Leukocyte Disorders

4 Leukocyte Disorders

Basic Leukocyte Concepts


Leukocyte responses in the patient are evaluated by the leukogram. The leukogram is the leukocyte portion of the complete blood count (CBC) and includes the total leukocyte (white blood cell [WBC]) count, differential leukocyte count (Diff), and description of WBC morphology. The relative leukocyte differential count (relative Diff) is the percentages of various leukocyte types (i.e., segmented neutrophils [segs], nonsegmented neutrophils [nonsegs], lymphocytes, monocytes, eosinophils, basophils). The absolute differential leukocyte count (absolute Diff) is the number of each type of leukocyte per volume (microliter or liter) of blood. Examination of leukocyte morphology on the stained blood smear is used to determine a relative Diff and detect various abnormalities. Selected hematologic techniques are described in Chapter 2. This chapter is intended to give an overview of understanding the leukocyte response and to answer common questions in diagnosis. Supplemental information regarding leukogram interpretation may be found in other textbooks.18,20,25,35,46

Leukocytes are inflammatory cells, and changes in the leukogram are mainly used to identify the presence of inflammatory disease and characterize inflammation as to severity and type. The leukogram is not highly sensitive in detecting mild, focal, or chronic inflammation; therefore, a normal WBC count and Diff does not exclude inflammatory disease from the diagnosis. Acute phase protein concentrations, such as C-reactive protein in dogs and serum amyloid A in cats, are much more sensitive tests to document the presence of inflammation. The manual Diff is imprecise; therefore, the clinician should use prominent changes in the number of types of WBCs for diagnosis.

The leukogram usually does not confirm infection, but some patterns, such as a very severe left shift together with very toxic neutrophils, strongly suggest severe infection. Infection is more consistently confirmed by finding the organism and associated inflammatory reaction with cytology (Chapter 16) and culture of tissues that look abnormal on ultrasound, radiographs, or physical exam. Similarly, the leukogram often does not confirm hematologic neoplasia such as malignant lymphoma, while cytology, histopathology, and histochemical and immunologic evaluation of hematopoietic tissues that appear abnormal on ultrasound, radiographs, or physical exam more consistently give a correct diagnosis (see later discussion of hematopoietic neoplasia under Leukemia).

Automated Versus Manual Differential Leukocyte Counts

The automated total leukocyte count (WBC) from most veterinary hematology instruments is accurate and precise. The automated differential leukocyte count (AutoDiff) of human hematology instruments has to a great extent replaced the manual Diff (ManDiff) in human medicine because this eliminates the cost of hiring a well-trained person to evaluate the smears and because of the greater precision with the AutoDiff. The AutoDiff has several uses in the dog and cat, but these uses vary with the instrument and the patient’s problem. Current veterinary instruments fail to identify all types of canine and feline leukocytes. No automated instrument enumerates the number of bands and younger neutrophils, and most instruments fail to identify nonsegs or basophils. Many instruments detect the total neutrophil and lymphocyte counts, and often eosinophil counts, well. A proper indication for use of an AutoDiff is to monitor treatment response of these types of leukocytes over days. This takes advantage of the instrument’s greater precision and cost savings in labor time.

Some instruments have sporadic errors in detection of eosinophils and monocytes. Some instruments offer only a three-cell Diff, which actually only indicates the number of total neutrophils and lymphocytes. Since a major use of the CBC and Diff is to document the presence and severity of inflammatory disease, it is necessary to use a manual Diff to document a left shift and toxic change in neutrophils. A ManDiff is often required to validate a monocytosis, eosinophilia, or basophilia recorded by an AutoDiff. The combination of precise data from hematology instruments and subjective observations from the blood smear give the greatest chance to make a proper diagnosis and prognosis during initial evaluation of an ill patient. Then, based on the instrument being used and its ability to correctly measure the hematologic abnormality documented by a full CBC, including WBC, AutoDiff, and manual Diff, the clinician may subsequently monitor that change over time and treatment using only automated results.

Absolute Versus Relative Differential Leukocyte Counts

Use of absolute WBC numbers allows more consistent evaluation of leukogram responses than use of relative percentages (Figure 4-1). For example, a WBC count of 10,000 leukocytes/µl with 65% segs has 6500 segs/µl. The 6500 segs/µl is normal, but 65% segs are not always normal. A WBC count of 1000 leukocytes/µl with 65% segs indicates severe neutropenia (i.e., 650 segs/µl). A WBC count of 50,000 leukocytes/µl with 65% segs indicates neutrophilia (i.e., 32,500 segs/µl).

Interpretation of the leukogram should begin with interpretation of the absolute cell count for each type of leukocyte. Then the changes are summarized by appropriate hematologic terms indicating an increase or decrease in a given leukocyte type. For example, “mild to moderate leukocytosis with mature neutrophilia, lymphopenia, and monocytosis” indicates that there was an increased total WBC count, an increase in mature segmented neutrophils but no increase in band neutrophils, a decrease in lymphocytes, and an increased numbers of monocytes, respectively. This particular description is typical for a recent glucocorticoid treatment or stress-type response.

Leukocyte Production, Circulation, and Emigration

To interpret the concentration of leukocytes in the blood, one must consider the rate of leukocyte production in bone marrow and release into blood, the distribution and circulating half-life of leukocytes in the vascular system, and the rate of emigration of leukocytes from blood into tissues. Understanding of normal hematopoiesis is also needed to understand classification of the leukemias (neoplasia of hematopoietic cells, discussed later).

Leukocyte Production

Granulocytes (i.e., neutrophils, eosinophils, basophils) and monocytes are produced in the bone marrow. Although the bone marrow produces some lymphocytes, most lymphocytes are produced by the peripheral lymphoid tissues (i.e., thymus, lymph nodes, spleen, tonsils, bronchial-associated lymphoid tissue, gut-associated lymphoid tissue). Leukocytes develop in the bone marrow from pluripotent and committed stem cells influenced by interleukins and colony-stimulating factors (Figure 4-2).26

Neutrophils compose the majority of leukocytes in blood, and usually leukocytosis is caused by neutrophilia. Kinetics of neutrophils has been well studied and is best understood. Thus the initial discussion here focuses on neutrophils. Cellular “pools” are used to conceptualize and describe the “location” of neutrophils within the bone marrow and blood and to simplify interpretation of bone marrow and CBC data (Figure 4-3). Bone marrow is divided into two pools. The first, the mitotic pool of myeloblasts, promyelocytes, and myelocytes, provides a steady supply of neutrophils to meet tissue demand for these cells. The second pool is maturation and storage, which consists of metamyelocytes, bands, and segs that lack mitotic ability. Precursor cells undergo progressive maturation and provide a reserve pool of segs to meet sudden increased tissue demands for neutrophils until the mitotic pool increases neutrophil production. It is uncommon in the dog and cat to have leukopenia during inflammatory diseases because this large storage pool is available for rapid release of neutrophils. The maturation and storage pools are combined in Figure 4-3. The most mature stages of neutrophil are preferentially released from the bone marrow into the blood first (segs, bands, metamyelocytes, myelocytes, and finally promyelocytes, in that order). As bone marrow stores of segs are depleted, nonsegs (e.g., bands, metamyelocytes, younger neutrophils) are released into the blood, and a left shift occurs: A left shift is a specific indicator of inflammation, and the severity of the left shift reflects the severity of inflammation.

The maturation and storage pool constitutes 80% of the myeloid cell population, whereas the mitotic pool usually accounts for 20% of the myeloid series. In contrast with neutrophils, promonocytes and monocytes are released into blood at a relatively young age. This lack of monocyte maturation and storage in the bone marrow explains why monocytes are observed infrequently in most bone marrow aspirates, unless severe neutropenia is present.

Leukocyte numbers and morphology within the bone marrow can be evaluated by bone marrow aspiration for cytology and core biopsy for histopathology. Aspirate smears of marrow allow qualitative and quantitative observations regarding cell morphology and maturation. Core biopsy provides the best estimation of bone marrow cellularity and detects stromal reactions (e.g., myelofibrosis, granulomatous osteomyelitis). Chapter 2 discusses the interpretation of a bone marrow examination.

Neutrophil Circulation

When neutrophils are released into the blood, about half hesitatively stick and roll along the endothelial cells (i.e., in the marginal pool) and are not in the central axial flow of blood within vessels from which blood is taken during a venipuncture (i.e., in the circulating pool). Those neutrophils that are in the central axial flow of blood within vessels and are taken into a blood sample (and counted in the WBC count) are said to be in the circulating pool. The marginal neutrophil pool is a “hidden” population associated with the endothelial lining of capillaries, especially the lungs and spleen. The circulating and marginal cell pools make up the total blood neutrophil pool (TBNP). Neutrophils distribute between circulating and marginal cell pools, circulate for a brief period of time (half-life of 7.4 hours), and emigrate from blood vessels into tissues. Shifts between these pools can affect the WBC count, especially in cats. In dogs, circulating and marginal pools are about equal. In cats, the marginal pool is two to three times the size of the circulating pool (Table 4-1). Therefore, if neutrophils are mobilized from the marginal pool to the circulating pool in response to fear, excitement, or strenuous exercise, the neutrophil count can potentially double in dogs and triple in cats. This effect is called physiologic leukocytosis and is seen mainly in young healthy cats.


TBNP × 108/kg 10.2 28.9
CNP × 108/kg 5.4 7.8
MNP × 108/kg 4.8 21.0

Total blood neutrophil pool (TBNP) in cats is larger than in dogs because of a very large marginal neutrophil pool. The relatively large feline marginal neutrophil pool (MNP), compared with that of the dog, allows a larger potential shift of neutrophils into the circulating neutrophil pool (CNP) with more dramatic leukocytosis during fear, excitement, or strenuous exercise.

Leukocytosis And Neutrophilia

Leukocytosis is usually synonymous with neutrophilia. For example, among 232 CBCs with a leukocytosis of greater than 17,000 WBCs/µl, 226 (97%) had neutrophilia.

Differential Diagnosis of Neutrophilic Leukocytosis

The three most common causes of neutrophilia and leukocytosis are (1) inflammation, (2) stress and corticosteroids, and (3) exercise and epinephrine. Leukemia is relatively uncommon (discussed later) but may cause massive to no increase in the WBC count. Inflammation is most specifically identified by the presence of a left shift, or an absolute increase in nonsegs (Figure 4-4; see later discussion of left shift and hyposegmentation). Inflammation is also suggested by leukocytosis greater than that usually expected with corticosteroid- or epinephrine-associated changes. When mild neutrophilia is present without a left shift, the specific cause of leukocytosis may be unclear. In such instances, the absolute lymphocyte count may be useful. Lymphopenia is commonly associated with an endogenous stress-associated or exogenous glucocorticoid treatment effect. Transient lymphocytosis may be caused by epinephrine-induced splenic contraction or an exercise-associated effect. Persistent lymphocytosis is often caused by chronic immune stimulus. Concurrent processes occur often. For example, inflammation usually causes stress-related lymphopenia. Corticosteroid treatment is very common.


Inflammation is a common and important laboratory diagnosis. Inflammation usually causes neutrophilia and is the major rule out for neutrophilic leukocytosis. Neutrophils predominate in tissues during acute phases of many inflammatory diseases (e.g., peritonitis, arthritis). Proliferation of macrophages and lymphocytes occurs in more subacute to chronic inflammation (especially within tissues other than blood). But many chronic inflammatory diseases (suppurative or exudative diseases) may still have primarily neutrophils. Other inflammatory cells, such as monocytes-macrophages, eosinophils, lymphocytes, plasma cells, and even basophils, increase in blood and other tissues in various types of inflammatory disease (see later discussions). Neutrophils are specialists at killing bacteria, and bacterial infection (i.e., sepsis) commonly causes neutrophilic types of inflammation (e.g., exudative, purulent, suppurative, abscess) as well as pyogranulomatous inflammation. However, neutrophilia occurs with other infections such as certain mycotic, protozoal, and viral infections (e.g., feline infectious peritonitis). Inflammation also may occur from nonseptic processes such as necrosis (e.g., pancreatitis, pansteatitis, immune-mediated hemolytic anemia, [IMHA]), chemical exposure (e.g., turpentine is an experimental method of abscess formation), immune-mediated diseases (e.g., systemic lupus erythematosus, IMHA), and toxins (e.g., endotoxin, snake bite). Neoplasms may cause inflammation in several ways, such as causing ulceration, causing necrosis in normal tissues, outgrowing or damaging the blood supply with subsequent necrosis in the tumor, predisposing the patient to infection, or producing a paraneoplastic effect wherein tumor products stimulate the bone marrow to produce neutrophils or eosinophils.

Left Shift

A left shift (increased absolute numbers of immature neutrophils) indicates inflammatory disease in the patient (see Figure 4-4). Identification of immature neutrophils requires blood smear evaluation. Immature neutrophils such bands, metamyelocytes, myelocytes, and younger neutrophils are termed nonsegmented neutrophils (nonsegs) in general. Identification of nonsegs is subjective and varies greatly among microscopists. Most experienced microscopists, who examine blood smears daily, clearly recognize increased immaturity and toxic changes in neutrophils during inflammation. However, the number of bands, metamyelocytes, and myelocytes reported will vary among observers. Exact numbers of these cells are often impossible to determine when severe toxic change is present, in which case a subjective description should be used; for example, “The blood had a severe degenerative left shift with severe toxic change in neutrophils, though exact numbers of each cell type could not be determined.” may be the most honest description. Even in nontoxic reactions the division between segs and nonsegs may be difficult, and the term hyposegmentation is then used to indicate that the neutrophils looked more immature than normal though the number of reported nonsegs was not increased.

Because of the effect of the observer’s impression in classification of nonsegs, one should use a definite increase in nonsegs for a certain conclusion of inflammation. A finding of greater than 1000 nonsegs/µl is a reasonable threshold for a left shift. (Note that 1000 nonsegs/µl equals 1.0 nonsegs × 109/L.) Small changes from day to day or slight changes from the reference values should be interpreted with caution because manual differential leukocyte counts are especially imprecise with nonsegs and cells found in low numbers, such as basophils. Mild left shifts (i.e., 300 to 1000 nonsegs/µl) occur in hemorrhagic, chronic, or granulomatous diseases. No left shift may be noted in many patients with inflammatory disease, thus the absence of a left shift or a very mild left shift does not exclude inflammation from the diagnosis.

The absolute number of nonsegs and their state of immaturity indicate the severity of the left shift. Immature neutrophils (nonsegs) observed in blood include bands (stabs), metamyelocytes (juveniles), myelocytes, and promyelocytes. Bands usually constitute most of the left shift because the more mature neutrophils are released from bone marrow first. Neutrophils younger than bands indicate an increasingly severe left shift associated with increasingly intense inflammation. If several myelocytes and metamyelocytes are found, the number of metamyelocytes, myelocytes, and promyelocytes should be reported individually (not simply grouped as nonsegs) to indicate severity of the left shift. Detectable numbers of blast cells (i.e., myeloblasts) or irregular maturation patterns may suggest granulocytic leukemia. More nonsegs than segs indicates a degenerative left shift and a poor prognosis.

Leukogram Changes in Inflammation

Figure 4-5 shows a likely pattern of leukocyte changes through a typical inflammatory response, with a distinct onset of inflammation and then progressing uniformly to resolution. Changes in individual patients may vary from this typical pattern due to treatment, rupture of an abscess, or the like. The greatest left shift is expected in early stages of the disease process, because as the preexisting bone marrow storage pool is depleted of segs, then more bands and metamyelocytes are released to meet early intense demand. With time, myeloid hyperplasia within the bone marrow expands neutrophil production. When neutrophil production and maturation time are sufficient, mainly mature segs are released into the blood and the severity of the left shift should diminish or disappear. If tissue inflammation stabilizes at a persistent low to moderate level, the bone marrow should reach a production rate sufficient for most neutrophils to mature before release. Thus chronic inflammation may be characterized by little to no left shift and minimal to no leukocytosis. Therefore, chronic or mild inflammation may be difficult to document by leukogram data alone. Acute phase proteins, such as C-reactive protein or serum amyloid A, are sensitive indicators of inflammation and may be used to complement the leukogram. Increased rouleaux (see Chapter 2) in canine blood smears or fever in the patient suggests inflammation. Increased rouleaux formation usually is associated with production of acute phase proteins such as fibrinogen. A normal leukogram appearance does not exclude inflammatory diseases, especially if inflammation is mild or chronic, or only involves a surface (e.g., cystitis).


Obviously factors other than neutrophil counts affect prognosis, such as the cause of the disease and site of inflammation. However, the neutrophil counts reflect the current balance of effective bone marrow production and tissue demand. If the bone marrow is responding typically to an inflammatory process with a mild to moderate neutrophilia and mild to moderate left shift, the prognosis is relatively good. Leukocytosis in dogs is usually less than 40,000 WBCs/µl. In 182 canine CBC exams with leukocytosis, 151 (83%) had 17,500 to 39,990 WBCs/µl. Leukocytosis in this range is thus mild to moderate and suggests a favorable prognosis. Only 5% had marked to extreme leukocytosis of 61,050 to 127,500 cells/µl. Leukemoid reactions of over 50,000 to 60,000 WBCs indicate a poor prognosis because, even in the presence of excessive numbers of leukocytes (usually neutrophils), the cause of the inflammatory response is not corrected. The magnitude of feline leukocytosis is usually less than that in dogs (i.e., 70% of cases are < 30,000 WBCs/µl). The severity of eosinophilia in eosinophilic inflammation is less than neutrophilia during neutrophil inflammation. Therefore, a leukemoid reaction of eosinophils (due to strong eosinophil inflammation, not leukemia or hypereosinophilic syndrome) is diagnosed when there are more than 25,000 to 30,000 eosinophils/µl.

Leukocyte count criteria, suggesting a poor prognosis, are summarized in Table 4-2 (see also later discussion of Toxic Neutrophils). A degenerative left shift, leukopenia, neutropenia, lymphopenia, leukemoid reaction, or a combination thereof is an atypical, unexpected response to inflammatory disease indicating severe disease, toxemia, severe stress, inadequate bone marrow production, problems interfering with an effective response, or a combination of these. A degenerative left shift has more nonsegs than segs, regardless of total leukocyte count. Finding more immature than mature neutrophils indicates that the bone marrow cannot produce neutrophils at a rate sufficient for them to mature completely prior to release. Either tissue demand for neutrophils has escalated dramatically, cell production is decreased, or both. Severity of change and trend over daily CBCs are important in assessing prognosis. A degenerative left shift, severe neutropenia and leukopenia, lymphopenia, and marked toxic change in most neutrophils often suggest gram-negative sepsis, such as a ruptured intestine or parvovirus enteritis.


Degenerative left shift Tissue demand exceeds bone marrow’s production of neutrophils or causes inadequate time for maturation of neutrophils
Leukopenia Tissue demand exceeds bone marrow’s production of neutrophils
Leukemoid reaction Even excessive numbers of neutrophils cannot correct the problem
Toxic neutrophils Moderate to many, moderately to severely toxic neutrophils are associated with longer hospitalization, higher treatment costs, and increased fatality
Severe or persistent lymphopenia Indicates severe and persistent stress

Both leukopenia and neutropenia are unfavorable prognostic signs. These findings suggest that bone marrow is incapable of producing sufficient numbers of neutrophils, that tissue consumption of neutrophils is overwhelming, or both. Neutropenia, whether primary (bone marrow disease) or secondary (excessive tissue consumption), severely predisposes the patient to infection and septicemia. Leukopenia is usually caused by neutropenia, but lymphopenia may also cause leukopenia despite normal neutrophil numbers. Lymphopenia usually indicates stress. Severe or persistent lymphopenia indicates severe or persistent stress. In severe leukopenia (e.g., <1000 WBCs/µl), a left shift is not concluded even if all neutrophils are nonsegs, because an increase in the absolute number of immature neutrophils greater than 1000 WBCs/µl is not possible. (Trying to perform a manual differential WBC count is also not necessary because the total WBCs already indicates a neutropenia and lymphopenia, and imprecision of a 25 to 50 ManDiff count with abnormally appearing cells is very great. Automated instrument differential counts are more accurate in severe leukopenia.)

A leukemoid reaction is a marked leukocytosis (>50,000 to 100,000 WBCs/µl) due to inflammatory disease and not leukemia. Leukemoid means leukemia-like because of the magnitude of leukocytosis. A leukemoid reaction indicates a poor prognosis because, despite abundant (and actually excessive numbers of) neutrophils, the inflammatory disease is not being corrected. Causes of leukemoid reactions are often severe localized infections (e.g., pyometra, abscess). Additional causes are IMHA, paraneoplastic syndromes with bone marrow stimulation (e.g., metastatic fibrosarcoma, renal carcinoma, rectal adenoma), rare parasitism (e.g., Hepatozoon canis infection), and neutrophil functional defects (canine leukocyte adhesion protein deficiency [CLAD] of Irish setters).39 With pyometra and some walled-off abscesses, there is an anatomic problem preventing healing. Pus and the infectious agent or other cause cannot drain out of the body, and antibiotics may not penetrate the lesion. With CLAD, dysfunctional neutrophils are incapable of correcting common infections even in high numbers. The leukemoid reaction in IMHA seems an exception, but acute massive destruction of erythrocytes and phagocytosis of debris by macrophages is a strong stimulus for an inflammatory reaction.

Differentiation of a leukemoid reaction from chronic granulocytic leukemia (CGL) is difficult. CGL is rare, so the odds favor diagnosis of a leukemoid reaction when massive neutrophilia exists. Both leukemoid reactions and CGL lack the blast cells or atypia seen in acute granulocytic leukemia (see Myeloid Neoplasms later in this chapter). Left shifts in both leukemoid reactions and CGL often involve mainly bands, and both can have a few more immature forms. Cytologic examination of lymphadenopathy is often a key in diagnosis of CGL. Lymph node aspirates (and even liver or spleen aspirates) with CGL look like bone marrow in having mixed hematopoiesis with a few to moderate number of immature myeloid cells, including myeloblasts. The number of blast cells is not obviously increased, so bone marrow aspirates in CGL are often not diagnostic. The leukocytosis of a leukemoid reaction should resolve after appropriate treatment (e.g., removal of pyometra uterus). Clinical signs of illness, toxic neutrophils, and evidence of diseases that cause leukemoid reactions (e.g., pyometra) suggest diagnosis of a leukemoid reaction. Dogs with CGL have persistent leukocytosis and often do not look sick.

Toxic Neutrophils

Toxic neutrophils were associated with increased fatality, length of hospitalization, and treatment costs in dogs.3 The prevalence of pyometra, parvovirus infection, acute renal failure, peritonitis, IMHA, disseminated intravascular coagulation (DIC), pancreatitis, septicemia, and neoplastic disorders was significantly higher among dogs with toxic neutrophils. Bacterial infections cause severe toxic changes in neutrophils, such as in secondary bacterial enteritis in parvovirus enteritis. However, toxic neutrophils occur in disease without infection (e.g., IMHA, pancreatitis, chemotherapeutic agents, renal failure). The presence of toxic neutrophils in cats was associated with a significantly higher prevalence of shock, sepsis, panleukopenia, peritonitis, pneumonia, and upper respiratory tract diseases, as were infectious (viral and bacterial) and metabolic disorders.36 Negative findings in cats with toxic neutrophils were milder than with dogs, suggesting that cats form toxic neutrophils with milder diseases than dogs.

Classification of toxemia may be quite detailed3 or more simplified (see Chapter 2). The number of neutrophils that appeared toxic (percentage; or few, moderate, many) and severity of morphologic change should be reported. A few (1+) toxic neutrophils are of minimal importance. However, moderate to many (2+ to 4+) toxic neutrophils should not be ignored (see Figure 2-9). Toxic change in neutrophils, though subjective, is sometimes the only indicator of disease because numerical results of the leukogram appear normal in many cases. A blood smear evaluation by a competent observer should always be included during initial evaluation of a sick patient.

Stress and Corticosteroid Response

Corticosteroid treatment and stress (endogenous cortisone release) are very common and cause prominent changes in the leukogram (Table 4-3). The classic leukogram pattern from recent corticosteroid treatment or acute stress is moderate leukocytosis with mature neutrophilia, lymphopenia, and eosinopenia. In dogs, mild to moderate monocytosis also may occur (e.g., 2500/µl). Leukocytosis from corticosteroid treatment in dogs may reach a maximum of 30,000 to 40,000 cells/µl, with a predominance of neutrophils, but more commonly there are 15,000 to 25,000 WBCs/µl. Neutrophilia develops in 4 to 12 hours after treatment with a glucocorticoid and returns to baseline values in less than 24 hours. In cats, leukocytosis after corticosteroid treatment is usually a little weaker (e.g., 22,000 WBCs/µl with 18,000 neutrophils/µl), without monocytosis.

Lymphopenia without neutrophilia is the most common change in the leukogram and usually indicates stress. Chronic stress (e.g., chronic renal failure), long-term corticosteroid treatment, or hyperadrenocorticism is suggested by lymphopenia. The leukogram in chronic stress may seem normal. Stress causes eosinopenia, but normal animals may have few eosinophils so that eosinopenia is often overlooked. Stress or corticosteroid treatment can help explain the lack of eosinophilia in patients with eosinophilic inflammatory diseases.

After corticosteroid exposure, the total blood neutrophil pool (TBNP) expands because of decreased emigration of neutrophils from the blood into the tissues and increased release of neutrophils from the bone marrow into the blood (Table 4-4). In addition, neutrophils are shifted from the marginal pool (hidden) to the circulating pool (where they are included in blood collected by venipuncture). A left shift is not expected with stress or corticosteroid treatment because neutrophil release from the bone marrow is usually too mild to stimulate release of bands and metamyelocytes in the presence of a normal bone marrow storage pool of neutrophils.

Nuclear hypersegmentation of neutrophils (called a right shift) is more likely because corticosteroids decrease emigration of and prolong the circulating half-life of neutrophils in the blood. As neutrophils age, progressive nuclear hypersegmentation or lobulation develops. Hypersegmented neutrophils have five or more nuclear lobes.

Acute corticosteroid-induced changes are transient; therefore, one or more of the expected changes may not be seen depending on how long after treatment the sample was taken. Maximal leukocyte changes occur at 4 to 12 hours and may be normalized by 24 hours. For example, Table 4-3 presents hematologic data from a healthy dog treated daily with dexamethasone (except Sunday). One day after initial treatment (Saturday), five of the expected steroid-stress features occurred (i.e., leukocytosis, neutrophilia, no left shift, eosinopenia, monocytosis). Lymphopenia was not present. On day 3 (Monday with no dexamethasone treatment on Sunday) there was lymphocytosis, monocytosis, and eosinophilia most resembling physiologic leukocytosis (described next). Only on day 5 (Wednesday) was the full classic corticosteroid or stress pattern observed.

Exercise and Epinephrine Response

Transient physiologic leukocytosis is noted mainly in young, healthy cats during epinephrine release from fear or after strenuous exercise (e.g., struggling during venipuncture). This response is unlike the steroid-stress response described previously. It is incorrect (at least hematologically incorrect) to call this epinephrine-mediated response “stress.” The TBNP remains unchanged, but a sudden shift of cells occurs from the marginal to the circulating neutrophil pool. This tends to cause a neutrophilic leukocytosis. Contraction of the spleen tends to cause lymphocytosis and polycythemia. There is no increased release of neutrophils from the bone marrow, nor decreased emigration of neutrophils from the capillary beds. Physiologic leukocytosis in cats is greater in magnitude than in dogs because cats have a larger marginal neutrophil pool (three neutrophils in the marginal pool for every neutrophil in the circulating pool; see Table 4-1). Physiologic leukocytosis in cats may be significant; the WBC count often reaches 20,000/µl, and neutrophilia may be overshadowed by lymphocytosis (6000 to 15,000/µl).20 Dogs have such weak physiologic leukocytosis that it is seldom recognized clinically. Physiologic leukocytosis has been noted in research dogs that are bled routinely by the same person and an individual animal’s reference values are available from previous hematology testing. Then, if they are suddenly exercised or frightened (e.g., new blood taker), the mild increases in WBCs, neutrophils, lymphocytes, and packed cell volume (PCV) can be detected.

Leukopenia And Neutropenia

Leukopenia and neutropenia occur infrequently in dogs and cats because they have a large bone marrow storage pool of neutrophils. Leukopenia indicates a poor prognosis. Neutropenia is usually caused by excessive tissue consumption of neutrophils during severe inflammation and/or reduced bone marrow production (Table 4-5). (See also the discussion of bone marrow in Chapter 2 and the discussed of myeloid hypoplasia in the section on Bone Marrow Problems Causing Neutropenia later.) A third cause of neutropenia, which is rare and more theoretical, is a temporary shift of neutrophils from the circulating to the marginal pool, where they cannot be counted. Endotoxin can cause this change. This transient form of neutropenia is actually “pseudoneutropenia,” because the TBNP is unchanged. Rarely, immune-mediated or “steroid-responsive” neutropenia occurs with lupus or some drug treatments.


  Animals Affected
Consumption of Neutrophils
Overwhelming sepsis/endotoxemia (important)
Parvovirus enteritis (important)
Immune-mediated destruction (rare)  
Bone Marrow Suppression
Feline leukemia virus (FeLV) (important)  
Feline immunodeficiency virus (FIV)  
Parvovirus (important)
Bone marrow toxicity
Estrogen (endogenous/exogenous)  
Cancer chemotherapy
Leukemia (important)
Immune-mediated destruction of neutrophil precursors (rare)

* Incomplete list of other drugs is in text.

(Courtesy of Dr. M.D. Willard.)

During excessive tissue utilization of neutrophils, neutropenia may be severe; this stimulates release of very immature neutrophils, even myelocytes and promyelocytes, from the bone marrow. The left shift is degenerative when nonsegs outnumber segs. An inflammatory process involving a large surface area, such as septic peritonitis, enteritis, or septicemia, tends to cause severe neutropenia and leukopenia. In contrast, localized infections (abscess or pyometra) with pyogenic bacteria usually cause leukocytosis. Gram-negative bacterial infections are often severe and cause consumptive neutropenia. When a degenerative left shift, marked toxic change, and leukopenia occur, gram-negative sepsis should be suspected.

Neutropenia due to overwhelming infection may be difficult to distinguish from that due to bone marrow depression. Neutrophils have a short life span in blood (e.g., 10 hours), so neutropenia develops before anemia or thrombocytopenia. Thus neutropenia without thrombocytopenia or anemia suggests severe inflammation. Bicytopenia or pancytopenia (decreases in cells of two or three cell lines, respectively) suggests primary bone marrow disease. However, overwhelming infection often causes DIC, which causes thrombocytopenia (bicytopenia). Inflammation causes anemia that may exist prior to a severe exacerbation of the disease. Erythrocytes have long life spans, so anemia is often not apparent early in primary bone marrow disease. Primary bone marrow disease may develop insidiously and lack clinical signs, whereas consumptive neutropenia develops rapidly in a very ill animal. A left shift, toxic changes in neutrophils, and rouleaux formation suggest neutropenia as the result of severe inflammation or infection.

Severe, primary neutropenia predisposes the animal to septicemia. Thus neutropenia due to bone marrow disease may first be noted when a secondary infection develops. Neutropenia and leukopenia are side effects of cancer chemotherapy. Neutrophil counts are often lowest 5 to 7 days after initiation of treatment. Neutrophil counts of less than 1000 to 2000 cells/µl require monitoring the patient for sepsis. Sepsis (probably from enteric bacteria) is presumed to be present if the patient has fewer than 500 to 1000 neutrophils/µl and is febrile. It is recommended to suspend chemotherapy with myelosuppressive agents if the neutrophil count drops below 2500 cells/µl or the platelet count is less than 50,000/µl.

Bone Marrow Problems Causing Neutropenia

Diagnostic testing of patients with persistent, undiagnosed neutropenia includes bone marrow aspiration biopsy, core biopsy, or both. This may detect myeloid hypoplasia, ineffective granulopoiesis, bone marrow necrosis, myelofibrosis, disseminated granulomatous inflammation, leukemia, and other diseases (see Chapter 2). A proper history may reveal treatments or toxins that can affect granulopoiesis (e.g., estrogen or phenylbutazone). Ineffective granulopoiesis confuses many clinicians. The leukopenia is accompanied by normal to increased numbers of myeloid cells (i.e., myeloid hyperplasia). Neutropenia due to myeloid hypoplasia seems more logical. In ineffective granulopoiesis, neutrophils are destroyed in the bone marrow by apoptosis before they mature and are released into the blood. Apoptosis (programmed cell death) occurs in healthy dogs as part of the mechanism to regulate effective neutrophil production. Apoptosis is affected by various mediators, and there is no morphologic change to allow diagnosis of a specific cause. Death of cells within the marrow may be excessive in various infections and drug treatments. Approximately half of feline leukemia virus (FeLV)–positive, neutropenic cats have marked granulocytic hyperplasia indicating excessive apoptosis, whereas half have myeloid hypoplasia suggesting viral destruction of hematopoietic tissue as the cause. Ineffective granulopoiesis may also be an idiosyncratic drug reaction (e.g., phenobarbital).

Damage to or depletion of myeloid cells may cause myeloid hypoplasia (see Chapter 2). Causes of myeloid hypoplasia include parvovirus infection, endogenous and exogenous estrogen toxicosis in dogs, Ehrlichia canis infection, cancer chemotherapy, irradiation, and idiosyncratic reactions to drugs such as phenylbutazone, trimethoprim-sulfadiazine, or chloramphenicol (see Chapter 3). Immune-mediated neutropenia has not been well proven in dogs and cats, but steroid-responsive neutropenias have been described.

Neutropenia may occur from laboratory error. The AutoDiff may be checked by inspection of the instrument’s leukocyte graphics (see Chapter 2) or by screening the blood smear. When in doubt, a full ManDiff should be performed. The total WBC count is seldom wrong, but instrument flags should alert the operator to a problem. Prominent leukocyte aggregation is uncommon but indicates the WBCs were not evenly distributed in the EDTA sample and therefore the WBC count may be incorrect. In such cases new blood samples with different anticoagulants should be obtained and analyzed without delay. Blood specimens from intravenous fluid administration lines may have excessive dilution by the fluid.

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Sep 10, 2016 | Posted by in SMALL ANIMAL | Comments Off on Leukocyte Disorders

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