Urs Giger, Prof. Dr. med. vet., MS, FVH, DACVIM & DECVIM-CA (Internal Medicine), DECVCP (Clinical Pathology)
School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
How I Diagnose and Treat Polycythemia
Although strictly speaking polycythemia implies a rise of all blood cell counts above normal, the occurrence of leukocytosis and thrombocytosis along with erythrocytosis is exceptionally rare in companion animals. Hence, polycythemia would be more appropriately called erythrocytosis and clinically refers to an increase to an above-normal red blood cell count, hematocrit or packed cell volume (PCV), and hemoglobin (Hb) concentration. Polycythemic animals will not show clinical signs until the PCV reaches >60% with some of the highest PCVs exceeding 85%. Because of an underappreciation of the normal upper limit of the PCV in cats (48%) versus dogs (56%), polycythemia is generally underdiagnosed in cats. Based upon blood volume and red cell mass, polycythemia can be divided into relative and absolute polycythemias, which represent completely different conditions, both requiring immediate but opposing therapeutic interventions.
Relative polycythemia is characterized by an elevated PCV in the presence of a normal (or even decreased) total red blood cell mass. This is usually due to a decrease in plasma volume associated with severe dehydration or increased serum total proteins (e.g., profound vomiting and diarrhea, or severe burns). The hematocrit is generally only mildly increased, therefore relative polycythemia is rarely associated with signs of hyperviscosity, and the clinical features of the underlying disorder prevail. Because of the obvious signs of dehydration, relative polycythemia is usually easily recognized and simply corrected with aggressive fluid therapy.
Absolute or true polycythemia is characterized by an expanded red blood cell mass. Splenic contraction is an unlikely cause in dogs and cats, as it only marginally increases the PCV. The blood volume and red cell mass could be determined by labeling red cells radioactively or with biotin. This is, however, rarely if ever needed in clinical practice, as dehydration can be readily excluded as cause of relative polycythemia. More difficult is the differentiation of absolute polycythemia into primary or secondary polycythemia, which depends on whether the condition is erythropoietin independent or dependent.
Some clinicians readily equate absolute erythrocytosis with polycythemia vera (P. vera) without considering other differential diagnoses. Clinical experience, however, suggests that P. vera may occur rarely compared to other forms of polycythemia. New insight into the causes of primary and secondary polycythemias has been gained in human and veterinary medicine. However, if the underlying condition cannot be corrected, lowering the PCV into a safe range in patients with absolute polycythemia may be successfully accomplished with repeated phlebotomy and, if needed, chemotherapy.
Primary polycythemia appears erythropoietin independent and has often been considered synonymous with P. vera in small animals, although additional forms of primary polycythemia need to be considered. In fact, animals with a presumptive diagnosis of primary polycythemia as well as cases with an early presentation in life that continues over a chronic course of many years, point strongly to the existence of other forms of primary polycythemia in dogs and cats. More research is needed in small animals to determine, if such processes are occurring in these polycythemic patients who do not clearly have P. vera.
Polycythemia vera is a myeloproliferative clonal disease that arises from a multipotent hematopoietic progenitor cell in the bone marrow. A single transformed stem cell gains a selective growth advantage and becomes the predominant source of marrow precursors, and the clonality of the bone marrow cells of human patients with P. vera has been documented. P. vera, therefore, results in the accumulation of morphologically normal red blood cells, and less commonly white cells and platelets, and their progenitor cells in the absence of a definable stimulus. Granulocyte and platelet counts in the blood would be expected to be increased, but are usually normal. The bone marrow aspirate is consistent with erythroid hyperplasia, but is not diagnostic for a myeloproliferative disease in humans. There are no cytologically characteristic features of the bone marrow cells in P. vera as hematopoietic cells appear to fully mature. Classically, human patients have serum erythropoietin levels in the low to normal range and erythroid progenitor cells that proliferate and mature independent of erythropoietin, but these culture assays are not robust and readily available. In humans with P. vera, Jak-2 mutations have been documented and in a couple of dogs Jak-2 mutations have been found but the test for Jak-2 mutation is not clinically available in veterinary medicine. Hence, the diagnosis of P. vera is still based on the exclusion of other causes of erythrocytosis.
Secondary polycythemia refers to a group of diseases triggered by an exaggerated erythropoietin-dependent stimulation of red cell production. This may be considered an appropriate response in which the erythron is responding normally to generalized tissue hypoxia or inappropriate in which the erythropoiesis is being stimulated by an aberrant production of erythropoietin or due to local renal hypoxia.
Appropriate PCV rises are seen in high altitudes and with cardiopulmonary disease such as congenital heart defects with right-to-left shunts (ventricular septal defects, reversed PDA, tetralogy of Fallot) and rarely chronic obstructive pulmonary diseases. Cats with cardiac shunting usually die before they can develop signs of polycythemia. Furthermore, an appropriate secondary polycythemia has been documented in several breeds of dogs and domestic shorthair cats with hereditary methemoglobin reductase deficiency, which results in the erythrocytes’ inability to carry oxygen. Similarly, chronic carbon monoxide intoxication can cause polycythemia with pink mucous membranes.
Inappropriate absolute polycythemia includes renal diseases, as well as tumors producing erythropoietin, and is typically associated with typically high serum erythropoietin levels. Various renal tumors, including nephroblastomas and carcinomas, may result in renal hypoxia and thereby cause elevations in serum erythropoietin and, consequently, inappropriate secondary polycythemia; whereas erythropoietinproducing tumors in other tissues have rarely been documented. Inappropriate secondary polycythemia of renal origin may also be rarely caused by amyloidosis, polycystic kidney disease, glomerulonephritis, and renal fibrosarcoma and lymphoma. In most cases increased serum erythropoietin concentrations were documented or an association was established based upon the resolution of the polycythemia following the resection of the mass in animals and humans.
The clinical signs of relative polycythemia are easily recognized and will not be further discussed here. Clinical signs of absolute polycythemia are characterized by manifestations of the underlying disease process and are associated with hyperviscosity and the expanded blood volume. They include hyperemic or cyanotic mucous membranes (due to cardiopulmonary disorders and methemoglobinemia), hemorrhage (epistaxis and hyphema), and neurologic disturbances such as lethargy and seizures. Neurologic signs are the most common presenting complaints, but with the advent of more frequent health screens including complete blood cell counts, the erythrocytosis may be discovered earlier as an incidental finding. Cyanosis or renal size abnormalities may suggest a particular organ failure as well as mechanism, and define the type of the polycythemia. However, secondary cardiac and renal changes due to erythrocytosis may also be observed and confound the interpretation. Polydipsia and -uria and splenomegaly have been seen in animals assumed to have P. vera and rarely with other polycythemias.
As relative polycythemias are readily recognized, confirmation of a normal blood volume may not be required in clinical practice. In fact, patients with absolute polycythemia often have an expanded blood volume. Diagnostic tests for absolute polycythemia include a complete blood cell count, absolute reticulocyte count, chemistry screen, urine analysis, blood gases and pulse oxymetry, chest and abdominal radiographs, cardiac examination and an ultrasound to evaluate the kidneys and liver. Cyanosis may only be noted caudally. Dark blood may be exposed to air to determine if it is deoxyhemoglobin or methemoglobin. Serum erythropoietin values, determined by a speciesvalidated assay, may be elevated in cases of secondary polycythemia, but a normal to low erythropoietin level does not rule out secondary polycythemia. An increased absolute reticulocyte count in light of a polycythemia supports the exaggerated hematopoietic response and documents the presence of an absolute polycythemia. However, a bone marrow aspirate for cytologic examination adds no new information, since it fails to differentiate between primary and secondary polycythemias: the myeloproliferative disease resulting in P. vera has no characteristic cytologic or pathologic features of malignancy.
The treatment of relative and absolute polycythemia is clearly different. In emergency situations, patients with relative polycythemia will respond to fluid therapy, whereas patients with absolute polycythemia may need to be treated by phlebotomy. If possible, renal and other tumors/masses should be removed or treated and cardiopulmonary distress should be corrected. Animals with methemoglobin reductase deficiency may not need to be treated except during severe stress situations with methylene blue (1 mg/kg IV once). In severely polycythemic patients repeated phlebotomies at no more than 20 ml/kg (10 ml in cats) per session with or without simultaneous fluid replacement is the initial approach to lower the PCV to <60%. Phlebotomies can be repeated on a daily basis until the target PCV has been reached. In animals with absolute polycythemia, fluid administration beyond replacement may be associated with cardiopulmonary failure as these animals are completely volume expanded. In cases that require multiple phlebotomies in a short period, replacement of coagulation factors and albumin with plasma may need to be considered. The target hematocrit is higher in dogs than in cats, as well as in cases with cardiopulmonary disease, but generally is greater than 50%.
Long-term control of absolute polycythemia may be achieved by periodic phlebotomies, radioactive phosphorus, and/or chemotherapy. Chemotherapy with hydroxyurea at 10–25 mg/kg twice daily to once every other day is commonly used. Animals treated with chemotherapy need to be monitored, not only by PCV measurements as for phlebotomized patients, but also by complete blood cell counts to identify drug-induced cytopenias. Hydroxyurea has also caused nail sloughing. Furthermore, antithrombotic doses of aspirin (1 mg/kg per day) may be considered, but there is no proof that it reduces the risk of thrombosis, and higher doses may lead to increased bleeding tendencies. Polycythemic animals may remain asymptomatic for weeks to years and, in some cases, can be successfully managed for years. Long-term follow-up has not been reported in animals, although the author has observed persistent polycythemia for more than a decade in certain animals.