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. 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. Polycythemia has also been mentioned in the literature as erythrocytosis. Absolute erythrocytosis is defined as an RBC mass greater than 125% of the predicted value adjusted for gender and body weight.
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.
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.
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.
Classification of 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. It is of two main types.
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. Secondary polycythemia can also be classified as congenital or acquired depending upon when the individual developed the defect. 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). These mutations are dominantly inherited. 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. The use of anabolic steroids in athletes has been reportedly associated with increased erythrocytosis.
Physiologically appropriate secondary polycythemia (tissue hypoxia):
Physiologically Inappropriate Secondary Polycythemia:
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. In spite of the absence of true erythrocytosis, patients with relative polycythemia are at a higher risk for thromboembolic complications.
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. Chuvash polycythemia is associated with both primary and secondary erythrocytosis due to the underlying pathophysiology involved.
In a study performed by Galeus et al. (2015), COPD, congenital heart disease, and severe pulmonary hypertension were found to be among the most common etiologies of secondary polycythemia. Data is lacking regarding the epidemiology of secondary polycythemia.
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. 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.
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.
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.
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. 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.
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.
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 in
routine clinical practice. 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.
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. 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.
In addition to these, a JAK2 mutation must be investigated for polycythemia vera. 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. Pulmonary function tests should be done to assess the cause of hypoxemia. A sleep study can help in identifying obstructive sleep apnea as the precipitating factor.
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. 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. The oxygen dissociation curve and globin gene sequencing help in evaluating the etiological factors with hemoglobin abnormalities.
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.
Gene mutations testing for EPOR, VHL, PHD2, and HIF2A can help to diagnose a congenital etiological factor.
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.
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.
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.
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. 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. Extrapolation of these results for secondary polycythemia is usually done, keeping in view the clinical judgment of the treating clinician.
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%.
Guidelines for the management of secondary polycythemia
Factors to consider before phlebotomy:
In a study assessing mortality outcomes in a multicity cohort performed by Galeas et al., the median time from diagnosis to mortality was 21.1 months which was about 50% of that for patients with polycythemia vera. Along with this, the study also reported a 5% incidence of thrombotic episodes in patients with secondary erythrocytosis. However, the prognosis has been closely associated with the underlying etiology and the development of complications.
Complications that can arise as a result of secondary polycythemia include:
The following consultations may be considered in a patient undergoing workup for secondary polycythemia and for its management:
Patients should be advised to avoid dehydration and the use of any medication before proper consultation with the primary clinician. Patients should quit smoking as well as discontinue the use of alcohol. They should be educated about the symptoms of thrombosis and advised to watch for them. Limited data suggest that the use of aspirin in low doses can prevent the risk of thrombosis.
Proper follow up with the primary clinician, and the specialists should be encouraged. Patients should be educated about the use of anabolic steroids and their avoidance. For patients living at high altitudes, relocation can be discussed. Long term oxygen therapy has been found helpful for patients with pulmonary diseases.
Elevation in the markers of coagulation activation is substantially more in polycythemia vera as compared to secondary polycythemia. As a result, secondary polycythemia has not shown any clinical evidence of posing the patient to a higher risk of thrombosis. Patients who have an elevated hematocrit but less than 60% may reflect an elevated RBC mass or, more commonly, a contracted plasma volume.
As secondary polycythemia is a rare disease, it may be a clinically challenging condition. Because this disease can be difficult to manage, patients should be referred to a specialized center in order to be managed by an interprofessional team. Secondary polycythemia lacks specific management recommendations as opposed to polycythemia vera. Many of the recommendations have been extrapolated from those of polycythemia vera due to a lack of high-level evidence.
|||Hocking WG,Golde DW, Polycythemia: evaluation and management. Blood reviews. 1989 Mar; [PubMed PMID: 2650777]|
|||Prchal JT, Molecular biology of polycythemias. Internal medicine (Tokyo, Japan). 2001 Aug; [PubMed PMID: 11518102]|
|||Vardiman JW,Thiele J,Arber DA,Brunning RD,Borowitz MJ,Porwit A,Harris NL,Le Beau MM,Hellström-Lindberg E,Tefferi A,Bloomfield CD, The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009 Jul 30; [PubMed PMID: 19357394]|
|||Randi ML,Bertozzi I,Cosi E,Santarossa C,Peroni E,Fabris F, Idiopathic erythrocytosis: a study of a large cohort with a long follow-up. Annals of hematology. 2016 Jan; [PubMed PMID: 26547864]|
|||Percy MJ,Furlow PW,Beer PA,Lappin TR,McMullin MF,Lee FS, A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. Blood. 2007 Sep 15; [PubMed PMID: 17579185]|
|||McMullin MF, Investigation and Management of Erythrocytosis. Current hematologic malignancy reports. 2016 Oct; [PubMed PMID: 27423232]|
|||Nadeem O,Gui J,Ornstein DL, Prevalence of venous thromboembolism in patients with secondary polycythemia. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2013 Jul-Aug; [PubMed PMID: 23007895]|
|||Maran J,Prchal J, Polycythemia and oxygen sensing. Pathologie-biologie. 2004 Jun; [PubMed PMID: 15217714]|
|||Patnaik MM,Tefferi A, The complete evaluation of erythrocytosis: congenital and acquired. Leukemia. 2009 May; [PubMed PMID: 19295544]|
|||Wang W,Cheng J,Mallon C,Al-Marrawi MY,Holder S,Joshi M,Kaag M,Talamo G,Drabick JJ, Symptomatic Secondary Polycythemia Induced by Anti-VEGF Therapy for the Treatment of Metastatic Renal Cell Carcinoma: A Case Series and Review. Clinical genitourinary cancer. 2015 Dec; [PubMed PMID: 26303589]|
|||Percy MJ,Furlow PW,Lucas GS,Li X,Lappin TR,McMullin MF,Lee FS, A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. The New England journal of medicine. 2008 Jan 10; [PubMed PMID: 18184961]|
|||Gale DP,Harten SK,Reid CD,Tuddenham EG,Maxwell PH, Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation. Blood. 2008 Aug 1; [PubMed PMID: 18650473]|
|||Long N,Bassi S,Pepito D,Akhondi H, Gerstmann syndrome complicating polycythemia secondary to anabolic steroid use. BMJ case reports. 2019 Jun 6; [PubMed PMID: 31175112]|
|||Pillai AA,Fazal S,Babiker HM, Polycythemia 2020 Jan; [PubMed PMID: 30252337]|
|||Weinreb NJ,Shih CF, Spurious polycythemia. Seminars in hematology. 1975 Oct; [PubMed PMID: 1198127]|
|||Krantz SB, Erythropoietin. Blood. 1991 Feb 1; [PubMed PMID: 1991159]|
|||Landolfi R,Marchioli R,Kutti J,Gisslinger H,Tognoni G,Patrono C,Barbui T, Efficacy and safety of low-dose aspirin in polycythemia vera. The New England journal of medicine. 2004 Jan 8; [PubMed PMID: 14711910]|
|||Marchioli R,Finazzi G,Specchia G,Cacciola R,Cavazzina R,Cilloni D,De Stefano V,Elli E,Iurlo A,Latagliata R,Lunghi F,Lunghi M,Marfisi RM,Musto P,Masciulli A,Musolino C,Cascavilla N,Quarta G,Randi ML,Rapezzi D,Ruggeri M,Rumi E,Scortechini AR,Santini S,Scarano M,Siragusa S,Spadea A,Tieghi A,Angelucci E,Visani G,Vannucchi AM,Barbui T, Cardiovascular events and intensity of treatment in polycythemia vera. The New England journal of medicine. 2013 Jan 3; [PubMed PMID: 23216616]|
|||Weisse AB,Moschos CB,Frank MJ,Levinson GE,Cannilla JE,Regan TJ, Hemodynamic effects of staged hematocrit reduction in patients with stable cor pulmonale and severely elevated hematocrit levels. The American journal of medicine. 1975 Jan; [PubMed PMID: 1115064]|
|||McMullin MF,Bareford D,Campbell P,Green AR,Harrison C,Hunt B,Oscier D,Polkey MI,Reilly JT,Rosenthal E,Ryan K,Pearson TC,Wilkins B, Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. British journal of haematology. 2005 Jul; [PubMed PMID: 16029446]|
|||Perloff JK,Marelli AJ,Miner PD, Risk of stroke in adults with cyanotic congenital heart disease. Circulation. 1993 Jun; [PubMed PMID: 8504509]|
|||Barenbrock M,Spieker C,Rahn KH,Zidek W, Therapeutic efficiency of phlebotomy in posttransplant hypertension associated with erythrocytosis. Clinical nephrology. 1993 Oct; [PubMed PMID: 8261683]|
|||Kornberg A,Rahimi-Levene N,Yona R,Mor A,Rachmilewitz EA, Enhanced generation of monocyte tissue factor and increased plasma prothrombin fragment1 2 levels in patients with polycythemia vera: mechanism of activation of blood coagulation. American journal of hematology. 1997 Sep; [PubMed PMID: 9298860]|