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
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 has a system to destroy it and recycle its components.
When old red blood 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 in the form of a yellow pigment called “bilirubin” for recycling. 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 are plucked out of circulation. In this way, red cells parasitized by infectious agents are also removed from circulation along with the geriatric red cells.
Red blood cells circulating through capillaries. When vessels are this small, the red cells must be flexible to make it through without bursting. (Videocredit: BSC CNS via YouTube.com)
WHAT HAPPENS DURING IMHA?
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/her tissues become yellow or orange. The extra bilirubin in the urine turns the urine orange or even brown.
Free hemoglobin 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 occlude blood vessels compromising circulations 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% mortality rate (depending on the study) has been reported with this disease.
Icteric Blood Sample. The sample has been separated into red blood cells on the bottom and serum on top. The serum is yellow from the extra bilirubin. Normal serum is nearly clear with very little color. (Photocredit: Lamiot via Wikimedia Commons)
In the jaundiced/icteric pet the whites of the eyes have become yellow. The gums and unhaired skin may also appear yellow. (original graphic by marvistavet.com)
SIGNS YOU NOTICE AT HOME
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.
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.
Spherocytes are special red blood cells produced when red blood cells are not complete 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.
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.
Arrows point to spherocytes. Note their uniform dense red color, as opposed to the normal red blood cells which are clear in the center (Photocredit: Public Domain Graphic via Wikimedia Commons)
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)
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”)
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.
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.
Compatible blood can last a good 3-4 weeks in the recipient’s body. 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. 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.
(original graphic by marvistavet.com)
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 be been targeted for removal so stopping antibody production is paramount. Further, corticosteroid 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 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 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.
This condition has a high mortality rate so many medications are commonly used in combination.
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.
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 universities to go to an every 3 year schedule for the standard DHLPP vaccine for dogs rather than the traditional annual schedule.
The 2002 Study by Drs. Anthony Carr, David Panciera, and Linda Kidd at the University of Wisconsin School of Veterinary Medicine reviewed 72 dogs with IMHA looking for trends. Here are their findings:
The only predisposed breed they found was the Cocker Spaniel.
Most patients were female.
The mean age was 6.8 years.
Timing of Vaccination was not associated with the development of IMHA.
94% of cases had spherocytes on their blood smears.
42% showed autoagglutination.
70% also had low platelet counts.
77% were Direct Coombs' positive.
58% were suspected of having Disseminated Intravascular Coagulation.
55% required at least one blood transfusion.
Mortality rate was 58%.
Of those that died, 80% had thromboembolism present on necropsy (autopsy).
Prognostic Factors for Mortality and Thromboembolism in Canine Immune-Mediated Hemolytic Anemia. A.P. Carr, D. Panciera, L. Kidd. Journal of Veterinary Internal Medicine. 2002; 16: 504-509.
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.
Evaluation of prognostic factors, survival rates, and treatment protocols for immune-mediated hemolytic anemia in dogs: 151 cases (1993-2002). T.K. Weinkle, S.A. Center, J.F. Randolph, K.L. Warner. S.C. Barr, H.N. Erb. Journal of the American Veterinary Medical Association. Vol 226, No 11, June 1, 2005.Â 1869-80.
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: 7/16/2019
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