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Pamela A. Davol, 76 Mildred Avenue, Swansea, MA  02777-1620.
pdavol@labbies.com


Canine Autoimmune Hemolytic Anemia

AIHA Letters

A compilation of selected letters from my archives addressing issues pertaining to AIHA in the dog.


Health Advisory

Potential Link Between ProHeart 6 and AIHA

Use of ProHeart 6 (moxidectin), an injectable, long-term heartworm preventative, is apparently increasing among veterinarians. In the past several months, I have had a couple of dog owners write to me regarding adverse reactions (anaphylaxis and auto-immune hemolytic anemia AIHA, the latter resulting in death) that have potentially been associated (temporally) with administration of ProHeart 6. Further investigation into ProHeart 6 has revealed that Fort Dodge has indicated the potential for adverse immune reactions with the use of this drug for which incidence became noted only after post-drug approval, wide-spread clinical use. With upcoming heartworm season, it is possible that more vets may come to use this drug in the clinic without knowledge of or without making it known to dog owners the potential for adverse side-effects (similar to what was observed when Rimadyl hit the clinical market).
      For more information on ProHeart 6 and its potential adverse reactions, please refer to:

The Senior Dogs Project ProHeart 6 page


Hi - We just lost our 6 year old chocolate lab last night and we are pretty convinced that it was caused by HeartGuard which caused Immune Mediated Hemolytic Anemia. Have you heard of this happening to other labs? Thank you for your response.

I'm so sorry to hear about your Lab. I know that it must have been quite a shock to have an apparently healthy companion suddenly become so very ill. In regard to the Heartgard causing this condition, there is no indication in the literature that ivermectin induces risk for autoimmune hemolytic disease. In fact, in some clinical studies, ivermectin and diethylcarbamazine citrate, both active components of different types of heartworm preventative, are actually used as treatment for parasite-induced autoimmune hematologic disorders (since parasites may cause secondary AIHA). It is important to keep in mind that many other factors have been implicated in AIHA.

Primary or immune-mediated hemolytic anemia (IMHA) occurs when an immune reaction is targeted directly against an inherent protein on the red blood cells. This occurs in: 1) "idiopathic" IMHA (in which no other disease process can be identified); 2) IMHA associated with systemic lupus erythematosis (SLE); 3) certain neonatal disorders; or 4) as a result of non-compatible blood transfusions. Secondary IMHA occurs as a result of an immune reaction in response to some foreign protein that binds to the red blood cells and thus leads to their destruction. Conditions associated with secondary IMHA include inherited enzyme disorders (i.e. pyruvate kinase deficiency, phosphofructokinase deficiency, chondrodysplasia, etc.), metabolic disorders (i.e. hypophosphotemia), cancer (lymphosarcoma or hemangiosarcoma), infectious diseases (bacterial or viral), toxin exposure (onion, zinc, methylene blue, copper) or drug-related (hypersensitivity to vaccines, penicillin, sulfa drugs, methimazole, cephalosporin, or other antibiotics).

Another factor that has a seemingly high association with onset of AIHA is seasonal conditions. It has been found that a high percentage of dogs that develop AIHA will do so in the spring or fall. This suggests an immune response to such things as seasonal pollen may also trigger the immune response responsible for AIHA. Age seems to be another factor that may play a role in AIHA since this disorder occurs more frequently in middle-aged or older dogs. It is well known that the normal function of the immune system is compromised as humans and animals age. Although most people think of this as meaning that older individuals are more susceptible to disease, which is true, another important aspect of the immune system is a process known as recognition. Immune components that play a role in immune recognition are important because they basically "tell" the immune system not to attack the individual's own cells. Age also impairs the immune system's recognition process. This is also why age predisposes to autoimmune conditions (such as systemic lupus erythmatosis, rheumatoid arthritis, etc.). Therefore, it is suspected that some older dogs may be predisposed to developing AIHA because age has compromised the recognition components of their immune systems. As such, any stimuli that may trigger an immune response (vaccine, a minor infection, seasonal allergies, etc.) will lead to autoimmune disorders.

In many cases of AIHA, the underlying cause is never known. Sadly, as you like so many other dog owners have experienced, the outcome is often poor because a successful treatment plan for AIHA has not been clearly established and secondary complications arising from the disease as well as treatment protocols have presented limitations to effective treatment.

I hope this addresses some of your questions. Again, my deepest sympathies for your loss.

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Just returned from a visit to our vet. Our dogs are fine but he's got a patient who has the above mentioned disease and hasn't had much luck treating the dog so far. He's tried all the medication mentioned in your article except Danazol. I passed that info on to him by e-mail. (I told him I'd search the internet for whatever info I could find about the disease.)

Unfortunately, not many new treatments have been explored recently for CAIHA. Danazol has been used successfully in humans, but there have been no controlled clinical trials for this drug in dogs. When it is used in canines, typically it is combined with prednisone treatment because pred will act immediately to reduce symptoms while Danazol's effects may take some time to become apparent. Danazol usually is administered orally (10 mg/kg/day) with pred until the anemia improves, then pred is gradually tapered off and eventually discontinued while the danazol dosage is maintained. Once remission is maintained while the dog is on danazol alone, then danazol dose is lowered to 5 mg/kg/day. If the dog's condition remains stable after several months, then the danazol treatment is tapered off.

Once the treatment is completely stopped, the dog must undergo frequent monitoring to ensure against possible flare-ups of CAIHA. Two other forms of treatment that I did not mention in the original article on CAIHA include splenectomy and an experimental technique known as plasmapheresis. Because destruction of the red blood cells occurs primarily in the spleen, it has been found in both humans and canines with AIHA that removing the spleen often provides some benefit to these patients. In most cases, although not providing a complete remission, this procedure decreases the dose of immunosuppressive drugs required to maintain disease stability.

Plasmapheresis has appeared on the news lately because it has been successful in providing relief of severe symptoms and improving quality-of-life in human patients with MS. Basically, this technique filters autoantibodies and complement components from the blood. Partial improvements have been observed in some humans and dogs with AIHA who had been treated with this technique; some of these of whom were completely unresponsive to other forms of therapy.

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Hi....I have just this morning lost my 4 year old orange roan cocker to aiha.this is my 2nd. Cocker to be lost to this disease. I am completely devastated by this and have read your article on this. I stopped vacc.my dogs after their initial puppy jabs after I lost my first cocker. as I have 5 more cockers and also breed ,is there any evidence to suggest that this may be hereditary?? My 2 cockers who have died were not related. I would be very grateful for your reply.

I'm so sorry for your loss. AIHA may be secondary to several conditions: infectious diseases, toxin- or drug-related causes, autoimmune diseases, metabolic diseases, cancer, as well as inherited disorders. Cocker spaniels, along with English Springer spaniels, Collies, Poodles, Old English Sheep Dogs, and Irish setters are among the breeds that demonstrate an elevated risk for developing AIHA. One particular hereditary condition responsible for the increased risk for AIHA in Cockers is a genetic disorder known as Phosphofructokinase deficiency (PFK). PFK is an autosomal recessive (inherited) disorder of the red blood cells (erythrocytes) in Cocker Spaniels. It is caused by the deficiency of a glycolytic enzyme that is required to convert glycogen (a stored form of sugar) to glucose which is a source of energy for cellular metabolism. Dogs with this deficiency have a decreased tolerance for exercise, exhibit muscle weakness and cramping in addition to episodes of red blood cell lysis (usually coinciding with exertion). Though these dogs can live normal life spans, they often have recurring episodes of hemolytic crises that may be triggered by any environmental or physical stimuli that cause excitement or induce changes in metabolism. This makes treatment and ongoing care extremely difficult.

There is a DNA test currently available for screening breeding Cockers for PFK deficiency, which will detect both afflicted individuals as well as genetic, symptom-free carriers of this disorder to reduce risk in future offspring. Hope this info helps. Thank you for your patience in awaiting a response. Again, my deepest sympathy for your loss and should you have any further questions or require further assistance, please feel free to contact me.

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Are you aware of anyone who has used Decadron instead of Prednisone to treat an AIHA dog? My three year old lab-terrier mix is in her first relapse of AIHA. As is one of the side effects of Prednisone, she's gained twice her healthy weight. She's on a diet and is getting regular exercise; but the weight doesn't seem to want to come off. My vet is researching the idea of Decadron instead of Prednisone because Decadron isn't known for weight gain like Prednisone is.

I'm sorry to hear about (your dog's) condition. Dexamethasone (Decadron) has indications for use in the treatment of AIHA in humans and some livestock. The often high doses of glucocorticoids required to control AIHA and associated symptoms do make dexamethasone a preferred choice over prednisone in regard to reducing sodium retention, weight gain, etc. Unfortunately, there isn't much recent information regarding the use of dexamethasone to treat AIHA in dogs, however. A couple of early studies cite the use of dexamethasone treatment for AIHA in dogs, but I have not looked at the results of these studies specifically. The references are as follows:

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4734241&dopt=Abstract http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4933855&dopt=Abstract

One example of dexamethasone efficacy against AIHA in other species can be found in this reference: http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1644656&dopt=Abstract

Most of the studies that I've reveiwed regarding dexamethasone efficacy against AIHA have been anecdotal; citing results in only isolated cases. This is not surprising because it is believed that response to glucocorticoid therapy, in general, is dependent upon the individual patient. Therefore, your veterinarian will probably switch over to the dexamethasone and frequently monitor course of the disease. If results suggest that the dexamethasone is unable to control the symptoms as effectively as the prednisone treatment, then your dog should be returned to the prednisone regimen. My best hopes for your dog.

*****************************************************8

My ten-year old HEALTHY female sheltie died suddenly two weeks ago from AIHA. She died 48 hours after diagnosis. She received her booster shots on 2/28 and AIHA symptoms started 4/24. I strongly suspect that her immune system was compromised by the booster shot. Her vet NEVER warned me about the dangers. The consent form was so vague and did not provide full disclosure of the risks involved. She also received the shot last year. My question is -- Is 8 weeks too long a time between the receiving the shot and the start of the symptoms? The over vaccination is quite controversial within the vet community. I appreciate your help. Thank you.

Please accept my sympathy for the loss of your Sheltie. I know that it must have been quite a shock to have an apparently healthy companion suddenly become so very ill. Though viral antigens (either those found in vaccines or acquired by infection) have been associated with development of AIHA, in those cases believed to be associated with vaccination, symptoms of AIHA appear within one month of the immunization. It is important to keep in mind that many factors, of which vaccines are only one, have been implicated in AIHA. Another factor that has a comparatively higher association than vaccines with onset of AIHA is seasonal conditions. It has been found that a high percentage of dogs that develop AIHA will do so in the spring. This suggests an immune response to such things as seasonal pollen may also trigger the immune response responsible for AIHA. In any event, in cases of primary AIHA (as opposed to secondary AIHA that results from conditions like drug toxicity), afflicted dogs are believed to have an aberrant immune response that predisposes them to developing this condition.

Age seems to be another factor that may play a role in AIHA since this disorder occurs more frequently in middle-aged or older dogs. It is well known that the normal function of the immune system is compromised as humans and animals age. Although most people think of this as meaning that older individuals are more susceptible to disease, which is true, another important aspect of the immune system is a process known as recognition. Immune components that play a role in immune recognition are important because they basically "tell" the immune system not to attack the individual's own cells. Age also impairs the immune system's recognition process. This is also why age predisposes to autoimmune conditions (such as systemic lupus erythmatosis, rheumatoid arthritis, etc.). Therefore, it is suspected that some older dogs may be predisposed to developing AIHA because age has compromised the recognition components of their immune systems. As such, any stimuli that may trigger an immune response (vaccine, a minor infection, seasonal allergies, etc.) will lead to autoimmune disorders.

As discussed above, the fact that age compromises the immune system creates much controversy surrounding vaccination schedules for older dogs. Current recommendations for young adults by which the dog receives vaccines every 2-3 years, have many vets concerned in regard to applying this same schedule to older dogs. Because it is known that older dogs may have less capacity to mount an immune titer to vaccination, a 2-3 year schedule may not adequately protect our geriatric companions from infectious disease. This is a serious concern because infectious disease in a geriatric dog will usually lead to death. However, on the other hand there is a concern about potentially inducing fatal autoimmune reactions also as a side-effect of age-associated immune compromise. By either vaccinating or not vaccinating one is taking risk. There is no easy solution to this, and each vet must weigh risks associated with each side. In many cases a vet will choose to vaccinate because risks associated with infectious disease currently outweigh risks associated with development of autoimmune conditions, and I believe this is why your vet recommended annual vaccination for your girl.

Veterinarians (and human doctors as well) do not always discuss with their clients the weight of risks presented by each side of whether to vaccinate or not vaccinate. In many instances it is because even if the vet were to sit down with the client and discuss this, most individuals once aware of the risks presented on each side usually will select vaccination despite the risks because, in general, the risks of vaccinating are minimal compared to risks of not vaccinating. Therefore, do not second guess your decision to vaccinate in this case...take comfort in knowing that what decisions you made were made with your Sheltie's best interest at heart.

My thoughts are with you.

***************************************************

I understand that you have an enormous amount of e-mail I hope that you will find the time to respond to this. My ten year old female lab who has both fatty tumors and arthritis became extremely weak and dangerously ill this past Sunday. We raced her to a Animal ER where it was determined that she had either 1. auto immmune disorder 2. bleeding internally from cancer or 3. leukemia as her red blood count was nil and her white count exceedingly high. She has had three blood tests a bone marrow test (for the leukemia) and a sonogram. Leukemia test came back negative sonogram for bledding or tumors negative. Blood count still low panting, some nerve damage she has lost motor skills as in not able to stand for more than two or three minuts . But she is determined and so are we to fight whatever it is that is attacking her. Does this summation I give you sound like an Auto Immue Hemolytic Anemia to you? I have two vets working on this Please if you can give me some insight or observation that I can go by and pass along to a battery of people who are stumped I would apreciate it. Thank you in advance for your response.

I'm very sorry to hear about your dog. AIHA is a complex disease to diagnose because in addition to occurring as a primary or secondary disease, it is also classified into various subclasses of disease dependent upon the actual antibody type that is causing the destruction of the blood cells. Primary or immune-mediated hemolytic anemia (IMHA) occurs when an immune reaction is targeted directly against an inherent protein on the red blood cells. This occurs in: 1) "idiopathic" IMHA (in which no other disease process can be identified); 2) IMHA associated with systemic lupus erythematosis (SLE); 3) certain neonatal disorders; or 4) as a result of non-compatible blood transfusions. Secondary IMHA occurs as a result of an immune reaction in response to some foreign protein that binds to the red blood cells and thus leads to their destruction. Conditions associated with secondary IMHA include inherited enzyme disorders (i.e. pyruvate kinase deficiency, phosphofructokinase deficiency, chondrodysplasia, etc.), metabolic disorders (i.e. hypophosphotemia), cancer (lymphosarcoma or hemangiosarcoma), infectious diseases (bacterial or viral), toxin exposure (onion, zinc, methylene blue, copper) or drug-related (hypersensitivity to vaccines, penicillin, sulfa drugs, methimazole, cephalosporin, or other antibiotics).

Another factor that has a seemingly high association with onset of AIHA is seasonal conditions. It has been found that a high percentage of dogs that develop AIHA will do so in the spring or fall. This suggests an immune response to such things as seasonal pollen may also trigger the immune response responsible for AIHA. Age seems to be another factor that may play a role in AIHA since this disorder occurs more frequently in middle-aged or older dogs. It is well known that the normal function of the immune system is compromised as humans and animals age. Although most people think of this as meaning that older individuals are more susceptible to disease, which is true, another important aspect of the immune system is a process known as recognition. Immune components that play a role in immune recognition are important because they basically "tell" the immune system not to attack the individual's own cells. Age also impairs the immune system's recognition process. This is also why age predisposes to autoimmune conditions (such as systemic lupus erythematosis, rheumatoid arthritis, etc.). Therefore, it is suspected that some older dogs may be predisposed to developing AIHA because age has compromised the recognition components of their immune systems. As such, any stimuli that may trigger an immune response (vaccine, a minor infection, seasonal allergies, etc.) will lead to autoimmune disorders.

Unfortunately, there is no single laboratory test that can confirm a diagnosis of IMHA, though positive autoagglutination tests or positive direct Coomb's tests are consistent with a diagnosis of IMHA, the vet will usually have to depend on the entire clinical picture (symptoms and other laboratory findings) to make a diagnosis. Radiographs (x-rays) may also be helpful for eliminating some other potential causes including cancer or infections; radiographs are also sometimes helpful for detecting pulmonary blood clots, which are a complication and related cause of fatality in dogs diagnosed with IMHA. In many cases of AIHA, the underlying cause is never known. Sadly, the outcome is often poor because a successful treatment plan for AIHA has not been clearly established and secondary complications arising from the disease as well as treatment protocols have presented limitations to effective treatment.

First line treatment includes administration of glucocorticoids (prednisone) alone or in combination with cytotoxic drugs such as cyclophosphamide (Cytoxan) or azathioprine (Imuran). In dogs that fail to respond to first-line treatment, Cyclosporin A (Sandimmune) combined with cyclophosphamide and prednisone may offer a successful second-line treatment, albeit with higher risk for drug side-effects. Intravenous Globulin Gamma, another immunosuppressive drug used in humans with IMHA, has shown some advantages and disadvantages for treating dogs: dogs treated with IVGG show a good treatment response by a rapid increase in red blood cells, but these dogs have a higher incidence for developing pulmonary blood clots. Dexamethasone (Decadron) has indications for use in the treatment of AIHA in humans and some livestock. The often high doses of glucocorticoids required to control AIHA and associated symptoms do make dexamethasone a preferred choice over prednisone in regard to reducing sodium retention, weight gain, etc. Unfortunately, there isn't much recent information regarding the use of dexamethasone to treat AIHA in dogs, however. A couple of early studies cite the use of dexamethasone treatment for AIHA in dogs. Most of the studies that I've reviewed regarding dexamethasone efficacy against AIHA, however, have been anecdotal; citing results in only isolated cases. This is not surprising because it is believed that response to glucocorticoid therapy, in general, is dependent upon the individual patient. If results suggest that the dexamethasone is unable to control the symptoms as effectively as the prednisone treatment, then the patient should be returned to the prednisone regimen.

Other approaches to control AIHA include splenectomy and an experimental technique known as plasmapheresis. Because destruction of the red blood cells occurs primarily in the spleen, it has been found in both humans and canines with AIHA that removing the spleen often provides some benefit to these patients. In most cases, although not providing a complete remission, splenectomy decreases the dose of immunosuppressive drugs required to maintain disease stability. Plasmapheresis has appeared on the news lately because it has been successful in providing relief of severe symptoms and improving quality-of-life in human patients with MS. Basically, this technique filters autoantibodies and complement components from the blood. Partial improvements have been observed in some humans and dogs with AIHA who had been treated with this technique; some of these of whom were completely unresponsive to other forms of therapy.

AIHA is an extremely difficult disease to control and the complications associated with AIHA and its treatments (hemorrhage, bacterial or fungal infections, kidney failure and pulmonary blood clots) provide additional limitations to effective therapy. Therefore, consulting with an expert who has had experience dealing with AIHA may provide an advantage to controlling the disease.  One recommendation is for your veterinarian to contact Tufts University Vet-Fax (Tel. 508-839-5395; ask for Vet-Fax) as a potential source for information. It is a service provided only to veterinarians and requires sending medical records to Tufts so that they may be reviewed by internists with experience in this area. Referring veterinarians will be charged for this service.

I hope this information provides some assistance. My thoughts are with you and my best hopes for your dog.


Copyright 1997-2002. Pamela A. Davol. All rights reserved. Copyright & disclaimer.

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