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Basics ⬇

Outline

BASICS

Definition!!navigator!!

IMHA is a destruction of RBCs associated with immunoglobulin and/or complement attachment to either RBC antigens or foreign antigens coating the surface of RBCs.

Pathophysiology!!navigator!!

  • Can be primary or secondary (most common)
  • Primary IMHA occurs when the immune system produces specific autoantibodies to normal erythrocyte antigens (includes NI, or transfusion reaction)
  • Secondary IMHA most commonly occurs as a result of agents that:
    • Alter the RBC membrane, exposing antigens to which the host produces antibody (e.g. infectious agents, neoplasia)
    • Form immune complexes that adsorb to the RBC and fix complement (e.g. infectious agents)
    • Directly bind to the RBC and act as haptens that bind antibody (e.g. drugs)
    • Stimulate the immune system, resulting in production of antibodies with cross-reactivity to RBCs (e.g. infectious agents, neoplasia)
  • Antibody- and/or complement-coated RBCs are removed from the circulation by extravascular hemolysis (if removed by the reticuloendothelial system) and/or intravascular hemolysis (if complement mediated)

Systems Affected!!navigator!!

  • Hemic/lymphatic/immune
  • Cardiovascular/respiratory
  • Hepatobiliary
  • Renal
  • Gastrointestinal

Genetics!!navigator!!

Foals born to multiparous dams known to be RBC antigen Aa or Qa negative are at increased risk of developing NI.

Incidence/Prevalence!!navigator!!

  • Unknown
  • Weak anecdotal evidence suggests IMHA is a rare consequence of other disease states in adult horses
  • NI is reported in foals in most countries

Geographic Distribution!!navigator!!

N/A

Signalment!!navigator!!

Any breed, age, or sex.

Signs!!navigator!!

General Comments

Signs often reflect the primary, underlying disease process such as infection or neoplasia.

Historical Findings

  • History generally reflects an underlying disease process and may include chronic weight loss (e.g. neoplastic diseases) or signs of depression and inappetence (e.g. infectious diseases)
  • Exercise intolerance, weakness, and lethargy
  • There may be a history of exposure to blood transfusion(s) or certain drugs (typically in the previous 5–12 days)

Physical Examination Findings

  • Signs of anemia—proportional to the degree of anemia
  • Exercise intolerance, weakness, pale or icteric mucous membranes, fever, tachypnea, tachycardia, holosystolic heart murmur, abdominal pain, and hemoglobinuria
  • Foals with NI typically present with acute-onset weakness and icterus during the first few days of life
  • Severe debilitation and death may occur

Causes!!navigator!!

Primary Immune Mediated

  • NI
  • Autoimmune hemolytic anemia
  • Incompatible blood transfusion

Secondary Immune Mediated

  • Infectious—e.g. acute viral infections, EIA, Clostridium perfringens, Rhodococcus equi, or streptococcal organisms
  • Neoplastic—e.g. lymphoma
  • Drug associated—e.g. penicillins, trimethoprim–sulfamethoxazole, and potentially cephalosporins, rifampin (rifampicin), chloramphenicol and various NSAIDs

Risk Factors!!navigator!!

  • Foals born to multiparous dams that have previously had a blood transfusion(s), or the mare is RBC antigen Aa or Qa negative, are at increased risk of developing NI
  • Exposure to incompatible blood transfusion and certain drugs

Diagnosis ⬆ ⬇

Outline

DIAGNOSIS

Differential Diagnosis!!navigator!!

  • Other diseases causing anemia
  • Hemorrhage (acute or chronic)
  • Heinz body anemia

CBC/Biochemistry/Urinalysis!!navigator!!

  • PCV is often <0.20 L/L (<20%)
  • May have neutrophilic leukocytosis
  • RBC autoagglutination:
    • May be observed due to the presence of antibodies and/or complement on the surface of the RBCs
    • Must be distinguished from rouleaux formation. “In saline” agglutination test can be used to differentiate—place one drop of blood on slide, add 0.9% saline as 1:4 with blood. Normal RBCs disperse evenly on the slide, while agglutination results in clumping of cells
    • Spherocytes may be observed in blood smears, but are more difficult to identify in horses owing to the lack of central pallor in normal equine RBCs
  • Increased mean corpuscular hemoglobin suggests intravascular hemolysis, which may also result in discolored plasma
  • Increased serum total bilirubin concentration (indirect greater than direct)
  • Bilirubinuria and hemoglobinuria may be observed in the rarer cases when intravascular hemolysis occurs

Other Laboratory Tests!!navigator!!

  • Positive direct antiglobulin (Coombs) test (detects presence of antibody on the surface of RBCs). False-negative results are possible, particularly if there has been prior corticosteroid therapy. False-positive results also can occur, emphasizing the need to use multiple methods to confirm the diagnosis of IMHA
  • RBC osmotic fragility may be increased in IMHA, although this test can be positive with RBCs damaged by oxidant insults
  • Bone marrow aspiration reveals a diffuse, regenerative erythron (myeloid to erythroid ratio is <0.5)
  • Infectious causes of IMHA may have positive serology and/or evidence of hematologic parasites on direct or special stained blood smears:
    • Horses with EIA will be seropositive for virus on Coggins or C-ELISA tests
    • Horses with equine piroplasmosis may have organisms observed in Giemsa- or new methylene blue-stained blood smears, be seropositive or seroconvert on their convalescent titer, or be positive via PCR
    • Horses with equine granulocytic ehrlichiosis may have granular inclusion bodies observed in cytoplasm of neutrophils in Giemsa-stained blood smears, be seropositive or seroconvert with acute and convalescent samples, or be positive via PCR

Imaging!!navigator!!

No specific imaging findings would be expected for IMHA itself—abnormalities identified are related to the original disease process.

Other Diagnostic Procedures!!navigator!!

A thorough diagnostic workup should be performed to rule out neoplasia and infectious causes of secondary IMHA.

Pathologic Findings!!navigator!!

  • Necropsy findings may include an enlarged liver and spleen and pale or icteric tissues
  • Findings referable to the initial disease process

Treatment ⬆ ⬇

Outline

TREATMENT

Aims!!navigator!!

  • Treatment of IMHA involves identification and resolution (if possible) of any underlying infection or disease, reduction of the immune response, and provision of supportive care
  • Administration of any drugs should be discontinued as IMHA could be caused by an adverse drug reaction. If antimicrobial therapy is required, a molecularly dissimilar antibiotic should be used

Appropriate Health Care!!navigator!!

  • Most cases of IMHA are treated in hospitals, especially if severe
  • Balanced polyionic IV fluid therapy may be indicated to expand vascular volume if volume depleted, and to induce diuresis if significant hemoglobinuria is present
  • Emergency medical therapy with cross-matched blood transfusion is indicated if there is evidence of tissue hypoxia (PCV < 8–12%). In foals, washed RBCs from the dam or appropriate blood-typed blood is optimal

Nursing Care!!navigator!!

  • Serial analysis of PCV in order to monitor response to therapy should be performed
  • Close monitoring of vital signs and adjustment of fluid rate is essential in horses receiving fluid therapy
  • In foals with NI, provide adequate warmth and hydration, avoid stress, and confine mare and foal to restrict activity

Activity!!navigator!!

Minimize or eliminate activity, but allow the animal access to fresh air and sunshine if possible.

Diet!!navigator!!

  • Make efforts to keep the horse eating a balanced diet, with good quality hay and grain
  • Fresh water should be available ad libitum

Client Education!!navigator!!

  • Clients should be made aware that horses with primary (or autoimmune) IMHA often require long-term corticosteroid therapy
  • If an infectious cause is not identified, neoplasia is highly suspected, and the prognosis will be related to the neoplasia, rather than the IMHA
  • Corticosteroid administration may be associated with the development of laminitis
  • Clients should be educated in preventative measures for NI

Surgical Considerations!!navigator!!

None

Medications ⬆ ⬇

Outline

MEDICATIONS

Drug(s) of Choice!!navigator!!

  • In adults, corticosteroids (dexamethasone 0.1 mg/kg IV or IM every 24 h) are indicated until PCV ceases to decline. The dose may then be decreased by 0.01 mg/kg/day until the total dose is 20 mg/day (for a 500 kg horse), after which alternate-day oral prednisolone is recommended. Alternatively, oral prednisolone (1 mg/kg) may be used in place of dexamethasone at any time during therapy, although anecdotally dexamethasone is more efficacious
  • From 4 to 7 days often are needed for corticosteroids to have a therapeutic effect (with stabilization of PCV) and up to 10 weeks of treatment may be necessary
  • Horses without clinical signs of anemia may not need immunosuppressive therapy if the initiating cause can be effectively treated

Contraindications!!navigator!!

Corticosteroids may exacerbate underlying infectious diseases so should be used only in horses that are EIA (Coggins) negative.

Precautions!!navigator!!

  • Cross-match before blood transfusion
  • Corticosteroid therapy may predispose horses to laminitis and should be used with caution in pregnant mares

Possible Interactions!!navigator!!

N/A

Alternative Drugs!!navigator!!

The immunosuppressive agent azathioprine (3 mg/kg PO once daily) has been used in horses nonresponsive to corticosteroids, or when corticosteroids were contraindicated (e.g. the development of laminitis).

Follow-up ⬆ ⬇

Outline

FOLLOW-UP

Patient Monitoring!!navigator!!

PCV should be carefully monitored during dexamethasone treatment. The frequency of dexamethasone administration can be increased to twice daily in horses initially on once a day treatment if the PCV does not stabilize within 24–48 h.

Prevention/Avoidance!!navigator!!

  • Avoid drugs known to have caused secondary IMHA
  • Provide alternate colostrum source in foals born to mares at risk of NI

Possible Complications!!navigator!!

  • Pigment nephropathy secondary to intravascular hemolysis
  • Laminitis

Expected Course and Prognosis!!navigator!!

  • If the primary cause can be identified and successfully treated, the prognosis for IMHA is good
  • Red cell numbers recover as the immune-mediated response resolves, but may take several weeks
  • Horses requiring constant corticosteroid treatment may have an incurable underlying disease such as neoplasia (e.g. lymphoma) or have true autoimmune hemolytic anemia. The prognosis for survival in these horses is poor

Miscellaneous ⬆ ⬇

Outline

MISCELLANEOUS

Associated Conditions!!navigator!!

  • Pigment nephropathy
  • Laminitis

Age-Related Factors!!navigator!!

  • All ages can be affected
  • Foals with NI will develop signs within the first few days of life

Pregnancy/Fertility/Breeding!!navigator!!

Use corticosteroids cautiously in pregnant mares.

Synonyms!!navigator!!

  • Autoimmune hemolytic anemia
  • Immune-mediated hemolytic disease

Abbreviations!!navigator!!

  • C-ELISA = competitive–enzyme-linked immunosorbent assay
  • EIA = equine infectious anemia
  • IMHA = immune-mediated hemolytic anemia
  • NI = neonatal isoerythrolysis
  • NSAID = nonsteroidal anti-inflammatory drug
  • PCV = packed cell volume
  • PCR = polymerase chain reaction
  • RBC = red blood cell

Suggested Reading ⬆ ⬇

Kendall A, Pringle J. Immune-mediated haemolytic anaemia: drug induced or not? Equine Vet Educ 2014;26:234–236.

Sellon DC. Disorders of the hematopoietic system. In: Reed SM, Bayly WM, Sellon DC, eds. Equine Internal Medicine, 3e. St. Louis, MO: WB Saunders, 2010:730–776.

Author(s) ⬆

Author: Imogen Johns

Consulting Editors: David Hodgson, Harold C. McKenzie, and Jennifer L. Hodgson

Acknowledgment: The author and editors acknowledge the prior contribution of Nicholas Malikides.