Definition

Accelerated destruction or removal of RBCs due to a Type II hypersensitivity reaction.

Pathophysiology

• Antibodies form against endogenous unaltered RBC surface antigens (primary IMHA) or altered RBC membrane antigens (secondary IMHA).
• Infectious organisms, drugs, exposure of previously unexposed antigens, or adsorption of preformed antigen-antibody complexes to the RBC membrane can alter RBC membrane antigens.
• Immunoglobulin deposits on RBC membrane, causing either direct intravascular hemolysis or accelerated removal by the monocyte/macrophage system.
• Intravascular hemolysis occurs when adsorbed antibodies (usually IgG) activate complement.
• In vivo agglutination of RBCs occurs when IgM or high titers of IgG molecules cause bridging of RBCs.
• Extravascular removal of RBCs occurs primarily in spleen, liver, bone marrow.
• Nonregenerative IMHA is believed to be caused by immune-mediated destruction of RBC precursors in the bone marrow.
• Rarely cold-acting antibodies cause in vivo hemolysis and erythrocyte agglutination in peripheral vasculature.

Systems Affected

• Cardiovascular-tachycardia; low-grade heart murmur.
• Hemic/Lymphatic/Immune-immune-mediated destruction of RBCs, elaboration of proinflammatory mediators, DIC.
• Hepatobiliary-hyperbilirubinemia and icterus plus bilirubinuria when hepatic function is overwhelmed; centrilobular necrosis.
• Respiratory-tachypnea. PTE may result from hypercoagulable state.
• Skin-rarely cold-type IMHA may cause necrosis of extremities and ear tips.

Genetics

Cocker spaniels are at increased risk (absence of dog erythrocyte antigen 7).

Geographic Distribution

Secondary IMHA may have higher prevalence where associated infectious diseases are endemic.

Signalment

Signs

Causes and Risk Factors

Differential Diagnosis

CBC/Biochemistry/Urinalysis

• CBC-anemia, high MCV (3–5 days post-hemolytic episode), spherocytes, polychromasia, increased RBC distribution width, leukocytosis with neutrophilia and left shift, monocytosis, lymphocytosis (cats). Anemia is nonregenerative in 30% of dogs and 50% of cats.
• Serum biochemistry-hyperbilirubinemia, hemoglobinemia, high ALT.
• Urinalysis-hemoglobinuria, bilirubinuria.

Other Laboratory Tests

• Spontaneous saline agglutination test-before and after washing RBCs.
• Positive direct antiglobulin test (Coombs' test)-positive in up to 75% of animals with IMHA.
• Flow cytometric detection of membrane-bound immunoglobulin and complement.
• Reticulocytosis-absolute count >60,000/µL (dogs) or >50,000/µL (cats) in regenerative IMHA.
• Thrombocytopenia 60% of dogs.
• Prolonged APTT and PT, increased fibrin degradation products and d-dimer, decreased antithrombin in animals with DIC.
• Positive ANA titer and LE cell test (animals with SLE).
• Positive serologic titers or PCR in secondary IMHA due to infectious causes.
• Evidence of hematologic parasites in blood smears (secondary IMHA due to infectious causes).

Imaging

• Radiographic findings-hepatomegaly/splenomegaly; thorax usually normal; may see evidence of PTE (patchy alveolar pattern, interstitial pattern, pleural fluid), but dogs with pulmonary embolism may have normal thoracic radiographs.
• Ultrasonographic findings-hepatomegaly/splenomegaly; liver/spleen can be mottled and hyperechoic or hypoechoic.

Diagnostic Procedures

• Bone marrow aspirate usually reveals erythroid hyperplasia.
• With nonregenerative IMHA, maturation arrest or erythroid hypoplasia may be evident.
• In chronic IMHA, myelofibrosis may be present.

Pathologic Findings

• Hepatosplenomegaly, centrilobular hepatic necrosis
• Splenic and hepatic extramedullary hematopoiesis
• Reactive lymphadenomegaly
• PTE and DIC

Appropriate Health Care

• Inpatient during acute hemolytic crisis; outpatient when PCV stabilized, ongoing hemolysis controlled, and clinical signs of anemia resolved.
• Inpatient if complications such as DIC, PTE, thrombocytopenia, gastrointestinal bleeding, or a need for multiple transfusions.
• Chronic low-grade extravascular hemolysis can be treated on outpatient basis if the patient not exhibiting clinical signs secondary to anemia.

Nursing Care

• Fluid therapy to maintain vascular volume and correct dehydration.
• Packed RBCs typed or cross-matched for naive recipient. Blood should be cross-matched for recipients that have received prior transfusions. Whole blood acceptable if packed RBCs not available.
• Transfusion volume = recipient weight (kg) × 85 (dog) or 50 (cat) × desired PCV-current PCV/donor PCV.
• Transfusion rate 0.25 mL/kg/hr for first 30 minutes then 5–10 mL/kg/h.
• Monitoring for complications such as PTE, bleeding (especially GI), DIC, infection.
• Cage rest.

Client Education

• IMHA and complications (e.g., DIC, PTE) can be fatal.
• Life-long treatment may be needed; disease may recur.
• Side effects of treatment may be severe.

Surgical Considerations

• Splenectomy can be considered if medical management fails to control disease.
• Consider blood product administration preoperatively.

Drug(s) Of Choice

• Corticosteroids-prednisone 1–2 mg/kg/day q12h for 2–4 weeks. Use prednisolone in cats due to higher bioavailability.
• Once PCV above 30%, decrease dose to 1 mg/kg q12h. Then taper by a maximum rate of 25–50% per month over a 3- to 6-month period, depending upon PCV and severity of side effects. If after 3–6 months disease is in remission on a low q48h dose, try discontinuing the drug.
• Add additional immunosuppressive drug such as azathioprine (dogs) cyclosporine (cats) if poor response to prednisone after 5–7 days or if poor prognostic indicators (e.g., intravascular hemolysis, serum bilirubin >8–10 mg/dL, persistent autoagglutination, Evans syndrome).
• Azathioprine dose 2 mg/kg/day, can decrease to 0.5–1.0 mg/kg q48h if bone marrow suppression. Monitor for immunosuppression, hepatotoxicosis, pancreatitis.
• For prevention of thromboembolism (dogs) consider unfractionated heparin 300 U/kg SC q6–8h (dose adjusted based on APTT prolongation or measurement of anti-Xa activity) or ultra-low-dose aspirin 0.5–1.0 mg/kg/day or enoxaparin (low-molecular-weight heparin) 0.8 mg/kg SC q6h or 1.5 mg/kg q12h, or clopidogrel 2–3 mg/kg PO q24h (loading dose 10 mg/kg/day).
• Address underlying cause (e.g., infection and drugs) if secondary IMHA.

Contraindications

• No heparin, enoxaparin, or aspirin in dogs with severe thrombocytopenia (<80,000/µL).
• Do not use multiple cytotoxic drugs concurrently.

Precautions

• No azathioprine in cats because of risk of bone marrow toxicity.
• Prednisone/prednisolone can cause signs of Cushing's syndrome and may increase risk of PTE, pancreatitis, diabetes mellitus, secondary infection, gastric ulcers (consider gastric protectants).
• Cytotoxic drugs can cause bone marrow suppression, secondary infection, pancreatitis (azathioprine), GI upset (cyclosporine, azathioprine, mycophenolate mofetil), gingival hyperplasia, papillomatosis (cyclosporine), infertility.

Possible Interactions

Azathioprine and prednisone have been associated with development of pancreatitis.

Alternative Drug(s)

• Dexamethasone (0.25–0.5 mg/kg/day IV)-can be used instead of prednisone/prednisolone in animals that do not tolerate oral drugs, until oral intake is possible.
• Chlorambucil-for cats, 0.1–0.2 mg/kg PO q24h initially, then q48h.
• Cyclosporine-microemulsion, e.g., Atopica-dogs, 5–10 mg/kg/day PO divided twice daily; cats, 0.5–3 mg/kg q12h.
• Mycophenolate mofetil 10–17 mg/kg q24h.

Patient Monitoring

• Monitor heart rate, respiratory rate, temperature frequently.
• Monitor for adverse reactions to treatment (e.g., transfusion reactions/overhydration).
• If PTE suspected, monitor thoracic radiographs and arterial blood gases frequently.
• During first days of treatment, check PCV daily until stable, then every 1-2 weeks for 2 months; if still stable, recheck PCV monthly for 6 months, then 2–4 times per year; rechecks need to be more frequent if patient is on long-term medication especially cytotoxic drugs.
• CBC and reticulocyte count should be rechecked at least monthly during treatment,; if the neutrophil count falls <3,000 cells/µL, discontinue cytotoxic drugs until count recovers; reinstitute at lower dosage.
• Coombs' tests and reticulocyte counts to assist in drug tapering.

Prevention/Avoidance

Consider need for vaccination on case-by-case basis in dogs that developed IMHA after vaccination.

Possible Complications

• Pulmonary/multiorgan thromboembolism (up to 80% of all cases at necropsy).
• DIC.
• Centrilobular hepatic necrosis and renal tubular necrosis secondary to hypoxia.
• Infection secondary to immunosuppressive therapy.
• GI ulceration due to high-dose glucocorticoids.
• Iatrogenic hyperadrenocorticism.

Expected Course and Prognosis

• Mortality: 30–80% (dog), 25% (cat).
• Causes of death include thromboembolism, infection due to immunosuppression, DIC, persistent anemia.
• Hyperbilirubinemia >5 mg/dL, autoagglutination, intravascular hemolysis, severe thrombocytopenia, hypoalbuminemia are associated with poorer prognosis.
• Response to treatment may take weeks to months; nonregenerative IMHA may have more gradual onset than typical IMHA and may be slower to respond to treatment.
• IMHA may recur despite previous/current therapy.

Synonyms

• Autoimmune hemolytic anemia
• Immune-mediated anemia

See Also

• Anemia, Regenerative
• Chapters on causes of secondary IMHA
• Cold Agglutinin Disease
• Disseminated Intravascular Coagulation

Abbreviations

• ALT = alanine aminotransferase
• ANA = antinuclear antibody
• APTT = activated partial thromboplastin time
• DEA = dog erythrocyte antigen
• DIC = disseminated intravascular coagulation
• FeLV = feline leukemia virus
• FIV = feline immunodeficiency virus IMHA = immune- mediated hemolytic anemia
• LE = lupus erythematosus
• MCV = mean cell volume
• PCR = polymerase chain reaction
• PCV = packed cell volume
• PTE = pulmonary thromboembolism
• PT = prothrombin time
• RBC = red blood cell
• SLE = systemic lupus erythematosus

Client Education Handout Available Online