Immune-mediated hemolytic anemia: A metabolic disaster (Proceedings)

Immune mediated hemolytic anemia (IMHA) can be a common cause of acute lethargy, depression, weakness, and collapse in emergency patients. Dog breeds most commonly affected include Cocker spaniels, English Springer spaniels, Collies, Poodles, Old English sheepdogs, Lhasa Apsos, Shih Tzus, and Labrador retrievers, although any breed is susceptible. The most common age of onset is 5-6 years, and females are more likely to be affected than males. The disease may be primary (idiopathic) or it may be secondary to a drug or underlying disease process. Recognized causes of secondary IMHA include infectious diseases (babesiosis, ehrlichiosis, leishmaniasis, hemobartonellosis, and dirofilariasis), neoplasia (hemangiosarcoma, lymphosarcoma), drugs (cephalosporins, sulfa drugs, propylthiouracil) and vaccines. Primary IMHA is rare in cats and is usually secondary to neoplasia, infectious disease (hemobartonellosis, FeLV, FIV), or drugs.

Common physical examination findings include pallor, icterus, discolored urine (bright yellow, orange, or port-wine color), splenomegaly, tachycardia, and recent onset cardiac murmur. Petecchial hemorrhages may be present on the mucous membranes or inguinal and axillary regions if there is concurrent thrombocytopenia.

The diagnosis of IMHA is often made in the emergency room based on history and physical examination findings combined with the results of a blood smear and complete blood count. Most dogs with IMHA have a regenerative anemia with reticulocytosis, macrocytosis, polychromasia, and anisocytosis. Up to 30% of dogs with IMHA may have non-regenerative anemia, however, because of pure red blood cell aplasia or a peracute onset with insufficient time for a bone marrow response to occur. Spherocytes are seen in 60-70% of dogs with IMHA and this finding is highly suggestive, though not diagnostic, for IMHA. In severe cases, gross autoagglutination can be observed as cells form clumps along the sides of an EDTA blood tube. Autoagglutination is pathognomonic for IMHA. Two drops of blood can be mixed with an equal volume of saline on a slide and gently rocked back and forth. If clumps form, gross agglutination is present and the test is positive. Microscopic agglutination appears as clumps of red blood cells that resemble clusters of grapes. If autoagglutination is not seen, but IMHA is suspected, a direct antiglobulin test, or Coomb's test, should be performed. This test detects antibodies on the red blood cell membrane. The Coomb's test is positive in 60-70% of the cases. False negatives can occur with prior corticosteroid therapy or with improper testing techniques of dilution, cell washing, temperature control or antigen:antibody ratios. Prior blood transfusions may cause a false positive result.

Classic laboratory findings in patients with IMHA include anemia (usually < 20% hematocrit) with a normal total protein and hemolyzed or icteric serum. Up to 70% of reported cases have concurrent thrombocytopenia. Leukocytosis, with or without a left shift, is common because of the reactive bone marrow. Most dogs have mild to moderate elevations of liver enzymes and total bilirubin.

The most common type of IMHA involves extravascular hemolysis in the spleen or liver. Red blood cells are coated with antibody and bind to the FC receptors of macrophages resulting in phagocytosis by the mononuclear phagocyte system. With high levels of IgG or IgM antibody, complement is bound and activated resulting in intravascular hemolysis. The cardinal signs of intravascular hemolysis include port wine colored urine and hemoglobinemia. Autoagglutination and intravascular hemolysis are indicative of serious disease and warrant a guarded prognosis. Other negative prognostic indicators include serum bilirubin levels > 5 mg/dl, hypoalbuminemia, thrombocytopenia, lack of reticulocytes, and hematocrit < 10%.

In a recent report of 70 dogs with IMHA, the overall mortality rate was 70% (Reimer, 1999). At another referral hospital, the mortality rate was 60% (Miller, 1999). The low survival rate among dogs with IMHA is most likely the result of one or more of the following complications that commonly occur in dogs with IMHA.

1. Pulmonary thromboembolism is characterized by acute onset of dyspnea or tachypnea. Blood gasses reveal hypoxemia and normocapnea. Radiographs often are normal or mildly affected despite the severity of clinical signs.

Prevention includes heparin 200-250 U/kg subcutaneously q 8 h, low dose aspirin (1-5 mg/kg q 24 h), avoidance of central catheters, and promotion of adequate hydration and perfusion.

If pulmonary thromboembolism occurs, treatment with streptokinase is indicated. (90,000 U IV over 30 minutes followed by 45,000 U/h for 6-12 hours until respiration/hypoxemia improve.)

2. Refractory anemia can be treated with aggressive immunosuppressive therapy:

a. Prednisone 2.2 mg/kg q 12 h PO

b. Azathioprine 2.2 mg/kg q 24 h PO

c. Cyclosporin 5-10 mg/kg q 12 h PO

d. (Or Cyclophosphamide 200 mg/m2 IV q 7 days or 50 mg/m2 4 days/week PO

3. Transfusion reactions are common, often resulting in massive hemolysis. Transfusions should be avoided in animals with autoagglutination or hemolysis until immunosuppressive therapy has been administered for several days. Oxyglobin® can safely be administered to provide oxygen to tissues of severely anemic animals.

4. Gastrointestinal ulceration is common. Sucralfate (0.5-1 g PO q 8 h) and/or famotidine (0.5 mg/kg IV q 12-24 h) can be given to animals with melena or hematemesis.

5. Acute renal failure can occur in dogs that receive multiple transfusions that hemolyze.

6. Sepsis may occur in animals on high doses of immunosuppressive drugs.

7. Zinc toxicity and babesiosis are two causes of hemolytic anemia that must be ruled out in patients not responding to therapy. Babesia is treated with imidocarb 6.6 mg/kg IM twice 14 days apart. Zinc toxicity is treated by identification and removal of metallic objects from the gut.