Abnormalities of the leukogram include quantitative or numerical concentration abnormalities and morphological abnormalities.
Quantitative Leukogram Abnormalities
WBC concentration values are interpreted by comparison with species-specific reference values. Interpretations should be made only by considering the absolute numbers. For reference values for total WBC and differential WBC concentrations in absolute numbers for common domestic species, see the table .
The total WBC concentration is more variable and often higher in neonates than in adults. Age-related reference values should be used to evaluate leukograms in young animals, especially species such as ruminants, in which lymphocytes are more numerous (and neutrophils less numerous) in adults. Generally, differential WBC patterns of adults are reached at about the age of sexual maturity.
An abnormality in the total WBC concentration is useful only to alert the clinician to look for and interpret abnormalities in cell distributions in the differential. When the total WBC concentration is abnormal, one or more distributional abnormalities in the differential are likely. When the total WBC concentration is normal, there still could be one or more distributional abnormalities in the differential. As a result, evaluation of the differential absolute values is the most important component of the leukogram.
Leukocytosis is an increase in the total WBC concentration, whereas leukopenia is a decrease in the total WBC concentration. Changes in the concentrations of specific leukocyte types are more important for clinical interpretation purposes. See the table .
White Blood Cell Terminology
WBC Type | Increased Concentration | Decreased Concentration |
|---|---|---|
Neutrophil | Neutrophilia, neutrophilic leukocytosis | Neutropenia |
Lymphocyte | Lymphocytosis | Lymphopenia |
Monocyte | Monocytosis | Not clinically relevant |
Eosinophil | Eosinophilia | Eosinopenia |
Basophil | Basophilia | Not clinically relevant |
Metarubricytosis or rubricytosis is an increase in nucleated RBCs (nRBCs) in blood. Mastocytosis is an increase in mast cells in blood.
Decreases in concentration of a cell type are indicated by the suffix “penia.” This suffix is applied only to cell types in which a decrease has clinical relevance. It does not apply to cell types for which the concentration could be zero, such as monocytes, basophils, nRBCs, or any other abnormal cell type. Hence, neutropenia is a decrease in neutrophil concentration, lymphopenia is a decrease in lymphocyte concentration, and eosinopenia is a decrease in eosinophil concentration. Cytopenia is a nonspecific term indicating a decrease in cell concentration(s); however, the cell type is not specified. Pancytopenia indicates all major cell types are decreased, often to a severe degree.
Terms used to describe or qualify abnormalities most often associated with inflammatory responses include various left shifts and responses. A left shift is an increase in concentration of immature, nonsegmented neutrophils, typically bands, but can also include metamyelocytes or even more immature forms:
A regenerative left shift describes leukocytosis characterized by the combination of neutrophilia and a left shift. In this situation, the segmented neutrophils will be greater in concentration than bands and less mature forms.
A degenerative left shift describes a neutrophil pattern characterized by normal to decreased total neutrophil concentration, but with a left shift in which the concentration of bands and less mature forms is greater than segmented neutrophils. This is an indication of maximal release from bone marrow in response to inflammation and signifies the presence of an acute, severe lesion.
Morphological Leukogram Abnormalities
Abnormalities of WBC morphology can be associated with either acquired or inherited disease.
Toxic changes are identified only in neutrophils. The term originates from historical observation that certain cell features were associated with general, usually overwhelming, toxic states, such as systemic bacterial infections and severe, acute inflammatory lesions. The term is misleading, in that it implies neutrophil injury; however, the cells are not injured and have normal function.
Toxic change is best defined as a set of morphological changes observed on the blood smear that occur as a result of accelerated bone marrow production of neutrophils (see ). The accelerated production is in response to relatively severe inflammatory states that maximally stimulate the bone marrow. Morphological changes include (in order of frequency) diffuse cytoplasmic basophilia, Döhle bodies (small, blue-gray cytoplasmic inclusions that are aggregates of endoplasmic reticulum), and fine cytoplasmic vacuolation. Rarer changes include increased prominence of cytoplasmic azurophilic granules and nuclear immaturity.
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Photomicrograph of a blood smear from a dog showing a neutrophil with cytoplasmic basophilia, vacuolation, and small Döhle bodies (see blue arrows). Wright stain; original magnification 100X.
Courtesy of Dr. Darren Wood.
Toxic changes are almost always associated with the concurrent presence of a left shift. Toxicity is graded as mild, moderate, or severe by subjective evaluation of the more common changes noted on examination of a blood smear. Döhle bodies are unique in that they can be found in clinically healthy cats and therefore are not interpreted as toxic change in this species unless excessively frequent and accompanied by other features.
Reactive lymphocytes have increased, distinctly basophilic cytoplasm and can have irregular or clefted nuclei (see ). They can vary considerably in diameter. Reactive lymphocytes have condensed chromatin and therefore are not blasts. They are interpreted as immunologically stimulated B cells.
Photomicrograph of a blood smear from a dog with a reactive lymphocyte, a nonspecific indicator of immune stimulation. Note the large size and deeply basophilic cytoplasm. Wright stain; original magnification 100X.
Courtesy of Dr. Darren Wood.
Granular lymphocytes have condensed chromatin and increased pale blue-gray cytoplasm that contains several small pink or azurophilic granules. The nucleus can be round to clefted. These granular lymphocytes are either natural killer (NK) lymphocytes or cytotoxic T lymphocytes.
Blast cells are usually an indication of hematopoietic cell neoplasia if they are reproducible or present in large numbers. Their lineage can be tentatively identified by morphological criteria; however, flow cytometric analysis is required to definitively identify lineage.
Many of the following morphological changes are uncommon.
Chédiak-Higashi syndrome, described in Persian cats, mink, foxes, Hereford and Brangus cattle, mice, killer whales, and humans, is an autosomal recessive defect involving lysosomal granules. Fusion of granules results in large, eosinophilic cytoplasmic inclusions. Susceptibility to bacterial infections is increased, as is the tendency to bleed because of both neutrophil and platelet function abnormalities, respectively. Partial oculocutaneous albinism due to abnormal melanin granule formation can occur.
The mucopolysaccharidoses are a group of lysosomal storage disorders in which there is a defect in degradation of glycosaminoglycans. Both neutrophils and lymphocytes can contain accumulated mucopolysaccharide product in the form of purple or metachromatic intracytoplasmic granules. Lymphocytes can also be vacuolated. These disorders are associated with a variety of systemic clinical abnormalities and occur in dogs and cats.
Another group of lysosomal storage disorders recognized in dogs and cats can result in cytoplasmic vacuoles, predominantly in lymphocytes and occasionally in neutrophils. These disorders include gangliosidoses, alpha-mannosidosis, Niemann-Pick disease variants, acid-lipase deficiency, and fucosidosis. Most of these disorders result in severe, progressive neurological disorders resulting from accumulated product in neuronal tissue.
Locoweed toxicosis is regarded as an acquired form of lysosomal storage defect in large animals. It is due to toxins from the plants (Astragalus and Oxytropis spp) that inhibit one or more enzymes of oligosaccharide metabolism. This can result in vacuolation in lymphocytes.
Pelger-Huët anomaly is a nuclear hyposegmentation defect of granulocytes in humans, cats, rabbits, horses, and dogs that are heterozygous for the anomaly. Neutrophils have normal function but a near absence of segmented nuclear morphology (see ). Most or all of the neutrophils appear as bands and metamyelocytes and can appear as a marked left shift in an otherwise normal leukogram. Eosinophils and basophils, if present, also exhibit nuclear hyposegmentation. Affected heterozygote animals are clinically normal; the homozygous inheritance of the trait is lethal.
Photomicrograph of a blood smear from a dog. Three neutrophils with mature clumped chromatin and hyposegmented nuclei are present. Wright stain; original magnification 100X.
Courtesy of Dr. Darren Wood.
Hypersegmentation is an increased degree of nuclear segmentation resulting in multiple lobes connected by nuclear filaments. It is a nonspecific indication of increased time in circulation and is normal aging of the cell. Hypersegmentation can be observed with stress leukograms or corticosteroid administration.
Leukocyte agglutination can occur with either neutrophils or lymphocytes. This appears on low magnification as aggregates of 5–15 tightly clumped leukocytes (see ). Avid agglutination can result in a false low total WBC concentration on some cell counting instruments. This is likely due to the presence of a naturally occurring cold agglutinin that is operative only in vitro at laboratory temperature. Leukocyte agglutination has no known clinical significance.
Photomicrograph of a blood smear from a cat showing several mature lymphocytes clumped together. Wright stain; original magnification 100X.
Courtesy of Dr. Darren Wood.
Infectious disease inclusions are occasionally recognized. Canine distemper inclusions might be observed in neutrophils, monocytes, and lymphocytes, as well as in newly produced erythrocytes. The ehrlichioses of various animal species and canine hepatozoonosis can have cytoplasmic inclusions of respective organisms of these tickborne diseases. (See .)
Photomicrograph of a blood smear from a dog showing the morula of a rickettsial organism in the cytoplasm of a neutrophil (cell on left stained purple). The most likely infectious agent is Anaplasma phagocytophilum. Wright stain; original magnification 100X.
Courtesy of Dr. Darren Wood.
Specific Interpretative Leukogram Responses
The abnormal leukogram is typically interpreted as one of several responses, each of which can consist of one or more abnormalities in the differential. Some are also associated with concurrent changes in erythrocytes and platelets. Important species differences in leukogram responses are described below.
Corticosteroid-Induced or Stress Response
In this very common leukocyte response, endogenous corticosteroid release from stress or treatment with exogenous corticosteroids results in a leukogram with multiple changes. Lymphopenia is the most consistent change, and mature neutrophilia is usually present. Monocytosis and eosinopenia are expected changes in dogs but are more variable in other species. Eosinopenia cannot be determined when the lower reference value is zero. Neutrophilia is due to decreased adherence to the vascular endothelium, which inhibits margination and increases circulating time. As a result, neutrophils can also become hypersegmented. Increased marrow release of neutrophils can occur. Lymphocytes become redistributed to lymphoid tissues instead of remaining in circulation. This response can be misinterpreted as inflammation; however, a left shift and toxic changes are not usually present.
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Excitement or Epinephrine Response
Leukocytosis can occur as a result of exercise or excitement; this response is mediated by increased epinephrine concentration and can be thought of as a transient physiological response. Epinephrine flushes cells from the marginating to the circulating pool. The effect can double the total WBC concentration within minutes. In addition, concurrent splenic contraction releases WBCs and RBCs into the peripheral circulation. The leukocytosis is usually due to a mature neutrophilia without a left shift or toxic changes (see ). Lymphocytosis might be present, especially in young horses or cats. The effect in cats is often recognized as a prominent lymphocytosis—as much as 2 times the upper reference value. The excitement response is relatively uncommon in dogs.
Photomicrograph of a blood smear from a dog with neutrophilia. The mature, segmented cells lack toxic changes. Wright stain; original magnification 100X.
Courtesy of Dr. Darren Wood.
Inflammatory Response
The concentration of neutrophils in blood in response to inflammatory disease is highly variable and dynamic. It is best viewed as a balance between tissue demand and bone marrow production at all phases of the response. Important species differences in this balance are related to bone marrow storage reserve and proliferative capacity.
At the beginning of an inflammatory process, the bone marrow responds by delivery of its reserve of late-stage maturing neutrophils, including band cells. If consumption exceeds marrow delivery during this acute stage, neutropenia with a prominent left shift will develop. In dogs and cats, this indicates the inflammatory lesion's severity.
Subsequently, it takes 2–4 days for the marrow to accelerate neutrophil production by increased stem cell entry and expansion of proliferative stages that feed the maturation stages and amplify neutrophil delivery to blood. In dogs, the acute stage of the inflammatory response is usually characterized by mild to moderate neutrophilia, with the left shift being somewhat proportional to severity of demand.
After a few days, accelerated bone marrow production adds to the picture. Neutrophilia can increase along with a left shift and toxic changes. As the process becomes chronic, the balance between increased marrow output and consumption can favor the development of even higher magnitudes of neutrophilia.
The most chronic form of inflammatory response, present for weeks or even months, is described as a closed cavity process in which a lesion becomes somewhat walled off and therefore consumes fewer neutrophils, yet still stimulates maximal bone marrow production. Examples of closed cavity processes are pyometra in dogs and traumatic reticuloperitonitis (hardware disease) in cattle. In these conditions, the magnitude of total WBC concentration, consisting of neutrophilia, can be as high as 100,000/mcL (100 × 109/L) in dogs (1). Extreme neutrophilia, exceeding upper reference limits usually reached in inflammation, can be associated with leukemia, Hepatozoon canis infections, and, rarely, other neoplasms that produce colony-stimulating factors.
In contrast, cattle and most other ruminants have a relatively low reserve of bone marrow neutrophils and a lower capacity for accelerating granulopoiesis. This is reflected in the relatively lower neutrophil concentration in the blood of healthy ruminants. As a result, acute inflammation in cows is characterized by neutropenia that can be profound, and neutropenia in cattle does not correspond to the severity of inflammation as readily. After several days, the bone marrow response might establish a return of blood neutrophils in modest concentration, characterized by a marked left shift and toxic changes. Chronic closed cavity inflammatory lesions are associated with magnitudes of neutrophilia that rarely exceed 20,000/mcL (20 x 109/L) of blood (1). Cats and horses are intermediate in these responses, with cats being more like dogs and with horses being more like cattle. Pigs have an inflammatory leukogram similar to that of dogs.
Bovine leukocyte adhesion deficiency is a lethal, autosomal recessive disorder of Holstein cattle. It is associated with marked neutrophilia; the neutrophils have a deficiency of the glycoproteins (integrins) that are essential for normal leukocyte adherence and emigration from the vasculature. Recurrent bacterial infections, persistent neutrophilia, lymphocytosis, and death (usually between 2 weeks and 8 months of age) are characteristic (1). Affected calves often are stunted and have recurrent pneumonia, ulcerative stomatitis, enteritis, and periodontitis. On histological examination of tissues, there are few neutrophils, except within vessel lumens, because they persist in the circulation because of impaired entry into the tissues. Testing is available to detect carriers. A similar defect has been reported in some Irish Setter dogs.
Neutropenia can develop because of excessive tissue demand for neutrophils or decreased granulopoiesis. It can occur in all species in the presence of overwhelming bacterial infections, especially gram-negative sepsis or endotoxemia. Immune-mediated destruction of neutrophils is diagnosed by exclusion of other consumptive processes. Stem cell injury can occur from many causes, such as various viral infections (see the table ), chemical injury, and idiosyncratic drug reactions (eg, those caused by sulfonamides, penicillins, cephalosporins, and chloramphenicol in cats). These reactions typically affect all bone marrow cell lines but are recognized initially as neutropenia because of the relatively short lifespan of this cell type.
Viral Infections That Can Cause Transient Neutropenia
Species | Infection |
|---|---|
Dogs | Parvovirus, canine distemper (acute phase) |
Cats | Panleukopenia (parvovirus), feline leukemia virus |
Horses | Equine influenza, equine viral arteritis (acute phase), equine herpesvirus |
Cattle | Bovine viral diarrhea virus |
Pigs | Classical swine fever virus, African swine fever virus |
Neutropenia occurs in the now rare cyclic hematopoiesis syndrome of gray Collie dogs, also known as canine cyclic neutropenia. It is an inherited, autosomal recessive disease characterized by a profound recurrent neutropenia, associated overwhelming recurrent bacterial infections, bleeding, and coat color dilution. The defect is due to a mutation in a protein that may regulate neutrophil elastase activity. Neutrophil maturation is arrested at regular intervals of 11–14 days; the peripheral blood neutropenia lasts 3–4 days and is followed by neutrophilia. All other hematopoietic cells, including lymphocytes, also have cyclic production that is minimally evident because of the relatively long circulation time of other cell types.
Affected puppies often die at birth or during the first week of life, and rarely live longer than a year. Surviving dogs can be weak with stunted growth and develop serious recurrent bacterial infections during periods of neutropenia. Monocytosis can occur in the inflammatory pattern at any stage of its progression. Monocytosis is more likely and tends to be of greater magnitude if the disease becomes chronic.
Combined Corticosteroid-Induced and Inflammatory Response
Inflammatory disease processes commonly induce a concurrent endogenous corticosteroid response, recognized by the presence of lymphopenia in conjunction with an inflammatory neutrophil response (left shift). The neutrophil response to inflammation overrides and might be additive to the corticosteroid influence on neutrophils.
Lymphocytosis
Mild lymphocytosis and reactive lymphocytes can occur after vaccination. Modest lymphocytosis, between 7,000 and 20,000/mcL (7–20 × 109/L), should prompt consideration of a possible physiological excitement response, particularly in cats (1). If that is excluded, then a lymphoproliferative disorder should be considered. If examination of lymphocyte morphology reveals prolymphocytes and/or blast cells, then acute lymphocytic leukemia is the working interpretation. If the cells are all small with clumped chromatin, then chronic lymphocytic leukemia is a consideration requiring further evaluation (see ). Chronic ehrlichiosis can result in lymphocytosis of this magnitude in dogs. At higher concentrations, the lymphocytosis may be regarded as conclusive evidence of leukemia.
Photomicrograph of a blood smear from a dog with chronic lymphocytic leukemia. The leukocyte differential is predominated by small, mature lymphocytes. Wright stain; original magnification 100X.
Courtesy of Dr. Darren Wood.
Persistent lymphocytosis in cattle is defined by consistently high lymphocyte concentrations (2). It is due to a B-cell proliferation that occurs in a subset of animals infected with bovine leukemia virus (BLV). Affected cattle are usually clinically normal. The finding of persistent lymphocytosis is regarded as a positive indication of BLV infection in individual animals. A smaller subset of BLV-infected cattle, either with or without lymphocytosis, might progress to develop lymphoma or lymphocytic leukemia.
Lymphopenia
Lymphopenia is a common leukogram abnormality most commonly associated with stress (endogenous) or corticosteroid administration (exogenous). The most likely cause is steroid-induced apoptosis of lymphocytes. Lymphopenia is rarely due to other causes, such as extravasation of lymph (eg, lymphangiectasia, chylous effusion), some viral infections with tropism for rapidly dividing cells (eg, parvoviral infections), and hereditary immunodeficiency disease (eg, combined immunodeficiency disease of Arabian foals).
Stem Cell Injury and Pancytopenia
A number of factors can cause reversible or irreversible stem cell injury. These injuries can affect erythrocyte, platelet, lymphocyte, and/or granulocyte production. Because of short circulating lifespan, neutropenia is often the first abnormality observed. When chronic or irreversible, these injuries result in decreases in all three major blood cell lines, with the hemogram demonstrating leukopenia, nonregenerative anemia, and thrombocytopenia. General causes include the following:
overdoses of radiation and antineoplastic drugs
drug or plant toxicities (eg, estrogen toxicity in dogs, bracken fern toxicity in cattle, phenylbutazone toxicity in species other than horses)
hematopoietic cell neoplasia involving bone marrow (myelophthisis)
ehrlichiosis and viral infections that injure rapidly dividing cells and can cause transient neutropenia (see the table )
Eosinophilia and Basophilia
Eosinophilia, or the combination of eosinophilia and basophilia, prompts the consideration of the following processes:
allergic inflammation
parasitic infestation
subepithelial (skin, respiratory, GI) inflammation that is likely allergic in nature
paraneoplastic induction (less commonly)
Eosinophilia is common in most dogs with heartworm disease and can also occur in dogs and cats with flea infestation. Decreased concentration of these cell types in blood has no pathological relevance. (See .)
Photomicrograph of a blood smear from a dog. Note several eosinophils with bright orange-red cytoplasmic granules are present. Wright stain; original magnification 100X.
Courtesy of Dr. Darren Wood.
Hypereosinophilic syndrome has been reported in cats, dogs, and ferrets (1). This poorly understood syndrome is characterized by persistent marked eosinophilia and eosinophil tissue infiltration with associated organ dysfunction.
Metarubricytosis
Although typically absent, metarubricytes (nRBCs) occasionally become a major component of the total nucleated cell count (see ). The magnitude can be 10–50% of the nucleated cell population or more, with absolute numbers reaching 5,000–10,000/mcL (5–10 × 109/L) (3). This occurs rarely in early phases of an intense regenerative response to anemia. It might also be associated with endothelial injury (eg, heatstroke) resulting in abnormal release rate of nRBCs from bone marrow.
Photomicrograph of metarubricytes in a blood smear from a dog. The cell on the left is slightly more mature than the one on the right, with more condensed nuclear chromatin and less basophilic cytoplasm. Wright stain; original magnification 100X.
Courtesy of Dr. Darren Wood.
Most nRBCs will be counted as lymphocytes on cell counters with differential capability. This might result in a preliminary result of lymphocytosis being corrected later only by examination of the blood smear.
Hematopoietic Neoplasia and Leukemia
Most cases of hematopoietic neoplasia of either lymphocytic or myeloid origin will have some abnormal cells in blood. Sometimes, neoplastic cells are present in low numbers and are detected only by scanning the blood smear under low magnification. Finding abnormal hematopoietic precursor cells in blood in small numbers prompts investigation of bone marrow and/or other hematopoietic tissues (such as the spleen) for possible neoplastic disease.
The opposite extreme is marked leukocytosis with a predominance of the abnormal (neoplastic) cell population. In this situation, the blood sample is often diagnostic for leukemia. If poorly differentiated, the cells are classified as blasts, with possible cell lineage determined according to morphological appearance. If well differentiated, the cell lineage is usually clearer, because the cells are mature. Definitive diagnosis can be made using specialized techniques such as flow cytometry.
Lymphocytic leukemias are more common in domestic animals than are myeloproliferative neoplasms (ie, leukemias of granulocytes, erythrocytes, or platelets). Myelodysplastic syndrome (MDS; also referred to as myelodysplastic neoplasms) is a term used to describe peripheral blood cytopenias, a hyperplastic response in bone marrow, and dysplastic features in cells in peripheral blood and/or bone marrow.
A distinction is often made between acute and chronic leukemia. The terms are more in reference to the clinical course of the disease rather than the duration of the tumor. Acute leukemia of leukocytes often causes systemic clinical signs of illness and a poor short-term prognosis. Affected animals have variable numbers of poorly differentiated blast cells in circulation, as well as cytopenias in other cell lines. (See .) In contrast, chronic leukemia of leukocytes often causes few to no clinical signs, might be discovered incidentally, and can have a long clinical course. Animals affected thus usually have large numbers of well-differentiated cells in circulation and lack other cytopenias, except perhaps anemia.
Photomicrograph of a blood smear from a dog with acute myeloid leukemia. Several atypical large cells of hematopoietic origin with convoluted nuclei are present. Wright stain; original magnification 100X.
Courtesy of Dr. Darren Wood.
Considerable progress is being made in the use of monoclonal antibody labeling and flow cytometric analysis to better establish cell lineage, particularly when the morphology is equivocal (4). This is particularly useful for poorly differentiated leukemias, in which morphology alone is unreliable. The distinction between well-differentiated or chronic myeloproliferative neoplasms and extreme neutrophilic leukocytosis due to inflammation can be difficult. The latter is much more frequent, and a source of inflammation should be sought before concluding that changes indicate neoplasia.
Key Points
Changes in the concentration of different types of leukocytes can suggest certain mechanisms of disease and provide prognostic information.
Morphological abnormalities in leukocytes can provide additional pathological information, which reinforces the importance of blood smear examination in any animal with leukocyte concentration abnormalities.
Performing serial leukograms can provide insight into mechanistic trends, which can facilitate the interpretation of abnormalities.
For More Information
Schnelle AN, Barger AM. Neutropenia in dogs and cats: causes and consequences. Vet Clin North Am Small Anim Pract. 2012;42(1):111-122.
Nolen-Walston RD, Stefnaoski D, Conrado FO. Association of leukergy (in vitro leukocyte aggregation) with systemic inflammation in dogs and cats (2017-2022). Vet Clin Pathol. 2024;53(1):40-46.
Also see pet owner content regarding white blood cell disorders of dogs, white blood cell disorders of cats, and white blood cell disorders of horses.
References
Scott MA, Stockham SL. Leukocytes. In: Stockham SL, Scott MA, eds. Fundamentals of Veterinary Clinical Pathology. 3rd ed. Wiley; 2025:61-134.
Wood RD. Hematology of bovids. In: Brooks MB, Harr KE, Seelig DM, Wardrop KJ, Weiss DR, eds. Schalm's Veterinary Hematology. 7th ed. Wiley-Blackwell; 2022:1009.
Hollman F, Geisen V, Hartmann K, Doerfelt R. Nucleated red blood cells as a prognostic indicator in dogs with anemia. Front Vet Sci. 2025;12:1585168. doi:10.3389/fvets.2025.1585168
Evans SJM. Flow cytometry in veterinary practice. Vet Clin North Am Small Anim Pract. 2023;53(1):89-100. doi:10.1016/j.cvsm.2022.07.008
