Erythrocytosis in Dogs and Cats: Diagnosis and Management

CE Email comments/questions to [email protected], fax 800-556-3288, or log on to www.VetLearn.com Erythrocytosis in dogs and cats has various causes. Relative erythrocytosis is associated with a normal red blood cell (RBC) mass, whereas absolute erythrocytosis (primary and secondary) is characterized by increased numbers of RBCs. Primary erythrocytosis is a rare myeloproliferative disease of dogs and cats and is somewhat similar to polycythemia vera in humans. Secondary erythrocytosis is often associated with renal neoplasia but may also occur with other neoplasms, hypoxic cardiopulmonary disease, high-altitude environment, hyperadrenocorticism, and severe obesity. Abnormalities in erythropoietin (EPO) regulation and concentration are associated with the absolute forms of erythrocytosis. Measurement of serum EPO levels in animals may be helpful, but lack of speciesspecific assays for the dog and cat may limit the clinical utility of currently available tests. Long-term survival of both dogs and cats with primary erythrocytosis may be realized by treatment with intermittent phlebotomy and hydroxyurea. Successful therapy for secondary erythrocytosis depends on identification and treatment of the underlying cause. [PV]) has been reported in dogs and cats. Although appropriate erythrocytosis associated with cyanotic heart disease has been reported in dogs, most cases of absolute erythrocytosis are secondary, inappropriate, and usually attributed to underlying neoplasia, often of renal origin. NORMAL PHYSIOLOGY Oxygen transport is the primary function of RBCs. Erythroid precursors in the bone marrow, primarily colony-forming unit erythroid cells, are stimulated by the hormone erythropoietin (EPO) to undergo growth and maturation to maintain an RBC mass capable of providing optimal oxygen delivery to body tissues. In normovolemic dogs, optimal oxygen delivery occurs with a PCV of 40% to 45%; however, alterations in blood volume, cardiovascular status, hemoglobin structure, and oxygen dissociation curve can significantly influence tissue oxygenation independent of the measured PCV. COMPENDIUM 104 February 2004 February 2004 COMPENDIUM Erythrocytosis in Dogs and Cats 105 CE (Epogen, Procrit [both epoetin alfa], Amgen). This product is widely used in both human and veterinary medicine to treat a variety of anemias, most often those associated with chronic renal failure or antineoplastic chemotherapy. Although the biologic activity of EPO from other mammalian species is similar to that of human EPO, there are species-specific antigenic differences. Dog EPO and cat EPO show an 85% sequence homology to human EPO. Long-term use of rh-EPO in cats is known to result in anti-EPO antibody formation, with a resultant loss of effectiveness and a decline in RBC indices, although iron deficiency and impaired iron utilization (functional deficiency) caused by accelerated EPO-mediated erythropoiesis have also been suggested as causes of EPO-refractory anemia. These antigenic differences are also problematic for the use of human-based assays to accurately determine serum EPO levels in dogs and cats. Measurement of Erythropoietin Determination of serum EPO concentrations may be useful in some cases in which the cause is not clearly defined after a thorough diagnostic search, although a definitive diagnosis based on EPO levels alone is rarely achieved. EPO samples should be obtained before phlebotomy to prevent misleading results caused by phlebotomy-induced increases in EPO secretion. Accurate measurement of EPO concentration in veterinary patients is an area of controversy and is complicated by the lack of commercial canine and feline species-specific EPO assays. EPO bioactivity has historically been evaluated by in-vivo and in-vitro bioassays. The cumbersome exhypoxic or hypertransfused polycythemic mouse assay used to detect increased EPO activity has remained the standard with which all other assays are compared. Although it is reliable for detecting Breed differences are known to occur, with greyhounds and dachshunds often having higher values. In cats, this number is slightly lower (35% to 45%), probably because of the smaller size of the feline erythron. The site of origin of EPO has been debated. Although some controversy still exists, the kidney is the site of physiologically significant EPO production in mammals. Two morphologically distinct cell types reside within the renal interstitium: • Type 1 (stellate) cells, the interstitial fibroblasts, are presumed responsible for EPO production. • Type 2 cells appear more lymphocytic and are thought to function in antigen presentation because of the expression of cell surface major histocompatibility complex molecules. Type 1 cells reside at the level of the proximal convoluted renal tubule of the deep cortex and outer medulla and express cytoplasmic dendritic-like processes that contact both the renal tubule and the peritubular capillary. An abundance of rough endoplasmic reticulum suggests that these cells are synthetically active. The location of these cells, which are physiologic oxygen sensors, is considered both anatomically and functionally significant. At this level within the renal cortex, oxygen consumption is high and oxygen tension falls to 40 to 50 mm Hg. As oxygen tension declines (i.e., in hypoxia), a strategically placed sensor in this metabolically active region serves to protect function by increasing EPO production, with a subsequent increase in RBC numbers and a concomitant increase in oxygen-carrying capacity. ERYTHROPOIETIN EPO is a heavily glycosylated, 34-kD polypeptide hormone belonging to a large group of hematopoietic growth factors. As with most hormones, EPO production is governed by negative feedback control. Under normal conditions, hypoxia increases the renal synthesis of EPO, which, in turn, stimulates bone marrow erythropoiesis. The resultant increase in hemoglobin concentration increases oxygen-carrying capacity. Increased tissue oxygenation then reduces EPO production, with a corresponding decrease in erythropoiesis. These controls serve to maintain an optimal RBC mass for adequate oxygen delivery to body tissues. The half-life of canine EPO is 6 to 9 hours. Human, canine, and feline EPOs have been sequenced, but only recombinant human EPO (rh-EPO) is commercially available Erythrocytosis (confirmed)