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Polycythemia
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Polycythemia
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Polycythemia
Other namesErythrocytosis, Hypercythemia, Hypererythrocythemia
Diagram illustrating normal composition of blood compared to anemia and polycythemia
SpecialtyHematology

Polycythemia (also spelt polycythaemia) is a laboratory finding that the hematocrit (the volume percentage of red blood cells in the blood) and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called erythrocytosis, and there is significant overlap in the two findings, but the terms are not the same: polycythemia describes any increase in hematocrit and/or hemoglobin, while erythrocytosis describes an increase specifically in the number of red blood cells in the blood.[citation needed]

Polycythemia has many causes. It can describe an increase in the number of red blood cells[1] ("absolute polycythemia") or a decrease in the volume of plasma ("relative polycythemia").[2] Absolute polycythemia can be due to genetic mutations in the bone marrow ("primary polycythemia"), physiological adaptations to one's environment, medications, and/or other health conditions.[3][4] Laboratory studies such as serum erythropoeitin levels and genetic testing might be helpful to clarify the cause of polycythemia if the physical exam and patient history do not reveal a likely cause.[5]

Mild polycythemia on its own is often asymptomatic. Treatment for polycythemia varies, and typically involves treating its underlying cause.[6] Treatment of primary polycythemia (see polycythemia vera) could involve phlebotomy, antiplatelet therapy to reduce risk of blood clots, and additional cytoreductive therapy to reduce the number of red blood cells produced in the bone marrow.[7]

Definition

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Polycythemia is defined as serum hematocrit (Hct) or hemoglobin (HgB) exceeding normal ranges expected for age and gender, typically Hct >49% in healthy adult men and >48% in women, or HgB >16.5 g/dL in men or >16.0 g/dL in women.[8] The definition is different for neonates and varies by age in children.[9][10]

Differential diagnoses

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Polycythemia in adults

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Different diseases or conditions can cause polycythemia in adults. These processes are discussed in more detail in their respective sections below.

Relative polycythemia, also known as pseudopolycythemia,[11] is not a true increase in the number of red blood cells or hemoglobin in the blood, but rather an elevated laboratory finding caused by reduced blood plasma (hypovolemia, cf. dehydration). Relative polycythemia is often caused by loss of body fluids, such as through burns, dehydration, and stress.[citation needed] A specific type of relative polycythemia is Gaisböck syndrome; in this syndrome, primarily occurring in obese men, hypertension causes a reduction in plasma volume, resulting in (amongst other changes) a relative increase in red blood cell count.[12] If relative polycythemia is deemed unlikely because the patient has no other signs of hemoconcentration and has sustained polycythemia without clear loss of body fluids, the patient likely has absolute or true polycythemia.

Absolute or true polycythemia (also erythrocytosis) can be split into two categories:

  • Primary polycythemia, that is the overproduction of red blood cells due to a primary process in the bone marrow (a so-called myeloproliferative disease; eg. polycythemia vera). These can be familial or congenital, or acquired later in life.[13]
  • Secondary polycythemia, whenever additional red blood cells may have been received through another process — for example, being over-transfused (either accidentally or, as blood doping, deliberately).[citation needed]

Polycythemia in neonates

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Polycythemia in newborns is defined as hematocrit > 65%. Significant polycythemia can be associated with blood hyperviscosity, or thickening of the blood. Causes of neonatal polycythemia include:

  • Hypoxia: Poor oxygen delivery (hypoxia) in utero resulting in compensatory increased production of red blood cells (erythropoeisis). Hypoxia can be either acute or chronic. Acute hypoxia can occur as a result of perinatal complications. Chronic fetal hypoxia is associated with maternal risk factors such as hypertension, diabetes and smoking.[10]
  • Umbilical cord stripping: delayed cord clamping and the stripping of the umbilical cord towards the baby can cause the residual blood in the cord/placenta to enter fetal circulation, which can increase blood volume.[10]
  • The recipient twin in a pregnancy undergoing twin-to-twin transfusion syndrome can have polycythemia.[14]

Pathophysiology

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The pathophysiology of polycythemia varies based on its cause. The production of red blood cells (or erythropoeisis) in the body is regulated by erythropoietin, which is a protein produced by the kidneys in response to poor oxygen delivery.[15] As a result, more erythropoietin is produced to encourage red blood cell production and increase oxygen-carrying capacity. This results in secondary polycythemia, which can be an appropriate response to hypoxic conditions such as chronic smoking, obstructive sleep apnea, and high altitude.[4] Furthermore, certain genetic conditions can impair the body's accurate detection of oxygen levels in the serum, which leads to excess erythropoietin production even without hypoxia or impaired oxygen delivery to tissues.[16][17] Alternatively, certain types of cancers, most notably renal cell carcinoma, and medications such as testosterone use can cause inappropriate erythropoietin production that stimulates red cell production despite adequate oxygen delivery.[18]

Primary polycythemia, on the other hand, is caused by genetic mutations or defects of the red cell progenitors within the bone marrow, leading to overgrowth and hyperproliferation of red blood cells regardless of erythropoeitin levels.[3]

Increased hematocrit and red cell mass with polycythemia increases the viscosity of blood, leading to impaired blood flow and contributing to an increased risk of clotting (thrombosis).[19]

Evaluation

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History and physical exam

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The first step to evaluate new polycythemia in any individual is to conduct a detailed history and physical exam.[13] Patients should be asked about smoking history, altitude, medication use, personal bleeding and clotting history, symptoms of sleep apnea (snoring, apneic episodes), and any family history of hematologic conditions or polycythemia. A thorough cardiopulmonary exam including auscultation of the heart and lungs can help evaluate for cardiac shunting or chronic pulmonary disease. An abdominal exam can assess for splenomegaly, which can be seen in polycythemia vera. Examination of digits for erythromelalgia, clubbing or cyanosis can help assess for chronic hypoxia.[13]

Laboratory evaluation

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Polycythemia is often initially identified on a complete blood count (CBC). The CBC is often repeated to evaluate for persistent polycythemia.[13] If an etiology of polycythemia is unclear from history or physical, additional laboratory evaluation might include:[5]

Additional testing

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Polycythemia types

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Primary polycythemia

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Main article: Polycythemia vera

Primary polycythemias are myeloproliferative diseases affecting red blood cell precursors in the bone marrow. Polycythemia vera (PCV) (a.k.a. polycythemia rubra vera (PRV)) occurs when excess red blood cells are produced as a result of an abnormality of the bone marrow.[3] Often, excess white blood cells and platelets are also produced. A hallmark of polycythemia vera is an elevated hematocrit, with Hct > 55% seen in 83% of cases.[20] A somatic (non-hereditary) mutation (V617F) in the JAK2 gene, also present in other myeloproliferative disorders, is found in 95% of cases.[21] Symptoms include headaches and vertigo, and signs on physical examination include an abnormally enlarged spleen and/or liver. Studies suggest that mean arterial pressure (MAP) only increases when hematocrit levels are 20% over baseline. When hematocrit levels are lower than that percentage, the MAP decreases in response, which may be due, in part, to the increase in viscosity and the decrease in plasma layer width.[22] Furthermore, affected individuals may have other associated conditions alongside high blood pressure, including formation of blood clots. Transformation to acute leukemia is rare. Phlebotomy is the mainstay of treatment.[23]

Primary familial polycythemia, also known as primary familial and congenital polycythemia (PFCP), exists as a benign hereditary condition, in contrast with the myeloproliferative changes associated with acquired PCV. In many families, PFCP is due to an autosomal dominant mutation in the EPOR erythropoietin receptor gene.[24] PFCP can cause an increase of up to 50% in the oxygen-carrying capacity of the blood; skier Eero Mäntyranta had PFCP, which is speculated to have given him an advantage in endurance events.[25]

Secondary polycythemia

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Secondary polycythemia is caused by either natural or artificial increases in the production of erythropoietin, hence an increased production of erythrocytes.

Secondary polycythemia in which the production of erythropoietin increases appropriately is called physiologic polycythemia. Conditions which may result in physiologic polycythemia include:

  • Altitude related – Polycythemia can be a normal adaptation to living at high altitudes (see altitude sickness).[9] Many athletes train at high altitude to take advantage of this effect, which can be considered a legal form of blood doping, although the efficacy of this strategy is unclear.[26]
  • Hypoxic disease-associated – for example, in cyanotic heart disease where blood oxygen levels are reduced significantly; in hypoxic lung disease such as COPD; in chronic obstructive sleep apnea;[9] conditions that reduce blood flow to the kidney e.g. renal artery stenosis. Chronic carbon monoxide poisoning (which can be present in heavy smokers) and rarely methemoglobinemia can also impair oxygen delivery.[27][4]
  • Genetic – Heritable causes of secondary polycythemia include abnormalities in hemoglobin oxygen release, which results in a greater inherent affinity for oxygen than normal adult hemoglobin and reduces oxygen delivery to tissues.[28]

Conditions where the secondary polycythemia is not caused by physiologic adaptation, and occurs irrespective of body needs include:[4]


Testosterone Replacement Therapy (TRT) and Secondary Polycythemia

Testosterone replacement therapy (TRT) causes secondary polycythemia by stimulating the body's natural pathways that regulate red blood cell production, rather than from an inherent bone marrow disorder. Testosterone increases the production of erythropoietin (EPO) in the kidneys, a hormone that signals the bone marrow to make more red blood cells. At the same time, testosterone suppresses the liver hormone hepcidin, which normally limits the absorption and mobilization of iron. With less hepcidin, iron becomes more available for hemoglobin synthesis, further fueling red blood cell production. This combination of increased EPO signaling and enhanced iron supply amplifies erythropoiesis, leading to elevated hematocrit and hemoglobin levels. The effect is most pronounced with injectable forms of testosterone that create high peak serum levels, which strongly stimulate these pathways. Because the mechanism is driven by a hormonal stimulus and not by a primary bone marrow abnormality, the condition is classified as secondary polycythemia. Clinically, this distinction is important, as TRT-induced secondary polycythemia resolves or improves with dose adjustment, delivery method changes, or therapeutic phlebotomy, whereas primary polycythemia reflects a chronic clonal disorder of hematopoietic stem cells.

Altered oxygen sensing

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Rare inherited mutations in three genes which all result in increased stability of hypoxia-inducible factors, leading to increased erythropoietin production, have been shown to cause secondary polycythemia:

  • Chuvash erythrocytosis or Chuvash polycythemia is an autosomal recessive form of erythrocytosis endemic in patients from the Chuvash Republic in Russia. Chuvash erythrocytosis is associated with homozygosity for a C598T mutation in the von Hippel–Lindau gene (VHL), which is needed for the destruction of hypoxia-inducible factors in the presence of oxygen.[17] Clusters of patients with Chuvash erythrocytosis have been found in other populations, such as on the Italian island of Ischia, located in the Bay of Naples.[16] Patients with Chuvash erythrocytosis experience a significantly elevated risk of events.[6]
  • PHD2 erythrocytosis: Heterozygosity for loss-of-function mutations of the PHD2 gene are associated with autosomal dominant erythrocytosis and increased hypoxia-inducible factors activity.[31][32]
  • HIF2α erythrocytosis: Gain-of-function mutations in HIF2α are associated with autosomal dominant erythrocytosis[33] and pulmonary hypertension.[34]

Symptoms

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Polycythemia is often asymptomatic; patients may not experience any notable symptoms until their red cell count is very high. For patients with significant elevations in hemoglobin or hematocrit (often from polycythemia vera), some non-specific symptoms include:[9]

Epidemiology

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The prevalence of primary polycythemia (polycythemia vera) was estimated to be approximately 44–57 per 100,000 individuals in the United States.[30] Secondary polycythemia is considered to be more common, but its exact prevalence is unknown.[30] In one study using the NHANES dataset, the prevalence of unexplained erythrocytosis is 35.1 per 100,000, and was higher among males and among individuals between ages 50–59 and 60–69.[36]

Management

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The management of polycythemia varies based on its etiology:

  • See polycythemia vera for management of primary polycythemia, which involves reducing thrombotic risk, symptom amelioration and monitoring for further hematologic complications. Treatment can include phlebotomy, aspirin, and myelosuppressive or cytoreductive medications based on risk stratification.[7]
  • For secondary polycythemia, management involves addressing the underlying etiology of increased erythropoeitin production, such as smoking cessation, CPAP for sleep apnea, or removing any EPO-producing tumours.[6] Phlebotomy is not typically recommended for patients with physiologic polycythemia, who rely on additional red cell mass for necessary oxygen delivery, unless the patient is clearly symptomatic and experiences relief from phlebotomy.[6] It is unclear if patients with secondary polycythemia are at elevated thrombotic risk, but aspirin can be considered for patients at elevated cardiovascular risk or for patients with Chuvash polycythemia.[6] The first-line treatment for post-transplant erythrocytosis specificity is angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers.[30]

Relation to athletic performance

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Polycythemia is theorized to increased performance in endurance sports due to the blood being able to store more oxygen.[citation needed] This idea has led to the illegal use of blood doping and transfusions among professional athletes, as well as use of altitude training or elevation training masks to simulate a low-oxygen environment. However, the benefits of altitude training for athletes to improve sea-level performance are not universally accepted, with one reason being athletes at altitude might exert less power during training.[37]

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Polycythemia

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from Grokipedia
Polycythemia, also known as erythrocytosis, is a hematologic disorder characterized by an abnormal increase in mass, typically identified through laboratory findings of elevated levels (greater than 16.5 g/dL in men or 16.0 g/dL in women) and (greater than 49% in men or 48% in women). This thickening of the blood can impair circulation and raise the risk of complications such as , , or heart attack. The condition is broadly classified into two main types: primary polycythemia, most commonly (PV), a driven by acquired genetic mutations like JAK2 V617F in over 95% of cases, leading to autonomous overproduction of red blood cells by the ; and secondary polycythemia, which results from increased production due to extrinsic factors such as chronic hypoxia (e.g., from high altitude, , or lung disease), renal tumors, or certain medications. PV is a rare , while secondary forms are more common and often reversible upon addressing the underlying cause.

Introduction

Definition

Polycythemia, also known as erythrocytosis, is a hematologic condition characterized by an abnormal increase in mass (absolute polycythemia), which manifests as elevated and levels on laboratory testing. It is typically defined by a concentration exceeding 16.5 g/dL in men or 16.0 g/dL in women, or a greater than 49% in men or 48% in women, according to criteria. This elevation reflects an expansion of the erythroid lineage beyond normal physiological limits, distinguishing it from other conditions like or normal variants in red cell parameters. Apparent polycythemia can also occur in relative forms due to reduced plasma volume without an increase in mass. Relative polycythemia is not a true proliferation of s but results from conditions like that concentrate the . Absolute polycythemia involves a true increase in total volume independent of plasma changes and encompasses both primary and secondary subtypes, though detailed classification is addressed elsewhere. The physiological implications of polycythemia stem primarily from the expanded mass, which elevates and impairs microcirculatory flow. This hyperviscosity increases the risk of thrombotic events, including arterial and venous occlusions, as a major complication. Paradoxically, despite the heightened oxygen-carrying capacity from excess , tissue hypoxia may occur due to sluggish blood flow and localized ischemia in affected vascular beds. The condition was first clinically described in the late , with early reports of cases involving marked erythrocytosis. Its modern understanding evolved significantly in 1951, when William Dameshek proposed the concept of myeloproliferative disorders, grouping with related entities based on shared proliferative features in the .

Classification

Polycythemia is classified into primary, secondary, and relative forms based on the underlying mechanisms of erythrocytosis, with additional consideration for neonatal cases. Primary polycythemia arises from intrinsic disorders characterized by autonomous production that is independent of (EPO) regulation. The prototypical example is (PV), a driven by clonal proliferation of hematopoietic stem cells. Secondary polycythemia results from extrinsic factors that stimulate EPO-driven increases in mass. This form is subdivided into appropriate secondary polycythemia, where EPO elevation is physiologically responsive to tissue hypoxia (such as in chronic high-altitude exposure or chronic lung diseases), and inappropriate secondary polycythemia, where EPO levels rise abnormally due to non-hypoxic stimuli like EPO-secreting tumors or renal pathologies. Relative polycythemia, also known as spurious or pseudopolycythemia, involves an apparent elevation in due to reduced plasma volume rather than a true increase in mass; common causes include or stress-related conditions like Gaisböck . Neonatal polycythemia is a distinct entity in newborns, defined by a venous greater than 65% or exceeding 22 g/dL, often transient and resulting from placental transfusion or intrauterine adaptations to hypoxia. Differentiation among these forms relies on (WHO) diagnostic thresholds and criteria. For instance, overt erythrocytosis suggestive of polycythemia is indicated by levels above 49% in males and 48% in females at . Specifically for PV, the 2022 WHO requires all three major criteria—hemoglobin >16.5 g/dL in men or >16.0 g/dL in women (or >49% in men or >48% in women), hypercellularity with trilineage myeloproliferation, and presence of a JAK2V617F or JAK2 12 —or the first two major criteria plus the minor criterion of subnormal serum EPO levels.

Pathophysiology

Primary Polycythemia

Primary polycythemia, most commonly manifesting as (PV), arises from the clonal proliferation of mutated hematopoietic stem cells in the , driven by acquired somatic that confer a growth advantage independent of (EPO) stimulation. This intrinsic defect leads to EPO-independent , where erythroid progenitors proliferate autonomously without the need for external EPO signaling, resulting in excessive production and elevated levels. The neoplastic clone often suppresses normal hematopoiesis, contributing to the disease's progressive nature. The primary genetic driver in PV is the JAK2 V617F mutation, a substituting for at codon 617 in the pseudokinase domain of the (JAK2) gene, occurring in more than 95% of cases. This mutation causes constitutive activation of the , mimicking engagement and promoting uncontrolled proliferation of erythroid, myeloid, and megakaryocytic lineages even in the absence of ligands like EPO. In approximately 3% of cases, which are typically JAK2 V617F-negative, mutations in exon 12 of the JAK2 gene are identified, similarly enhancing JAK2 activity and leading to a restricted more to . These mutations were first described in seminal studies that revolutionized the understanding of . Pathophysiologically, the dysregulated JAK-STAT signaling induces panmyelosis, characterized by trilineage hyperplasia in the with marked hypercellularity, increased , , and megakaryopoiesis, often accompanied by atypical morphology. This results in elevated mass alongside and thrombocytosis, predisposing to microvascular disturbances and hyperviscosity. Serum EPO levels are typically low or undetectable, distinguishing PV from reactive processes. Over time, 10-20% of patients may progress to post-PV myelofibrosis after 10-15 years, marked by and , while 2-5% transform to within a similar timeframe, reflecting the clonal evolution and genomic instability inherent to the disease.

Secondary Polycythemia

Secondary polycythemia, also known as secondary erythrocytosis, arises from extrinsic factors that stimulate excessive production, primarily through elevated (EPO) levels, as a compensatory mechanism to improve oxygen delivery. Unlike intrinsic disorders, this condition represents a reactive process driven by environmental, physiological, or pathological triggers that affect tissue oxygenation or EPO regulation. The kidneys play a central role by sensing hypoxia via the hypoxia-inducible factor (HIF) pathway, which upregulates EPO synthesis and release to promote in the . Appropriate secondary polycythemia occurs as a physiologic to chronic hypoxia, where reduced oxygen availability appropriately triggers increased EPO production to enhance oxygen-carrying capacity. Common examples include residence at high altitudes, where lower atmospheric oxygen pressure stimulates renal EPO release; (COPD), which impairs in the lungs; and congenital heart diseases with right-to-left shunting, such as , leading to systemic . In these scenarios, the elevated red cell mass normalizes oxygen delivery but can result in hyperviscosity if unchecked. In contrast, inappropriate secondary polycythemia involves pathologic overproduction of EPO independent of hypoxia, often due to autonomous secretion by tumors or other abnormalities. This subtype is frequently associated with , which accounts for a significant proportion of cases through paraneoplastic EPO elaboration; cerebellar hemangioblastomas, which similarly produce EPO ectopically; and other EPO-secreting neoplasms like or . These tumors disrupt normal feedback mechanisms, leading to unchecked despite adequate oxygenation. Additional causes of secondary polycythemia include factors that induce a hypoxic-like state or directly stimulate . elevates levels, which binds oxygen more tightly than and reduces tissue oxygen delivery, mimicking chronic hypoxia and prompting EPO elevation. therapy or abuse, such as in use, directly enhances activity and EPO-independent red cell production. causes intermittent nocturnal hypoxia, contributing to sustained EPO stimulation and polycythemia over time. Metabolic syndrome, characterized by obesity, hypertension, dyslipidemia, and insulin resistance, is associated with erythrocytosis (particularly secondary forms), with studies showing higher odds of metabolic syndrome in individuals with polycythemia, especially in younger middle-aged men; this link may be mediated by cardiometabolic risk factors and conditions such as obstructive sleep apnea (already noted) or obesity hypoventilation syndrome. In neonates, secondary polycythemia often stems from perinatal hypoxic insults or , leading to . , as seen in , triggers fetal compensatory due to chronic hypoxia. results in the recipient twin receiving excess blood volume, elevating levels. Delayed umbilical cord clamping can also cause relative polycythemia from increased placental transfusion. These mechanisms increase the risk of complications like poor if exceeds 65%. A hallmark laboratory feature distinguishing secondary polycythemia from primary forms is markedly elevated serum EPO levels, reflecting the underlying stimulatory drive; normal or low EPO would suggest alternative , though mild elevations can occur in some cases. This measurement is crucial for initial differentiation and guiding further evaluation of the precipitating factor.

Clinical Presentation

Symptoms

Elevated hematocrit in polycythemia may reflect absolute polycythemia due to increased red blood cell mass or relative polycythemia due to reduced plasma volume, most commonly from dehydration. Both share overlapping symptoms related to hemoconcentration and increased blood viscosity, including headache, dizziness, fatigue, and weakness. Dehydration typically features additional distinctive symptoms such as extreme thirst, dry mouth, dark-colored urine, reduced urination, dry skin, and sunken eyes. In contrast, absolute polycythemia—particularly polycythemia vera—often includes more specific symptoms such as aquagenic pruritus (itching after contact with water, often after warm baths or showers), facial plethora (flushed or red skin), blurred vision, shortness of breath, unusual bleeding (e.g., nosebleeds), and early satiety (feeling of fullness after eating) due to splenomegaly. Polycythemia, characterized by an increased mass, leads to elevated and a heightened of , resulting in common subjective symptoms such as , , , weakness, visual disturbances, and —a burning pain in the extremities often affecting the hands and feet. In secondary polycythemia, these hyperviscosity symptoms may be accompanied by manifestations of the underlying , such as in chronic hypoxic conditions. A distinctive symptom in (PV), the primary form, is , a severe, histamine-independent itching triggered by contact with water at any temperature, which can significantly impair and occurs in up to 68% of patients. In advanced stages of PV, patients may experience constitutional symptoms including unexplained , , and due to expansion. Notably, approximately 50% of PV cases are at , often discovered incidentally through routine tests.

Signs

Patients with polycythemia often exhibit a plethoric appearance characterized by a ruddy , plethora, and conjunctival injection due to the increased mass causing flushing and skin plethora. In (PV), this ruddy hue extends to the palms and is a classic observable finding on . Splenomegaly is a prominent in PV, palpable in approximately one-third of cases as a result of and increased blood volume. occurs less frequently, observed in about 30% of PV patients, particularly in advanced stages where hepatic involvement becomes evident. Vascular signs include retinal vein engorgement and tortuosity, attributable to hyper impeding venous drainage in the retina. is also common, stemming from elevated blood viscosity that increases peripheral resistance and cardiac workload.

Diagnosis

History and Physical Examination

The initial clinical assessment for suspected polycythemia begins with a thorough to identify potential etiologies and risk factors. A detailed history is essential, as tobacco use is a leading cause of secondary polycythemia through chronic hypoxia. Occupational exposures to carbon monoxide or residence at high altitudes should be explored, as these environmental factors stimulate erythropoietin production. Family history of myeloproliferative neoplasms or hereditary erythrocytosis is pertinent, particularly for primary forms. Medication review must include androgens, testosterone, or anabolic steroids, which can induce secondary erythrocytosis. Travel to high-altitude regions or areas endemic for hypoxia-inducing conditions may also contribute. Symptom inquiry focuses on the onset, duration, and triggers of manifestations that raise suspicion for polycythemia. To differentiate relative erythrocytosis due to dehydration (hemoconcentration from reduced plasma volume) from absolute erythrocytosis, patients should be questioned about symptoms suggestive of dehydration, such as extreme thirst, dry mouth, reduced urine output, dark-colored urine, dry skin, and sunken eyes. Overlapping nonspecific symptoms such as headache, dizziness, fatigue, and weakness may occur in both conditions. Patients should also be questioned about symptoms more specific to primary polycythemia vera, including recurrent headaches, (itching after water exposure, particularly warm baths or showers), (burning pain in extremities), early satiety or feeling of fullness after eating (due to splenomegaly), blurred vision, shortness of breath, flushed or red skin, and unusual bleeding (e.g., nosebleeds). A history of thrombotic events, such as deep vein thrombosis, , or , or bleeding tendencies like epistaxis or gastrointestinal hemorrhage, serves as critical red flags indicating hyperviscosity or . In neonates, perinatal history is key, including maternal conditions like or , and delivery complications such as twin-to-twin transfusion, , or delayed cord clamping, which increase risk for transient neonatal polycythemia. The targets signs of increased red cell mass and complications. assessment may reveal secondary to hyperviscosity. General inspection often discloses facial plethora, conjunctival injection, or ruddy skin discoloration, with excoriations from chronic pruritus in some cases. Abdominal palpation is crucial to detect (present in up to 75% of primary cases) or , suggesting . Fundoscopic examination can identify retinal vein engorgement, hemorrhages, or due to hyperviscosity effects. In neonates, exam findings include generalized plethora and ruddy appearance, alongside potential or .

Laboratory Evaluation

Laboratory evaluation begins with a (CBC), which typically reveals elevated levels greater than 16.5 g/dL in men or 16.0 g/dL in women, and greater than 49% in men or 48% in women, indicating increased mass in polycythemia. In primary (PV), the CBC often shows concomitant (white blood cell count >11 × 10^9/L) and thrombocytosis (platelet count >450 × 10^9/L), reflecting panmyelosis, whereas secondary polycythemia usually isolates erythrocytosis without these additional elevations. The peripheral blood smear may demonstrate formation due to high red cell concentration and increased reticulocytes, supporting active , though these findings are nonspecific and require correlation with other tests. Erythropoietin (EPO) level measurement is crucial for differentiation: subnormal or low EPO levels (< normal range) strongly suggest primary polycythemia, as autonomous erythropoiesis suppresses EPO production, while elevated EPO levels indicate secondary causes driven by hypoxia or tumors. According to World Health Organization (WHO) criteria, low EPO is a minor diagnostic feature for PV when major criteria are met. Molecular testing for the JAK2 V617F mutation is a cornerstone for confirming primary polycythemia, present in approximately 95-97% of PV cases and serving as a major WHO diagnostic criterion alongside elevated hemoglobin/hematocrit and bone marrow findings. Quantitative assessment of JAK2 V617F burden aids in risk stratification, with burdens >50% associated with higher thrombotic risk, though testing is recommended for all suspected cases regardless of initial status. If JAK2 V617F is negative, evaluation for 12 mutations (present in 3-5% of PV) or rare variants via next-generation sequencing (NGS) is pursued to identify alternative clonal drivers. Bone marrow biopsy, while not always mandatory if other major criteria are fulfilled, reveals hypercellularity with trilineage myeloid proliferation, pleomorphic megakaryocytes, and absent iron stores in primary PV, distinguishing it from secondary forms that show isolated erythroid without panmyelosis. Indications for include borderline CBC values or need to rule out overlapping . Recent advances in NGS have enhanced detection of additional non-JAK2 mutations (e.g., TET2, ASXL1) in PV cases, improving prognostic yield though these are less common and primarily inform research contexts.

Additional Testing

Additional testing is pursued when laboratory evaluations suggest polycythemia but require further confirmation of absolute erythrocytosis or identification of underlying etiologies, such as elevated levels indicating secondary causes. These specialized assessments help differentiate primary from secondary forms and rule out familial or acquired drivers, guiding targeted management. In cases of suspected familial or idiopathic erythrocytosis, sequencing of the (EPOR) gene is recommended, particularly when lifelong sustained erythrocytosis is present without identifiable acquired causes. This test detects gain-of-function mutations in EPOR, which can lead to hypersensitivity to and increased red cell production, as seen in primary familial and congenital polycythemias. Targeted next-generation sequencing panels, including EPOR exons, are utilized for this purpose in specialized laboratories. Imaging modalities play a key role in evaluating potential secondary causes. Abdominal ultrasound or computed tomography (CT) scans are employed to assess for splenomegaly, renal tumors such as renal cell carcinoma, or other masses that may inappropriately elevate erythropoietin levels in secondary polycythemia. Echocardiography is indicated to detect intracardiac shunts or right-to-left shunting, which can cause hypoxia-driven erythrocytosis. Pulmonary function tests (PFTs) and sleep studies are essential for investigating hypoxia-related secondary polycythemia, particularly in patients with risk factors for (COPD) or . PFTs quantify ventilatory impairment and abnormalities contributing to chronic , while identifies nocturnal desaturations in that stimulate release. These tests are prioritized when arterial is low on initial screening. The red cell mass (RCM) study remains the gold standard for confirming absolute polycythemia by distinguishing it from relative increases due to plasma volume contraction, though it is infrequently performed in modern practice due to the availability of molecular markers like JAK2 mutations. This isotopic assay involves labeling autologous red blood cells with chromium-51 (51Cr) and measuring their dilution in total blood volume, typically requiring simultaneous plasma volume assessment with iodine-125-labeled albumin for accuracy. Results exceeding 25% above predicted values confirm true erythrocytosis. In neonates with polycythemia, cranial is a critical non-invasive tool to evaluate for hyperviscosity-related complications, such as (IVH), which arises from impaired cerebral blood flow due to elevated levels. This detects parenchymal venous hemorrhage or IVH grading, facilitating early intervention in at-risk infants with venous above 65%.

Epidemiology

Incidence and Prevalence

Polycythemia encompasses both primary (PV) and secondary forms, with the latter being more common overall but often underreported due to its association with underlying conditions such as chronic hypoxia or tumors. The annual incidence of PV is estimated at 1.5 to 2.6 cases per 100,000 population in the United States and , with higher rates observed in men (2.8 per 100,000) compared to women (1.3 per 100,000). Secondary polycythemia occurs more frequently, particularly in populations with predisposing factors like (where prevalence ranges from 6% to 10%) or high-altitude residence, though global incidence data remain limited due to diagnostic variability. Prevalence of PV is approximately 44 to 57 cases per 100,000 in the and , with estimates varying by region and diagnostic criteria, implying roughly 145,000 to 188,000 cases in the as of based on a population of about 330 million. It is notably higher among individuals of Ashkenazi Jewish descent, where incidence rates can reach 11.4 per million (1.14 per 100,000), reflecting a . Secondary polycythemia lacks precise global figures but is recognized as more widespread than PV, often linked to reversible causes and thus not captured in chronic disease registries. PV predominantly affects older adults, with a median age at of 64 years and peak incidence between 60 and 70 years; there is a slight predominance across populations. Neonatal polycythemia, a distinct form typically secondary to placental or fetal factors, occurs in 1% to 5% of newborns, rising to higher rates (up to 15% to 33%) in high-risk groups such as those with or born to diabetic mothers. Geographic variations are prominent for secondary polycythemia, with elevated rates in high-altitude regions such as the and , where chronic hypoxia drives excessive and can exceed 10% in susceptible populations. In contrast, PV shows less pronounced regional differences but follows similar patterns in industrialized nations with robust diagnostic access. Incidence and of polycythemia have remained stable over recent decades, aided by improved detection through routine complete blood counts, though underdiagnosis persists for milder secondary cases; recent reviews as of 2024 confirm no major shifts. Mortality trends for PV have shown ongoing declines since 1999, with age-adjusted mortality rates decreasing from 1.15 to 0.81 per 100,000 by 2023, though disparities persist (higher in men, rural areas, and the Midwest).

Risk Factors

Risk factors for polycythemia vary depending on whether it is primary (, PV) or secondary, encompassing genetic predispositions, environmental exposures, underlying medical conditions, iatrogenic causes, and neonatal factors. In primary PV, genetic factors play a central role, with mutations in the JAK2 gene (particularly V617F) present in 95% or more of cases, leading to uncontrolled . Familial clustering is observed in 5-10% of PV patients, indicating shared genetic susceptibility loci that increase the risk of acquiring somatic mutations. Environmental risk factors are primarily associated with secondary polycythemia. Chronic smoking elevates levels, reducing oxygen delivery and stimulating production. Residence at high altitudes above 2,500 meters induces chronic hypoxia, similarly promoting secondary erythrocytosis. Occupational exposure to toxic chemicals, such as , has been linked to an increased incidence of myeloproliferative disorders including PV. Medical conditions underlying secondary polycythemia include chronic lung diseases like (COPD) and severe , which cause . Congenital heart disease with right-to-left shunting also contributes by impairing oxygenation. Additionally, obesity and lead to and recurrent hypoxia, elevating the risk. Iatrogenic factors can induce secondary polycythemia through exogenous stimuli. Testosterone therapy, often used for , increases and directly stimulates erythroid progenitors, resulting in erythrocytosis in up to 10-20% of recipients. Misuse of recombinant (EPO) for athletic doping similarly drives excessive production. Neonatal polycythemia, a distinct form affecting newborns, is associated with maternal , which correlates with macrosomia and promoting fetal . Post-term delivery and further heighten the risk by altering placental oxygen transfer and fetal blood volume.

Management

Primary Polycythemia Treatment

The primary treatment for (PV) focuses on reducing blood viscosity and preventing thrombotic complications through cytoreductive measures and antithrombotic therapy. remains the cornerstone of initial management, involving the regular removal of blood to maintain a level below 45%, which has been shown to significantly lower the risk of cardiovascular events compared to higher targets. This procedure is typically performed weekly or as needed until the target is achieved, with subsequent frequency adjusted based on individual response and monitoring to minimize and symptoms like . All patients with PV, absent contraindications such as active or aspirin , should receive low-dose aspirin (81 mg daily) as standard prophylaxis to reduce the incidence of arterial and by approximately 60%. This recommendation stems from landmark trials demonstrating its efficacy in suppressing production without excessive risk in this population. For high-risk patients—defined by age over 60 years or prior —cytoreductive is added to and aspirin. Hydroxyurea, a non-specific , is the first-line agent, starting at 500 mg daily and titrated to control blood counts, with evidence from randomized studies showing a 25% reduction in thrombotic events versus observation alone. In cases of hydroxyurea intolerance or resistance, , a selective JAK1/2 inhibitor approved by the FDA in 2014, offers an alternative by targeting the underlying JAK2 mutation, achieving control in over 60% of refractory patients; as of 2025, ongoing trials explore combinations with interferon-alpha or , showing potential for improved event-free survival in resistant cases. Interferon-alpha, particularly pegylated formulations like ropeginterferon alfa-2b, is preferred for younger patients (under 60 years) or those planning pregnancy due to its immunomodulatory effects and potential to induce molecular remissions by reducing the JAK2 mutant allele burden. Guidelines position it as a first-line option in these groups, with response rates exceeding 80% in hematologic control and a favorable safety profile avoiding teratogenicity concerns associated with other agents. Emerging therapies include rusfertide, a synthetic mimetic that regulates iron metabolism to suppress ; phase 3 VERIFY trial results presented in 2025 demonstrated a significant reduction in requirements (mean of 0.5 vs. 1.8 in ) and control below 45% in 62.6% of patients (vs. 14.4% with ) when added to standard care, earning FDA designation in August 2025 for phlebotomy-dependent patients. For patients with high-risk progression to myelofibrosis or , allogeneic offers the only curative potential, with 5-year survival rates of 50-70% in selected cases, though it carries substantial risks of . Response to these interventions is monitored through serial complete blood counts every 2-4 weeks initially, then quarterly once stable.

Secondary Polycythemia Treatment

The primary management strategy for secondary polycythemia focuses on identifying and treating the underlying cause to reduce erythropoietin-driven production and alleviate symptoms. Unlike primary forms, this approach prioritizes causal correction over aggressive reduction, as the condition resolves with effective management. For hypoxia-related cases, such as or high-altitude exposure, low-flow is recommended to normalize and subsequently lower levels. is essential in smokers' polycythemia, as it directly addresses carbon monoxide-induced hypoxia and has been shown to improve hematological parameters. In patients with erythropoietin-producing neoplasms, such as , surgical resection of the tumor is curative and leads to normalization of red cell mass. Phlebotomy is reserved for symptomatic hyperviscosity, such as headaches or visual disturbances, or prior to , with a target of 45-55% to avoid exacerbating tissue hypoxia; it is not routinely used due to limited evidence of thrombotic benefit. Cytoreductive agents are generally avoided, as they do not target the root cause and are reserved only for complications like . In special cases, discontinuing androgen therapy, such as testosterone replacement, is critical for drug-induced secondary polycythemia, often leading to resolution without further intervention. For , (CPAP) therapy effectively treats nocturnal hypoxia and reduces erythrocytosis. Neonatal secondary polycythemia, often due to or twin-twin transfusion, requires partial if exceeds 70% with symptoms of hyperviscosity, such as poor feeding or respiratory distress, though evidence for routine use is limited. Preliminary basic research into traditional Chinese medicine for high-altitude polycythemia, a subtype of secondary polycythemia caused by chronic hypoxia, has primarily utilized animal models simulating high-altitude conditions. These studies have identified potential mechanisms including inhibition of excessive erythropoietin production, countering oxidative stress, improving blood rheology, and protecting organs such as the heart, brain, and kidney. However, these findings are from preclinical investigations and require further clinical validation to establish efficacy and safety in humans. Thrombosis prevention with low-dose aspirin may be considered in high-risk patients with a history of events.

Monitoring and Prognosis

Patients with (PV) require regular monitoring to assess control, detect complications early, and evaluate for progression. (CBC) testing is recommended every 3 to 6 months to monitor levels and ensure they remain below 45%, along with for signs of or bleeding. risk assessment in PV typically uses conventional criteria, classifying patients as high-risk if they are over 60 years old or have a history of , guiding decisions on cytoreductive therapy. re-biopsy is indicated if there is suspicion of progression, such as worsening cytopenias or . Key complications in PV include arterial and venous thrombosis, which affect 39-41% of patients and account for approximately 45% of deaths due to cardiovascular causes like and . The lifetime risk of major thrombotic events is estimated at 20-30%, with higher rates in untreated or poorly controlled cases. Bleeding occurs at a rate of about 0.9% per patient-year, often linked to acquired von Willebrand syndrome in those with extreme thrombocytosis. Hyperuricemia from increased cell turnover can lead to , manifesting as joint pain and inflammation, particularly in the lower extremities. Disease transformation to myelofibrosis occurs in about 20% of cases over 20 years, while progression to affects approximately 10%. Prognosis for PV has improved with modern treatments, with median survival exceeding 15 years overall and over 35 years for patients diagnosed under 40. For secondary polycythemia, outcomes depend on the underlying cause; resolution of the precipitant, such as treating hypoxia or removing a tumor, often leads to normalization of red cell mass and better prognosis, with median survival around 21 months in broader cohorts but longer when managed effectively. Neonatal polycythemia typically resolves spontaneously in most cases, with a good outlook for mild hyperviscosity if addressed promptly, though severe untreated cases carry risks of neurologic and other organ complications. Recent 2024 updates to European LeukemiaNet (ELN) risk stratification for PV better identify high-risk phenotypes for , enabling refined low-risk management strategies. In endurance athletes, can induce relative polycythemia by hemoconcentration, temporarily elevating and increasing risk, but this is not recommended or safe for performance enhancement due to potential cardiovascular complications.

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