow coloring of the tissues called “jaundice” or “icterus” as well as an assortment of life-threatening complications. Mortality approaches 70% so an aggressive approach is necessary. Multiple blood transfusions and immune-suppressive drugs are needed.

Red blood cells are coated with Y-shaped antibodies which mark them for removal / destruction
(original graphic by marvistavet.com)

LET'S STEP BACK AND LOOK AT HOW RED BLOOD CELLS ARE NORMALLY REMOVED FROM THE BODY 

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 cells called "spherocytes" (see below).

TO REVIEW:

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 small red clumps inside it. This finding is especially foreboding. The spontaneous clumping of red blood cells is called autoagglutination. The formation of an actual clot from all the clumping is called embolization (especially if the clot travels in the circulation). When the embolism lodges in a small vessel like a plug and occludes circulation, this event is called thrombosis. The condition where embolism is happening and vessels are being plugged is called thromboembolic disease and it is the main cause of death in IMHA patients.

Under the microscope, autoagglutinating red blood cells form clumps. Normal red blood cells appear as distinct cells but there are very few in this blood smear. (Photocredit: Prof. Erhabor Osaro via wikimedia commons)

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.

ADDITIONAL HELPFUL TESTS

COOMB’S TEST (ALSO 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.

The Coomb's test has been around a long time and is not perfect. 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). Despite its limitations, the Coomb's test is helpful in clinching the IMHA diagnosis if other findings are confusing.

SERUM LACTATE LEVELS
Lactate or Lactic acid is the natural by-product of anaerobic metabolism. In other words, when the body's organs are deprived of oxygen (say, because there aren't enough functioning red blood cells circulating or there are agglutinated red blood cells clogging the capillaries), the organs will switch to anaerobic metabolism. Lots of lactate circulating means lots of tissue does not have enough oxygen and it is a bad sign. It is such a bad sign that it can be used to predict disease survivors within the first several hours of hospitalization.

In a study of 173 dogs with IMHA (Holahan et al), non-survivors had significantly higher lactate levels at presentation compared to survivors. Dogs that were able to normalize serum lactate levels within 6 hours of hospitalization all survived. Many hospitals monitor lactate levels in IMHA patients as part of the regular assessment of ability to oxygenate tissue.

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.

Babesia organisms in an infected red blood cell. (Photocredit: CDC Public Health Image Library)

TREATMENT AND MONITORING DURING THE CRISIS

The patient with IMHA is often 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 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 and thromboembolism must be prevented. We will review these aspects of therapy.

IMMUNE SUPPRESSION

Corticosteroid hormones in very 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 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 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 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.

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 very serious drug reserved for serious diseases. Please follow the link 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 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. Please click the link to our Pharmacy Library for details on side effects potential.

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.

Do not be surprised if your veterinarian adds a second medication to the prednisolone or dexamethasone and do expect months of therapy to be needed.

IMHA has a relapse rate of 11-15%.

PREVENTION OF THROMBOEMBOLIC DISEASE

This particular complication is the leading cause of death for dogs with IMHA (between 30-80% 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.

While it is generally agreed that the IMHA patient needs to be anti-coagulated, a definitive drug protocol for doing so has not emerged. Heparin is a natural protein that can be administered by injection or by continuous drip. The trick is to keep the already anemic patient from bleeding once coagulation mechanisms have been disrupted. A more pure form of heparin called "low molecular weight heparin" appears to represent an improvement but this form of heparin is substantially more expensive and may be impractical.

Another approach to anticoagulation is to block platelet function by using low doses of aspirin. The problem with aspirin is getting a dose that will inactivate platelets without also increasing the risk of ulceration of the GI tract since aspirin and corticosteroids are generally not compatible. A newer drug called clopidogrel has emerged as an alternative but none of these medications (the heparins not the platelet blockers) have been shown to definitively improve survival rate.

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.

MISCELLANEOUS THERAPY

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 reticuolo-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, availability of the product is limited and it is very expensive.

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, 60-75% 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 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.

There is some thinking that vaccination can trigger IMHA but reports have been conflicting. 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.

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 Mycoplasma hemofelis. Underlying cause should be sought and addressed specifically in addition to immune suppressive therapy.

COMPLICATIONS OF IMHA

Another Study:

IMHA is a very 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.

Page last updated: 3/4/2021