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April 2010
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The immune system is a marvelous defense network of white blood cells, antibodies, and other substances used to fight off infections and reject foreign proteins. It is a police force patrolling the body, designed to recognize "self" cells from "non-self" cells by markers found on the surface of every cell in the body. It is this ability that causes the body to reject skin grafts, blood transfusions, and organ transplants. Like anything else, the immune system can fail, either by not doing its job or by doing it too well.

Autoimmune disease (immune-mediated disease) is essentially an immune system failure. In this situation, the ability of the immune system to recognize the "self" marker is lost, and it begins to attack and reject the body's own tissue as foreign. One specific tissue type such as red blood cells may be affected, or a generalized illness such as systemic lupus may result. What causes the immune system to short circuit and start rejecting normal body tissue? Many theories exist, but the ultimate answer is "We don't know."

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 which of several studies are examined, 60-75% of IMHA cases do not have apparent causes.

Some theories include environmental pollutants, food additives and even vaccines that over-stimulate the immune system. There is strong evidence for a genetic predisposition in the development of autoimmune disease in many species. Other causative factors include hormonal influences, infections and stress.

The following is a list of some of the documented potential causes of immune-mediated disease. Please note that not every animal that meets these criteria will develop immune-mediated disease. In fact MOST animals will NOT develop this condition.


  • Viral: transient or persistent upper respiratory or gastrointestinal viral diseases. In cats, feline leukemia virus infection has been implicated.
  • Bacterial: leptospirosis, hemobartonellosis, other various acute infections (e.g., abscess, pyometra, discospondylitis, etc.)
  • Parasitic: babesiosis, leishmaniasis, dirofilariasis, ehrlichiosis, intestinal parasites. In cats, infection with a red blood cell parasite called Mycoplasma hemofelis (previously known as Hemobartonella felis) is a known cause.


  • Sulfonamides
  • Cephalosporins
  • Penicillin
  • Procainamide
  • Methimazole


  • Lymphoma
  • Multiple myeloma
  • Leukemia
  • Solid tumors such as hemagiosarcoma


  • Insect bites or stings
  • Recent vaccinations


  • American Cocker Spaniel (1/3 of all cases)
  • English Springer Spaniel
  • Old English Sheepdog
  • Irish Setter
  • Poodle
  • Dachshund
  • Miniature Schnauzer

Female dogs appear slightly predisposed, even when spayed.


There are 2 common types of immune-mediated disease seen in dogs and cats. Immune-Mediated Hemolytic Anemia (IMHA) and Immune-Mediated Thrombocytopenia (ITP). These diseases can have similar origins and treatments, but are best discussed spearately because of their differences.

Occasionally immune-mediated hemolytic anemia and immune-mediated thrombocytopenia occur together. This is called Evan's Syndrome.


This disease was formerly known as Autoimmune Hemolytic Anemia. "Autoimmune" literally means immunity against the self. "Hemolytic" is the destruction of red blood cells. "Anemia" is defined as a decrease in the number of red blood cells resulting in a decrease in the oxygen- carrying capacity of the blood.

In IMHA, markers called antibodies, stick to the red blood cells and cause the body to believe the red blood cells are a "foreign invader". This causes the immune system to attack the red blood cells and destroy them. The mechanism by which the immune system mistakes the red blood cells for a "foreign invader" varies somewhat according to the cause. It usually involves adherence of the offending agent (parasite, drug or toxin) to the surface of the red blood cells. The immune system attacks the offending agent, but manages to injure the red blood cells as well. When the spleen and the rest of the immune system is working to rid the body of the old, diseased or damaged red blood cells, it is doing its job properly. However, when a large percentage of the cells are affected, and they are removed faster then they are replaced, IMHA results.


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 the red blood 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 other things. The spleen uses immunological cues on the surface of red blood cells to determine which cells need to be plucked out of circulation. In this way, red cells parasitized by infectious agents are removed from circulation along with the old, damaged red cells. 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 the tissues become colored yellow/orange.

Making matters worse, a 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 to 80% mortality (depending on the study) have been reported with this disease.



The symptoms or clinical signs of IMHA can appear very suddenly or they may be gradual and progressive. The most common signs are usually related to the lack of oxygen in the blood from the anemia and manifest themselves in the following ways:

  • Weakness
  • Lethargy
  • Increased heart rate and respiration rate
  • Pale mucous membranes (gums, ears, eyelids)
  • Icteric/jaundiced (yellow-tinged rather than pale mucous membranes)
  • Vomiting and/or abdominal pain
  • Fever
  • Dark orange/brown discoloration of urine or stool


A diagnosis of IMHA is made on the basis of these clinical signs as well as blood testing. A complete blood count (CBC) and a chemistry panel are usually the first tests done. The chemistry panel will often show a dramatic increase in bilirubin level (the pigment causing the yellow discoloration of the skin and mucous membranes). The CBC will show a dramatic decrease in the patient's red blood cell count and hematocrit (% of red blood cells per voume of blood). The constitutes anemia.


Responsive Anemia

Anemia due to poor red blood cell production by the bone marrow is called a "non-responsive anemia". Such anemias are caused by chronic inflammatory diseases, kidney failure, cancer or certain drugs (especially chemotherapy). Normally when red blood cells are lost, the drop in blood oxygen that results causes hormonal changes leading to increased production of red blood cells by the bone marrow. These are called responsive anemias because the bone marrow is responding. Bleeding and immune-mediated red blood cell destruction are both “responsive anemias.”

There are several ways to determine from the blood panel results if the anemia is responsive or not. The CBC will include red blood cell count, and size, shape, and maturity of red blood cells, as well as white blood cell types and ratios. A patient with a responsive anemia will have a very active bone marrow. Red blood cells will be released early leading to a variety of sizes and colors of red blood cells. Furthermore, red blood cell precursors called reticulocytes are released. These findings indicate the anemia is responsive. This means either red blood cells are being lost via bleeding or they are being destroyed by the immune system.

*It should be noted that 4 to 7 days are required for the bone marrow to generate a response. If hemolysis occurs suddenly there may not have been adequate time for a response. When this occurs, if there is any question about the responsive nature of the anemia, continued monitoring of the complete blood count will show a clear response in an appropriate time period.


Spherocytes

The destruction of red blood cells often leaves recognizable cellular debris in the blood stream. In particular, a form of damaged red blood cell known as a spherocyte oocurs. Finding spherocytes on a blood smear almost guarantees that some form of hemolytic anemia is occurring. 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.


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.

Leukemoid Reaction

Classically, in IMHA the stimulation of the bone marrow is so strong that even the white blood cells lines are stimulated. This leads to white blood cell counts that are spectacularly high.
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 or in the event of prior blood transfusion. 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.

Other Causes of Hemolysis

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 there is a diagnosis of immune mediated hemolytic anemia, efforts to determine an underlying cause should be made. Any or all of the following tests should be performed:

  • Radiographs of the chest and abdomen to look for tumors or zinc foreign objects
  • Abdominal Ultrasound
  • Tests for tick-borne infectious agents such as Ehrlichia, Anaplasma, and Babesia
  • Heartworm test
  • Fecal Analysis to rule out intestinal parasites


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.

Transfusion

There are several products that may be helpful in treating IMHA. If the patient is in a crisis and needs immediate therapy, artificial blood may be a good choice. Artificial blood (Oxyglobin®) is made from hemoglobin harvested from cow’s blood. Because the patient does not receive actual red blood cells, the artificial blood does not further stimulate the immune system. The disadvantage of artificial blood is that it does not last in the body like a well-matched blood transfusion does. The body begins removing artificial blood immediately so that the entire transfusion is probably gone in 48 hours or so. In IMHA, this may buy some time but since IMHA tends to have a long treatment course, it is likely that the patient will end up right where they started. If a compatible donor is not readily available, sometimes an artificial blood transfusion buys enough time to find a compatible donor.

Well-matched whole blood or packed red blood 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? For this reason, it is not unusual for several transfusions to become necessary to treat the condition.

Corticosteroid hormones in 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. Remember, in patients with IMHA,  the red blood cells have been inappropriately coated with anitbodies. The body then attempts to destroy the antibody coated cells. Stopping antibody production is an important part of therapy.

Corticosteroids may be the only immune suppressive medication 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 at least 4 months; many pets require lifelong treatment with a low dose to prevent recurrence.

Corticosteroids in high doses produce excessive thirst, excessive urination, increased hunger, re-distribution of body fat, thin skin, panting, a predisposition for urinary tract infections and other signs  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.

More 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 azathiaprine and cyclophosphamide. These are serious drugs reserved for serious diseases.

Cyclosporine is an immune-modulator, made popular in organ transplantation technology. It has the advantage over azathioprine and cyclophosphamide of not being suppressive to the bone marrow cells. It has been a promising adjunctive therapy in IMHA but can be costly and requires blood level monitoring to ensure that the dosage is appropriate.


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. 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.

Heparin, a natural anticoagulant, may be used in hospitalized patients (or in patients with predisposing factors for embolism) as a preventive.





A platelet is a cloud-shaped blood cell, neither related to the red blood cell line nor the white blood cell line. Platelets assist in the clotting of blood by seeking out damaged areas of blood vessels. When a damaged vessel is found the platelets aggregate there, piling onto each other and binding together to form a small plug to seal the hole in the leaking blood vessel. While piled on each other, they release assorted biochemicals that initiate a more permanent fibrous seal of the tear. Of course, large tears are too big for platelets to seal, but when it comes to small bleeds and normal blood vessel wear and tear, platelets are the star of the show.

A small bleed unstaunched by a platelet aggregation quickly becomes a large bruise. Spontaneous bruising is a sign of reduced platelet numbers or poor platelet function.


Platelets come from the bone marrow where a large cell called a megakaryocyte splits off little active pieces of itself. These pieces are platelets, ready to enter the circulation where they will live for an average of 8 to 12 days in a dog or 6 to 8 days in a human before a bleeding capillary calls them to their destiny. At any given time some 200,000 to 500,000 platelets are on patrol in circulatory system, though only about 20,000 to 50,000 are considered the bare minimum to prevent spontaneous bruising and bleeding. About 1/3 of the circulating platelets are stored in the spleen, like boats in a harbor, ready to mobilize if necessary. When platelets become too old to be useful, the spleen has cells called phagocytes that essentially eat old cells and recycle their inner materials.


For reasons unknown, platelets can be mistaken by the immune system as invaders. When this happens, antibodies coat the platelets and the spleen’s phagocytes remove them in numbers up to 10 times greater than the normal platelet removal rate. The megakaryocytes in the bone marrow respond by getting larger and growing in numbers so that they may increase their production of platelets. The platelets produced under these circumstances tend to be larger and more effective than normal platelets and are called stress platelets. The bone marrow attempts to overcome the accelerated platelet destruction rate; unfortunately, as immune-mediated destruction is occurring, a platelet can expect to survive only one to two days in the circulation instead of its normal 8 to 12 days. If antibody levels are very high, a platelet may survive only minutes or hours after its release from the bone marrow and, making matters worse, the antibody coated platelets still circulating do not function normally.


In many cases, a cause for the immune-mediated thrombocytopenia is never found; however, in most cases a primary reaction in the immune system precedes the platelet destruction. Keep in mind that the immune system responds to the shapes of proteins present on a cell’s surface. These shapes are similar to ID cards. The immune system recognizes shapes defined as “self” and does not attack but when it sees a cell expressing protein shapes that are “non-self,” it will respond.

If the immune system is responding to a blood parasite, tumor, drug, or other cell type (as in lupus or immune-mediated hemolytic anemia), it will be producing antibodies against enemy shapes. Some of these shapes may, unfortunately, resemble some “self” shapes such as some of the shapes on the surface of the platelets. The platelets are then misidentified as the enemy and are attacked.


Dramatic reduction in platelet numbers is almost always caused by immune-mediated destruction, though certain tick-borne blood parasites could also be responsible: Ehrlichiosis or Neorickettsia rickettsii (Rocky Mountain Spotted Fever) are the most common. If an infectious agent such as one of these is responsible for the immune-mediated platelet destruction, obviously specific therapy against the infection is warranted in addition to therapy for the platelet destruction.

Very low platelet counts can also occur in response to the suppression of megakaryocytes within the bone marrow. This might be caused by certain medications or chemotherapy drugs, bone marrow cancer, or disseminated intravascular coagulation (DIC) - a life-threatening, disastrous uncoupling of normal blood clotting and clot dissolving functions in the body. One of its hallmark signs is a drop in platelet count, along with a constellation of other signs.

If platelet numbers are normal but it is obvious that platelet function is not, some other causes to look into might include: Von Willebrand's disease (a hereditary clotting disorder), metabolic toxins (liver or kidney failure), over use of aspirin or similar NSAID drugs, or pancreatitis.


The usual patient is a middle-aged dog. Poodles appear to be predisposed although Cocker Spaniels and Old English Sheepdogs also seem to have a higher than average incidence of this condition.

Spontaneous bruising is the major clinical sign. The gums and oral surfaces as well as the whites of the eyes are obvious areas to check, as are the hairless areas of the belly. Small spots of bruising in large conglomerations called petechiae (pet-TEEK-ee-a) are the hallmark sign. A large, purple expansive bruise might also be seen, which is called ecchymosis. Large internal bleeds are not typical of platelet dysfunction, though bleeding small amounts in urine, from the nose, or rectally may also indicate a platelet problem.

When these sorts of signs are seen, a platelet count is drawn, along with usually an array of clotting parameters, red blood cell counts to assess blood loss, and other general metabolic blood tests. Since testing to detect actual anti-platelet antibodies is not available, the veterinarian must determine if any other possible causes of low platelet count make sense.


Once a diagnosis of immune-mediated platelet destruction has been made, the goal in therapy is to stop the phagocytes of the spleen from removing the antibody-coated platelets and cutting off antibody production. This, of course, means suppression of the immune system using whatever combination of medication seems to work best for the individual patient.

Prednisone or Dexamethasone

These steroid hormones are the first line of defense and, often all that is necessary to bring platelet counts back up. Unfortunately, long-term use should be expected and this means steroid side effects are eventually inevitable: excessive thirst, possible urinary tract infections, panting, poor hair coat etc. The good news is that these effects should resolve once medication is discontinued. If side the effects are especially problematic, other medications can be brought in to reduce the dose of steroid needed.

Vincristine

This injectable chemotherapeutic medication is mildly immune suppressive but also seems to stimulate a sudden burst of platelet release from the marrow megakaryocytes. The platelets released in response to vincristine contain a phagocyte toxin so that when they are ultimately eaten by spleen phagocytes, the phagocytes will die. While repeated injections of vincristine ultimately do not yield the same effect, at least a one-time dose may be extremely helpful. Vincristine is extremely irritating if delivered outside of the vein. It must be given IV cleanly or the overlying tissue will slough.

Azathioprine or Cyclophosphamide

These are stronger immune suppressive agents typically used in cancer chemotherapy. If steroid side effects are unacceptable or if the patient does not respond to steroids alone, one of these medications may be indicated. Cyclosporine, a newer medication made popular in organ transplantation, also may be used but expense has been problematic.

Transfusion

You might think that a transfusion of blood or at least “platelet rich plasma” might be helpful in the treatment of a platelet dysfunction. The problem is that platelets do not survive well after removal from a blood donor. You have about 12 hours to deliver the freshly withdrawn blood to the recipient before the platelets become inactive. After the platelets are delivered they are likely to live only hours. In general, most efforts are spent on establishing immune suppression.

Splenectomy

If medication simply does not work or the condition keeps recurring once medications are discontinued, the solution may be to simply remove the spleen. After all, this is where the phagocytes removing the platelets are primarily located. In humans, immune-mediated platelet destruction is generally treated with splenectomy first. Response in dogs has not been as predictably good thus in veterinary medicine it is generally one of the last therapies invoked.


Prognosis for both immune-mediated hemolytic anemia and immune-mediated thrombocytopenia is highly variable and depends on the underlying cause if one is present, complications related to the disease or drug therapy, and the response to treatment. The initial phase of the disease and the animal's response to it are very important when determining the long term prognosis. 50% of animals may not survive the initial crisis. Keep in mind that relapses can occur months to years after the initial episode, even if initial responses were favorable. Overall, if there is no severe underlying illness or significant complications and if your pet responds to therapy, prognosis for both diseases is generally good.




If suspect your dog or cat has signs of an immune mediated disease such as those listed above, please call the Merrick Veterinary Group at 516-379-6200 to schedule your pet for a physical examination, bloodwork, and other diagnostic tests today. Early detection and treatment can result in a better outcome for your pet.




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