Expert: Kaza - 3/16/2008

Question
QUESTION: Our Bichon became very lethargic 2 weeks ago and would not eat or drink. We kept her hydrated using syringe until vet was available. Vet ran many test including blood and found red cell count extremely low and told us it looked like a canine form of Lupus and said prognosis was not good and recommended we go to U. of Illinois Vet School hospital. This we did and after running many test they diaganosed Immune Mediated Hemooytic Anemia (IMHA). She is now back home and slowly responding to aspirin and steroids. She is constantly hungery and red cell count has risen from 14 to 28 - normal is 40. The question is: what can you tell me about IMHA in layman terms and what is long range prognosis? Our Bichon is a 13 month old female named Mitzi. Thanks for whatever info you can provide.
dickcoh@insightbb.com

ANSWER: Hi there , Sadly Im not going to be very positive here but I will be as honest as I can for you....
I will give you the info then suggest a course of action that will not be for all.
I will be honest with you , this is a terrible condition, even the treatment isnt great......

Primary immune mediated hemolytic anemia (IMHA) is caused by an autoantibody directed against an epitope on red blood cells. Unlike secondary immune mediated hemolytic anemia, the event inducing an antibody is unknown in primary IMHA. Secondary immune mediated hemolytic anemia is induced by the formation of antibodies induced by microorganisms, drugs or previous transfusions. Although the primary body system affected is the erythron, immune mediated thrombocytopenia can occur concurrently. In addition to the hematopoietic system, other body systems are affected by sequela such as pulmonary thromboembolism, systemic thromboembolism, disseminated intravascular coagulation, hepatic dysfunction and drug side effects. IMHA occurs worldwide. Neither the incidence nor prevalence has been determined. Several studies report an increase in cases during the summer months .

Many breeds of dogs have been reported to be predisposed to the development of IMHA. The strongest evidence for a breed predilection to IMHA is in the cocker spaniel; which has been implicated in several studies . Other breeds reported to have an increased incidence are: English springer spaniels, collies, poodles and miniature schnauzers. The range of ages for dogs diagnosed with IMHA is 1-13 years with a median of 6 years. Females or spayed females are overrepresented in cases of IMHA.

A type II hypersensitivity reaction mediates destruction of red blood cells in IMHA. Antibodies specific for a component of the red blood cell membrane binds to red blood cells. Red blood cell destruction occurs in the spleen (extravascular) or, following complement fixation, hemolysis occurs intravascularly. Antibodies may be directed at red blood cell precursors resulting in a nonregenerative variant of IMHA. Antibodies are of either IgG or IgM class. Several studies have attempted to identify a link between vaccination and development of IMHA. Only one study has found an increase in IMHA in dogs that have been vaccinated The presence of dog erythrocyte antigen 7 in cocker spaniels has been shown to be protective against the development of IMHA.


Owner administration of acetaminophen, onion ingestion or administration of vitamin K may cause hemolytic anemia. A careful history should be obtained to identify these causes of hemolysis and to treat them appropriately. Clinical signs are vague and usually referable to acute anemia. They include an acute onset of depression, anorexia, weakness and lethargy. The owners may report discolored urine. Physical examination reveals pale mucous membrane which are often icteric. Pigmenturia results from either hemoglobinurina or bilirubinurina. If the anemia is severe, the dog may be tachycardic and a heart murmur may be ausculted. Palpation will reveal hyperdynamic pulses. Abdominal palpation identifies hepatomegaly or splenomegaly in 25% of cases Petechiae appear if concurrent immune mediated thrombocytopenia is present. Occasionally, lymphadenopathy is present.


Definitive Diagnosis
The diagnosis of IMHA is not typically made based on the history or physical examination findings. A minimum database is obtained during the evaluation of an acutely ill dog. The results of these tests indicate a hemolytic process. Identifying a hemolytic disorder and eliminating causes of secondary immune mediated hemolytic anemia make the definitive diagnosis of IMHA. No single positive test result is diagnostic for IMHA.

Several disease processes can cause hemolytic anemia in dogs. Those diseases include zinc toxicosis, infectious diseases, neoplasia (hemangiosarcoma or lymphoma), drug toxicity or onion toxicity.

Laboratory Findings
A standard minimum database, CBC, biochemical profile and urinalysis features characteristic findings of hemolysis. The CBC demonstrates a regenerative anemia, polychromasia, macrocytosis, anisocytosis and spherocytosis. A neutrophilic leukocytosis, with or without a left shift, is common in dogs with IMHA and has been linked to the presence of tissue injury. Histological findings commonly include centrolobular necrosis of the liver or pulmonary thromboemboli. Biochemical profile findings include: hemoglobinemia and/or bilirubinemia and elevated hepatic transaminases. Hemoglobinuria or bilirunuria are common features of urinalysis in dogs with IMHA. Thrombocytopenia occurs in approximately 70% of dogs with IMHA. Abnormal hemostatic profiles are common with disseminated intravascular coagulation a frequent finding. D dimer elevations have been reported in 75% of dogs, especially those with pulmonary thromboembolism. Approximately 75% of dogs diagnosed with IMHA have a positive Coombs test . It is a strong indicator that hemolysis is due to an immune process. It is important to remember some dogs may have an infectious disease such as anaplasmosis (ehrlichiosis) or babesiosis as the cause of the immune mediated hemolysis; and consequently, a positive Coombs test does not "prove" a diagnosis of IMHA.

Radiography and Ultrasonography
Radiography and ultrasonography do not contribute to the diagnosis of IMHA. They are used to rule out causes of secondary IMHA such as zinc toxicosis or underlying neoplasia.

Infectious Disease Testing
Infectious disease testing required in dogs with IMHA is dependant on the travel history of the dog and the infectious diseases commonly identified in the region. Diseases to be considered include: anaplasmosis (ehrlichiosis), mycoplamosis (hemobartonellosis), babesiosis and bartonellosis.


The prominent feature finding on postmortem finding is macro- and microthrombi coupled with systemic fibrin deposition . Pulmonary thromboemboli are a commonly associated with acute death in dogs with IMHA. Multiple organ thrombosis has been recognized and in one study was most common in the spleen.

Tissue necrosis is another postmortem finding in dogs with IMHA. Following obstruction of blood flow by an embolus, tissue necrosis or infarction occurs. Infarction is frequent in the spleen, heart and kidneys. Necrosis occurs independent of embolism and is postulated to result from anemia induced hypoxia as evidenced by centrolobular necrosis in the liver. The spleen and liver may also be affected.

Complications of therapy for IMHA are often identified during postmortem evaluation. Secondary infections, such as pneumonia or pyelonephritis, occur as a result of immunosuppressive therapy. Perforating gastric ulcers have been described as a sequela to prednisone therapy.

TREATMENT
Because the published studies of treatment of dogs with IMHA originate from teaching hospitals, there is likely a bias towards inclusion of sicker dogs and towards inpatient management of this disease. Consequently, reported cases are managed as inpatients and the average hospital stay is 6 days.

Antibiotic Therapy
While the results of infectious disease testing are pending, doxycycline should be administered. In dogs developing secondary infections from immunosuppressive agents, the type of infection will dictate antibiotic choice.

Immunosuppressive Agents
Most veterinarians would agree prednisone is the first line therapy for this disease, despite the fact that its usage has not been evaluated in a clinical trial. The benefit of adding additional immunosuppressive agents to prednisone is somewhat unclear since the data is conflicting. Currently several different agents are recommended if additional immunosuppressive agents are required in dogs with IMHA. Mounting retrospective and prospective data suggest cyclophosphamide administration does not benefit dogs with IMHA Evidence from 3 retrospective studies suggests the use of intravenous immunoglobulin may be effective in controlling hemolysis on a short term basis in dogs with IMHA, but a randomized controlled trial must be performed to confirm this interpretation of the available evidence . Although recommended for the treatment of IMHA for decades, the information on the outcome of treatment with azathioprine is mixed. All studies of azathioprine usage are retrospective. One study showed no survival advantage in dogs with administered azathioprine in addition to prednisone and 3 showed a survival advantage Because the dogs studied were not randomly allocated to the various treatment groups, the possibility exists that dogs treated with azathioprine in some way had a better prognosis than those not treated with azathioprine and the improved outcome is due to a selection bias rather than a treatment effect. As with intravenous immunoglobulin, a randomized, controlled clinical trial will be required to determine if azathioprine treatment is more effective than prednisone alone. Currently, little data is available on the outcome in dogs with IMHA administered cyclosporine.

Anticoagulant Therapy
Mixed molecular weight heparin, low molecular weight heparin and aspirin have been studied in dogs. To date, no dosage of heparin which prevents thromboembolic disease has been identified. An ultralow dosage of aspirin 0.5 mg/kg daily was associated with improved survival in dogs with IMHA, but aspirin's effect on the rate of thromboembolism was not reported in these dogs. Identification of the optimal protocol to prevent pulmonary thromboembolism is essential to improving outcome in this disease.

Transfusion Therapy
The majority of dogs receive packed red blood cell transfusions as a treatment for anemia and those with disseminated intravascular coagulation receive fresh frozen plasma. Transfusion of all dogs with fresh frozen plasma is not recommended since it does not prevent pulmonary thrombosis. Theoretically, providing increased oxygen carrying capacity with a hemoglobin solution lacking the antigenic red blood cell membrane of intact red blood cells should provide a treatment advantage in dogs with IMHA. The opposite was shown in the results of one study, which, because of its retrospective design, cannot be considered definitive evidence against the use of hemoglobin based oxygen carriers in IMHA.

FOLLOW UP
Patient Monitoring
Dogs released from the hospital should be examined once a week until the CBC indicates a consistent improvement or stabilization of the hematologic values. Owners should monitor the pet for recurrent lethargy or discolored urine which would suggest anemia is recurring. Dogs maintained on long term prednisone therapy or any other immunosuppressive agents, should have urine obtained for culture every three months to identify any subclinical cases of urinary tract infections.

Long-term Management
Because of the side effects from immunosuppressive drugs, the goal to gradually taper therapy over approximately 12 months following control of hemolysis; however, relapse is common. Dogs may relapse while still on immunosuppressive therapy or after immunosuppressive therapy is discontinued. Prednsione is typically administered at a dosage of 1-2 mg/kg twice daily. Once hemolysis ceases, the dosage is decreased approximately 25% every 2-6 weeks until a dosage of 0.5 mg/kg every other day is reached. The dog should be maintained on this dosage for 6 or more months. Tapering the dosage of azathioprine is often done after the prednisone dosage reaches an every other day regimen.

Prognosis
The rate of death is highest in the first 2 weeks after diagnosis. One year after diagnosis, approximately 50% of dogs are still alive. Dogs may die acutely from pulmonary thromboembolism even if anemia has responded to immunosuppressive therapy.

Im sorry I cannot be more positive.The use of steroids will make the dog constantly hungry and can lead to other conditions.
If it was any dog of mine I would consider euthanasia, I know that is harsh, but its a reality that the dog will suffer, I am so very sorry, but I feel that you want me to be honest .

If you need further support please log into my site
www.eurobichons.com

---------- FOLLOW-UP ----------

QUESTION: It has been 2.5 months since Mitzi was diagnosed with IMHA by Univ. of Illinois Vet hospital. She has been on a treatment of prednisone and special dry food diet. Her blood count is back in normal range, she is seeing vet every 2 weeks, she is always hungry and gained weight(14 lbs). She likes to go for walks but sleeps a lot and is not real active. She does not make her sudden spurts of running and jumping, doesn't play with her toys or try to steal socks. Do you think this behavior will change as prednisone is reduced? Any other comments? Thanks, Dick.

Answer
It may do yes, but I will be very honest, prednisilone is a steroid and as such further conditions may arise. I would actually take her to hydrotherapy in your area, get her moving a bit more, watch her food intake, the steroids will make her hungry, if so feed her superspeed foods such as carrots, cucumber, apple etc green beans.

I know Mitzi is going through hell, as you are but this condition is quite aggressive and her quality of life will indeed suffer, not all the time but on a few occasions, the best thing you can do is to be positive, but importantly you should get her to exercise a little more.

Good luck