Proceeding of the LAVC Latin American Veterinary Conference Oct , 2009 Lima, Peru

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1 Close this window to return to IVIS Proceeding of the LAVC Latin American Veterinary Conference Oct , 2009 Lima, Peru Reprinted in the IVIS website with the permission of the LAVC

2 Dr. Michael Fry COMMON LEUKOGRAM ABNORMALITIES IN DOGS AND CATS ANEMIA CLASSIFICATION, LABORATORY EVALUATION, MECHANISMS OF DISEASE CYTOLOGY BASICS AND COMMON SKIN/SUBCUTANEOUS LESIONS Página 200

3 COMMON LEUKOGRAM ABNORMALITIES IN DOGS AND CATS Neutrophilia occurs in response to a number of different stimuli, none of which are mutually exclusive. Major mechanisms of neutrophilia are shown below: We will focus on the conditions that are most common in small animals. Glucocorticoid excess, either because of endogenous production or exogenous administration, results in a pattern known as the stress leukogram, characterized by the following: mature neutrophilia (i.e., increased concentration of segmented neutrophils), lymphopenia, and, especially in dogs, monocytosis. Eosinopenia is another feature of the stress leukogram, although in many situations this is inapparent because the normal reference values for eosinophils are so low (in some laboratories, the lower reference value is zero). Mechanisms contributing to glucocorticoid-mediated neutrophilia include: Increased release of mature neutrophils from the bone marrow storage pool. Decreased margination of neutrophils within the vasculature, with a resulting increase in the circulating pool. Decreased migration of neutrophils from the blood stream into tissues. Página 201

4 The magnitude of neutrophilia tends to be species dependent, with dogs having a more pronounced response (up to 35,000 cells/µl) than cats (up to 30,000 cells/µl). With longterm glucocorticoid excess, neutrophil numbers tend to normalize, whereas lymphopenia tends to persist. Epinephrine release results in a different pattern, known as physiologic leukocytosis, characterized by mature neutrophilia (like the glucocorticoid response) and lymphocytosis (unlike the glucocorticoid response). This phenomenon is short lived (< 1 hour). Neutrophilia occurs primarily because of a shift of cells from the marginated to the circulating pool. Physiologic leukocytosis is common in cats (especially when they are highly stressed during blood collection) and uncommon in dogs. Of course, neutrophilia may also indicate inflammation, and inflammatory stimuli of varying magnitude and duration produce different patterns of neutrophilia. A classic hematologic finding in patients with increased demand for neutrophils is the presence of immature forms in the blood, known as a left shift. Not all inflammatory responses have a left shift, but the presence of a left shift almost always signifies active demand for neutrophils in the tissue. The magnitude of a left shift is assessed by the number of immature cells and their degree of immaturity. The mildest form is characterized by band neutrophils that are increased in number but in relatively low proportion compared to mature, segmented neutrophils. Increasingly severe forms are characterized by increased numbers or proportions of bands and, in some cases, progressively immature predecessors (a left shift is considered orderly if the number of immature cells decreases as they become progressively immature). The term degenerative left shift is sometimes used to describe cases where the number of immature forms exceeds the number of segmented neutrophils. As with glucocorticoid-mediated neutrophilia, the typical magnitude of neutrophilia due to inflammation varies by species, with dogs having the most pronounced response. It is important to point out that inflammation can also cause neutropenia, although this is not a common occurrence in dogs and cats (which have a relatively large storage pool of neutrophils in the bone marrow compared to large animals, especially cattle). It is quite an alarming finding when it does occur, since it signifies a major imbalance between neutrophil supply and tissue demand. The acquired neutrophil morphologic abnormality known as toxic change reflects accelerated production of neutrophils as part of the inflammatory response. Features of toxic Página 202

5 change include increased cytoplasmic basophilia, the presence of small blue-gray cytoplasmic inclusions known as Döhle bodies (often noted incidentally in cats), and in more severe cases, indistinct cytoplasmic vacuolation. Toxic change may accompany any inflammatory response, but in general the more marked the toxic change, the higher the index of suspicion for infection or endotoxemia. Toxic change occurs during granulopoiesis and thus is technically a form of dysplasia (e.g., Döhle bodies are foci of aggregated endoplasmic reticulum), but is not associated with clinically significant impaired neutrophil function. It may be useful to think of neutrophil kinetics in terms of a producer-consumer model in which the bone marrow is the factory, and the tissues (where the neutrophils eventually go) are the customers. The bone marrow storage pool is the factory inventory, the neutrophils in the blood stream are in delivery to the customer. Within the blood vessels, circulating neutrophils are on the highway, with marginated neutrophils temporarily pulled off to the side of the road. During health, there is an even flow of neutrophils from the factory to the customer. Thus the system is in steady state, and neutrophil numbers remain relatively constant and within the normal range. However, disease states may perturb this system at multiple levels: Condition Analogy Left shift Factory meets increased customer demand by shipping out unfinished goods. Persistent, established Factory has had time to adjust to increased inflammation (characterized demand and is meeting it more efficiently by mature neutrophilia) by increasing output. Toxic change Factory is accelerating output and shipping out imperfect goods. Página 203

6 Lymphopenia is a common CBC finding in sick animals with many different types of disease. Usually the precise mechanism of lymphopenia is not clear. It is often presumed to be mediated at least in part by endogenous glucocorticoid excess. Lymphopenia may occur because of various mechanisms, including: Altered distribution of lymphocytes (increased trafficking of lymphocytes to, and decreased egress from, lymphoid tissues) Lymphotoxicity (direct damage to lymphocytes or suppression of lymphopoiesis) of therapeutic (e.g., glucocorticoids) or infectious (e.g., canine distemper virus) agents Loss of lymphocyte-rich lymphatic fluid Congenital disorders. Normal lymphocyte trafficking may be altered because of disruption of the normal architecture of lymphoid tissue (e.g., because of neoplasia or inflammation), or in response to chemical signals. Glucocorticoid excess may cause lymphopenia via redistribution from the blood to lymphoid tissue, or via direct lymphotoxic effects. Anticancer treatments (chemotherapy or radiotherapy) and immunosuppressive drugs may also be lymphotoxic. Some hereditary immunodeficiencies (such as severe combined immunodeficiency or thymic aplasia) can cause lymphopenia. There are numerous causes of lymphocytosis. Young animals normally have higher numbers of lymphocytes than older animals, and normal healthy young animals may have counts that exceed adult reference values. As discussed above, lymphocytosis is also a feature of epinephrine-mediated physiologic leukocytosis, resulting from redistribution of lymphocytes into the blood circulating pool. Epinephrine-mediated lymphocytosis may be more marked than neutrophilia, particularly in cats (lymphocyte counts of >20,000/µL are not uncommon). Antigenic stimulation may result in lymphocytosis, even in rare cases in marked lymphocytosis (up to approximately 30,000 cells/µl in dogs, and 40,000/µL in cats); however, this is not usually the case, even when there is clear evidence of increased immunologic activity in lymphoid tissues. I n cases of antigenic stimulation, it is common for a minority of lymphocytes to have a reactive morphology larger in size than small, mature lymphocytes, and with more abundant, deeply basophilic cytoplasm and incompletely condensed chromatin. Just as glucocorticoid excess can cause lymphopenia, glucocorticoid deficiency (hypoadrenocorticism) can cause lymphocytosis, or lack of lymphopenia under conditions of stress that typically result in glucocorticoid-mediated lymphopenia. Página 204