Polycythemia/Erythrocytosis

By Catherine Sumner, DVM, DACVECC
www.angell.org/emergency
emergency@angell.org
781-902-8400
MSPCA-Angell West, Waltham

When a patient is found to have a significantly elevated red blood cell (RBC) count, we usually report that they have polycythemia.  However, there is often confusion between the terms polycythemia and erythrocytosis.  Polycythemia can be used more appropriately to describe situations in which all blood cell lines are increased (RBCs, leukocytes, and thrombocytes/platelets).  Erythrocytosis is defined as an increase in solely RBCs.  This increase can be determined by measuring packed cell volume (PCV), hematocrit (Hct), hemoglobin (Hb) or RBCs, all of which would be increased.  In our patients, increases in leukocytes and platelets are not usually noted concurrent with erythrocytosis.  For the purposes of this article, the terms polycythemia and erythrocytosis will be used interchangeably, as this is how they are generally used clinically.

The first question to consider is at what PCV the presence of erythrocytosis is described.  In dogs, the upper limit for PCV is considered to be 55%.  In cats, the upper limit for PCV is lower and is stated to be 45-48%.  At PCVs above these cut offs, erythrocytosis is reported.  Clinical signs of erythrocytosis do not usually appear until the PCV reaches 60%, and PCVs described in the literature can be upwards of 85%.  Some breeds (Greyhounds, some other sight hounds, and some Dachshunds) normally have a higher PCV.

Once erythrocytosis has been identified, the next question is whether it is a relative erythrocytosis (far more common) or an absolute erythrocytosis.  This can usually be determined based on the patient’s history and physical exam.

Relative erythrocytosis occurs when there is a decrease in the blood plasma volume, rather than a true increase in the number of RBCs present.  Causes include a decrease in fluid intake, a rapid loss of fluid, such as would occur with gastrointestinal signs or burns, or fluid shifts.  This is a situation of hemoconcentration and can also be termed a spurious polycythemia.  A transient relative erythrocytosis can occur in dogs with splenic contraction, but typically this will not result in an increase in PCV over 60%.  Patients with a relative erythrocytosis should show concurrent signs of dehydration (tachycardia, prolonged CRT, hypotension, concentrated urine, pre-renal azotemia, etc.), typically do not show clinical signs attributed to erythrocytosis, and have a history supporting the development of dehydration.  Additionally, there should be an increase in total protein along with the increased PCV.  However, one exception to this could be a dog with hemorrhagic gastroenteritis.  In these cases we can see a very high PCV but with a normal or even low total protein level due to gastrointestinal losses.  In cases of relative erythrocytosis, the PCV typically does not exceed 65% and will return to normal with appropriate fluid therapy, which is the mainstay of therapy for these cases.

It is also important to consider iatrogenic causes for erythrocytosis.  Aggressive blood transfusions could result in erythrocytosis.  Additionally, patients receiving erythropoietin (EPO) supplementation could develop a high PCV if EPO therapy is excessive.

Absolute erythrocytosis occurs when there is a true increase in the number of red blood cells present.  Typically, this is due to increased erythropoiesis (production of RBCs), rather than a longer survival of existing RBCs.  Erythropoiesis is controlled by oxygen delivery to the kidney and EPO, a hormone.  EPO synthesis is increased as a result of renal hypoxia; acceptable or over supply of oxygen to the kidneys will result in decreased EPO synthesis.  Absolute erythrocytosis cases can be further classified into primary and secondary, and testing for suspected cases should include labwork (CBC with reticulocyte count, chemistry panel, blood gas analysis, urinalysis), imaging (thoracic radiographs, abdominal radiographs or ultrasound, echocardiogram) and EPO level.  Unfortunately, examination of the bone marrow is not helpful in distinguishing the cause of erythrocytosis; typically, the bone marrow will exhibit erythroid hyperplasia regardless of the cause.  Measurement of EPO levels can be difficult, as human assays are often the only available method and there can be overlap in measured values between affected patients and normal animals.

Primary erythrocytosis is defined as cases in which increased erythropoiesis is not due to an increase in EPO.  These cases can be either congenital or acquired, and EPO levels should measure low in these patients.  In primary congenital cases, there are EPO receptor mutations or EPO receptor hypersensitivity.  These patients are usually diagnosed with erythrocytosis at a young age, would not be expected to have concurrent thrombocytosis or leukocytosis, and their disease will not progress.  In acquired cases, a myeloproliferative disease of the bone marrow results in clonal expansion of a single hematopoietic stem cell, and this can be termed polycythemia vera. In these cases, one could theoretically see increases in all 3 blood cell lines (RBCs, WBCs, platelets).  These patients can progress to having leukemia or myelofibrosis.  Polycythemia vera is a diagnosis of exclusion; there is no test in animals to differentiate polycythemia vera and congenital erythrocytosis, other than considering the history and time of diagnosis.

Secondary erythrocytosis is defined as cases in which increased erythropoiesis is due to an increase in EPO.  These cases can be considered either appropriate or inappropriate – this classification is based on the presence of systemic hypoxia causing an increase in EPO (appropriate) or the absence of systemic hypoxia but with an increased EPO level (inappropriate).  Measurement of EPO levels can be helpful in diagnosis of secondary polycythemia, as an elevated level is diagnostic; levels can be increased up to 50 times normal.  However, on occasion, EPO levels can measure as normal or low in these cases, so a low level does not rule out secondary erythrocytosis.

Secondary appropriate erythrocytosis is diagnosed in patients with concurrent systemic hypoxia.  These patients will have an arterial oxygen saturation <92%.  The vast majority of these cases are due to situations that result in right to left shunting of blood.  This results in circulating blood that is less oxygenated than normal, as some of it is not passing through the lungs.  Many congenital heart defects can result in right to left blood shunting, including ventricular septal defects (VSD), tetralogy of Fallot, and reversed patent ductus arteriosus (rPDA).  Other causes of secondary appropriate erythrocytosis could include chronic pulmonary disease or chronic upper airway obstruction (i.e. bulldogs), but usually an extreme increase in RBC count is not noted in these cases.  Rarely, patients may have defective hemoglobin that is not able to carry oxygen as effectively; examples include patients with methemoglobinemia.  Also, animals living at high altitude may have a higher PCV due to chronic hypoxia.  Carbon monoxide toxicity can cause erythrocytosis when there is recurrent exposure.  Clinically, these cases can be divided based on the presence or absence of cyanosis: patients with heart defects, airway disease, or methemoglobinemia will exhibit cyanosis, whereas those at a high altitude or with carbon monoxide exposure will not.  Patients with heart defects usually have a concurrent heart murmur, except for rPDAs, which often do not.

Secondary inappropriate erythrocytosis is the term used to describe patients that have an increase in EPO, but are not suffering from systemic hypoxia.  Conditions of the kidney can cause this, including neoplasia (carcinoma, lymphoma, nephroblastoma), amyloidosis, infection, or inflammation.  Tumors that secrete EPO can also be located elsewhere in the body other than the kidneys; they have been reported in dogs in the cecum (cecal leiomyosarcoma) and liver (hepatoma).  These neoplasias can be either benign or malignant.

Of all of the causes of erythrocytosis discussed above, it appears that the most common cause for absolute erythrocytosis is neoplasia – classified as a secondary inappropriate erythrocytosis.  In these cases, there is usually a neoplastic process in a kidney.

Most clinical signs of absolute erythrocytosis are related to an increase in blood viscosity.  As viscosity increases, there is a decrease in blood flow in capillaries, resulting in tissue hypoxia, sludging, and thrombosis.  This impairment of the microcirculation occurs in the brain and is responsible for neurologic clinical signs including behavior changes, ataxia, blindness, and tremors that can progress to seizures.  These neurologic signs are what prompt most owners to present their pet for evaluation.  Patients may also develop hemorrhage due to increased viscosity; epistaxis, hyphema and GI bleeding have been noted.

It is crucial to distinguish relative erythrocytosis from absolute erythrocytosis, as the treatment varies significantly.  In cases of relative erythrocytosis, the treatment is aggressive IV fluid, as discussed above.  With absolute erythrocytosis, initial treatment is removal of whole blood.  This is most often performed via phlebotomy, but leeches could also be considered.  Recommendations are for removal of 10-20 mL/kg of blood at a time consecutively until clinical signs are improved.  The removal of 20 mL/kg of whole blood should decrease the PCV by roughly 15%.  The goal PCV varies somewhat based on the cause of erythrocytosis.  For cases with secondary appropriate erythrocytosis, a higher PCV (60%) is acceptable after phlebotomy, whereas for cases of primary erythrocytosis, the goal is PCV <55% (dogs) or 50% (cats).  Typically, blood removal is performed via jugular phlebotomy.  If repeated removal of blood is expected in a short time period, a jugular catheter that bleeds back may be helpful.  If leeches are used, each leech is reported to remove between 5-10 mL of blood.  As blood is removed, it is important to consider the patient’s volume status and provide IV fluid therapy as needed to preserve blood volume.  In patients exhibiting seizures, traditional anti-seizure medications alone are unsuccessful.

If the underlying cause for erythrocytosis can be corrected, it should be treated (i.e. removal of an EPO secreting tumor, prevention of carbon monoxide exposure).  Prior to surgery, the patient should be stabilized via phlebotomy and IV fluids, as indicated.  However, most patients diagnosed with absolute erythrocytosis do not have a curable condition and need to be treated throughout their lifetime.  Often, signs can be controlled with intermittent phlebotomy, every 1-2 months based on sequential PCV/TS monitoring.  Chronic phlebotomy can result in hypoproteinemia and iron deficiency; administration of plasma and iron supplementation can be considered in these cases.  If the PCV and clinical signs cannot be controlled with phlebotomy, myelosuppressive drug therapy with hydroxyurea can be considered.  Hydroxyurea therapy should be initiated following phlebotomy to reach the goal PCV for the patient, and it has been used successfully in veterinary patients with primary and secondary erythrocytosis.  CBCs must be carefully monitored during therapy to determine the appropriate dose as well as to monitor for myelosuppressive complications.  Radioactive phosphorus has also been used as a myelosuppressive agent.  Antithrombotic therapy can also be considered in patients with absolute erythrocytosis.

As erythrocytosis is a rarely diagnosed condition, there is a scarcity of data regarding survival.  In general, the prognosis for patients with primary erythrocytosis is guarded, whereas the prognosis for patients with secondary erythrocytosis depends on the underlying cause.  Patients with suspected erythrocytosis can benefit from referral to Angell.  In patients with acute neurologic signs, the emergency and critical care service can stabilize these patients and help to decrease the PCV rapidly to resolve signs.  Our specialists can then perform advanced diagnostic tests to look for the underlying cause for erythrocytosis.  While a rare condition, erythrocytosis should be considered in patients with an elevated PCV without other signs and in particular in patients with an elevated PCV and concurrent neurologic signs.

For more information about Angell’s Emergency/Critical Care service, please visit www.angell.org/emergency or call MSPCA-Angell West in Waltham at 781-902-8400.

References:

Nitsche, EK “Erythrocytosis in Dogs and Cats: Diagnosis and Management” Comp Vet Med 2004: 26(2); 104-119.

Giger, U “Chapter 72: Polycythemia and Erythrocytosis” in Textbook of Veterinary Internal Medicine, 7th edition, ed: Ettinger SJ, Feldman EC.  279-283.