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Hematology » Leukogram changes » Leukogram patterns
Leukogram patterns
Changes in total and differential leukocyte count are usually grouped into patterns, which facilitate interpretation. These patterns are:
Stress leukogram Physiologic leukocytosis Inflammatory leukogram Leukemia: More on leukemia is given in a separate section.
Stress leukogram
This is due to increased endogenous (or exogenous administered) corticosteroids. The classic leukogram pattern from increased corticosteroids (either exogenous or endogenous) includes a neutrophilia, lymphopenia, monocytosis, and eosinopenia. Not all of these changes will be present in any given animal. The most consistent finding is the lymphopenia, followed by a mature neutrophilia (increase in segmented neutrophils, but not usually bands). Monocytosis from corticosteroids is fairly common in dogs, seen occasionally in cats, and seen only rarely in horses and cattle. Although stress leukograms are frequently transient, chronically stressed animals may have a persistent stress leukogram. The mechanisms for corticosteroid related leukogram changes are as follows:
Neutrophilia is mainly due to a shift from MGP to CGP. A small portion of the neutrophilia may also be due to increased release from bone marrow and delayed apoptosis. Generally, the neutrophil count is usually not increased more than 1x above the reference limit (the MGP to CGP ratio is 1:1), but can be as high as 2 3x the upper reference limit in cats (since they have a higher MGP:CGP ratio than other species). In general, a stress leukogram should not increase a segmented neutrophil count >30,000/μL and >20,000/μL in horses and ruminants. Lymphopenia is due to multiple mechanisms, including decreased efflux from lymph nodes and lymphotoxic effects The mechanism for the monocytosis is unknown, but it could be due to a shift from marginating to circulating pool, if these pools exist for this leukocyte. Eosinopenia is due to decreased release from the bone marrow.
Care must be taken when using the term “stress response” to refer to a leukogram. A stress leukogram is specifically referring to the results of corticosteroids. It is tempting to use the term stress leukogram when describing a nervous animal, but these animals are likely to have an epinephrine response rather than a corticosteroid response. So only use the term “stress leukogram” when referring to changes that you are attributing to corticosteroids.
Causes of a stress leukogram are:
Endogenous stress: Chronic or acute increases in corticosteroids. This is expected in most ill animals. Hyperadrenocorticism
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Exogenous corticosteroid administration: In dogs, this may be accompanied by increased liver enzymes (especially ALP).
Other changes in clinical pathologic results that may be seen with a stress leukogram are:
Hyperglycemia: Due to corticosteroids Increase in ALP: Only in dogs and with chronic endogenous corticosteroids
Physiologic leukocytosis
This is due to epinephrine or norepinephrine and is called a “flight or fight” response. Changes on the leukogram due to epinephrine responses are most commonly seen in cats (of any age), horses, and younger animals. The typical pattern is mild neutrophilia (mature cells with no left shift) and lymphocytosis (sometimes called a “physiologic lymphocytosis”). These changes are usually transient, and will diminish within about 30 minutes after the animal calms.
The neutrophilia is due to a shift from the MGP to the CGP. The lymphocytosis is due to release from the spleen. It is uncommon for the lymphocyte count to exceed 10 thousand/μL, but we have seen rare cases in cats of an epinephrine related lymphocytosis of about 20 thousand/μL. An eosinophilia and basophilia may accompany the above changes.
Other changes in clinical pathologic results that may be seen with a physiologic leukocytosis are:
Hyperglycemia: Due to epinephrine.
Inflammatory leukogram
The blood neutrophil count with inflammation represents the balance between tissue demand and bone marrow supply. The leukogram pattern can be variable depending on the source and severity of the inflammation. One of the following patterns is often identified on the CBC, but it is possible to have inflammation in an animal that does not show an inflammatory leukogram. This occurs particularly with localized inflammation that is not inciting a systemic inflammatory response (with associated clinical and clinical pathologic manifestations, such as fever, an inflammatory leukogram, hypoferremia and increased globulins). If there is other clinical or laboratory evidence of inflammation in an animal, do not let the lack of an inflammatory leukogram dissuade you from considering that an inflammatory process may be occurring. Also remember, that a single hemogram is but a “snapshot” in time. Since changes in the hemogram can occur frequently, monitoring hemogram results frequently (every 12 to 24 hours) can be very helpful in determining the course of an inflammatory response and response to treatment. Regardless, never treat laboratory data, always treat the patient.
With the classic inflammatory leukogram, the bone marrow senses an increased demand for neutrophils (through cytokine stimulation). The bone marrow initially responds to this demand by releasing the storage pool of post mitotic mature and band neutrophils, which results in a neutrophilia with a left shift (not degenerative), in most species, other than cattle. Cytokines (such as granulocyte and granulocyte monocyte stimulating factor) also kick in and stimulate granulopoiesis within 3 5 days. Thus, the following changes are seen with a classic inflammatory leukogram:
Neutrophilia (anything from very mild to very severe, occasionally over 100 thousand/μL, depending on the severity of the inflammation). In general, dogs tend to have the highest degree of neutrophilia than other animals. Left shift in neutrophils: The more severe the left shift (with more immature neutrophils, such as metamyelocytes, myelocytes and rarely progranulocytes, not only bands, being released), the more severe the inflammatory stimulus. Toxic change: This usually, but does not always, accompany an inflammatory leukogram. Mild, chronic or resolving inflammation may not result in toxic change (which indicates immaturity and accelerated release versus a true toxic effect on these cells). Cytokine stimulation without infection, e.g. cytokine secretion stimulated by cancer (paraneoplastic response) and immune mediated hemolytic anemia in dogs can have a moderate to marked neutrophilia with a left shift (sometimes to metamyelocytes and myelocytes), with little evidence of toxic change. Usually, a moderate to severe inflammatory response, particularly that due to bacterial sepsis (but not limited to bacterial sepsis) will result in a left shift in neutrophils and toxic change. Monocytosis: This may or may not be part of an inflammatory leukogram. A monocytosis is usually seen with inflammation when it is more long standing or resolving. However, in some animals, the increase in monocytes is quite mild. Concurrent lymphopenia (and eosinopenia): A lymphopenia (and eosinopenia) frequently accompany an inflammatory leukogram. This could be due to concurrent endogenous stress (corticosteroid release), although inflammatory cytokines may directly cause a lymphopenia (through shifting hematopoiesis to granulocytic lineages).
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Overwhelming inflammation ↓ ↑ to ↑↑ ↓ N Yes Yes
Sequestered inflammation ↑↑ ± N or ↓ N or ↑ ± May be difficult to find
- A stressed animal may have localized, chronic or mild inflammation. ** Acute inflammation in cattle will result in a neutropenia with a left shift as indicated above.
Leukemia
Leukemia is defined as the presence of neoplastic cells in circulation and/or the bone marrow. Leukemias are classified in two ways, by stage of maturation (acute or chronic) and by lineage (myeloid or lymphoid). There is also a third “designation” of leukemia, which is a leukemia that is secondary to lymphoma (an extramedullary tumor of lymphoid tissues). The most common types of leukemia we see are chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), which can consist of any myeloid (non lymphoid) lineage. Acute lymphoid leukemia (ALL) is less common in most species. Chronic myeloid leukemia (CML) is quite rare.
Acute leukemia (ALL or AML): These are immature cells (blasts) in blood or an excess number of blasts in bone marrow. The typical hemogram pattern with acute leukemia is anemia, neutropenia, and thrombocytopenia (i.e. pancytopenia), usually with a large number of blasts in the leukogram. Some animals may have few or no blasts (this is typical in horses with acute leukemia). Blasts are identified as large cells (larger than a neutrophil), with a relatively large nucleus, fine chromatin, and possibly prominent nucleoli. Some immature cells, particularly with ALL, are small to intermediate and can be difficult to distinguish from normal lymphocytes (they usually have more euchromatin than a normal lymphocyte, i.e. the chromatin pattern is fine versus smudged or blocky). Chronic leukemia: This is a neoplastic proliferation of a differentiated or mature blood cell type, and has a more prolonged, indolent clinical course and a much better prognosis than acute leukemia. The only type of chronic leukemia you are likely to see in practice is chronic lymphocytic leukemia (CLL). Animals with CLL have a good prognosis and can often live for months or years with little or no treatment. The disease is commonly diagnosed as an incidental finding on a hemogram. With CLL, the leukogram shows a marked lymphocytosis (often more than 20 thousand/μL, and sometimes more than 100 thousand/μL) where the lymphocytes are morphologically fairly normal (small with clumped chromatin). This must be differentiated from other causes of lymphocytosis (e.g. hypoadrenocorticism, reactive lymphocytosis) but the latter are a far less common cause of lymphocytosis than CLL in dogs and cats. Lymphoma with associated leukemia (or circulating cells): Cells from a primary lymphoma can be seen in blood and/or bone marrow and is called stage V. The cells will mimic their tissue counterparts and will be small, intermediate or large in a small, intermediate or large cell lymphoma, respectively. Since normal blood lymphocytes are generally small, with some intermediate cells, it is difficult to identify a leukemia associated with a small cell lymphoma or intermediate cell lymphoma, unless there are many of the tumor cells in blood and/or bone marrow. Even then, we need to distinguish between a primary lymphoma with an associated leukemia or a primary leukemia (CLL or ALL). Blasts from AML, ALL, and stage V large cell lymphoma all have a similar microscopic appearance, so to distinguish them we must rely on other information from the physical examination, hemogram, bone marrow cytology, and specialized testing such as flow cytometry and cytochemical staining. The classic patterns for each of these are summarized in the table below, although in reality these distinctions are not always this clear and there are always exceptions.
Acute myeloid leukemia Acute lymphoid leukemia Stage V lymphoma
Physical examination Mild or no enlargement of lymphoid organs
Mild or no enlargement of lymphoid organs
Moderate to severe enlargement of lymphoid organs
Hemogram Large number of blasts; multiple cytopenias (anemia, neutropenia, thrombocytopenia)
Large number of blasts (or small to intermediate cells); multiple cytopenias (anemia, neutropenia, thrombocytopenia)
Variable number of blasts or lymphoma cells; typically few cytopenias other than anemia.
Bone marrow Large number of blasts (>20% of marrow cells) with low numbers of normal blood cell precursors
Large number of blasts or tumor cells (>20% of marrow cells, diffuse infiltrate) with low numbers of normal blood cell precursors
Variable numbers of blasts; may still have some normal blood cell precursors. Blasts usually in foci or patches and usually <20% of all marrow cells.
Flow cytometry and Positive for monocyte, Positive for B or T lymphoid Positive for B or T lymphoid markers
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immunocytochemistry granulocyte, or megakaryocytic markers (erythroid markers are lacking)
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Useful hints
When interpreting WBC results on a hemogram, it is useful to ask the following questions:
- Is this a young animal? (or should I expect an age or epinephrine associated lymphocytosis?)
- Is there evidence of endogenous corticosteroid release (“stress”) or is the animal on corticosteroid treatment? This would be supported by a lymphopenia and/or eosinopenia. A neutrophilia, without a left shift, with or without a lymphopenia or eosinopenia could be due to inflammation or corticosteroids, so you would need to evaluate other findings (clinical and laboratory) for evidence of inflammation.
- Is there an inflammatory leukogram? This would be supported by a left shift (immature neutrophils in the circulation) and toxic change in neutrophils (which are usually found together, but not always).
- If there is an inflammatory leukogram, how severe is it? This can be ascertained by the severity of the left shift (degenerative generally supports a severe inflammatory response) and degree of toxicity in neutrophils (marked toxic change in neutrophils would support severe inflammation).
- If there is inflammation, is the bone marrow responding? If there is a neutrophilia and mature neutrophils outnumber immature neutrophils (and there is a decent left shift, say >1,000/uL of band or immature neutrophils), this would support a bone marrow response. Some clinical pathologists use the term “regenerative left shift” under these conditions, since they suspect a bone marrow response is occurring (i.e. myeloid hyperplasia), but it is possible for the bone marrow to release a few immature neutrophils along with mature neutrophils in the storage pool in response to inflammation before the bone marrow has had time to increase granulopoiesis (i.e. first few days after onset of inflammation). So this all depends on the degree of neutrophilia and left shift, and with severity of inflammation.
- If there is inflammation, who is winning? The animal or the inflammation? This can be difficult to determine from a single hemogram and is somewhat species dependent. For example, a degenerative left shift, more immature than mature neutrophils in the face of a reduced (neutropenia) or within reference interval mature (segmented) neutrophil count in a dog, cat, horse or camelid would suggest depletion of marrow stores and failure of the bone marrow to keep up with the demand from the tissue, i.e. the inflammation is winning. In ruminants, species who have only low marrow stores that can be released in response to acute inflammation, a degenerative left shift with neutropenia is an expected finding in an acute inflammatory response (e.g. mastitis, metritis) and does not mean the inflammation is winning. But if the ruminant still has a degenerative left shift 3 4 days later, than the inflammation is winning. If the animal has a high mature neutrophil count (neutrophilia) and more immature than mature neutrophils, this tells us that the marrow has had time to respond (there is a myeloid or neutrophilic hyperplasia) but the inflammation is acutely worsening or a new inflammatory focus (severe) has developed (with cytokines causing release of immature cells from the marrow). Here, we are not sure who is winning. So how do we tell? When in doubt, always do serial hemograms – every 24 hours (or less if really needed)! If the mature neutrophil count goes up and evidence of toxic change and immature neutrophil count goes down…that is a good thing – the animal and you as the veterinarian are winning. If the mature neutrophil count is going down and toxic change or immature neutrophil count is going up….that is bad – the animal is “circling the drain” as it were.
- Are there abnormal cells in the blood (“big blue cells“) or an unexplained lymphocytosis? If yes, then you may have a leukemia (acute or secondary to lymphoma). Please refer to the leukemia section for further diagnostic algorithms on leukemia.
Note, that a left shift in blood does not always mean there is a bone marrow response (myeloid or neutrophilic hyperplasia). A mild left shift in animals other than ruminants, can be seen with release of the storage pool in response to inflammation or if marrow reserves have been previously depleted. A more severe left shift is expected in ruminants in acute inflammation without a myeloid hyperplasia. Also, the lack of a left shift does not mean there is no myeloid hyperplasia. If the bone marrow is responding to granulocytopoietic cytokines or an inflammatory stimulus and is keeping up with demand, you may see no left shift at all, but you would expect to see a neutrophilia (high mature or segmented neutrophil count). You are also unlikely to see toxic change in neutrophils in this scenario because the marrow is keeping up with demand. This is typical in the case of sequestered inflammation or paraneoplastic leukocytosis, where tumor cells release granulocytopoietic cytokines.
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