Immune-Mediated Hematologic Disease and Bone Marrow Failure

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For causes, symptoms and diagnosis, please visit Part 1 of this series, “Immune-Mediated Hemolytic Anemia and Companion Animals.”

Background

Immune-mediated hematologic disease is being reported with increasing frequency in animals and humans. In the dog, this syndrome is often associated with bone marrow failure. Affected animals usually have one or more of the following signs: autoagglutinating red blood cells; Coombs positive hemolytic anemia; spherocytes; nonregenerative or poorly regenerative erythroid response; severe thrombocytopenia; profound leukopenia; other autoimmune diseases especially thyroiditis; active erythrogenesis, granulocytopoiesis or megakaryocytopoiesis with maturation arrest at the early stem cell level; and poor response to standard treatment protocols with corticosteroids and other immunosuppressive drugs. In many cases a recent stress (e.g. vaccination; drug; chemical or toxic exposure; surgery; hormonal influence; infection; injury) could be identified as a potential triggering event within the previous 30 days.

Treatment Protocol for Dogs with IMHA

Treatment generally involves use of initially high doses immunosuppressant drugs such as corticosteroids, and more potent drugs like cyclosporine and mycophenolate and possibly a cross-matched or true “universal” blood donor type blood transfusion. Thyroid hormone can be given to stimulate new blood cell production, regardless of the thyroid function status of the patient. Hematinics containing iron, vitamin B12 and folic acid are beneficial, as is a liver sparing diet to offset the liver dysfunction from the drugs being given. Therapy is costly. Recovery can be slow and prognosis is guarded.  Studies have been conducted on the various drug protocols and dosages.

Protocol

1)  Autoimmune thyroiditis/hypothyroidism is frequently present; affected dogs are often of breeds or cross-breeds susceptible to thyroid disease.

2) Aggressive and more sustained treatment with corticosteroids is needed.  Suggested doses are: Prednisone or prednisolone given at 2-3 mg/lb/day divided BID for 5-7 days, or dexamethasone equivalents at 0.25-0.35 mg/l b/day divided BID. Therapy is reduced weekly by ½ and maintained for at least six weeks. Alternate day steroid therapy may be needed for some time thereafter on a long term, low level basis.

3) For severe cases, other immunosuppressive therapy is given. We much prefer cyclosporine (Neoral, 100 mg/ml oral syrup, or Atopica) instead of cyclophosphamide (Cytoxan) and give it at 10 mg/kg for 5 days rest 2 days, then at 5mg/kg for another 5 days. The lower dose is repeated after a 2 day rest on a 5 days on, 2 days off cycle as long as is needed (usually 2-3 courses of 5 days). This drug induces rapid T-cell suppression within about 48 hours and has been safe, effective, and well-tolerated at these doses. In cases where sustained more potent immunosuppression is required for clinical stabilization, azathioprine (Imuran) should be instituted along with cyclosporine. Dose is 1 mg/lb/day for 7-10 days initially followed by a downward tapering over several weeks. Azathioprine may be needed every other day or less often, on a long term basis. As azathioprine takes about 10 days to effectively suppress T-cells, clinical responsiveness will not occur immediately. Cyclosporine is therefore given concurrently in the early stages of the disease to provide rapid immunosuppression until the azathioprine takes hold.

The goal of this immunosuppressive therapy is to stabilize the ongoing immune destructive process. The dosage guideline we use is adjusted to maintain the absolute lymphocyte count as about 1/3 of the normal range (750-1500/ul).

4) Other immune suppressive drugs for refractory cases include: mycophenolate (Cell Cept), but we do NOT recommend leflunomide (Arava) as it can cause adverse effects on the liver.

5) Those breeds most often affected in our case population are cocker spaniels, poodles (all  varieties), golden retrievers, Doberman pinschers, dachshunds, miniature schnauzers, Akitas, beagles, rottweilers, Lhasa apsos, German shepherds, shih tzus, terriers, and mixed breeds of these backgrounds. Any of the nearly 50 breeds predisposed to thyroid disease are at risk for an immune-mediated condition. Thyroid supplementation at 0.1 mg/10lb given twice daily is essential for cases with concomitant thyroid disease and is helpful to stimulate the bone marrow whether or not thyroid tests indicate hypothyroidism. It also enhances platelet function.

6) For truly refractory cases, compounded anabolic steroid (nandrolone decanoate, Deca Durabolin, 2-5 mg/kg given once a week for 4-6 doses) is given to help stimulate the marrow.

7) Hematinics containing iron, folic acid, and vitamin B12 have been helpful. Meals should be small and often and grain-free (no wheat, corn or soy), so that his liver can handle the drugs and the food he needs.  See attached homemade diet recipe. Liver cleansing herbs like milk thistle and SAMe are advisable as well, as the liver enzymes usually become elevated. Please see my Liver Cleansing Diet.

8) In poorly responsive immune thrombocytopenias (ITP), an initial dose of vincristine (Oncovin, 0.01 mg/lb IV) may be helpful to release remaining platelet stores, and danazol (Danacrine, 2.5-5 mg/lb BID initially and then tapered to SID) has been effective along with steroids and thyroid for long term maintenance.

9) The most severe cases with autoagglutinating red cells or profound thrombocytopenia may recover completely with the aggressive therapeutic approach outlined above, although a  subset of these dogs convert to having a chronic low-grade nonresponsive anemia over the long term.

10) Cases with the best overall prognosis tend to be younger animals in which the underlying primary “trigger” of the immune-mediated disease was hypothyroidism, a drug which is withdrawn, or a recent vaccination/toxic exposure. Correction of the thyroid disease with serial monitoring of thyroid function to establish the appropriate maintenance dose of hormonal supplement is important.

W. Jean Dodds, DVM
Hemopet / NutriScan
11561 Salinaz Avenue
Garden Grove, CA 92843

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