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Basics ⬇

Outline

BASICS

Definition!!navigator!!

  • Heinz bodies are small, round, blue-black, refractile aggregations of oxidized, precipitated hemoglobin, present near the margin of RBCs
  • Heinz body anemia occurs as a result of exposure to certain oxidizing agents
  • Heinz bodies damage the RBC membrane, resulting in lysis (intravascular hemolysis) and removal of the damaged RBCs from the circulation by the reticuloendothelial system (extravascular hemolysis)

Pathophysiology!!navigator!!

  • Mild oxidative stress is associated with normal oxygen transport within RBCs
  • There are protective enzyme systems in place to counteract the oxidative stress; however Heinz body hemolytic anemia can result if these systems are overwhelmed
  • Denatured hemoglobin precipitates to form Heinz bodies, which attach to the RBC membrane and cause increased cell fragility with resultant intravascular or extravascular hemolysis
  • Many oxidant toxins also oxidize ferrous iron (Fe2+) in the hemoglobin molecule to the ferric form (Fe3+), resulting in methemoglobin production. Methemoglobin decreases the oxygen-carrying capacity of the blood, resulting in tissue hypoxia

Systems Affected!!navigator!!

  • Hemic/lymphatic/immune—regenerative anemia with bone marrow RBC hyperplasia and splenomegaly. Release of hemoglobin and other products of hemolysis may result in pyrexia
  • Cardiovascular and respiratory—tachycardia and tachypnea, holosystolic heart murmur, mucous membrane pallor
  • Renal/urologic—intravascular hemolysis may result in hemoglobinuria, hemoglobinuric nephropathy, and acute anuric renal failure
  • Hepatobiliary—hyperbilirubinemia and icterus, hypoxic hepatocellular damage
  • Gastrointestinal—hypoxic damage to intestines may result in motility disorders and colic
  • Musculoskeletal—hypoxic damage to laminae may result in laminitis

Genetics!!navigator!!

N/A

Incidence/Prevalence!!navigator!!

Data currently unavailable.

Geographic Distribution!!navigator!!

Acer rubrum (red maple) is widespread throughout eastern and central North America.

Signalment!!navigator!!

Can occur in horses of any breed, age, or sex.

Signs!!navigator!!

Historical Findings

  • Exercise intolerance or sudden onset of dullness, lethargy, inappetence, and/or colic are common presenting signs
  • Acute, apparently unexplained death
  • There may be history of access to wilted or dried leaves or bark of red maple (A. rubrum) or other oxidative toxins (e.g. phenothiazine, wild onions)

Physical Examination Findings

  • Weakness, pale or icteric mucous membranes, tachypnea, tachycardia, and holosystolic heart murmur. Pyrexia may be associated with hemolysis
  • With concurrent methemoglobinemia there may be muddy-brown, cyanotic mucous membranes, and brownish blood
  • Pigmenturia/hemoglobinuria and oliguria (or polyuria) may occur due to hemoglobin-induced nephropathy
  • Rectal examination may reveal an enlarged spleen
  • Severely affected horses may develop ataxia, and death may occur

Causes!!navigator!!

  • Ingestion of wilted or dried red maple leaves or bark, wild or domestic onions, members of the Brassica family
  • Phenothiazine, methylene blue, or acetylphenylhydrazine toxicities
  • Reported in a case of lymphoma possibly due to failure of the reticuloendothelial system to remove Heinz bodies
  • Reported with EIA

Risk Factors!!navigator!!

  • Exposure to toxins (e.g. wilted or dried red maple leaves (more likely in the fall), onions)
  • Lymphoma
  • EIA infection
  • When RBCs from a Saddlebred colt with glucose-6-phosphate dehydrogenase deficiency were exposed to acetylphenylhydrazine, more and smaller Heinz bodies were produced
  • Thin horses may be at greater risk of phenothiazine toxicosis
  • Selenium deficiency results in decreased glutathione peroxidase (involved in RBC counteraction of oxidative stress) and, therefore, may contribute to Heinz body formation
  • Equine RBCs have less developed protective mechanisms to reverse the oxidation of hemoglobin

Diagnosis ⬆ ⬇

Outline

DIAGNOSIS

Differential Diagnosis!!navigator!!

  • Causes of anemia include hemorrhage, hemolysis, and decreased RBC production
  • Hemorrhage is usually easily differentiated based on history and physical examination findings. Hemorrhage is usually also associated with hypoalbuminemia as well as anemia (after the initial 12 h), which is not a feature of hemolysis
  • Anemia of chronic inflammation may be associated with inflammatory, infectious, or neoplastic disorders, e.g. lymphosarcoma (usually a more complex history and other clinical signs associated with affected organ system) or purpura haemorrhagica (usually a history of respiratory disease)
  • Horses with immune-mediated hemolytic anemia will be positive on flow cytometry for erythrocyte-bound immunoglobulins and may have a positive Coombs test (poor sensitivity)
  • EIA cases will have a positive Coggins or C-ELISA test
  • Piroplasmosis cases may have intracellular organisms on Giemsa- or new methylene blue-stained blood smears and/or be seropositive or seroconvert on convalescent titer
  • Cases of anaplasmosis may have intracytoplasmic inclusion bodies in neutrophils on Giemsa-stained blood smears and/or a positive PCR result
  • Envenomation and heavy metal toxicosis (e.g. chronic consumption of lead, copper, or selenium) must be differentiated based on history of exposure
  • Familial methemoglobinemia has been described in Standardbreds
  • Nitrate/nitrite toxicity can be differentiated based on history of exposure

CBC/Biochemistry/Urinalysis!!navigator!!

  • Variable anemia; PCV is often <20%
  • Direct blood smears may reveal eccentrocytes, RBC fragments, and anisocytosis
  • An inflammatory leukogram may be present (neutrophilia is common)
  • Increased mean corpuscular hemoglobin reflects hemoglobinemia associated with intravascular hemolysis
  • Biochemical abnormalities usually include increased total and indirect bilirubin, azotemia (associated with hemoglobinuric nephropathy), and increased hepatic enzyme activity (associated with hypoxic injury to the liver)
  • Urinalysis may reveal bilirubinuria, hemoglobinuria (no microscopic hematuria), methemoglobinuria, and proteinuria

Other Laboratory Tests!!navigator!!

  • Heinz bodies will be visualized on crystal violet or new methylene blue-stained smears. Initially, a very high percentage of RBCs have Heinz body inclusions but later, as these are removed from the circulation, the number of affected cells decreases
  • Increased RBC osmotic fragility
  • Bone marrow aspiration may reveal a regenerative response with an myeloid to erythroid ratio <0.5
  • Co-oximetry can be performed to ascertain methemoglobin content (normal is ≤1.77%)

Imaging!!navigator!!

Splenic/hepatic ultrasonography may be used to detect splenic/hepatic enlargement—may appear hyperechoic or hypoechoic with some loss of architecture due to increased fluid component.

Other Diagnostic Procedures!!navigator!!

A thorough diagnostic workup is indicated to ascertain underlying etiology.

Pathologic Findings!!navigator!!

  • Gross—pale or icteric tissues, enlarged liver and spleen, renal congestion, possible signs of congestive heart failure
  • Histopathology—renal tubular nephrosis with hemoglobin casts, centrilobular hepatic degeneration and necrosis, and phagocytized RBCs and hemosiderin in the spleen and liver

Treatment ⬆ ⬇

Outline

TREATMENT

Appropriate Health Care!!navigator!!

  • In-hospital medical management may be necessary depending on the severity of the anemia and associated clinical signs
  • Activated charcoal and mineral oil should be administered via nasogastric intubation to reduce further absorption of toxin
  • IV fluid therapy with isotonic crystalloids should be initiated to improve perfusion, prevent hemoglobin-induced nephropathy, and promote diuresis (however excessive hemodilution should be avoided)
  • Cross-matched blood or packed RBC transfusion should be considered if PCV decreases to <8–12%, or if there is persistent tachycardia, tachypnea, weak pulse pressure, or a poor response to isotonic fluid therapy
  • Oxygen therapy is ineffective if oxygen-carrying capacity is decreased owing to methemoglobinemia

Nursing Care!!navigator!!

Close monitoring of vital signs, IV fluid rates (to avoid excessive hemodilution), CBC/biochemistry, urine output, and renal function is recommended.

Activity!!navigator!!

Exercise and stress should be avoided to prevent increased oxygen demand.

Diet!!navigator!!

Palatable and nutritious feeds should be provided to encourage voluntary intake.

Client Education!!navigator!!

Clients should be warned of the hazards of exposure to wilted red maple leaves (including red maple hybrids) and other toxins.

Surgical Considerations!!navigator!!

Anemia and methemoglobinemia put these cases at increased anesthetic risk and therefore surgery should be postponed if possible (or blood transfusion may be required before an emergency procedure).

Medications ⬆ ⬇

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MEDICATIONS

Drug(s) of Choice!!navigator!!

Treatment is largely supportive, as there is no specific therapy.

Contraindications!!navigator!!

  • Methylene blue therapy may exacerbate Heinz body formation and has been associated with decreased survival
  • Corticosteroid use has also been associated with decreased survival

Precautions!!navigator!!

N/A

Possible Interactions!!navigator!!

N/A

Alternative Drugs!!navigator!!

Vitamin C (ascorbic acid) (30 mg/kg twice daily, diluted in IV fluids) has been used for methemoglobin-associated conditions (no proven efficacy).

Follow-up ⬆ ⬇

Outline

FOLLOW-UP

Patient Monitoring!!navigator!!

  • The PCV should be monitored closely and should remain stable or slowly increase over time (reflective of bone marrow regeneration and therapeutic response)
  • Renal function and urine output should also be monitored, as well as for signs of laminitis

Prevention/Avoidance!!navigator!!

  • Limiting access to potential toxins including wilted red maple leaves and onions
  • Minimizing use of phenothiazines or, if absolutely necessary, attempt to use the minimum effective dose

Possible Complications!!navigator!!

  • Laminitis
  • Nephropathy/renal failure
  • Abortion, weak foals
  • Coma and death

Expected Course and Prognosis!!navigator!!

  • Prognosis is variable depending on the severity of the anemia and whether or not there is concurrent methemoglobinemia
  • Horses with red maple toxicity have a guarded to poor prognosis, with a 60% fatality rate

Miscellaneous ⬆ ⬇

Outline

MISCELLANEOUS

Associated Conditions!!navigator!!

  • Methemoglobinemia
  • Pigment nephropathy

Age-Related Factors!!navigator!!

N/A

Zoonotic Potential!!navigator!!

N/A

Pregnancy/Fertility/Breeding!!navigator!!

Pregnant mares may abort or deliver a weak foal.

Synonyms!!navigator!!

  • Oxidant-induced hemolysis
  • Oxidative hemoglobinemia

Abbreviations!!navigator!!

  • C-ELISA = competitive enzyme-linked immunosorbent assay
  • EIA = equine infectious anemia
  • PCR = polymerase chain reaction
  • PCV = packed cell volume
  • RBC = red blood cell

Suggested Reading ⬆ ⬇

Alward A, Corriher CA, Barton MH, et al. Red maple (Acer rubrum) leaf toxicosis in horses: a retrospective study of 32 cases. J Vet Intern Med 2006;20:1197–1201.

Carlson GP, Aleman A. Heinz body hemolytic anemia. In: Smith BP, ed. Large Animal Internal Medicine, 5e. St. Louis, MO: Elsevier Mosby, 2015:1062–1064.

Author(s) ⬆

Author: Rana Bozorgmanesh

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

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