In severe cases (autoagglutination, hemolytic crisis with rapid decline in hematocrit, and/or intravascular hemolysis), azathioprine
(2.2 mg/kg PO q 24 h) is added to suppress T-cell function as well as to decrease immunoglobulin production. Side effects
of azathioprine include bone marrow suppression, gastrointestinal upset, hepatotoxicity and possible exacerbation of pancreatitis.
In most cases, it is well tolerated by dogs but should not be used in cats. Retrospective studies of dogs with IMHA have shown
the longest survival times in dogs receiving the combination of prednisone and azathioprine.
Cyclosporine was originally used in humans to prevent rejection of organ transplants. It suppresses interleukin-2 and other
cytokines, thereby blocking the proliferation of activated T-cells. It is now available as a veterinary product (Atopica,
Neoral) and has been used for immune-mediated diseases such as perianal fistulas, histiocytosis and inflammatory bowel disease.
Although it is expensive, it may be effective in refractory cases of IMHA, especially those that are nonregenerative. It is
given at a dose of 5-10 mg/kg divided BID to achieve plasma trough levels >200 mg/ml. Large-breed dogs can be dosed concurrently
with ketoconazole (10 mg/kg daily) to allow reduction of the cyclosporine dose through inhibition of hepatic microenzymes,
making treatment more economical.
Cyclophosphamide seems to be falling out of favor as an adjunctive treatment for IMHA, as recent retrospective studies have
shown no benefit over prednisone alone. Furthermore, the potential side effects are serious and include marked myelosuppression,
gastrointestinal signs and hemorrhagic cystitis. Cyclophosphamide can be given orally at a dosage of 1-2 mg/kg (50 mg/m2 ) for four days a week. Alternatively, it can be given as a weekly injection of 100-200 mg/m2 IV.
Human intravenous immunoglobulin (IVIG) has shown some benefit in IMHA animals that are refractory to conventional treatment.
It is given at a dose of 0.5-1.5 g/kg IV over 12 hours. It binds the Fc receptors on mononuclear phagocytes and down-regulates
immunoglobulin production. It has both immediate and long-term effects, but is very expensive.
Mycophenolate mofetil (MMF, CellCept, Roche Labs) is a novel immunosuppressive drug used in people to prevent transplant rejection.
Because of its relative specificity for lymphocytes, myelosuppression is not a common side effect. The drug has been used
in people to treat psoriasis, vasculitis, systemic lupus, nephrotic syndrome and uveitis. In dogs, limited use has shown a
beneficial response in those with IMHA, myasthenia gravis and glomerulonephritis. It is given in conjunction with prednisone
(2.2 mg/kg q 12-24 h) at a dosage of 12-17 mg/kg PO SID or divided BID.
Another drug that may show promise in dogs with IMHA is leflunomide (Arava, Aventis Pharmaceuticals, Kansas City, Mo.). At
a dosage of 4 mg/kg PO daily with a trough concentration of 20 mcg/ml, leflunomide showed beneficial results in a limited
number of dogs with IMHA, systemic histiocytosis and immune-mediated thrombocytopenia. The drug is very expensive, but was
effective in reducing or negating the need for glucocorticoids.
Because the spleen is the major site of RBC removal in dogs with IMHA, splenectomy has been recommended in dogs refractory
to immunosuppressive therapy. Results are often discouraging because the dogs are poor surgical candidates when splenectomy
is considered as a last resort therapy. However, a recent preliminary study has shown improved survival in dogs receiving
early splenectomy in conjunction with prednisone and azathioprine therapy. Splenectomy is not recommended if there is any
suspicion of hemoparasites.
The fourth goal of therapy is to prevent serious side effects of IMHA. The most life-threatening consequence of IMHA is pulmonary
thromboembolism (PTE). Various doses of heparin have been advocated to prevent this life-threatening complication in dogs
with IMHA. Recent evidence reveals that doses lower than 300 U/kg SC q 6 h are usually ineffective in achieving desired target
levels of heparin. Subtherapeutic doses of heparin may actually exacerbate the tendency toward thrombosis. Most success has
been in administering heparin as a constant-rate infusion at a dose of 18 U/kg per hour following an IV bolus of 80 U/kg IV.
The activated partial thromboplastin time (APTT) should be monitored twice daily and the infusion adjusted to keep its activity
at 1.5 to 2 times baseline. Low molecular weight heparins have increased bioavailability, a longer half life, and are safer
than unfractionated heparin; but low molecular weight heparins are more expensive. Unfortunately, preliminary trials have
not been encouraging.
The best preventive against PTE, disseminated intravascular coagulation, hypercoagulable state and tendency toward thrombosis
in dogs with IMHA appears to be ultra-low-dose aspirin (0.5 mg/kg PO q 24 h). Dogs that received prednisone, azathioprine
and ultra-low-dose aspirin had the longest survival times.
Other supportive care includes gastrointestinal protectants (sucralfate and an H2 blocker) during the initial high doses of glucocorticoids. Doxycycline (5 mg/kg q 12 h for 14-21 days) is often administered
if there is thrombocytopenia or any suspicion of tick-borne disease.
Dogs should not be vaccinated again or receive any penicillin, sulfa or cephalosporin drugs. All dogs previously diagnosed
with IMHA will relapse, so extended initial drug therapy for IMHA, not using certain drugs and not vaccinating are ways to
decrease the likelihood of an IMHA relapse.
Johnny D. Hoskins
Dr. Hoskins is owner of DocuTech Services. He is a diplomate of the American College of Veterinary Internal Medicine with
specialities in small animal pediatrics. He can be reached at (225) 955-3252, fax: (214) 242-2200 or e-mail: firstname.lastname@example.org