Mar Vista Animal Medical Center

3850 Grand View Blvd.
Los Angeles, CA 90066

(310)391-6741

www.marvistavet.com

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 

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, problems begin. 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 becomes “jaundiced” or “icteric” which means his tissues become colored yellow/orange.

Making matters worse, a special 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.  A life-threatening crisis has emerged; in fact 20-80% mortality (depending on the study) have 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)

 

The jaundiced/icteric pet has a  yellow color in the gums and  whites of the eyes
(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

Spherocytes are special red blood cells produced when a red blood cell is 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)

 

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 forboding.

(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.

 

 

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

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.

 

 

TRANSFUSION

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 3-4 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.

(original graphic by marvistavet.com)

IMMUNE SUPPRESSION

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.

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.

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.
There is some thinking that vaccination can trigger IMHA. Insect bites have also been implicated. Both have been temporally associated with the development of IMHA. The 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.

Cocker Spaniel
(Photocredit: Morguefile.com)

Standard Poodle
(Photo Credit: Final4One via Wikimedia Commons)


Old English Sheepdog
(Photocredit: Morguefile.com)


Irish Setter
(Photocredit: Morguefile.com)

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 (previously known as Hemobartonella felis).

 

COMPLICATIONS OF IMHA

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.

 

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.

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.  1869-80.

 

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:

http://id3424.securedata.net/peppypaws/IHMA&AIHA.html

Page last updated: 6/13/2017