Erythrocytosis

© Strait, KR et al http://www.vet.uga.edu/vpp/clerk/strait/index.php

Introduction

Erythrocytosis, also called polycythemia, is defined by an increase in total red blood cell (RBC) number, packed cell volume (PCV), and hemoglobin (Hgb) concentration above reference intervals. Erythrocytosis occurs frequently in dogs and cats and can arise from a number of causes. Erythrocytosis may be relative, due to a decrease in total plasma fluid volume, or absolute, due to an increase in RBC production. Absolute erythrocytosis may be further classified as primary or secondary. In secondary erythrocytosis, either a physiologically appropriate or inappropriate response may be present. Since erythrocytosis is a common abnormality found on complete blood cell count (CBC) results, it is important for the practitioner to distinguish between the different etiologies so that a proper treatment is instituted.

Classification of Erythrocytosis

Erythrocytosis can be classified as either relative or absolute.⁶ With relative erythrocytosis, the total red cell mass in the body is normal, but the RBC count, PCV, and Hgb values are increased due to a decrease in plasma fluid volume (hemoconcentration).⁹ Absolute erythrocytosis is characterized by an increase in total RBC mass due to increased erythropoiesis.⁴ The RBC count, PCV, and Hgb values are elevated.

Absolute erythrocytosis may be either primary or secondary, with secondary causes further categorized as physiologically appropriate or inappropriate. Absolute primary erythrocytosis, also called polycythemia vera, is a neoplastic myeloproliferative disorder.^3,6 It is independent of erythropoietin effects.^3,6,9 In contrast, absolute secondary erythrocytosis is caused by an increase in erythropoietin secretion.^3,6,9 Erythrocytosis is still under regulatory control and may resolve if the concentration of erythropoietin decreases. Hypoxia is the defining mechanism that differentiates appropriate from inappropriate absolute secondary erythrocytosis.^3,6

A third category of erythrocytosis is iatrogenic.⁶ Although a specific case of iatrogenic erythrocytosis has not been described in veterinary literature, excessive blood transfusion could theoretically lead to an abnormally elevated RBC mass.⁶ This cause should be considered in a polycythemic animal following a blood transfusion.

Pathophysiology

Erythropoietin Production and Effect

Erythropoietin (Epo) is the principal hormone responsible for regulating erythrocyte production in the bone marrow. Epo is produced primarily in the kidneys, and to a lesser extent in the liver, in response to oxygen tension in the blood.⁶ When oxygen tension is low, such as at high altitudes, Epo is produced which then signals erythroid precursors in the bone marrow to undergo growth and maturation.^3,6 Since RBCs carry oxygen to tissues throughout the body, an increase in RBC mass will increase the oxygen carrying capacity in the body. Epo production is regulated by the classic negative feedback system. When oxygen tension in the blood returns to an appropriate level, Epo production in the kidney slows and Epo levels decrease.

Although controversy still exists on the exact location of Epo production in the kidney, most evidence points to type I interstitial cells.⁶ These fibroblastic kidney cells are located at the level of the proximal convoluted tubule near the deep cortex and outer medulla.⁶ Type I cells act as physiologic oxygen sensors at a level where renal oxygen consumption is high and the oxygen level falls.⁶ When oxygen tension in the blood is low, heme proteins are in the deoxy conformation.³ This triggers the production of Epo. The subsequent number of RBCs recruited by Epo is directly related to the degree of hypoxia.³ In this way, the body is able to efficiently regulate the oxygen carrying capacity of the blood as needed (Fig. 1).

Figure 1. In the erythropoietin (Epo) cycle, low blood oxygen tension stimulates Epo production in the kidney by type I interstitial cells. Epo subsequently promotes erythropoiesis in the bone marrow. When red cell mass increases and the oxygen tension in the blood returns to reference values, the increased production of Epo is countermanded in a negative feedback response.

Since Epo is directly related to circulating RBC mass, measuring Epo concentration is a theoretically helpful diagnostic approach in some animals with erythrocytosis.⁶ Epo assays must be conducted by a laboratory, and canine- and feline-specific tests are not available.⁶ Although there are two human assays for Epo that have been approved for use in dogs and cats, the accuracy of the tests is limited by the incomplete homology of Epo between species.³ Canine and feline Epo is only 85% homologous to the human molecule.⁶ Furthermore, current veterinary research has not determined a reference range for Epo concentration in dogs and cats.

In human medicine, primary and secondary absolute erythrocytosis can be differentiated by decreased or increased Epo levels, respectively.⁶ Unfortunately, this has not been found to be universally true in veterinary medicine. While elevated levels of Epo are diagnostic in animals with secondary absolute erythrocytosis, many have normal, or even decreased levels of this hormone.^3,6 Similarly, in animals with primary absolute erythrocytosis, Epo levels are not necessarily depressed and may be within reference ranges.^1,3,6 Although Epo is a theoretically important diagnostic tool, in practice it is often of limited accuracy and importance.

Relative Erythrocytosis

Relative erythrocytosis is a transient increase in circulating RBCs due to plasma fluid loss in excess of RBC loss or splenic contraction.^3,6 Although RBC mass is within reference intervals, the RBC count, PCV, and Hgb concentration are elevated. Total plasma protein concentration may be increased, within the reference interval, or decreased, depending on concurrent fluid loss or shift, but it is usually elevated.⁶

Relative erythrocytosis most commonly occurs secondary to dehydration. Excessive sweating, decreased fluid intake, vomiting, diarrhea, and cutaneous losses from burns can promote dehydration.^3,6 In dogs, catecholamine-induced splenic contraction in response to fear, excitement, or intense pain can also cause a transient increase in circulating RBCs.^3,6,9

Primary Absolute Erythrocytosis

Primary absolute erythrocytosis, called polycythemia vera, is a rare myeloproliferative disorder of erythroid precursor stem cells, specifically the colony forming unit – erythroid (CFU-E) cells.^3,6 In this disorder, the normal Epo signaling system breaks down and RBCs are produced without Epo input. Epo is not needed for RBC growth, differentiation, or clonal expansion, and levels of Epo in the body are often markedly decreased.^1,3,6

Although veterinarians typically refer to primary absolute erythrocytosis as polycythemia vera in their animal patients, this is technically incorrect. Before a diagnosis of polycythemia vera can be confirmed in humans patients, the individual must have an increased RBC mass that is independent of Epo concentration, a normal arterial oxygen saturation (>92%), leukocytosis, thrombocytosis, and splenomegaly.⁶ In animal patients, leukocytosis, thrombocytosis, and splenomegaly are not always present, making primary absolute erythrocytosis the preferred terminology.^3,6,9

Primary absolute erythrocytosis is rare in veterinary medicine, but has been reported in both dogs and cats.^3,6,8,9 Cats with primary erythrocytosis are typically older animals, with males showing a higher prevalence than females.⁹ Dogs can be affected at any age, and females tend to be more likely than males to develop the disease.⁹ Data, however, is incomplete, and disease prevalence has been determined only on a limited number of cases.

Appropriate Secondary Absolute Erythrocytosis

Appropriate secondary absolute erythrocytosis is characterized by an increase in RBC mass in response to systemic hypoxia. Under hypoxic conditions, an increase in RBC mass increases oxygen carrying capacity, therefore enabling the body to increase oxygen delivery to tissues.⁶ Systemic hypoxia is defined by an arterial oxygen saturation of <92%.⁶ This can be measured using standard blood gas analysis. Since secondary erythrocytosis is Epo-dependant, Epo levels may be increased.^1,3,6,9

High altitude (>1800 m) is the most common cause of appropriate secondary absolute erythrocytosis in veterinary patients.^3,6,9 Other causes include cyanotic heart disease with right-to-left shunting of blood (reverse patent ductus arteriosis, tetrology of Fallot), severe chronic respiratory disease, hemoglobin function abnormalities, and severe obesity (Pickwickian syndrome).^3,6 Erythrocytosis due to severe respiratory disease or hemoglobin functional abnormalities are extremely rare in veterinary medicine.³

Inappropriate Secondary Absolute Erythrocytosis

Inappropriate secondary absolute erythrocytosis is defined by an increase in RBC mass without evidence of hypoxia. Although oxygen saturation is within reference intervals, Epo is often elevated.^1,3,6,9 The most common cause of this condition in veterinary patients is neoplasia.^3,6 Both benign and malignant tumors have been implicated, with renal neoplasia being the most common.^6,8,2 Other tumors cited include hepatomas, uterine leiomyomas, and cerebellar hemangioblastomas.²

Several theories have been proposed to describe the pathogenesis of this paraneoplastic syndrome. In patients with renal tumors, impaired renal blood flow from an infiltrating mass may produce local hypoxia within the kidney, raising Epo secretion.^2,6 Patients with non-renal tumors may also produce local tissue hypoxia in the kidney or liver, but the mechanism is unknown.⁶ Although there has been no definitive proof that tumors themselves produce Epo or Epo-like substances, this explanation makes intrinsic sense and may prove correct in future studies.^2,3,6

Other diseases implicated in inappropriate secondary absolute erythrocytosis include renal cysts, pyelonephritis, and hydronephrosis.^6,8

Diagnosis in Patients with Erythrocytosis

Clinical Signs

Clinical signs associated with erythrocytosis are directly related to an increase in blood viscosity.³ Plethora (an excessive amount of blood) often results in hyperemia of skin and mucous membranes which may be the most prominent finding on physical examination (Fig. 2).⁶ Diarrhea, vomiting, epistaxis, engorged retinal vessels, polyuria and polydipsia may also be observed, although less commonly.^2,3,6 Animals with relative erythrocytosis will show signs of dehydration such as tacky mucous membranes, decreased skin turgor, and an increase in capillary refill time, whereas animals with secondary absolute erythrocytosis often exhibit clinical signs associated with the underlying condition, such as respiratory difficulty or renal azotemia.^3,6

Figure 2. Hyperemia of the oral mucous membranes and sclera are present in a dog with primary erythrocytosis (polycythemia vera).

In patients with erythrocytosis, blood flow is sluggish and microcirculation decreases.³ At a PCV of 70%, blood viscosity is 2.5X greater than normal.⁵ Up to 50% of patients with absolute erythrocytosis may show CNS signs related to local tissue hypoxia in the brain.³ Seizures, ataxia, changes in mentation, lethargy, and blindness have all been documented.^3,6 Hyperviscosity also increases the risk of thrombosis and vessel rupture.⁶ Additionally, sluggish blood flow can increase the workload on the heart, leading to cardiac hypertrophy.³

Diagnostic Plan

A diagnosis of erythrocytosis is based on an increased RBC count, PCV, and Hgb concentration. Although a measurement of total RBC mass is useful, it is rarely needed for diagnostic purposes in a clinical setting.⁴ Since treatment and prognosis vary by type of erythrocytosis, it is always important to pursue further classification of disease.⁴ The following diagram is useful for formulating a step-by-step diagnostic plan (Fig. 3). It is important to keep in mind that Greyhounds and Dachshunds normally have higher PCV values than other breeds of dogs.^3,6

Figure 3. Flow diagram depicting a logical clinical approach to the diagnosis of erythrocytosis in dogs and cats.

* The upper limits of the reference intervals for the PCV, RBC, and Hgb concentration are as follows:

PCV - dog = 55%, cat = 45%.

RBC - dog = 8.5 x 10⁶ /µL, cat = 10x10⁶ /µL.

Hgb - dog = 18g /dL, cat = 14 g /dL.

Treatment of Erythrocytosis

Relative Erythrocytosis

The basis for treating relative erythrocytosis is to address the underlying cause of disease and replace lost fluid volume intravenously.^3,4,6 The choice of fluid and rate of administration should be based on biochemical test results and the level of dehydration. Prognosis is generally good once the patient’s hydration status is normalized.⁶ Relative erythrocytosis due to splenic contraction is transient and should resolve once the patient is calm.^3,6

Primary Absolute Erythrocytosis

Primary absolute erythrocytosis is initially treated by phlebotomy to reduce the circulating RBC mass.^3,4,6 Enough blood should be removed to lower the PCV to 55% in dogs and 50% in cats, and an equal amount of a balanced isotonic fluid should be administered intravenously to replace lost blood volume.^3,4 Ideally only 5ml/kg of blood should be removed at one time though up to 10-20ml/kg is allowable.^3,9 For every 20ml /kg of blood removed, there is a subsequent drop in PCV by ~15%.⁶ A treatment interval should be established that keeps the patient PCV in the high end of the reference range.⁵ If the animal becomes iron deficient over time (50 mg of iron is lost with each 100 ml of blood removed), phlebotomy intervals may be decreased and the administration of supplemental iron should be considered.⁶

In many cases of primary erythrocytosis, phlebotomy alone may control clinical signs of disease and associated risks of blood hyperviscosity.³ If phlebotomy is required more than every four weeks, chemotherapy is indicated.⁶ Hydroxurea is a myelosuppressive compound that has been successfully used to treat primary erythrocytosis.^3,5,6 In one study, four dogs with reverse patent ductus arteriosis were successfully treated with hydroxurea, and the owners showed a preference to this treatment over intermittent phlebotomy.⁵ Although the exact mechanism is unknown, hydroxurea appears to inhibit DNA synthesis while sparing RNA and protein synthesis.⁷ Additionally, hydroxurea does not lead to iron deficiency.⁵ The dosage of hydroxyurea in the cat and dog begins at 50mg /kg by mouth once a day for seven days, followed by 15 mg/kg once daily until remission. The dosage of hydroxyurea is then tapered to the lowest effective concentration by monitoring the PCV.^7,8 Gastrointestinal signs (vomiting, diarrhea) and myelosupression (especially a decreased leukocyte count) are the most commonly noted side effects.⁷ Cats are at the greatest risk for myelosupression and need to be monitored more frequently than dogs.⁸ Hydroxurea may be combined with phlebotomy as another treatment alternative.^3,6 The prognosis for animals with primary erythrocytosis is guarded; however, a survival time of six years in a patient undergoing treatment was reported in one study.³

Appropriate Secondary Absolute Erythrocytosis

Under hypoxic conditions, an optimal physiologic response occurs at a PCV between 55-60%.⁶ Phlebotomy is contraindicated in these cases. When the PCV reaches a point at which clinical signs are observed, phlebotomy and isotonic fluid replacement (equal to the amount of blood removed) are indicated.⁶ Fluid replacement should be used with caution in animals with cardiovascular disease, and the patient should be monitored carefully for fluid overload.⁶

Phlebotomizing to a PCV of 55% in the dog and 50% in the cat is ideal.³ It is best to remove no more than 10-20 ml /kg of blood at one time. Therefore, several treatments may be necessary to achieve the desired effect, depending on the initial PCV.³ A treatment interval should be established that keeps the patient comfortable and free of clinical signs.

In addition to phlebotomy, treatment aimed at addressing the underlying cause of the erythrocytosis will give the most satisfactory clinical results.^3,6 Prognosis varies from good to guarded, depending on the underlying cause of disease.

Inappropriate Secondary Absolute Erythrocytosis

In cases where neoplasia is the suspected underlying cause of disease, excision of the tumor will precede resolution of the erythrocytosis.⁸ Preoperative phlebotomy and fluid replacement may be indicated to reduce surgical complications associated with hyperviscosity of the blood.⁶

For non-neoplastic cases of inappropriate secondary absolute polycythemia, removal of the underlying disease should cause remission of erythrocytosis (e.g., treatment of pyelonephritis).^6,8 If the underlying disease cannot be treated, intermittent phlebotomy and fluid replacement will help alleviate the clinical signs. The prognosis for inappropriate secondary absolute erythrocytosis varies based on the underlying cause of disease. Furthermore, disease may be difficult to assess in these patients.⁶

1. Brockus CW, Andreasen CB: Erythrocytes. In: Latimer KS, Mahaffey EA, Prasse KW (eds): Duncan and Prasse’s Veterinary Laboratory Medicine: Clinical Pathology, 4th ed. Iowa State Press, Ames, IA, 2003, pp. 42-43.

2. Crow SE, Allen DP, Murphy CJ, Culbertson R: Concurrent renal adenocarcinoma and polycythemia in a dog. J Am Anim Hosp Assoc 31:29-33, 1995.

3. Hasler AH, Giger U: Polycythemia. In: Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, 5th ed. W.B. Saunders Company, Philadelphia, 2000, pp 203-206.

4. Latimer KS: Clinical Pathology Class Notes, University of Georgia College of Veterinary Medicine, 2002.

5. Moore KW, Stepien RL: Hydroxurea for treatment of polycythemia secondary to right-to-left shunting patent ductus arteriosis in 4 dogs. J Vet Int Med 15:418-21, 2001.

6. Nitsche EK: Erythrocytosis in dogs and cats: Diagnosis and management. Compend Cont Educ Pract Vet 26:104-118, 2004.

7. Plumb DC: Plumb’s Veterinary Drug Handbook, 4th ed. Blackwell Professional, Ames, IA, 2002, pp 442-443.

8. Raskin RE: Erythrocytes, leukocytes, and platelets. In: Birchard SJ, Sherding RG (eds): Saunders Manual of Small Animal Practice, 2nd ed. W.B. Saunders Company, Philadelphia, 2000, p. 164.

9. Watson ADJ.: Erythocytosis and polycythemia. In: Feldman BF, Zinkl JG, Jain NC (eds): Schlam’s Veterinary Hematology, 5th ed. Lippincott Williams and Wilkins, Philadelphia, 2000, pp. 216-221.