Blood Vascular System

The blood vascular system is conceptually divided into two compartments: the central pool and the marginal pool. The marginal pool consists of the microcirculation, ie, at the capillary–tissue interface. The central pool consists of larger vessels. Blood samples taken by venipuncture are inherently representative of the central pool. Flow rate, fluid movement to the extravascular space, and selective WBC adhesion to endothelium are factors that may contribute to marked differences in cell concentration in the two pools. Furthermore, these pools are in hemodynamic equilibrium with each other and the extravascular space. Therefore, WBC concentration may change appreciably due to movement of cells and/or fluid from one pool to the other as a result of a change in equilibrium. In most species, WBC are roughly equally distributed between the two pools. Cats have a greater distribution of leukocytes within the marginal pool. WBC in the circulating pool can be increased by certain mechanisms: epinephrine can redistribute WBC from the marginal pool to the circulating pool, and corticosteroids can inhibit neutrophil endothelial adherence and tissue migration.

Granulocytes

Granulocytes consist of neutrophils, eosinophils, and basophils, which are produced in the bone marrow by a common stem cell subsystem. The proliferative (mitotic) elements consist of myeloblasts, promyelocytes, and myelocytes. Promyelocytes first form azurophilic primary granules (lysosomes) that become inapparent in later stages. The storage (maturation) pool consists of metamyelocytes, band neutrophils, and segmented neutrophils that are functionally mature. Specific granules, which define final cell types, are first produced at the myelocyte stage. Cell types are recognized by characteristic granule staining affinity, eg, basophilic granules for basophils, eosinophilic granules for eosinophils, and neutral or nonstaining granules for neutrophils.

Neutrophils

In blood, neutrophils normally are mature (segmented), with rare immature band forms. Neutrophils from bone marrow enter the blood, where they remain for an average of 8 hr. They tend to adhere to the microcirculatory endothelium and then unidirectionally enter tissues, where they may participate in host defense. Given the rapid turnover of neutrophils in the blood, maintenance of blood neutrophil concentration depends on a relatively high, steady delivery from bone marrow. This balance may change dramatically when there is either increased tissue consumption associated with the development of a tissue inflammatory process or a stem-cell injury that reduces the marrow production rate. During initiation of an inflammatory lesion, local mononuclear cell release of colony stimulating factor(s) rapidly stimulates bone marrow to release neutrophil reserve and accelerate granulopoiesis. When the tissue demand is intense, marrow production and release accelerate, resulting in left shift and toxic change.

Extreme neutrophilia, exceeding upper limits seen in inflammation, may be associated with myelomonocytic leukemia, Hepatozoon canis infections, and rarely neoplasms that produce colony-stimulating factors.

Bovine leukocyte adhesion deficiency is a lethal, autosomal recessive disorder of Holstein cattle. It is associated with marked neutrophilia, and the neutrophils have a deficiency of the glycoproteins (integrins) that are essential for normal leukocyte adherence and emigration. Recurrent bacterial infections, persistent neutrophilia (often >100,000/μL), lymphocytosis, and death (usually between 2 wk and 8 mo of age) are characteristic. Calves often are stunted and have recurrent pneumonia, ulcerative stomatitis, enteritis, and periodontitis. On examination of tissues, there are few neutrophils, except within vessel lumens, because they persist in the circulation and have impaired entry into the tissues. Testing is available to detect carriers.

Neutropenia may occur due to excessive tissue demand for neutrophils or reduced granulopoiesis. It may occur with overwhelming bacterial infections, especially gram-negative septicemia or endotoxemia, in all species. Immune-mediated destruction of neutrophils is diagnosed by exclusion of other consumptive processes. Stem-cell injury may occur as a result of many causes such as certain viral infections, chemical injury, and idiosyncratic drug reactions, eg, sulfonamides, penicillins, cephalosporins, and chloramphenicol in cats. These reactions typically affect all marrow cell lines but are recognized initially as neutropenia because of the relatively high turnover of this cell type.

Neutropenia is seen 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 periodic neutropenia, associated overwhelming recurrent bacterial infections, bleeding, and coat color dilution. The molecular basis is thought to be a cyclic bone-marrow maturation defect at the level of the pluripotential hematopoietic stem cells. Neutrophil maturation is arrested at regular intervals of 11–14 days; the peripheral neutropenia lasts 3–4 days and is followed by a neutrophilia. All other hematopoietic cells, including lymphocytes, also have cyclic production that is minimally evident because of the relatively long circulation time of other elements. Affected puppies often die at birth or during the first week and rarely live >1 yr. Surviving dogs may be stunted and weak and develop serious recurrent bacterial infections during periods of neutropenia.

Eosinophils

Eosinophils function in parasite killing and also contain enzymes that modulate products of mast cells released in response to antigen-IgE receptor mast cell detonation in allergic disease. For example, histamine released by mast cells is modulated by histaminase in eosinophils. Eosinophilia is primarily induced by allergic inflammatory responses and tissue invading parasitic infestations. Hypereosinophilic syndrome has been reported in cats. This poorly understood syndrome is characterized by consistent marked eosinophilia and eosinophil tissue infiltration with associated organ dysfunction. Less commonly, neoplasia may be associated with paraneoplastic induction of eosinophilia. Localized eosinophilic tissue lesions do not necessarily produce a peripheral eosinophilia, eg, the eosinophilic granuloma dermatopathies and oral lesions of cats. Eosinopenia is a component of corticosteroid-induced (stress) leukograms.

Basophils

Basophils are rare in all common domestic animals. Basophil granules contain histamine, heparin, and sulfated mucopolysaccharides; understanding of their function is limited. As a result, there is no clear interpretation for basophilia. Basophilia is uncommon but occasionally accompanies eosinophilia, and it is the latter that is interpreted. Contrary to claims on hematology instrumentation, there are no data or documentation to support that these instruments can identify animal basophils. Although blood basophils and tissue mast cells have similar enzymatic contents, basophils do not become mast cells. They appear to arise from separate marrow stem systems.

Monocytes

Monocytes are formed in the bone marrow and mature from monoblasts to promonocytes to monocytes. Monocytes enter the peripheral blood for ~24–36 hr and exit into tissues to mature into tissue macrophages. Monocytes and macrophages perform phagocytosis of organisms and cellular debris at sites of inflammation or tissue injury. They may form multinucleated giant cells, particularly in response to foreign bodies or complex organisms that elicit granuloma formation. Monocytes and macrophages are a major source of colony-stimulating factors and cytokines that regulate inflammatory responses, and they function as antigen-processing cells. Monocytosis may be associated with inflammation, particularly when chronic. Monocytosis is also a component of a steroid response, most notably in dogs.

Lymphocytes

Lymphocytes originate from a marrow stem cell and mature in lymph nodes, spleen, and other subepithelial lymphoid tissues. Mature lymphocytes consist of 2 major subpopulations, B cells and T cells. B cells (B for bone marrow or bursa equivalent) are potential precursors of plasma cells that produce antibodies for humoral immunity. T cells (T for thymus) engage in cellular immunity (eg, histocompatibility and delayed-type hypersensitivity). Lymphocytes in tissue may return to the vascular bed and recirculate. Some lymphocytes are long-lived compared with other WBC types.

Lymphocytosis

Common causes of lymphocytosis are an excitement (epinephrine) response and lymphocytic leukemia. Immune (antigenic) stimulation associated with chronic inflammation does not cause lymphocytosis but may result in responsive lymphoid cell expansion in lymphoid tissues. Immune stimulation may also result in reactive (immunologically stimulated) lymphocytes noted on blood film examination. Reactive lymphocytes may be seen in any disease that causes moderate to marked systemic immunostimulation. Large reactive lymphocytes are normal in juvenile animals. Large granular lymphocytes are normal in rare numbers. Lymphocyte concentrations of up to 17,000/μL, with frequent large granular lymphocytes, have been reported in dogs with chronic Ehrlichia canis infection. Persistent lymphocytosis in cattle is defined by lymphocyte concentrations consistently >7,500/μl. 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 asymptomatic. The finding of persistent lymphocytosis is regarded as a positive indication of BLV infection in the individual. A smaller subset of BLV-infected cattle, either with or without lymphocytosis, may progress to develop lymphoma or lymphocytic leukemia.

Lymphopenia

Lymphopenia is a common leukogram abnormality. It is most commonly associated with endogenous (stress) or exogenous corticosteroids. The most likely cause is steroid-induced apoptosis of lymphocytes. Lymphopenia also rarely occurs due to other causes, such as extravasation of lymph (eg, lymphangiectasia, chylous effusion), some viral infections with tropism for rapidly dividing cells, and hereditary immunodeficiency disease (eg, combined immunodeficiency disease of Arabian foals).

Last full review/revision July 2011 by Glade Weiser, DVM, DACVP