IMMUNE MEDIATED HEMOLYTIC ANEMIA (IMHA)
IMMUNE MEDIATED HEMOLYTIC ANEMIA or “IMHA”
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
LET'S STEP BACK AND LOOK AT HOW RED BLOOD CELLS ARE NORMALLY REMOVED FROM THE BODY
CLINICAL FINDINGS AND TEST RESULTS
To clinch the diagnosis of IMHA, the patient will not only have bright yellow serum (see graphic) but the blood sample will show special red blood cells called “spherocytes” when it is examined under the microscope. Further, the intense effort of the patient’s bone marrow to generate replacement red blood cells will be evident as well. The marrow will be releasing young red blood cells somewhat prematurely out of desperation and these cells will be large and of varying degrees of redness. The activity of the bone marrow often carries into all blood cell lines and there is typically an elevation in white blood cell numbers as well. In severe cases, the blood cells may show “autoagglutination” where they spontaneously clump (see below). Icterus with spherocytes is basically all that is needed to diagnose IMHA but there may be additional supportive findings seen and there may be further testing for underlying disease causes recommended.
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.
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. 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.
Corticosteroid hormones in very high doses are the cornerstone 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 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 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 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.
Leflunomide is a new immuno-modulator that is meant for patient with immune mediated diseases when corticosteroids either do not work or cannot be used. It is expensive (approx $600 per month) but we may be hearing more about it in the future.
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.
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 is emerging as an alternative but none of these medications (the heparins not the platelet blockers) have been shown to improve survival rate.
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 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.
Breeds predisposed to the development of IMHA include: cocker spaniels, poodles, Old English Sheepdogs, and Irish setters.
COMPLICATIONS OF IMHA
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. We have found these site especially noteworthy and recommend them highly:
Page last updated: 6/13/2017