Polycythemia Vera in a Dog Presenting With Uveitis

Case Report

A 2-year-old, castrated male, mixed-breed dog (German shorthaired pointer/Labrador retriever) was referred with a 1-month history of red eyes. The dog had been treated for conjunctivitis with topical antibiotics for 2 weeks with no improvement, followed by a topical antibiotic-steroid product for 2 weeks with only mild improvement. The dog also had a 2-week history of polyuria (PU) and polydipsia (PD) and intermittent vomiting for 1 month. The dog was vaccinated for canine distemper virus, canine adenovirus–type 2, parvovirus, parainfluenza virus, and lyme borreliosis 9 months prior to presentation and was on monthly prophylactic heartworm medication.^a

On physical examination, the dog was lethargic, had brick-red mucous membranes, and was 5% dehydrated; no other abnormalities were noted. Biomicroscopy^b demonstrated miotic pupils, severe conjunctival hyperemia and scleral injection, moderate ventral corneal edema, moderate (2+) aqueous flare, and congested iridial vessels as well as apparent rubeosis irides (i.e., new blood vessel growth in the iris) in both eyes, indicating a moderate bilateral anterior uveitis. Severe vascular congestion, dilatation, and tortuosity with segmentation of retinal vessels were seen in both eyes on indirect ophthalmoscopy.^c One area of grayish discoloration with irregular, indistinct margins (approximately 3 disk diameters in length × 1 disk diameter in width) was also visible in the peripheral dorsotemporal region of the tapetum in the right eye; this indicated a mild, focal, active chorioretinitis. Intraocular pressures, measured by applanation tonometry,^d were 8 mm Hg and 12 mm Hg in the right and left eyes, respectively.

The most likely differential diagnoses for the retinal vessel abnormalities included hyperviscosity syndrome (e.g., polycythemia or hypergammaglobulinemia), hypertension (e.g., primary or secondary to renal, cardiac, or metabolic disease), or both. The presence of anterior uveitis and chorioretinitis expanded the potential etiologies to include disorders that were infectious (e.g., rickettsial, fungal, bacterial, viral), parasitic (e.g., dirofilariasis, toxocara), immune mediated (e.g., Vogt-Koyanagi-Harada-type syndrome), toxic (e.g., ethylene glycol), trauma induced, lens induced, neoplastic, and circulatory (e.g., 1° polycythemia, 2° polycythemia, systemic hypertension, hyperviscosity syndrome, coagulopathies, hyperlipidemia), as well as idiopathic.

Blood was submitted for a complete blood count (CBC), serum biochemistry analysis, rickettsial serology (e.g., Rocky Mountain spotted fever, ehrlichiosis, and borreliosis),^e and Lyme Western Blot analysis.^f Abnormalities included a markedly elevated packed cell volume (PCV), a moderately increased red blood cell (RBC) count (with normal cellular morphology), and a moderate hyperhemoglobinemia [see Table]. A mild hyperproteinemia (9.0 g/dL; reference range, 5.2 to 8.2 g/dL) and mildly elevated renal values (blood urea nitrogen [BUN], 30 mg/dL; reference range, 7 to 27 mg/dL; creatinine, 2.3 mg/dL; reference range, 0.5 to 1.8 mg/dL) were also present. Urinalysis disclosed a urine specific gravity of 1.011. Blood pressure, measured indirectly using a Doppler ultrasonic transducer,^g was 125 mm Hg systolic and 85 mm Hg diastolic. Blood gas analysis of samples taken from the right digital artery and right metatarsal artery revealed oxygen pressures (PaO₂) of 92 mm Hg and 74 mm Hg, and oxygen saturations (O₂ SAT) of 96% and 94%, respectively.

Dehydration was corrected using intravenous (IV) fluids (lactated Ringer’s solution with 20 mEq potassium chloride /L). Following rehydration (as determined by administration of the estimated deficit [5% body weight], normalization of the total protein, a decrease in skin tent time, and weight gain), the PCV remained markedly elevated at 75%. Palliative therapy with serial phlebotomies and replacement IV fluid therapy was initiated. Phlebotomy was difficult because of the hyperviscosity of the blood. A total of 1 liter of blood was removed over a 24-hour period. As a result of the high incidence of ocular manifestations of Lyme disease in the northeastern United States, systemic antibiotic therapy was initiated with ampicillin^h (22 mg/kg body weight, IV, q 6 hours). Topical ophthalmic therapy for the anterior uveitis consisted of 1% prednisolone acetateⁱ q 6 hours and 1% atropine sulphate^j q 12 hours in both eyes.

Advanced diagnostics were pursued in an attempt to rule out the causes of secondary polycythemia, in addition to ruling out fungal disease and neoplasia as the cause of the anterior uveitis and chorioretinitis. Thoracic radiography illustrated subjectively prominent pulmonary vasculature. Results of abdominal radiography, abdominal ultrasonography, and Doppler echocardiography were unremarkable. Following phlebotomy and replacement fluid therapy, the PCV was 54% and the serum biochemistry profile was within reference ranges. The dog tested negative for ehrlichiosis, Rocky Mountain spotted fever, and borreliosis; systemic antibiotics were discontinued. Bone-marrow cytopathology and biopsy revealed erythroid hyperplasia with normal maturation and differentiation. The serum erythropoietin level was 5.8 mU/mL (reference range, 5 to 15 mU/mL).

A diagnosis of polycythemia vera (PV) was made, and hydroxyurea^k was initiated (30 mg/kg body weight, per os [PO] q 24 hours for 7 days) and then decreased (15 mg/kg body weight, PO q 24 hours) until remission was achieved. Following phlebotomy and initiation of hydroxyurea, the ocular signs resolved rapidly, and the dog was tapered off topical steroids within 2 weeks of beginning therapy. The dog has not required further phlebotomies in the 33 months since diagnosis, and he remains clinically normal on maintenance hydroxyurea (11 mg/kg body weight, PO q 24 hours) with a current PCV of 40% and a normal hemogram. Ophthalmic signs have not recurred.

Discussion

Polycythemia is a clinical condition characterized by an abnormal increase in the concentration of circulating RBCs. Polycythemia can be classified as relative or absolute.¹² Relative polycythemia occurs when the PCV is increased in the presence of normal or reduced total RBC mass and a normal or decreased plasma volume.¹³ Relative polycythemia occurs transiently with splenic contraction from stress or severe pain.^14–6 It may also occur with disturbances in fluid balance leading to a decrease in plasma volume, such as occurs with severe dehydration or extensive burns.¹⁷⁸

Absolute polycythemia is characterized by an elevated PCV and total RBC mass. It may be subdivided into primary or secondary forms.¹²⁵ Secondary polycythemia arises as a result of altered erythropoietin regulatory activity, where high concentrations of erythropoietin develop because of a physiologically appropriate or inappropriate response to tissue oxygenation.^1245910

Erythropoietin is a glycoprotein hormone that stimulates erythroid precursors and RBC production in the bone marrow.⁹¹⁰ The kidney is the only site of erythropoietin production in the dog.¹⁰ Production of this hormone is normally controlled by a classic feedback mechanism where tissue hypoxia stimulates its release and a high level of oxygenation inhibits its release.^359–11 Appropriate, secondary polycythemia may occur with cardiac diseases that cause right to left shunts; hemoglobinopathy; high-altitude, pulmonary alveolar hypoventilation and parenchymal disease; and extreme obesity (e.g., pickwickian syndrome).^2459–14 Inappropriate, secondary polycythemia occurs when excessive erythropoietin or erythropoietin-like substances are secreted in the absence of systemic tissue hypoxia. Inappropriate polycythemia can occur in association with a variety of neoplasms (e.g., renal carcinomas, renal lymphosarcoma, renal fibrosarcoma, cerebellar hemangioblastoma, hepatoma, uterine leiomyoma, ovarian carcinoma, pheochromocytoma, adrenocortical adenoma),^41214–16 hormone stimulation (e.g., hyperadrenocorticism),¹⁴ and renal diseases (e.g., renal cysts, pyelonephritis, localized renal hypoxia, hydronephrosis).^124–61116

Primary polycythemia, or PV, is a chronic, myeloproliferative disorder that is characterized by clonal proliferation of noncommitted pluripotent or multipotent stem cells leading to an increased RBC mass marked by an elevated PCV, RBC count, and hemoglobin saturation.¹¹¹¹⁷ These changes occur independently of erythropoietin levels.⁶¹⁸ The cause of PV is unknown; however, results of a human study indicate that an endogenous, deregulated expression of Bcl-x, an inhibitor of apoptosis, may contribute to the erythropoietin-independent survival or erythroid-lineage cells in PV.¹⁹

Primary PV occurs in humans,^11118–21 dogs,^47–9121417 cats,⁹¹⁴ horses,²² cattle,⁹²³ and mice.⁹ It is rare in all species, with <24 documented canine cases in the literature. In the dog, it is a disease of young to middle-aged adults without breed or sex predilection.⁷⁸¹²¹⁷ There has been a recognized familial incidence of PV in a family of 14 Jersey calves;²³ however, there has been no evidence of a possible genetic predisposition in the dog. Leukocytosis, hepatomegaly, and splenomegaly (commonly associated with PV in humans)³ have been reported rarely in the dog⁴⁵⁸¹² and were not present in this case. Transformation to myelofibrosis or acute myeloid leukemia will occur in 10% to 15% of humans with PV, likely because of the genetic instability of mitotic clonal cells;²⁰ however, this has not been documented in animals to date. An unusual case of spontaneous remission was reported in one human with PV following 11 years of phlebotomy therapy only,²¹ but spontaneous remission has not been recorded in dogs.

Common clinical signs reported in dogs with PV include hyperemic mucous membranes (mm), lethargy, anorexia, bleeding episodes, weakness, vomiting, restlessness, exercise intolerance, weight loss, PU/PD, hematuria, depression, and other central nervous system signs.^157111224 Published ocular manifestations of polycythemia include retinal vascular tortuosity,⁷ dilatation,⁷²⁴ segmentation,²⁵ retinal hemorrhage, retinal detachment,²⁵ blindness,¹² and secondary glaucoma.^26–28 The dog in this case exhibited the clinical signs of hyperemic mucous membranes, lethargy, vomiting, and PU/PD. Anterior uveitis and chorioretinitis, as well as severely dilated, tortuous, and segmented retinal vessels were also present. To the authors’ knowledge, there have been no cases published in the literature suggesting PV as a potential cause of anterior uveitis or chorioretinitis.

The clinical signs seen with polycythemia are attributable to an elevated blood viscosity, leading to decreased peripheral perfusion of oxygenated blood.^1–3 Systemic oxygen transport begins to decline when the PCV is >60%.⁴ At a PCV of 70%, viscosity is 2.5 times normal²⁹ and, together with expansion of the cellular components of circulating blood volume²⁴ (which also occurs in polycythemia), will result in obstruction of blood flow through small blood vessels. These changes lead to vascular stasis, infarction, thrombosis, tissue injury, and rupture of small blood vessels.^2681228 These vascular changes could in turn cause breakdown of the blood-ocular barrier and lead to the signs of anterior uveitis (e.g., miosis, corneal edema, aqueous flare, rubeosis irides) and chorioretinitis noted in this case. Rubeosis irides (i.e., reactive hypertrophy of vessels in the interior iris stroma) is a controversial clinical finding when histopathological evidence (e.g., preiridal fibrovascular membranes) is unavailable; however, it has been previously documented in one case of stress polycythemia in a human following strenuous activity.³⁰ Most other potential causes of uveitis were methodically ruled out with diagnostic tests, and the systemic signs and ocular signs (including anterior uveitis and chorioretinitis) improved as the PV went into remission, thereby supporting this hypothesis.

Primary PV is a diagnosis made by exclusion. Relative polycythemia and causes of secondary polycythemia must be exhaustively ruled out. Direct measurement of total RBC mass using radioisotopes, such as radioactive sodium chromium (⁵¹C), is commonly performed in humans to distinguish relative from absolute polycythemia.¹⁸ This test has been performed in small animals in research settings, but it is rarely performed in a clinical setting.^4–612 Radioactive chromium assay is an important test in humans, because PV may occur with a normal hematocrit as a result of a concurrent and substantial elevation in plasma volume.¹¹

A PCV >60% has been reported to reliably predict an elevated RBC mass in humans.⁸ A PCV >70% has been similarly suggested as consistent with PV in dogs.³¹ In dogs, a response to fluid therapy is the primary method used to differentiate relative from absolute polycythemia.⁴⁵⁹¹⁰ The PCV in this patient was originally 82%, and although the dog was mildly dehydrated on presentation, the PCV continued to remain markedly elevated at 75% following rehydration, thereby ruling out relative polycythemia as the cause of increased PCV.

Appropriate causes of secondary polycythemia were ruled out using advanced diagnostic procedures. The blood gas analysis of the right metatarsal artery revealed a PaO₂ of 74 mm Hg, whereas the PaO₂ of the right digital artery was within the reference range at 92 mm Hg. This discrepancy was likely secondary to the severe sludging of the blood, which decreased the transit time of the blood and allowed more oxygen to be off-loaded into the surrounding tissues. The O₂ SATs, which are considered more reliable in diagnosing chronic tissue hypoxia,¹¹¹ were within the reference range (at 94% and 96%, respectively). Moreover, no evidence of cardiac, lung, or kidney disease was revealed upon evaluation of a CBC, complete serum biochemistry profile, urinalysis, Doppler echocardiography, chest radiography, abdominal radiography, or abdominal ultrasonography. The bone-marrow biopsy revealed hyperplasia with a normal myeloid to erythroid ratio, consistent with PV.¹⁷ These diagnostic tests also allowed the authors to rule out inappropriate causes of secondary polycythemia. The diagnosis of PV was confirmed by a low-normal serum erythropoietin assay.⁴⁵¹⁰

Treatment of PV in most cases involves phlebotomy initially; this has also been recommended as the sole treatment.^1111417 Removal of 20 mL/kg body weight of blood will successfully decrease the PCV by 15%.¹²¹⁴ However, repeated phlebotomy may result in thrombotic complications or iron deficiency.²⁰ Thrombosis-induced death is more likely to occur in the early stages of treatment when phlebotomy is the only therapy.⁶²⁰ Phlebotomy also leads to iron deficiency, as removal of 100 mL of blood results in a loss of 50 mg of iron.³ Iron deficiency is accompanied by a RBC microcytosis, which was initially considered advantageous in humans with PV, as it maintained PCV within the reference range for longer periods of time.³² However, microcytosis is often accompanied by hypochromia, which results in less malleable RBCs. This, in turn, increases blood viscosity and the risk of thrombosis-induced death.²⁹ Abnormal RBC morphology, including microcytosis and hypochromia, was not seen in this case following phlebotomy. Hyperlipidemia and myocardial infarcts are additional complications associated with humans undergoing treatment with phlebotomy; however, these do not commonly occur in the dog.¹¹²⁰ For the above reasons, systemic myelosupppressive therapy is recommended if phlebotomies are required more frequently than every 6 to 8 weeks.⁴⁹

A number of different chemotherapeutic drugs have been used to treat primary PV, including busulphan,⁷ chlorambucil,⁶ cyclophosphamide, melphalan, radioactive phosphorus,²⁴ interferon alpha, and hydroxyurea.⁸¹¹¹² Radioactive phosphorus and the alkylating agents have been associated with a high incidence of leukemia, thrombosis, and the development of other myelodysplastic conditions,⁴⁸¹²²⁴ and as a consequence, hydroxyurea is considered the drug of choice.⁴⁶¹⁴¹⁷

Hydroxyurea inhibits the conversion of ribonucleotides (RNA) to deoxyribonucleotides (DNA) through destruction of RNA diphosphate reductase. This inhibits DNA synthesis without affecting RNA or protein synthesis, and it may cause reversible bone-marrow depression.² Side effects associated with hydroxyurea administration include anorexia, vomiting, reversible bone-marrow hypoplasia, alopecia, and spermatogenic arrest. Darkening of the skin has also been reported in two dogs.¹³ Although sloughing of nails has been described as a side effect of this drug in animals,³³ there are no case reports supporting this theory. These side effects may be eliminated through the discontinuation of hydroxyurea and avoided by restarting the drug at a slightly lower dose or dosing frequency. Prognosis for resolution of primary PV is guarded in dogs, yet remissions lasting several years have occurred in some cases.²⁴ To date, the dog of this report remains free of clinical signs >33 months postdiagnosis, with a PCV within reference range while on 11 mg/kg body weight of hydroxyurea therapy.

Clinical signs seen with PV result from severe hyperviscosity and associated decreased oxygen delivery to tissues, and they resolve as the RBC mass returns to within reference ranges. In this case, the clinical signs of lethargy, PU/PD, vomiting, and chorioretinitis resolved without specific treatment. The anterior uveitis would have possibly resolved without treatment as the hyperviscosity was controlled; however, topical prednisolone acetate and atropine sulphate were administered in order to prevent potential sequelae, including posterior or peripheral anterior synechiae and secondary glaucoma. Following phlebotomy and initiation of hydroxyurea, the ocular and clinical signs resolved quickly; the dog was tapered off topical steroids and atropine within 2 weeks, thereby supporting the authors’ hypothesis that the panuveitis was attributable to PV.

Conclusion

To the authors’ knowledge, this is the first case report of confirmed canine PV associated with anterior uveitis and chorioretinitis; PV must be considered as a potential etiology of uveitis in the dog.

Acknowledgments

The authors acknowledge Dr. P. McIsaac from the Granby Animal Clinic, Granby, Massachusetts, for her collaboration and Dr. Carl D. Porter for his assistance with the preparation of this manuscript.