Immune Mediated Hemolytic Anemia


Immune Mediated Hemolytic Anemia (IMHA) or Autoimmune hemolytic anemia (AIHA)

In hemolytic anemia, a loss of red blood cells (rbcs) occurs due to destruction of the rbcs. The destruction occurs due to antibodies which stick to the the rbc and cause the body to react, leading to destruction of the cell. This can be the direct result of a drug, toxin, blood parasite, virus or other primary cause or it can be an unexplained immune mediated reaction. It can occur inside the blood stream (intravascular hemolysis) or outside the bloodstream (extravascular hemolysis). In most cases in dogs, hemolysis occurs outside the blood stream in the spleen, liver and bone marrow. The destruction of red blood cells often leaves recognizable cellular debris in the blood stream. In particular, a form of damaged rbc known as a spherocyte occurs. Finding spherocytes on a blood smear almost guarantees that some form of hemolytic anemia is occurring. It does not really give a clue as to whether the IMHA is due to a primary cause or if it is occurring for no apparent reason, though. Since this disorder does not stop the production of red blood cells, there are usually immature red blood cells in the bloodstream which can be detected on the blood smears as well (a regenerative anemia).

The mechanism by which the immune system mistakes red blood cells for a "foreign invader" varies somewhat according to the cause. It usually involves adherence of the offending agent (parasite, drug, toxin, etc) to the surface of the rbc. The immune system wishes to attack this agent but manages to injure the rbc as well.

Dogs with IMHA usually experience a sudden onset of clinical signs, including depression, lethargy, pale gums or conjunctiva, sometimes jaundice or a heart murmur and bruising. Vomiting or abdominal pain may be present. It is unusual for overt blood loss to occur, such as nose bleeds or excessive bleeding from a minor injury. Death can occur rapidly, even with appropriate treatment.

Whenever hemolytic anemia is present it is wise to carefully rule out initiating causes that might be treatable. Examples of problems that can lead to hemolytic anemia include ehrlichiosis (a blood parasite), reactions to sulfa antiseptics or penicillin antibiotics, zinc toxicosis -- which can occur due to the ingestion of pennies. If any of these problems can be identified and treated the prognosis is much better.

The combination of clinical signs and spherocytes on a blood smear give a strong indication of this condition very rapidly. It can be confirmed using a Coomb's test to check for antibodies adhered to red blood cells. This test is usually done at body temperature and at a colder temperature (4 degrees Celsius). A small percentage of dogs that have IMHA will not test positive on the Coomb's test.

This condition will often respond well to very high doses of corticosteroids, such as prednisone. These medications suppress the immune system, allowing the rbcs to escape destruction. Improvement usually occurs within 1 to 3 days, if the dog is going to respond. If signs of icterus (jaundice) are present, the prognosis is usually worse. Dogs with this symptom may benefit from very aggressive treatment with anticoagulants and cyclophosphamide, a potent immune system inhibitor. Blood transfusions can be used in dogs with IMHA if necessary but they can make the condition worse so most vets reserve this approach for dogs that appear to be in imminent danger of dying due to severe anemia. It is necessary to treat most dogs for a fairly long time to prevent recurrence of the disease and some dogs seem to require lifelong use of corticosteroids or other immunosuppressants. Splenectomy is done in resistant cases since it is a major site of red blood cell destruction.

The Basenji, West Highland White terrier, English springer spaniel, Alaskan malamute, poodle and beagle breeds can be congenitally predisposed to this condition due to defects in enzymes (such as pyruvate kinase) or in the red blood cells.

Mike Richards, DVM

Immune mediated hemolytic anemia (IMHA) - Crisis Treatments

Question: Hello Dr. Mike

We wrote to you on February 25th about our Collie-mix female named Sprocket who started exhibiting abnormal signs when she started eating & vomiting dirt in early February. Her first PCV (on Feb. 10th) was 15, and she gradually dropped to 10 by Feb. 12th. A transfusion on Feb. 13 brought her to 25, which dropped gradually over ten days to 13. Initially, IMHA was not considered, but after no response to Procrit, she was given three tablets of Cyclophosphamide 50mg; and has been on Azathioprine; ¾ of a 50mg tablet every 48 hours. She started these last two drugs on Feb. 25th. Over that weekend, she started getting noticeably slower, and by the evening of Tuesday the 27th, she was very weak and her gums were nearly white. I took Sprocket to her doctor the next day (Feb. 28th), and her PCV was 7. She stayed for cross-matching and her second transfusion. She came home late afternoon.

Over the next few days she started losing her appetite, so we fed her bland human foods from an approved list the clinic gave us. She was VERY finicky with these too; liking some foods one day and not the next. She s had a RBC check every day since her transfusion: March 1: 25; March 2: 23, and this morning (March 5) it was down to 19. She has not been vomiting; she continues to drink excessively, due to the Prednisone. Her clinic suggested Imodium for the diarrhea, which has had just a tiny effect.

We visited Dr. B again this afternoon, and her outlook seems bleak. Sprocket has not responded to any of the medications. She has not even stabilized at any level. She is alive only because of the transfusions with help from Prednisone. The doctors only suggestion was to try another three-day trial of the Cyclophosphamide. If there is no response after that, (or perhaps a THIRD round of Cyclophosphamide), Dr. B said that we should consider putting Sprocket to sleep, or wait until her RBC is so low we are forced to put her to sleep. We are very sad.

Have you heard of Cyclophosphamide not working the first time but being successful on repeated doses? I was searching your website, and read about a splenectomy being performed when medications don t work. Do you think that s a possible option for us? I also read about Oxyglobin being used when RBC transfusions don t work but perhaps that s relative. Before Sprocket s first transfusion, I asked them about Oxyglobin but they were convinced that it only lasts a few days, and is typically used in extreme situations. Is there any chance that Oxyglobin would fare better than the RBC transfusions Sprocket s been getting? Are there any other medications we should be considering? What is the longest response time to medications; i.e. are we hoping for a positive response whose deadline has passed? Also, what s an acceptable number of transfusions, and how often?

We got our first VetInfo Digest what a wealth of information!

Thanks very much in advance. Tom and Susan

Answer: Tom and Susan-

I think that you do have to accept that the prognosis is poor for Sprocket at this time. However, if you wish to continue to pursue therapy at least until the effect of this transfusion wears off, you do have some options in therapy left.

Regarding oxyglobin, a recent study found that using Oxyglobin was a risk factor for a poor prognosis in the treatment of immune mediated hemolytic anemia (IMHA). At this time, until further studies are done, it would be best to avoid its use.

The medications that can be helpful when prednisone doesn't work well enough include azathioprine, cyclophosphamide, danazol, cyclosporin and leflunomide have all been used.

In studies, azathioprine and cyclophosphamide did not have much short term benefit, taking a while to produce a beneficial effect. Danazol has supporters but studies do not support a beneficial effect for the use of this medication.

Based on anecdotal reports, cyclosporin at 5mg/lb initially can have a rapid beneficial effect. It is important to note that this has not been proven through clinical trials but due to this reputation it might be a good choice. Leflunomide is mentioned in the new Ettinger's "Textbook of Veterinary Internal Medicine" as being similar to cyclosporin in effect but no dosage is given for this medication.

Splenectomy seems to help some patients, probably because the spleen is involved in the removal of red blood cells from the blood stream. The spleen also makes blood cells in many patients. For this reason, it is a good idea to have a bone marrow examination done prior to removing the spleen, to be sure that the bone marrow is at least making red blood cells.

There is a procedure, plasmapherisis, in which blood is removed, separated into plasma and red blood cells and then only the red blood cells are put back. New plasma is made by the body, which is supposed to have less antibodies in it. I have never actually heard of anyone doing this procedure but it is published in several textbooks.

To sum this up, I think that the current thinking is that the fastest acting agent in crisis situations involving IMHA, other than corticosteroids, is cyclosporin. So it might be worth trying this. The alternative is to keep using prednisone and azathioprine or cyclophosphamide until the medications have a chance to work. My understanding of the situation is that it is best to just keep using these continuously until the work or do not work. We have only used azathioprine and this is the approach we take. Danazol is an option if things get desperate. Splenectomy may help but you would have to decide on taking the risk of surgery pretty quickly, before the hematocrit gets low again and you would have to consider having a bone marrow examination to really be careful in this decision.

I am really reluctant to give up on patients with diseases that have the potential to be turned around. Sometimes I think that is a bad trait, especially when patients don't make it after going through difficult treatments to no avail. This is a disorder in which you have to trust your instincts about when to go on and when to stop. Your vet is giving you a realistic view of the prognosis but you have to decide when to stop based on your endurance and your best guess about Sprocket's ability to accept continued therapy.

Mike Richards, DVM 3/10/2001

Immune mediated hemolytic anemia in Giant Schnauzer

Question: I have a very sick giant schnauzer with hemolytic anemia. It seems to have been brought on three months after a parvo vaccine. She has been on cyclosporin, imuran abd dexamethasone. She has far days and absolutely horrible days. Today is a horrible day. For some unknown reason she has developed a problem with her breathing. It is very labored. There does not seem to be an answer. Do you have any ideas? Our specialist also seems to be at a loss and she is excellent. Do you have any suggestions? We need help and very soon! Thank you. Delta

Answer: Delta-

There is a good review of the newest therapies for immune mediated hemolytic anemia in the most recent Kirk's Current Veterinary Therapy XIII (Bonagura, 1999). If your vet has this book, he or she might let you read through it.

In the article that established the link between vaccinations and IMHA, the average time to onset of IMHA was about 2 weeks and the longest interval prior to IMHA was 27 days (Duval and Giger, Journal of Veterinary Internal Medicine, 1996). This would make me want to look for another cause for the IMHA in your dog, since the interval before appearance of the disorder was much longer than this -- but I wouldn't rule out a connection. It just seems prudent to consider other causes.

Malignant cancers have been the most common cause of resistance to therapy for IMHA in our practice when a cause could be identified. Unfortunately, there are a lot of dogs who don't have an underlying cause for IMHA and some of these dogs do not respond well to therapy, either. Another cause of resistance to therapy is ehrlichiosis. We don't see that disease too often but it is more common in some areas of the country than it is here in Virginia.

The list of potential medications for treatment of IMHA include corticosteroids, azathioprine (Imuran Rx), cyclophosphamide (Cytoxan Rx), cyclosporin A and intravenous gamma globulin (IVGG). All of these medications have some complications associated with them and they are often used in combination. It sounds like that is what the specialist is doing already, though.

Thromboembolism is a definite possibility for the breathing problem, as is a worsening of anemia. In either case, it would be a good idea to have someone check your schnauzer as soon as possible. I'd actually recommend having someone check her tonight, if possible. Oxygen therapy can make a big difference in thromboembolism and severe anemia may require therapy, as well.

I wish that I had better advice.

Mike Richards, DVM 6/20/2000

Drug treatment options following hemolytic anemia

Q: Dear friend, Would appreciate any info on drug choices such as danazol or options such as splenectomy following getting hemolytic anemia crisis resolved using prednisone...Our pet is presently responding to 40 mg pred, following first relapse, but want other choices to circumvent Cushinoid symptoms, if he must stay on maintenance meds for life....Some articles say splenectomy gives great results...Would appreciate any insights or referrals!!!!!!!!!!!!

Devoted pet owner PS Our vet knows little about either, except to say they're last resort.....wonder if he knows latest research......

A: T-

It would be easier to reply to your inquiry if there were a lot of current research on this condition. As far as I can tell this is still a condition for which a consensus on the best treatment approach has not been reached.

Splenectomy is advocated by some veterinarians and avoided by others. The long term problems seen in people who have had splenectomies do not seem to occur in dogs so they are probably a little safer to consider in dogs than in humans. A middle of the road approach to splenectomy would be consider this option if there is not a good response to corticosteroids or to corticosteroids and a second immunosuppressive medication such as azathioprine (Imuran Rx) or danazol (Danocrine Rx). It is hard to imagine wanting to do a surgery involving an organ with the blood supply of the spleen in a patient with a bleeding disorder but it should be considered as an option in patients who are not responding to therapy. Even though I have a medical mindset as opposed to a surgical mindset, I have done splenectomies in several patients with suspected IMHA and have seen some improve and others who did not do well. The last two times I was considering splenectomies the surgical outcome was affected by the discovery of cancers leading to the suspected IMHA so the surgeries were beneficial in providing a diagnosis even though we didn't complete the splenectomies.

A major cause of death in IMHA is supposed to be the development of DIC (disseminated intravascular coagulation) and other thromboembolic disorders. the current therapy for these problems is heparinization, which probably should also be considered most patients with IMHA that does not respond rapidly to immunosuppressive medications.

Danazol is an androgenic steroid. For some reason androgens seem to inhibit immune mediated disorders. Danazol is usually used in conjunction with corticosteroids but may be used as the sole maintenance medication in some controlled cases of IMHA (Miller, Seminars in Small Animal Surgery, August 1997). The dose is between 5 and 10mg/kg every 12 hours with most recommendations sticking to the low side of the dose range.

I keep hearing about the use of cyclosporin in dogs with IMHA and yet I can't find much information on it. If everything else isn't working I am pretty sure I'd be willing to try it, though.

I am pretty sure that the consensus among veterinarians would be to use corticosteroids alone (or with heparin) if they are working well. Most vets are very familiar with these medications and more adept at dealing with dosing issues, side effects and withdrawal procedures than with the other medications. There is a lot to be said for using medications that one is familiar with when they are working as expected.

Hope this helps.

Mike Richards, DVM

IMHA recovery

Q: Dear Dr. Mike, My dog is suffering with AIHA. Do any dogs ever fully recover? What are the percentages for recovery? Thank you,TR-

A: TR - Some dogs do recover from immune mediated hemolytic anemia (IMHA), also known as auto-immune hemolytic anemia (AIHA). The chances for full recovery depend a lot on the cause of the condition, which may be difficult to determine. I have seen estimates as low as 10% for long term survival in cocker spaniels and as high as 90% for IMHA that occurs as the result of a drug that can be withdrawn or a curable underlying condition. I think the 10% figure is a little low for cockers, just based on our practice.

I hope that your dog has done well.

Mike Richards, DVM

Anipryl and Immune mediated hemolytic anemia

Q: Dear Mike: Our bichon was recently diagnosed with Cushing's Disease. The vet. put her on Anipryl for four days straight with one tablet each week thereafter, for four weeks. Into the third week she became very weak, and upon her vomiting...I rushed her to the vet... We have now been told that they think she has auto immune hemolytic anemia. She tested neg to the Coomes test....even thought that doesn't mean she doesn't have it. They began giving her steroids and within 34 hours her red blood cell count had climbed from 9,000 to 12,000.. they said they had hoped for higher...they will increase the amount of steroids today...her wbc is very high as well... My question....Do you think that the Anipryl brought on a drug -induced immune hemolytic anemia? or is this just a part of having Cushing's? and lastly never having been down this road before...should I prepare myself for days of sadness ahead? I so appreciate having found this supportive site on the web...not in anyway do I discount the abilities of my asking you these questions...I only hope to gain further insight into this horrible disease that anyone has. With appreciation, Mrs. J.

A: Mrs.J- I think that it is necessary to consider the possibility that l-deprenyl (Anipryl Rx) could have lead to a immune mediated hemolytic anemia as a drug reaction. I am not familiar enough with this medication to know how likely that might be, though. I have forwarded your email to a veterinarian I know who is involved with the research on this medication and maybe he will know more. I'll pass on any information I get.

There are other medications for hyperadrenocorticism (Cushing's disease). Ketaconazole is pretty safe and mitotane (Lysodren Rx) has been used with success many times, although overall it is more likely to cause side effects than either ketaconazole or l-deprenyl, probably.

If the immune mediated hemolytic anemia is a drug reaction it will normally respond to treatment and it is not likely to recur with other medications. I hope that everything is improving now.

Mike Richards, DVM

Continued: Cushing's Disease with immune mediated hemolytic anemia from 5/23

Q: Dear Mike: My question....Do you think that the Anipryl brought on a drug -induced immune hemnolytic anemia? or is this just a part of having Cushing's? and lastly never having been down this road before...should I prepare myself for days of sadness ahead? I so appreciate having found this supportive site on the web...not in anyway do I discount the abilities of my asking you these questions...I only hope to gain further insight into this horrible disease that anyone has. With appreciation, Mrs. J.

A: Mrs. J. - I spoke with Dr. Bruyette about your concerns. He has done much of the research on l-deprenyl. He thought that perhaps you may be confused about which medication was being used to treat your bichon because l-deprenyl (Anipryl Rx) is used on a once daily basis continuously rather than being used for several days daily and then once/week. The dosing schedule you describe is more commonly used with mitotane (Lysodren Rx).

Anipryl is not very likely to cause immune mediated hemolytic anemia. Dr. Bruyette feels that this isn't a side effect of Anipryl. It is occasionally seen as a side effect of Lysodren administration, however.

If your dog is receiving Lysodren, it is possible that Anipryl would be a good drug to substitute for it. There is one requirement though -- the Cushing's disease must be pituitary in origin and not due to adrenal gland tumors in order for Anipryl to be an effective alternative.

Hope this helps. Please let me know which medication was being used after you check on this.

Mike Richards, DVM

Vaccinations and Immune mediated hemolytic anemia

Q: Cleo was either a full-blooded basset or basset/beagle mix. Someone found her in our neighborhood the last week of October, 1996. She appeared to be about six months old when she came to live with us. Cleo was a chow hound; she ate all the time. She also was a chewer and chewed everything in sight. She was a very active dog. We also have two other basset hounds. All of our dogs are kept in our fenced back yard with the gates locked for their safety. Around Memorial Day weekend (May 24, 1997) she seemed to slow down on eating, stopped chewing everything; she also did not jump up on us when we went outside. We thought the Texas heat was affecting her appetite and that she had finally outgrown the chewing and jumping. The only other visible problem that she had was she limped on her right hind leg and sometimes when standing, she would hold it up and stand on three legs. Cleo had also stopped running and playing with either bassets.

On June 19th I noticed that one of the dogs had vomited a clear watery bile on the patio. Cleo was not real active that day; she just seemed to sit mostly. The following night we noticed that she could barely walk and had difficulty holding her head up. The next morning, June 21, Cleo's eyes were nearly swollen shut and she could barely get up to come into the house. We took her to our vet as she was very lethargic, not eating, and had lost weight. Cleo weighed 46.6 lbs which meant that she had lost 5.9 lbs since April 30th when she had been at the vet for her shots (rabies, canine distemper, canine parainfluenza, canine adenovirus 2, canine parvovirus, canine caronavirus, and leptospirosis). The vet said that Cleo's mouth was very ulcerated. The vet did a CBC, blood chemistry, fluid therapy and Vitamin K and Dexamethasone and penicillin g injections. The blood work indicated a very high white cell count and her red blood cell count was 10. We had mentioned that Cleo had found a dead rat in the back yard and had played with it before we found it. The rat had eaten rat poison that we had put under a tool shed. Cleo could not have gotten the rat poison, but we were concerned that she had played with the dead rat. We also remembered that Cleo had chewed up a vinyl lawn chair and we were concerned that a piece of the vinyl could have been lodged in her system. The vet said Cleo was in a very dangerous zone because of the very low red blood count and that we needed to take her to the Emergency Animal Hospital for the weekend.

When we got to the Emergency Clinic 45 minutes later, Cleo's face was very swollen (eyes, nose, bumps all over her ears and top of her head); she would not let us touch her face. The vet decided that she had an allergic reaction to one of the medications that our vet had given her. They gave her a shot of benadryl and that helped the swelling. The clinic did a blood smear and got the same results of very high white blood cells and red blood cells at 10. Her blood clotting time was 3 minutes and 15 seconds. Her lymph nodes were swollen and her abdomen was tender. The clinic gave her a blood transfusion and IV's. They X-rayed her uterus for infection, but it was okay. They X-rayed her for blockages, but did not find anything apparent. Cleo's red blood cell count went up to 24 after the transfusion. The emergency clinic's probable diagnosis was auto-immune hemolytic anemia (AIHA) or ehrlichiosis. We told them that we had never seen a tick at our house. They agreed that she could have been bitten by a tick before she came to us at the end of October and that this could have remained dormant. We asked the vets whether Cleo's vaccinations on April 30th, could be the cause of her problem, but they all said that was too long ago (seven weeks). On Monday June 23rd I took Cleo back to our vet. Our vet took blood smears for the AIHA and ehrlichiosis. The test results for ehrlichiosis was negative and the test for AIHA were one positive and one negative. Our vet felt that Cleo had AIHA and put her on 5mg of Prednisone along with an antibiotic Doxycycline in case there was an undetected infection in her system. We asked our vet re whether or not the AIHA could be a result of her vaccinations on April 30th. He also said that was too long ago.

Wednesday, June 25th, her temperature was normal which the vet said was a sign that the Prednisone was working. Thursday morning she would not eat and we noticed that her left lip (inside) had a hugh bulge so we took her back to our vet. Our vet said the AIHA could affect the vascular system. Our vet redid the CBC and the results were still a very high white blood cell count and the red blood cell count was 14. The vet increased the Prednisone to 20mg and we again took Cleo home.

Friday morning, June 27th, she did not want to eat once again, but we managed to get her to eat the soft prescription a/d canned dog food. When we got home Friday around 7:00 pm, we found that Cleo had passed away probably a few hours earlier. She had vomited and urinated. She also had watery blood coming from her mouth and nose. We were very sad that Cleo had passed away and will miss her. Our other bassets are very sad too as they were all best buddies. Today, Saturday, June 28th I went to see our vet and told him about Cleo. He was very saddened about Cleo's passing. He felt sure that she had AIHA. Today I got on the Internet to see if I could find any information about Canine AIHA. I found one website about Diseases or syndromes involving immune reactions. The paragraph about AIHA stated that "Cases have occurred after exposure to parvovirus or modified live parvovirum vaccine..... This leads me to believe that Cleo's vaccinations (for which she got the Canine parvovirus) could have been the cause of her AIHA. My question to you is: do you agree that Cleo could have contracted AIHA as a result of her vaccination? Sorry for the lengthy EMail, but I felt you needed all of the facts. I would appreciate a response from you. Thanks, Charlene

A: Charlene-

Immune mediated hemolytic anemia (also known as auto-immune hemolytic anemia) can occur as a primary problem -- no discernible cause-- or as a secondary problem to many illnesses and stresses. It has been reported to occur as a side effect of vaccination. This usually happens within the first few days to weeks after vaccination, though. There was a study done on IMHA and vaccinations that was reported in the Veterinary Internal Medicine journal last year. If I understood the data correctly there is no increase in susceptibility to IMHA in dogs that were vaccinated more than one month previously, indicating that vaccinations are unlikely to be a factor if the reaction occurs more than one month after vaccination. Even though we know that there often is a primary cause for IMHA it does not seem necessary for there to be a cause in all cases -- many times it just seems like this problem occurs. Due to the timing I am sure there will always be some question in your mind as to the cause. Overall it is probably still much safer to go ahead with vaccinations since the risk of the diseases vaccines protect against is also present. It is important to assess all risks in making a decision to vaccinate or not vaccinate and this should ideally be done with consideration of the individual risks for each particular patient.

Mike Richards, DVM

Hemolytic anemia

Q: Dear Dr. Mike, Can you tell me if autoimmune hemolytic anemia is the same as hemolytic anemia? Susan

A: Susan- Anemia is the condition in which there are fewer red blood cells than normal. Hemolytic anemia describes the condition in which this loss of red blood cells occurs because the red cells break up (lyse). This can happen inside the blood vessels (intravascular hemolysis) or outside of the blood vessel (extravascular hemolysis). Hemolytic anemia can occur for many reasons, including heat stroke, parasites, viral infections. toxins and other conditions. One of the things that can cause hemolytic anemia is immune system disease --- in this case the disorder is known as immune mediated hemolytic anemia (IMHA). This is the term currently preferred for the condition formerly known as auto-immune hemolytic anemia (AIHA). The reason for the subtle name change is the recognition that much of the time the immune system really is attacking an invader -- it just happens to be one that is stuck on the red blood cell so both get destroyed.

So the short answer is that immune mediated hemolytic anemia is one particular cause of hemolytic anemia but there are other causes.

Mike Richards, DVM

Last edited 01/30/05


Michael Richards, D.V.M. co-owns a small animal general veterinary practice in rural tidewater Virginia. Dr. Richards graduated from Iowa State University's College of Veterinary Medicine in 1979, and has been in private practice ever since. Dr. Richards has been the director of the PetCare Forum...