How many times have you seen wonky RBCs under the microscope and thought, “now what’s up with that?”

In this article, I’m going to give you the low-down on how to make sense of RBC morphologic abnormalities so you can figure out what’s going on in your patient.

Acanthocytes: 

Acanthocytes exhibit blunt, irregularly spaced spicules. They can form due to increased membrane cholesterol or fragmentation injury, and liver disease is the most common disease associated with increased membrane cholesterol. Fragmentation injury and subsequent acanthocyte formation can occur with any condition in which RBCs are damaged while they pass through the vasculature (e.g. disseminated intravascular coagulation, glomerulonephritis, hemangiosarcoma) or when the RBCs are particularly fragile (e.g. iron-deficiency). Acanthocytes may also be seen in association with general gastrointestinal disease.

Eccentrocytes: 

Eccentrocytes contain a distinct, hemoglobin-free area of the RBC. They’re also called “hemi-ghosts” because of this. The membrane that covers this hemoglobin free space can rupture, resulting in a smaller, more hemoglobin dense RBC. These are termed pyknocytes and can be easily mistaken for spherocytes. Eccentrocytes form due to oxidative damage. Oxidative damage can occur secondary to toxins (e.g. red maple toxicity in horses, onions, zinc toxicity, moth balls, garlic, acetaminophen, and skunk spray). It can also occur in general illness due to endogenous oxidation (in particular, diabetes and lymphoma are known causes of oxidative stress).

Echinocytes: 

Echinocytes exhibit evenly spaced spicules. They’re also known as burr cells or crenated cells. There are three types of echinocytes. The overarching mechanisms of their formation includes depletion of ATP or cell dehydration which may be caused by some drugs or diseases/conditions. Drugs that can cause echinocytosis include chemotherapeutics (e.g. doxorubicin) or furosemide. Specific diseases that can cause this include renal disease (e.g. glomerulonephritis), electrolyte abnormalities, rattlesnake envenomation, and pyruvate kinase deficiency. However, despite the number of pathologic causes for echinocytes, they are most often seen as an artifact of aged blood or of preparation. Thus, their presence does not often provide additional diagnostic information. It’s important not to confuse “end-on” spikes of echinocytes with RBC parasites. When viewing a blood smear, the spicules of echinocytes projecting towards the viewer will appear as red, uniform, focal dots on the RBC. 

Elliptocytes: 

Elliptocytes are elongated RBCs. Type I elliptocytes are oval shaped. Type II elliptocytes are rounded to oval shaped. Type III are elongated (these are the type seen normally in camelids). When seen in appreciable numbers, pathologic considerations for their formation include liver disease or myelofibrosis. In particular, hepatic lipidosis may cause significant elliptocyte formation. Elliptocytosis can also be an inherited disorder, though it is very rare.

Ghost RBCs:

Ghost red blood cells are very pale and exhibit a very thin/faint outline with essentially no hemoglobin component (therefore, they do not appear red as they normally would). Ghost RBCs can be seen as an artifact of preparation or in pathologic states where intravascular hemolysis is occurring. Various causes of intravascular hemolysis include immune-mediated disease, oxidants, bacterial infections, hypophosphatemia, Vitamin K, and propofol. 

Hypochromic RBCs:

Hypochromic RBCs have an increased zone of central pallor due to the lack of a normal amount of hemoglobin. This can occur either due to defective hemoglobin production or inhibited hemoglobin production. In dogs and cats, defective hemoglobin production is due to iron-deficiency. Inhibition of hemoglobin production is most often seen with lead poisoning, though the anemia in those cases is typically normocytic, normochromic (i.e. you don’t often see hypochromic RBCs).

Keratocytes:

Keratocytes are also called “blister cells”, because they often appear as a large blister-like extension from the RBC. When the blister is not intact, the keratocyte exhibits 1-2 elongated spicules extending from the RBC membrane. Keratocytes can be seen in low numbers with no clear clinical significance. However, they are also seen with a number of pathologic processes including fragmentation injury (e.g. hemangiosarcoma, disseminated intravascular coagulation, vasculitis), liver disease (especially in cats), and oxidant injury (e.g. toxins, metabolic disturbances).

Schistocytes:

Schistocytes are fragments of RBCs and may have pointed edges (appearing like a boomerang. In dogs, they are formed by mechanical injury and can occur with shearing by irregular vasculature and/or turbulent blood flow or with RBC fragility as is seen in cases of iron-deficiency. Mechanical injury may occur with disseminated intravascular coagulation (fibrin strand deposition in the vessels shear RBCs as they pass by), hemangiosarcoma (abnormal vessels), glomerular disease, vasculitis, portosystemic shunts, and myelofibrosis. In cats, schistocytes are most often seen with other poikilocytes with liver disease.

Spherocytes:

Spherocytes appear smaller than normal RBCs and lack central pallor. Since RBCs in cats are normally smaller than dogs and lack central pallor, it is often difficult to impossible to distinguish spherocytes from normal cat RBCs. Spherocytes are most often associated with immune-mediated hemolytic anemia (IMHA); the majority of IMHA patients (but not all) exhibit spherocytosis in moderate to high numbers. When seen with IMHA, they form secondary to antibody/complement fixation and subsequent removal of a portion of the membrane by macrophages. Although spherocytes are most often seen with IMHA, they can occur in other conditions and should not be considered pathognomonic for IMHA, especially when present in low numbers. Other conditions in which spherocytes (or pyknocytes that mimic spherocytes) can be seen include those that cause fragmentation injury and oxidant injury, coral snake envenomation, bee stings, and inherited disorders (spectrin deficiency in Dutch Golden Retrievers, pyruvate kinase deficiency in Basenjis). Notably, although spherocytes appear smaller on the blood smear, they actually contain a normal corpuscular volume; thus, the MCV is expected to remain within normal range.

Target Cells (Codocytes): 

Target cells appear as a “bulls-eye” with a central focal spot of hemoglobin surrounded by a clear zone and a peripheral rim of hemoglobin. They are typically seen in dogs and form due to a relative increase in membrane when compared to the cell volume. This is a normal finding in young RBCs/polychromatophils. Pathologies that can cause target cells to form include iron-deficiency, liver disease (increased phospholipid and cholesterol in the RBC membrane), hypothyroidism (increased cholesterol in the RBC membrane).

Drying artifact: 

This is a very common artifactual change and occurs when a blood smear is stained prior to completely drying or when there is water contamination in the stains. The appearance of this artifact is somewhat variable; it can cause a “moth-eaten” or “scalloped edge” appearance or high-contrast, refractile inclusions in the RBCs. It’s important to recognize this is an artifact and not confuse this with parasites.

 

Smudge cells:

Lipemia causes RBC membrane fragility. As a result, RBCs from lipemic patients may lyse and appear “smudged” as a result of smear preparation.

 

Hemoglobin crystals:

These occur when hemoglobin precipitates with the RBC, causing a rhomboid, dark red inclusion. The cause is unknown, but it does not appear to be of any clinical significance in veterinary medicine.

 

Quatrefoil RBCs:

This pattern describes two RBCs that have formed around each other. On a blood smear, they take on a 4-leaf clover type appearance. Their cause or significance is unknown, though one study noted an association with older age in dogs.

 

Torocytes: 

Torocytes are often mistaken for hypochromic red blood cells. They exhibit an increase in central pallor, however, the delineation between the pale center and the hemoglobin component is stark in comparison to the more gradual gradient between the hemoglobin and pale center of hypochromic cells.

#practicepearls 

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 About the Author: Kate Baker, DVM, MS, DACVP (Clinical Pathology)

 

Dr. Kate Baker grew up in Nashville, Tennessee and completed her DVM at the University of Tennessee in 2012. She then went on to complete a small animal rotating internship and then a clinical pathology residency and Masters degree at the University of Illinois. Dr. Baker became board certified in 2016 and currently works as an educator, diagnostician, and consultant. Her professional passion is creating resources and experiences for veterinarians to learn and thrive in practice.