Autoimmune Hemolytic Anemia and Thrombocytopenia

These are the most common Type II reactions. Antibody and complement attach to RBC either directly or indirectly via an absorbed antigen and mediate RBC destruction, resulting in a severe, life-threatening anemia. Concurrent thrombocytopenia is found in 60% of cases. Type II reactions can be associated with systemic lupus erythematosus (SLE [more common in dogs]) or with lymphoreticular malignancies (more common in horses and cats). Drugs, vaccines, or infections also can precipitate attacks of hemolytic anemia or thrombocytopenia in most species. More often than not, the triggering cause is unknown. However, as more information becomes available about rickettsia, these intracellular pathogens may be found responsible for many of the idiopathic immune-mediated disorders.

Autoimmune hemolytic anemia (AIHA) has 4 basic forms: peracute, acute or subacute, chronic, and pure red cell aplasia. Most forms are treatable, and relapses are uncommon. (See also Hemolytic Anemia .)

Peracute AIHA is seen mainly in middle-aged, larger breeds of dogs. Affected dogs are acutely depressed and within 24-48 hr have a fulminant decrease in PCV with bilirubinemia, variable icterus, and sometimes hemoglobinuria. Initially, the anemia is nonresponsive, but it becomes responsive within 3-5 days. Thrombocytopenia and thrombotic phenomena may be accompanying features. The Coombs’ test is often negative, and spherocytes may or may not be present, but in-tube or slide agglutination of RBC is marked. The autoagglutination is not dispersed by saline dilution, hence the term hemolytic anemia with in-saline agglutinins. The serum usually contains autoantibodies that cause agglutination of most donor RBC (including heterospecies). The prognosis of peracute AIHA is poor even with prompt and vigorous therapy. The most effective therapy involves immediate use of high dosages of glucocorticoids plus cyclophosphamide. Incompatible blood transfusions should be avoided if possible, because they will provide more foreign material to provoke the failing immune system. If incompatible blood must be used, the animal should first be heparinized and maintained on heparin for the first 10 days. Even without transfusion, heparinization may be beneficial for the first 2 wk or more. Bovine hemoglobin blood substitute and human immunoglobulin can be used to support the patient until immunosuppressive treatment reduces the destruction of RBC.

Acute AIHA is the most common form of the disease, with a breed predilection in Cocker Spaniels. Initial signs are pallor, fatigue, and less commonly, icterus. Hepatosplenomegaly is a prominent sign. The WBC count often is increased due to bone marrow hyperplasia. Autoagglutination of RBC is uncommon, and the Coombs’ test is generally positive. These animals usually respond well to glucocorticoid therapy. If a favorable response is not seen within 7-10 days, cytotoxic drugs (cyclophosphamide or azathioprine) should be added to the regimen.

Chronic AIHA differs from the acute form in that the PCV falls to a constant level and remains there for weeks or months. The bone marrow is either normal or hyperresponsive, and the Coombs’ test is often negative. Chronic AIHA is relatively more common in cats than in dogs. Usually, the anemia is responsive early in the course of disease but responds minimally or not at all by the time it becomes severe. Initial treatment is with glucocorticoids; if there is no response within 2 wk, cytotoxic drugs are added to the regimen.

Pure red cell aplasia ( Primary Bone Marrow Diseases) is a variant of the above disorders and is most common in dogs. It occurs in 2 forms, one in postweanling to adolescent puppies and the other in adults. Unlike AIHA, the bone marrow shows a selective depression of erythroid elements; granulocytes and platelets are unaffected. Therefore, the peripheral anemia is unresponsive. The immune attack apparently is directed at RBC precursors, and the Coombs’ test is usually negative. However, there is often some difficulty in identifying compatible donors. Treatment is usually as for chronic AIHA.

Autoimmune thrombocytopenia is common, especially in dogs. It occurs more often in females than males. The most frequent clinical signs are hemorrhages of the skin and mucous membranes. Melena, epistaxis, and hematuria may be accompanying features and can cause profound anemia. Hemolytic anemia and thrombocytopenia sometimes occur together. Autoimmune thrombocytopenia usually is diagnosed on the basis of low peripheral platelet counts despite a pronounced megakaryocytosis in the marrow. Occasionally, megakaryocytes may be selectively absent from the marrow—a condition analogous to pure red cell aplasia. Tests for antiplatelet antibodies are difficult to conduct and may be positive in £70% of cases. The diagnosis is usually made on clinical appearance and response to therapy, rather than on antiplatelet antibody tests. (See also Congenital Thrombocytopenia .)

Animals with autoimmune thrombocytopenia that show only petechial and ecchymotic hemorrhages, with no significant blood loss and megakaryocytes in the marrow, are usually treated initially with glucocorticoids alone. The clinical signs should abate and the platelet count begin to rise after 5-7 days. If the platelet count has not increased significantly by days 7-10, either cyclophosphamide, azathioprine, or vincristine can be added to the glucocorticoid regimen. In animals with megakaryocytes in the marrow and severe blood loss, a more rapid response to therapy is desirable. Such animals are treated with a single injection of vincristine combined with daily glucocorticoids; a favorable response usually occurs after 3-5 days. If the blood loss is life-threatening, platelet-rich whole blood should be administered. If the platelet count has risen by day 7, remission is maintained on glucocorticoids alone. If there is no response after 7 days, a second dose of vincristine is given. If the platelet count is still low after 2 wk, vincristine is discontinued and either cyclophosphamide or azathioprine is added. Animals with thrombocytopenia and no megakaryocytes respond much more slowly to glucocorticoids, or to glucocorticoids and vincristine. Preferred treatment for these animals is with prednisolone and cyclophosphamide, and a response should not be expected much earlier than 1-2 wk after beginning therapy. Therapy can be discontinued in most animals with autoimmune thrombocytopenia 1-3 mo after the platelet count returns to normal. Some animals have more or less persistent thrombocytopenia despite drug therapy, or they can be maintained in remission only with chronic high-dose treatment. The alternatives are to allow the animal to live with the thrombocytopenia if signs are minimal or to use longterm combination drug therapy with glucocorticoids and either vincristine, azathioprine, or cyclophosphamide. Splenectomy may be helpful; it is seldom curative by itself but may allow use of lower and safer dosages of immunosuppressive drugs.

Cold agglutinin (hemolytic) disease is an AIHA that has been recognized most often in dogs and horses. It is often idiopathic but can be secondary to a chronic infection, other autoimmune diseases, or a neoplastic process. The IgM autoantibodies can be agglutinating or nonagglutinating. Complete agglutination is not seen at body temperature but rather at some lower temperature, thus it is more frequent in colder climates and seasons. Initial signs may be of a hemolytic disease; in the agglutinating type, there also may be microcapillary stasis with subsequent acrocyanosis and necrosis of the nose, tips of the ears and tail, digits, scrotum, and prepuce. Diagnosis is based on a reversible autoagglutination that occurs only at a cool temperature. The direct Coombs’ reaction is usually negative for IgG, frequently positive for C3, and usually positive for IgM if the reaction is performed in the cold. Mortality is high. In the absence of precipitating disorders, eg, infection or neoplasia, the disease is best controlled with high doses of glucocorticoids used in combination with cyclophosphamide. Cyclophosphamide is withdrawn when the anemia disappears and cold agglutinins are no longer detected.