Practice Essentials
Polycythemia refers to increased red blood cell mass and is often used interchangeably with the term erythrocytosis.
Polycythemia can be primary or secondary. Primary polycythemias are caused by inherited or acquired mutations resulting in dysregulated erythroid development, whereas secondary polycythemias are caused by increased erythropoiesis-stimulating factors. Relative polycythemia, or pseudoerythrocytosis, is caused by an apparent red blood cell mass increase due to plasma volume reduction (eg, due to severe diarrhea with subsequent dehydration), resulting in increased hemoconcentration.
This article will review both primary and secondary polycythemias. A specific type of primary polycythemia, polycythemia rubra vera (often just called polycythemia vera) is an acquired myeloproliferative disorder which is discussed in detail elsewhere (Pediatric Polycythemia Vera).
Laboratory Definitions
The following laboratory terms are used to document polycythemia.
Hematocrit
The hematocrit (Hct) is the percentage of blood that red blood cells occupy. An adult patient with an Hct of over 48% (in women) or more than 52% (in men) is considered to be polycythemic. In pediatric patients, the Hct must be corrected for age, including gestational age for neonates. [1]
Hemoglobin concentration
The protein hemoglobin, found in red blood cells, is responsible for oxygen delivery. An adult patient in whom the hemoglobin concentration (Hgb) is above 16.5 g/dL (in women) or over 18.5 g/dL (in men) is considered to be polycythemic. In children, the Hgb, like the Hct, must be corrected for age.
Symptoms of polycythemia
These include the following:
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Headache, dizziness, vertigo
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Weakness, malaise, or myalgias
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Visual disturbances
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Tinnitus
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Diaphoresis
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Pruritus - Especially after exposure to warm water
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Erythromelalgia - Burning pain, warmth, and redness of extremities
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Dyspnea
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Arthropathies
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Epigastric discomfort, satiety, constipation, weight loss
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Chest pain
Workup in polycythemia
The following laboratory findings can be seen in polycythemia:
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Complete blood count (CBC) - Leukocytosis and thrombocytosis are commonly observed but not universal in patients with polycythemia; large platelets are often seen; red cell mass is greater than 36 mL/kg in men and greater than 32 mL/kg in women
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Serum erythropoietin (Epo) - Elevated serum Epo levels can be used to distinguish polycythemia vera (PV) from secondary polycythemia
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Elevated sedimentation rate
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Spurious hyperkalemia or hypokalemia
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Increased blood viscosity
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Artifactual prolongation of coagulation studies
Management of polycythemia
Treatments for primary polycythemia include the following:
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Phlebotomy - The goal of phlebotomy is to maintain normal red cell mass and blood volume, with a target hematocrit level of 42-46% for men and 39-42% for women
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Hydroxyurea - Hydroxyurea as a myelosuppressive agent is also widely used in high-risk patients with polycythemia vera (ie, >60 y, history of thrombosis) who require cytoreductive therapy, reducing the need for phlebotomy [2]
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Interferon - Interferon-alpha is effective in eliminating JAK2V617Fexpression and inducing hematologic remission
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Tyrosine kinase inhibitors
Phlebotomy is used for symptomatic hyperviscosity in secondary polycythemia.
Pathophysiology
Normal Red Blood Cell Development
Red cell development, or erythropoiesis, is a carefully ordered sequence of events. This process initially occurs in fetal liver cells and subsequently takes place in the bone marrow of children and adults. Normal erythropoiesis begins with multipotent hematopoietic stem cells, which differentiate into erythroid progenitors, eventually to develop into the mature red blood cells. The hormone erythropoietin (Epo) is essential to this process. In the fetus, Epo is produced by monocytes and macrophages found in the liver. After birth, the majority of Epo is produced in the kidneys. The major stimulus for Epo production is hypoxia. Anemia, decreased hemoglobin oxygen saturation, decreased oxygen release from hemoglobin, and reduced oxygen delivery can all be sensed in the kidney and lead to the increased production of Epo. Erythropoiesis is carefully regulated with negative feedback inhibition from increased oxygen delivery, which down-regulates Epo production.
Upon Epo binding to its receptor, EpoR, signaling through the Janus kinase 2 (JAK2) pathway activates multiple signaling cascades, leading to reduced cell death and expansion and differentiation of progenitor cells to mature red blood cells. The hypoxia-inducible factor (HIF) pathway regulates a cascade of genes allowing survival in low-oxygen conditions. The transcription factor HIF consists of two subunits, α and β. The α subunit becomes stabilized in low-oxygen conditions, translocates to the nucleus, and dimerizes with the β subunit to promote gene transcription. In oxygen sufficient environments, HIF is degraded by the von Hippel-Lindau (VHL) tumor suppressor complex. [3]
Primary Polycythemia
Primary polycythemias are due to factors intrinsic to red cell precursors caused by acquired or inherited mutations. These polycythemias include the diagnoses of polycythemia vera and primary familial and congenital polycythemia.
Primary familial and congenital polycythemia (PFCP) is caused by germline mutations in the EpoR leading to constitutive activation of EpoR. The constantly activated "on switch" leads to excessive erythroid progenitor proliferation and differentiation, resulting in polycythemia. This autosomal dominant trait does not necessarily carry an adverse prognosis early in life but is associated with an increased risk of thrombotic and vascular mortality later in life. [4]
Polycythemia vera is caused by an acquired gain-of-function mutation of JAK2 tyrosine kinase. The JAK2V617F mutation is detectable in more than 95% of patients diagnosed with polycythemia vera. [5] Several other mutations of JAK2 have since been described (eg, exon 12, JAK2H538-K539delinsI). [6, 7] The JAK2 mutations cause the enzyme to be constitutively active, allowing these cells to be hypersensitive to Epo. [5]
Chuvash polycythemia, a congenital polycythemia first recognized in an endemic Russian population, is a variant of primary familial and congenital polycythemia. It results from a mutation in the von Hippel-Lindau (VHL) gene, a negative regulator of erythropoiesis, resulting in impaired ability of VHL to down-regulate Epo and erythropoiesis. [4]
Secondary Polycythemia
Secondary polycythemia is due to circulating extrinsic factors that stimulate erythropoiesis, most often Epo. Physiologic elevation of Epo may result from functional hypoxia secondary to pulmonary, cardiac, renal, or hepatic disease. Polycythemia can also develop owing to Epo-secreting tumors, including renal cell carcinomas, nephroblastomas, and endocrine tumors.
High-altitude erythrocytosis is evident within the first week of high-altitude exposure. A sharp increase in Epo production is noticeable, with associated mobilization of iron stores with evidence of iron-deficient erythropoiesis. [4]
Abnormal high-affinity hemoglobin mutations are characterized by left shift in the oxygen-hemoglobin dissociation curves. The resulting tissue hypoxia stimulates Epo production, leading to erythrocytosis. Similarly, in familial polycythemia with defects in 2,3-DPG metabolism, a left shift in the oxygen-hemoglobin curve is noted with a physiologic response of polycythemia. [4]
Secondary polycythemia of the newborn is fairly common and is seen in 1-5% of all newborns in the United States. It results from either chronic or acute fetal hypoxia or from delayed cord clamping and stripping of the umbilical cord. [8]
Pathology
The clinical manifestations of polycythemia stem from increased red cell mass, which leads to increased blood viscosity. Blood viscosity increases logarithmically with increases in hematocrit, resulting in impaired blood flow and increased cardiac workload.
In the neonatal period, polycythemia-induced hyperviscosity can lead to altered blood flow and can subsequently affect organ function. Infants with polycythemia are at increased risk for necrotizing enterocolitis, renal dysfunction, hypoglycemia, and increased pulmonary vascular resistance with resultant hypoxia and cyanosis. However, a study by Hopfeld-Fogel et al, involving 119 term infants with polycythemia and 117 controls, did not find neonatal hypoglycemia to be more common in the presence of neonatal polycythemia. The investigators suggested that when the two conditions do occur together neonatally, this represents the effect of common risk factors. [9]
Although initially thought to cause neurologic dysfunction, the decrease in cerebral blood flow seen in newborns with polycythemia is a physiologic response and does not appear to cause cerebral ischemia. [8]
Epidemiology
The incidence, morbidity, and mortality of polycythemia depends on the underlying etiology, varying greatly. The epidemiology specifically of polycythemia vera has been studied extensively and is reviewed below.
Frequency
United States
Primary polycythemia is rare; in the United States, the overall prevalence of polycythemia vera is 45-57 cases per 100,000 people. [10, 11] The combined annual incidence is 0.01-2.61 per 100,000 people. [12] The median age is 60 years, with 0.01% of those cases observed in individuals younger than 20 years. [13] Less than 50 cases of pediatric polycythemia vera have been reported in the literature. Polycythemia vera is less likely in blacks than in individuals of European ancestry, with a higher incidence in Ashkenazi Jews.
International
Polycythemia vera has a similar incidence in Western Europe as in the United States, and occurrence rates are very low in Africa and Asia (as low as 2 cases per million per year in Japan).
Mortality and Morbidity
Death rates for children are unavailable. The complications found in polycythemia vera are related to two primary factors. The first includes complications related to hyperviscosity. The second involves bone marrow–related complications. Untreated, the median survival time for these patients is 18 months. However, if patients are treated, survival is greatly extended, as many as 10-15 years with phlebotomy alone. The causes of death in adults are as follows:
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Thrombosis/thromboembolism (30-40%) - Myocardial infarctions, deep vein thrombosis, pulmonary embolus, portal splenic and mesenteric vein thrombosis
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Other malignancies (15%)
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Hemorrhage (2-10%)
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Myelofibrosis/myeloid metaplasia (4%)
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Other (25%)
Race
In the United States, higher rates of polycythemia vera are observed in the Ashkenazi Jewish population, and lower rates are seen in blacks.
Sex
Polycythemia vera is somewhat more common in males, with the male-to-female ratios in several studies, ranging from 1.2-2.2. In children, it appears to affect males and females equally. [4]
Age
The median age for polycythemia vera between age 60-80 years. [4, 13] Less than 1% of polycythemia cases occur in people younger than 20 years.
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Bone marrow film at 400X magnification demonstrating dominance of erythropoiesis. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
