Pamela A. Davol, 76 Mildred Avenue, Swansea,
A disease characterized by increased destruction of red blood cells (erythrocytes) by the dog's own immune system, canine autoimmune hemolytic anemia (AIHA) is one of the most common blood (hematologic) disorders affecting canines. Though much attention has been given recently to AIHA due to evidence linking the process of vaccinating with the manifestation of this sometimes life-threatening disease, immunization is only one potential cause for this condition. The following article provides a detailed explanation of AIHA in terms of the disease process, diagnosis and treatment, and explores factors that may play a role in the development of this disorder in the canine.
The blood is considered an organ having its own complex and diverse development, structure and functions. Its unique form, cellular tissue suspended in fluid plasma, allows it to serve as a main distribution system throughout the body. Cellular tissues composing the blood include: the red blood cells, which provide oxygen to tissues of the body; the white blood cells, which prevent invasion of microorganisms or other foreign substances; the lymphocytes, which carry out immune surveillance; and the platelets, which are involved in keeping the components of the blood in balance. Remarkably, all of these cellular components originate from a common source called stem cells located in the bone marrow. These stem cells give rise to a mature colony of cells which as they continue to divide and mature undergo a series of changes, a process known as differentiation, and eventually develop into the specialized blood cells indicated above.
Anemia is a condition brought on by abnormalities which lead to a deficiency in the number of red blood cells. Although the average life span of a circulating red blood cell is brief in most organisms (approximately 4 months), under normal circumstances the red blood cell mass is maintained at a constant level because new red blood cells are made as old red blood cells are destroyed and removed from circulation by the white blood cells. When this balance is disturbed and the level of red blood cells decrease to a point where the demand exceeds the capacity of the bone marrow to produce them, anemia develops. Because integrity and function of other organs in the body are dependent upon red blood cells to deliver oxygen to their tissues, if the red blood cell number decreases to a point where the body is unable to compensate for the decrease in oxygen transport, serious and irreparable tissue and organ damage may occur. Conditions which may cause a decrease in the circulation of red blood cells include excessive blood loss (hemorrhage), impaired ability of the bone marrow to produce new red blood cells, or increased rate of red blood cell destruction.
AIHA is a disorder in which the survival of red blood cells is shortened because the dog's immune system targets and destroys its own red blood cells. This type of immune dysfunction in which the host develops a reaction to and damages its own tissues is termed autoimmunity (see Vaccines, Infectious Diseases, and the Canine Immune System). In most cases, the dog's body will attempt to compensate for red blood cell loss by increasing production of new red blood cells. However, if red blood cell loss proceeds at a rate faster than the rate of replenishment, a condition of life-threatening anemia will develop.
The exact mechanisms which trigger the dog's immune system to attack and destroy its own red blood cells are unknown, however, the disease process is believed to occur when antibodies coat the surface of the red blood cells tagging them for destruction by the white blood cells. When the body is invaded by an infectious microorganism or agent, the body produces a number of antibodies that range in specificity for that particular invading antigen. Some of the antibodies are highly specific, however, others will bind with less specificity. In the normal immune system, suppressor T-cells (see Vaccines, Infectious Diseases, and the Canine Immune System) ensure that these non-specific antibodies do not react with normal host tissues. However, it is believed that some dogs may have poorly regulated T-cell suppression that allows these non-specific antibodies to attack their own cells. Such a genetic predisposition for AIHA has been suspected in several breeds of dogs including Old English Sheep Dogs, Cocker Spaniels, Poodles, Lhasa Apsos and Shih Tzus. Alternatively, some clinical studies exploring potential causative mechanisms have identified several non-genetic factors that may play a role in development of this disease. For example, the observation that dogs afflicted with AIHA also demonstrated increased antibody titers to viral antigens for canine parvovirus and distemper virus suggests that certain viral infections may trigger an autoimmune reaction. Under such circumstances it is believed that there is adsorption of the virus to the red blood cell. When the immune system launches anti-viral antibodies to destroy the virus, these antibodies target and destroy not only the virus, but the red blood cell as well. Similarly, some drugs (such as antibiotics, analgesics, cardiovascular drugs, etc.) as well as viral antigens composing modified-live vaccines are also believed to induce AIHA through this type of mechanism.
Symptoms of AIHA depend on the severity of the underlying autoimmune reaction which is influenced by the level of autoantibodies directed at destroying the red blood cells as well as the efficiency of the white blood cells to target the red blood cells and the ability of the bone marrow to replenish circulating red blood cells. In cases of acute hemolytic anemia, the dog may experience fever, depression, weakness, fatigability , and pallor of the mucus membranes. In some cases, the spleen may be noticeably enlarged.
Because hemolytic anemia can occur as a symptom of a number of diseases such as infections, cancer, and other underlying autoimmune disorders (eg. systemic lupus erythematosis), causes other than AIHA must be ruled out. Though blood chemistry is often used as a primary method for evaluation of hemolytic anemia, a specific method for diagnosing AIHA is the direct antiglobulin test (DAT) which identifies the presence of antibodies on the surface of the red blood cells. Though a positive DAT is indicative of AIHA, it is important to note that reportedly 40% of AIHA cases may yield a negative result due to clinical and experimental variables that may effect the accuracy of the test. In situations where the DAT is negative but there is a strong suspicion of AIHA, a bone marrow biopsy would confirm the presence of AIHA.
The most frequent course of therapy for AIHA is the administration of high doses of corticosteroids such as prednisone, which have a pronounced anti-inflammatory and immunosupressive action that impairs functions of various components of the immune system. Once the disease is in remission, low dose, intermittent therapy is continued for several months. Some dogs, however, do not respond to corticosteroid treatment and require more potent immunosuppressive drugs that are often combined with corticosteroid treatment. Such drugs include cytotoxic agents such as azathioprine and cyclophosphamide. Other therapies which have been indicated in the treatment of AIHA because of their ability to mediate immune response include Danazol, which in addition to its immunosuppressive characteristics, is incorporated into and stabilizes the red blood cells making them more resistant to destruction, intravenous gamma globulin, and cyclosporine.
The clinical course of AIHA can range from mild and in some cases even subclinical, to severe and fatal. Fatality is most often associated with severe and rapid red blood cell destruction. Fatalities, however, may also occur as a result of secondary complications. For example, breakdown of red blood cells releases coagulants into the blood circulation that may result in pulmonary blood clots. Additionally, fragments of destroyed red blood cells are believed to produce kidney damage that may lead to kidney failure. Dogs experiencing life-threatening hemolysis and requiring transfusion are at higher risk to developing these secondary complications and therefore, are considered to have a poor prognosis for recovery.
The Merck Veterinary Manual, O.H. Siegmund, editor, Merck and Co., Inc., Rahway, NJ, 1979.
Bucheler, J. and Cotter, S.M. Canine Immune Mediated Hemolytic Anemia. In: Kirk's Current Veterinary Therapy XI, R.W. Kirk and J.D. Bonagura, editors, W.B. Saunders Company, Philadelphia, 1995. pp 152-157.
Rosse, W. Autoimmune hemolytic anemia. In: Blood: Principles and Practices of Hematology. R.I. Handin, S.E. Lux, and T.P. Strossel, editors, J.B. Lippincott Company, Philadelphia, 1995. pp. 1819.
Recent Medical Publications on Treatments for AIHA:
SA, Barton C. Influence of drug treatment on survival of dogs with immune-mediated
hemolytic anemia: 88 cases
(1989-1999). J Am Vet Med Assoc 2001 Feb 15;218(4):543-6
Zaucha JA et al. Severe canine hereditary hemolytic anemia treated by nonmyeloablative marrow transplantation. Biol Blood Marrow Transplant 2001;7(1):14-24
Burgess K, Moore A, Rand W, Cotter SM. Treatment of immune-mediated hemolytic anemia in dogs with cyclophosphamide.J Vet Intern Med 2000 Jul;14(4):456-62
Reagan WJ, Scott-Moncrieff C, Christian J, Snyder P, Kelly K, Glickman L. Effects of human intravenous immunoglobulin on canine monocytes and lymphocytes. Am J Vet Res 1998 Dec;59(12):1568-74
Kellerman DL, Bruyette DS. Intravenous human immunoglobulin for the treatment of immune-mediated hemolytic anemia in 13 dogs. J Vet Intern Med 1997 Nov-Dec;11(6):327-32
Bartges JW. Therapeutic plasmapheresis. Semin Vet Med Surg (Small Anim) 1997 Aug;12(3):170-7
RG, Schoeman T. Immune-mediated haemolytic anaemia: possible association with Ancylostoma
caninum infection in
three dogs. J S Afr Vet Assoc 2001 Mar;72(1):52-4
E et al. Haemolytic anaemia and exercise intolerance due to phosphofructokinase deficiency
in related springer
spaniels. J Small Anim Pract 2001 Jun;42(6):298-300
PM, Craig LE. Correlation between leukocytosis and necropsy findings in dogs with
anemia: 34 cases (1994-1999).J Am Vet Med Assoc 2001 Apr 15;218(8):1308-13
Lee KW, Yamato O, Tajima M, Kuraoka M, Omae S, Maede Y.Hematologic changes associated with the appearance of eccentrocytes after intragastric administration of garlic extract to dogs. Am J Vet Res 2000 Nov;61(11):1446-50
Stewart GW, Turner EJ. The hereditary stomatocytoses and allied disorders: congenital disorders of erythrocyte membrane permeability to Na and K. Baillieres Best Pract Res Clin Haematol 1999 Dec;12(4):707-27
Morgan LW, McConnell J. Cobalamin deficiency associated with erythroblastic anemia and methylmalonic aciduria in a border collie. J Am Anim Hosp Assoc 1999 Sep-Oct;35(5):392-5
Noble SJ, Armstrong PJ. Bee sting envenomation resulting in secondary immune-mediated hemolytic anemia in two dogs.J Am Vet Med Assoc 1999 Apr 1;214(7):1026-7, 1021
Birkenheuer AJ, Levy MG, Savary KC, Gager RB, Breitschwerdt EB. Babesia gibsoni infections in dogs from North Carolina. J Am Anim Hosp Assoc 1999 Mar-Apr;35(2):125-8
Yamato O, Hayashi M, Yamasaki M, Maede Y. Induction of onion-induced haemolytic anaemia in dogs with sodium n-propylthiosulphate. Vet Rec 1998 Feb 28;142(9):216-9
Duval D, Giger U. Vaccine-associated immune-mediated hemolytic anemia in the dog. J Vet Intern Med 1996 Sep-Oct;10(5):290-5
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