Polycythemia Vera – Causes, Symptoms, Treatment

Polycythemia, derived from poly (many) and cythemia (cells in the blood), is a condition defined as an abnormal increase in the red blood cell (RBC) mass. For a normal healthy adult, the RBC mass is 23 to 29 mL/kg in females and 26 to 32 mL/kg in males.[rx][rx] Patients with hematocrit? values greater than 51% and 48% and hemoglobin? values greater than 185g/L and 165 g/L in males and females respectively usually have an elevated RBC mass.[rx][rx] Polycythemia has also been mentioned in the literature as erythrocytosis.[rx] Absolute erythrocytosis is defined as an RBC mass greater than 125% of the predicted value adjusted for gender and body weight.[rx][rx]

Absolute or true erythrocytosis differentiates from relative polycythemia where the hematocrit is increased, but the red cell mass lies within the normal range. The elevated hematocrit can be due to the contracted plasma volume.[rx]

An elevated erythropoietin (EPO) level, usually as a secondary response to chronic? hypoxemia?, leads to secondary polycythemia. Chronic hypoxemia can be secondary to various conditions, including lung pathologies like chronic obstructive pulmonary disease? (COPD?), airway pathologies like obstructive sleep apnea? as well as muscular abnormalities like obesity hypoventilation syndrome?.[rx]

Types of Polycythemia

Classification of Polycythemia

On the basis of the response of the erythroid progenitor cells to the circulating cytokines, polycythemia can be further classified into primary or secondary.[rx][rx]

Primary Polycythemia

Primary erythrocytosis is due to the increased proliferation of erythroid progenitor cells secondary to an intrinsic cellular defect. These patients have a suppressed erythropoietin level.[rx][rx][rx] It is of two main types.

• Polycythemia vera – This neoplastic disorder is the result of increased erythroid progenitor cells as well as increased sensitivity to erythropoietin secondary to a mutation called JAK mutation.
• Pure erythrocytosis – The subset of patients with pure erythrocytosis have an isolated elevated RBC mass in the absence of any other precipitating factor.[rx]

Secondary Polycythemia

This is a heterogeneous group of disorders characterized by an elevated RBC mass due to either a physiologically appropriate response to tissue hypoxia? or physiologically inappropriate secretion of erythropoietin and/or other contributing factors.[rx] Secondary polycythemia can also be classified as congenital? or acquired depending upon when the individual developed the defect.[rx][rx] Studies have revealed the presence of around 100 mutations that result in more than 50 variants of alpha and beta globulin genes associated with an increased oxygen affinity as well as mutations affecting the affinity of 2,3-bisphosphoglycerate (2,3-BPG).[2] These mutations are dominantly inherited?.[rx][rx][rx] Familial erythrocytosis results from a mutation in the hypoxia-inducible factor (HIF). A mutation in the HIF transcription factor leads to abnormal oxygen sensing and, as a result, increased production of erythropoietin and hence increased red cell mass.[rx][rx] The use of anabolic steroids in athletes has been reportedly associated with increased erythrocytosis.[rx]

Physiologically appropriate secondary polycythemia (tissue hypoxia)

Acquired

• Central hypoxic process
• Chronic lung disease (COPD, Pickwickian syndrome)[rx][rx]
• Right-to-left cardiopulmonary vascular shunts, cyanotic heart disease[8]
• Carbon monoxide poisoning
• Smoker’s erythrocytosis
• Hypoventilation syndromes including obstructive sleep apnea?, obesity hypoventilation syndrome[rx]
• High-altitude habitat
• Renal? disease (local renal hypoxia, renal artery? stenosis?)

Congenital

• Hemoglobinopathy with high-oxygen-affinity
• Decreased levels of erythrocyte 2,3,-DPG
• Bisphosphoglycerate mutase deficiency
• Methemoglobinemia
• Hereditary? ATP increase
• Oxygen sensing pathway gene mutations (EpoR,3 VHL,8-10 and PHD216)[rx][rx]

Physiologically Inappropriate Secondary Polycythemia

• Tumors with excessive production of erythropoietin or erythropoietin related factors (renal cell carcinoma?, hepatocellular carcinoma, pheochromocytoma, cerebellar hemangioblastoma, uterine leiomyoma?, ovarian carcinoma, meningioma, parathyroid carcinoma/adenomas)
• Drug associated: erythropoietin administration, androgen administration[rx]
• Renal diseases including cysts, polycystic kidney? disease, hydronephrosis?, nephrotic syndrome?, diffuse parenchymal disease, Bartter’s syndrome, end-stage? renal disease, long-term hemodialysis, post-renal transplant erythrocytosis)
• Adrenal cortical hypersecretion[rx]
• Idiopathic? polycythemia[rx]

Relative Polycythemia (Gaisbock’s Syndrome, Spurious, or Stress Erythrocytosis)

• Relative polycythemia is an elevated hematocrit marked with a normal to high normal RBC mass and low normal to decreased plasma volume.[rx] In spite of the absence of true erythrocytosis, patients with relative polycythemia are at a higher risk for thromboembolic complications.[rx]

Chuvash Polycythemia (CP)

• This endemic and recessively inherited congenital polycythemia is named after the Chuvash people in central Russia. EPO levels have been found to be significantly higher than normal. In addition to the higher EPO levels, the erythroid progenitor cells in patients with CP are hypersensitive to EPO. It is associated with a significantly increased mortality in early years secondary to thrombotic and hemorrhagic events.[rx] Chuvash polycythemia is associated with both primary and secondary erythrocytosis due to the underlying pathophysiology involved.[rx]

Pathophysiology

Erythropoiesis is the physiological process that leads to the production and maintenance of RBC mass. This process is regulated by a variety of hormones, receptors, and factors.[rx] EPO is the most important of all the RBC mass regulators. It is produced by the kidneys? and the erythroid progenitor cells as well. Normally, EPO is produced as a response to hypoxemia and anemia?. Hypoxia stimulates the production of hypoxia-inducible factors, which in turn leads to increased gene expression of EPO.[rx][rx]

Red blood cells are essential for oxygen transport. An increase in RBC mass will lead to increased oxygen-carrying capacity of the blood. Patients with secondary polycythemia due to a physiologically appropriate response require higher RBC mass than normal for a proper tissue oxygen delivery.[rx]

It has been reported that a hematocrit higher than 45% is associated with hyperviscosity in normovolemic subjects. A hematocrit higher than 45% has also been associated with decreased cerebral blood flow, which is corrected after phlebotomy. There is a fine balance between the hyperviscosity and normal tissue oxygenation in such patients that is the therapeutic goal.[rx]

Causes of Polycythemia Vera

Secondary polycythemia is due to an increased level of EPO or other transcription factors that, in turn, lead to an increase in the production of RBC mass. It should be noted that unlike primary polycythemia, there is no intrinsic defect in the erythroid progenitor cell lineage. The increase in the levels of EPO can be due to a number of factors, including genetic and acquired, which are discussed below.[rx][rx]

Diagnosis of Polycythemia Vera

History and Physical

A detailed history and thorough physical examination usually provide clues pointing towards secondary polycythemia. A detailed history, including questions for each of the various etiological factors for secondary polycythemia, can aid in the diagnosis.

Patients usually have nonspecific symptoms on the presentation that include fatigue, headache, and dizziness. In some cases, due to the hyperviscosity of blood, transient ischemic attacks lead to a transient visual defect.[rx] History should be focused on identifying the underlying cause. The patient should be asked about the smoking status, any history of weight loss, cough, palpitations, dyspnea, snoring, as well as the family history that is pivotal in the diagnosis of congenital causes. The patient should be asked about the usage of any anabolic steroids for muscle mass, as well as any prescription medication being used or recently used.

On physical examination, scratch marks may be visible in these patients due to pruritus. Cyanosis and clubbing may also be seen. In patients that smoke, nicotinic staining of the nails and teeth can point to the underlying etiology as well. The body mass index of the patient, as well as the alertness, can help in identifying obstructive sleep apnea. A physical examination may reveal splenomegaly. Splenomegaly may, in turn, lead to early satiety as well. Hepatomegaly may be present in some patients. In cases with renal artery stenosis, a bruit may be heard on auscultation.[rx][rx]

Evaluation

The investigation of secondary polycythemia includes a complete blood count, which shows a raised hemoglobin and hematocrit. After an initial raised lab value, it is necessary to repeat labs once after a reasonable time interval in order to rule out a single elevated lab value. Further testing with renal function tests, liver function tests, ferritin levels, abdominal ultrasound, and a chest x-ray should also be performed.[rx]

In order to establish the diagnosis of polycythemia, chromium 51-red cell mass can be evaluated along with plasma volume. However, the test is not widely available and is rarely performed inroutine clinical practice.[rx] One of the frequently encountered problems is seen due to the fact that the supply of radioisotope is not available worldwide, and as a result, the RBC mass calculation is difficult to perform in many centers.[rx]

Early in the investigative workup, an erythropoietin assay must be obtained to assess the levels of EPO as it guides the further workup strategy. It differentiates between primary and secondary polycythemia.[rx] An elevated EPO level points to a diagnosis of secondary polycythemia, but a normal level does not rule out secondary polycythemia as the elevations in EPO can be intermittent. In-vitro culture of the erythroid cells can also be done to diagnose secondary polycythemia. In patients with polycythemia vera, the colony formation of the progenitor cells is not dependent on the levels of erythropoietin, whereas in cases of secondary polycythemia, the colony formation requires the presence of erythropoietin in the culture system.[rx]

In addition to these, a JAK2 mutation must be investigated for polycythemia vera.[rx] When a raised red cell mass is detected, it is necessary to rule out the presence of polycythemia vera. In order to rule out polycythemia vera (PV), iron levels and cytogenetic analysis are required. A bone marrow examination may also help in ruling out PV.

Pulse oximetry is essential. Oxygen saturation less than 92% suggests hypoxia, which is one of the common causes of secondary polycythemia. Measurement of arterial oxygen saturation is necessary for patients with carboxyhemoglobinemia. This is present usually in patients that smoke. In these patients, although the arterial oxygen tension is normal, oxygen saturation levels are decreased.[rx] Pulmonary function tests should be done to assess the cause of hypoxemia. Asleep study can help in identifying obstructive sleep apnea as the precipitating factor.[rx]

In patients with hemoglobinopathies that have high oxygen affinity, the oxygen dissociation curve can aid in the diagnosis. A better test in these patients is a PaO2-50, which is less than 20 in these patients.[rx] PaO2-50 is the partial pressure of oxygen, where 50% of hemoglobin is saturated. This can be easily calculated from venous blood samples as well and serves as the best screening test to detect high oxygen affinity.[rx] The oxygen dissociation curve and globin gene sequencing help in evaluating the etiological factors with hemoglobin abnormalities.[rx]

Renal diseases are also closely associated with secondary polycythemia. In order to evaluate the presence of any renal etiology, an intravenous pyelography, renal ultrasound, renal function tests, and computed tomography (CT) scan are required. In addition to that, liver ultrasonography, CT scan abdomen, and radionuclide scan are also warranted with possible hepatic etiology. A CT scan of the brain with special attention to the posterior fossa can detect a cerebellar hemangioblastoma.[rx][rx]

Gene mutations testing for EPOR, VHL, PHD2, and HIF2A can help to diagnose a congenital etiological factor.[rx]

A frequently encountered difficulty is the avascular nature of adipose tissue that is abundant in obese individuals, making the interpretation of these results cumbersome. Studies have shown that RBC mass expressed on the basis of body weight is lower in obese individuals. As a result, the RBC mass is expressed in relation to body surface area or utilizing a formula that standardizes the red cell mass with the height and weight of the patient.

If investigations reveal that red cell mass is normal, whereas the plasma volume is decreased, the raised value of hematocrit can be attributed to relative polycythemia.[rx]

Treatment of Polycythemia Vera

The treatment approach in secondary polycythemia depends on the etiology involved. The general approach is the correction of the precipitating factors that will, in turn, lead to the correction of the hematologic abnormality.[rx]

Patients that smoke should be advised to quit and should be offered the appropriate supportive, psychological, and pharmacological intervention.

The prescription of diuretics should be reviewed as they are associated with a contraction in the plasma volume. These should be discontinued and replaced with an appropriate alternative or dose adjusted if possible. The use of androgens is discouraged, and they should be either discontinued, or the dosage should be decreased. These patients have a higher than normal requirement for iron in order to produce red cells that are normocytic and normochromic and can carry out oxygen delivery as required. Iron should be replaced in order to avoid any iron-deficient state that leads to the production of microcytic hypochromic red blood cells that are associated with a hyperviscosity state.

Low flow oxygen therapy can correct hypoxia and hence the secondary polycythemia, especially in patients with chronic obstructive pulmonary disease. The use of oxygen should be judicious and closely monitored in accordance with the pulse oximetry in order to avoid any oxygen toxicity and respiratory depression in COPD patients.

For patients with obesity hypoventilation syndrome, weight loss is a corrective measure that can be achieved through lifestyle modifications, pharmacological therapy, and bariatric surgery.[rx]

Surgical removal of erythropoietin producing tumors is therapeutic in patients with this etiology. Treating benign renal lesions is also curative. In some patients with secondary polycythemia, phlebotomy can be performed for temporary relief as well.

The management approach of secondary polycythemia also varies with the development of complications. Low dose aspirin may be useful in preventing thromboembolic episodes.[rx] This is derived from the extrapolation of studies performed for polycythemia vera. On a similar note, venesection has been found to be associated with a decreased risk of cardiovascular death and thrombosis in polycythemia vera.[rx] Extrapolation of these results for secondary polycythemia is usually done, keeping in view the clinical judgment of the treating clinician.[rx]

In contrast to patients with secondary polycythemia due to physiologically appropriate erythrocytosis who benefit from the elevated red cell mass, patients with physiologically inappropriate erythrocytosis do not. In these patients, phlebotomy is therapeutic with goals to maintain hematocrit values of 42% to 46%. Phlebotomy should be performed in any patient with secondary polycythemia prior to any elective surgery. In patients with physiologically appropriate erythrocytosis, as the increased red cell mass is a compensatory mechanism of the body, phlebotomy should not be performed in order to maintain proper tissue oxygenation. In these patients, the therapeutic goal is the fine balance between adequate tissue oxygenation and hyperviscosity.

The underlying diseases and individual responses are the determining factors for the therapeutic goal for the hematocrit. For a general idea, the goal should be to maintain hematocrit values of less than 60%.[rx]

• In patients with COPD, phlebotomy has shown a reduction in pulmonary arterial resistance and arteriovenous oxygen content difference, as well as an improved right ventricular function and hemodynamic response to exertion. These improvements are notable with hematocrits between 50% to 55 %.[rx][rx][rx] In patients with hypoxic pulmonary disease who do not respond to venesection, there is some limited evidence to recommend drugs like an angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers.[rx]
• The goal hematocrit should be carefully tailored to the patients underlying etiology and on a case to case basis. Isovolumic phlebotomy has the advantage of preventing acute hemodynamic effects due to a reduction in blood volume.[rx]
• In patients with cyanotic heart disease, isovolumetric venesections have been recommended to be helpful in reducing viscosity. However, it should be kept in mind that excessive venesections are associated with iron deficiency.[rx][rx]
• In patients diagnosed with idiopathic erythrocytosis, if the hematocrit is above 54%, then reduced to a target of 50% may be considered. For patients with comorbid conditions predisposing to a thrombotic risk and ischemia, a lower target of 45% may also be considered if already greater than 54%. In this specific group of patients, cytoreductive therapy is contraindicated.[rx][rx]
• Avoiding a secondary factor that predisposes to dehydration and usage of ACE inhibitors is recommended in patients with erythrocytosis secondary to post-renal transplant. The target hematocrit for this subset of patients is less than 45%.[rx][rx]

Guidelines for the management of secondary polycythemia

• Determination of the underlying etiology if possible
• Recognizing and eliminating all aggravating factors
• Avoiding severe iron deficiency
• Applying specific measures in accordance with the etiology and therapeutic goal
• Considering phlebotomy for hematocrit maintenance
• Avoiding any myelosuppressive therapy

Factors to consider before phlebotomy

• Physiologically appropriate or inappropriate
• Adverse effects of increased red cell mass
• Presence of symptoms including dizziness, dyspnea, angina
• Previous thrombotic episodes[rx][rx]

Differential Diagnosis

The differential diagnosis for secondary polycythemia includes but is not limited to:[rx][rx]rx[rx][rx]

• Dehydration (causes relative polycythemia)
• Chronic obstructive pulmonary disease[rx]
• Polycythemia vera
• Chronic smoking
• Atrial septal defect
• Ventricular septal defect (children)[rx]
• Cor pulmonale
• Obstructive sleep apnea[rx]
• Drug abuse[rx]
• Post-renal transplant
• Renal vascular pathology including arteriovenous malformation and renal artery stenosis
• Adrenal tumors including incidentaloma
• Cancer including craniopharyngiomas, renal cancer, liver cancer, adrenal carcinoma

Complications

Complications that can arise as a result of secondary polycythemia include:

• Strokes due to increased erythrocytosis (also reported in the anabolic steroid use in athletes)[rx]
• Venous thromboembolism (low dose aspirin used for the prevention)[rx]
• Pulmonary hypertension leading to hemoptysis and cardiomegaly[rx][rx]
• Iron deficiency
• Increased whole blood viscosity
• Impaired blood supply and oxygenation
• Decreased mentation
• Fatigue
• Generalized weakness
• Poor exercise tolerance
• Hyperviscosity