Diagnostic approach to the patient with erythrocytosis/polycythemia

INTRODUCTION — Erythrocytosis (also called polycythemia) refers to an increased hemoglobin concentration and/or hematocrit in peripheral blood. Diagnosing the specific cause of polycythemia is important for proper management of the patient.

This topic discusses the causes of erythrocytosis and our approach to evaluation and diagnosis. The approach to confirming a diagnosis of polycythemia vera is discussed separately. (See "Clinical manifestations and diagnosis of polycythemia vera".)

TERMINOLOGY — The following terms are important for diagnosing and classifying erythrocytosis; note that we use erythrocytosis and polycythemia interchangeably:

●Erythrocytosis – Erythrocytosis (polycythemia) is an abnormal elevation of hemoglobin (Hb) and/or hematocrit (Hct) in peripheral blood. We consider the following values to constitute polycythemia [1]:

•Increased hemoglobin – >16.5 g/dL (10.3 mmol/L) in men or >16.0 g/dL (10.0 mmol/L) in women

•Increased hematocrit – >49 percent in men or >48 percent in women

Normal values for red blood cell (RBC) parameters in adults are presented in the table (table 1). For children, normal values for RBC parameters vary according to age (table 2).

●Relative polycythemia – Hemoconcentration, or an elevation of Hb and/or Hct due to a decrease in plasma volume alone (ie, without an increase of the RBC mass) is referred to as relative polycythemia. (See 'Relative polycythemia' below.)

●Absolute polycythemia – Absolute polycythemia refers to an increase of RBC mass, which has multiple causes (table 3) and can be categorized as either primary or secondary polycythemia. (See 'Causes of absolute polycythemia' below.)

●Primary polycythemia – Primary polycythemia refers to an increase of RBC mass caused by a mutation (either acquired or inherited) in RBC progenitor cells. Causes of primary polycythemia are described below. (See 'Primary polycythemia' below.)

●Secondary polycythemia – Secondary polycythemia refers to an increase of RBC mass caused by elevated serum erythropoietin (EPO), as described below. Causes of secondary polycythemia are described below. (See 'Secondary polycythemia' below.)

Further description of RBC parameters and their determination in a complete blood count are described separately. (See "Automated complete blood count (CBC)", section on 'RBC parameters'.)

PHYSIOLOGY OF ERYTHROPOIESIS — Red blood cells (RBCs), like all mature blood cells, are derived from multipotent hematopoietic stem and progenitor cells in the bone marrow through a hierarchical process of lineage commitment and differentiation, as described separately. (See "Overview of hematopoietic stem cells".)

Erythropoietin (EPO) is the primary driver of proliferation and differentiation of RBC progenitors in normal physiology. Ninety percent of circulating EPO in humans is produced by the kidneys as a physiologic response to hypoxia. EPO-producing renal cells detect hypoxic signals due to reduced hemoglobin (anemia) (figure 1), hypoxemia (eg, reduced oxygen saturation or release by hemoglobin), or impaired oxygen delivery to the kidney (eg, vascular occlusion). EPO production is linked to oxygen delivery via a complex negative feedback loop, as described separately. (See "Regulation of erythropoiesis".)

RELATIVE POLYCYTHEMIA — Because hemoglobin (Hb) and hematocrit (Hct) reflect the concentration of various RBC components in peripheral blood, a reduction in plasma volume alone, even in the absence of an increase in RBC mass, can cause relative polycythemia (ie, hemoconcentration). The most common reasons for plasma volume depletion are diuretic use, vomiting, or diarrhea.

Smokers may develop erythrocytosis from a combination of reduced plasma volume and increased RBC mass; these abnormalities generally return to normal with cessation of smoking [2,3]. There is controversy regarding the existence of a distinct entity called Gaisböck's syndrome (also referred to as spurious polycythemia or stress polycythemia), which was classically described as erythrocytosis in tense/anxious patients with hypertension, no splenomegaly, and reduced plasma volume [4-6]. Hypertension with diuretic use and smoking may account for the relative polycythemia in many of these individuals.

CAUSES OF ABSOLUTE POLYCYTHEMIA — Increased RBC mass (absolute polycythemia) may be caused by autonomous production of RBCs (primary polycythemia) or as a response to elevated serum erythropoietin (EPO; secondary polycythemia). The causes of absolute polycythemia (table 3) vary according to the patient population and the clinical setting.

Evaluation to diagnose the cause of erythrocytosis is described below. (See 'Initial evaluation' below.)

Primary polycythemia — Primary polycythemia is caused by a mutation (either acquired or inherited) in RBC progenitor cells that results in increased RBC mass. Most commonly, primary polycythemia is caused by an acquired condition, such as polycythemia vera (PV) or another myeloproliferative neoplasm (MPN) in association with JAK2 V617F or other mutation. (See "Clinical manifestations and diagnosis of polycythemia vera" and "Overview of the myeloproliferative neoplasms".)

Examples of inherited germline mutations that cause polycythemia include Chuvash polycythemia (mutation of the VHL gene), mutations of the EPO receptor, high-oxygen-affinity hemoglobinopathy, and other rare conditions (table 3), which are discussed separately. (See "Hemoglobin variants that alter hemoglobin-oxygen affinity" and "Molecular pathogenesis of congenital erythrocytoses and polycythemia vera".)

Evaluation of the patient with suspected primary polycythemia is described below. (See 'Suspected PV/MPN' below and 'Familial polycythemia' below.)

Secondary polycythemia — Secondary polycythemia refers to an increase of RBC mass caused by elevated serum EPO. Most often, this is due to an appropriate physiologic response to tissue hypoxia, but secondary polycythemia can also result from autonomous EPO production (eg, an EPO-secreting tumor) (table 3), as described in the following sections.

Evaluation of the cause of elevated EPO in a patient with polycythemia is discussed below. (See 'Elevated serum EPO' below.)

Hypoxia-associated polycythemia — Polycythemia due to increased EPO in response to hypoxia has numerous possible causes (table 3). Most commonly, elevated EPO as a cause of erythrocytosis is due to cardiopulmonary disease (eg, chronic pulmonary disease, cyanotic heart disease, obstructive sleep apnea). Systemic hypoxia may also be caused by residence at high altitude (diminished partial pressure of oxygen in inspired air), while functional tissue hypoxia can result from decreased release of oxygen to peripheral tissues from high oxygen affinity hemoglobin (eg, carbon monoxide [CO] toxicity or rare inherited disorders).

In smokers, erythrocytosis is often multifactorial, including hypoxia, CO exposure, smoking-related diseases, and volume contraction [2,7].

Increased EPO production may also be caused by diminished oxygen sensing by the kidney. Examples include reduced blood flow to the kidney (eg, renal artery stenosis) and other intrinsic renal disorders (eg, kidney cysts, hydronephrosis).

Erythrocytosis occurs in up to one-quarter of patients following renal transplantation. In many patients, the polycythemia is associated with elevated EPO, but other mechanisms may also contribute, including other hematopoietic growth factors, androgens, and activation of the renin-angiotensin system, as described separately. (See "Kidney transplantation in adults: Posttransplant erythrocytosis".)

Tumor-associated polycythemia — Autonomous production of EPO (ie, independent of oxygen sensing) by various tumors can cause paraneoplastic polycythemia. Tumors that are most commonly associated with the overproduction of EPO include hepatocellular carcinoma, renal cell carcinoma, hemangioblastoma, pheochromocytoma, and uterine myomata:

●Erythrocytosis was reported in one-quarter of patients with hepatocellular carcinoma, and this is generally due to secretion of EPO by the cancer [8]. However, elevated serum EPO is more frequently seen than polycythemia, presumably due to the inhibition of erythropoiesis by the malignancy and bleeding (eg, esophageal varices and/or coagulopathy from reduced hepatic production of clotting factors). (See "Clinical features and diagnosis of hepatocellular carcinoma", section on 'Paraneoplastic syndromes'.)

●Erythrocytosis occurs in 1 to 5 percent of patients with renal cell carcinoma, and is related to increased production of EPO due to aberrant regulation of hypoxia-inducible transcription factors by mutations of VHL, the gene that encodes the von Hippel-Lindau (VHL) tumor suppressor [9,10]. (See "Clinical manifestations, evaluation, and staging of renal cell carcinoma", section on 'Erythrocytosis'.)

●Hemangioblastomas are slow-growing tumors of the central nervous system that may occur sporadically or can be a manifestation of VHL disease. Mutations of VHL are present in many of these tumors, which may account for impaired sensing of the ambient oxygen tension and paraneoplastic production of EPO. (See "Hemangioblastoma", section on 'Symptoms'.)

●Uterine leiomyomata (fibroids) may be associated with secondary polycythemia due to EPO production by the tumor cells [11-13]. (See "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history".)

Other causes — Erythrocytosis may be due to other, miscellaneous causes.

●SGLT2 inhibitors – SGLT2 (sodium-glucose cotransporter-2) inhibitors (eg, canagliflozin, empagliflozin, dapagliflozin, ertugliflozin) are antidiabetic agents that are also used in patients with heart failure and chronic renal disease. SGLT2 inhibitors are increasingly recognized as a cause of erythrocytosis.

A case series of 30 patients with SGLT2 inhibitor-associated erythrocytosis reported that two-thirds were male, and the median age was 64 years; one-quarter of patients had another erythrocytosis-predisposing factor (eg, sleep apnea, smoking) [14]. Median peak hematocrit was 54.4 percent in males and 51.2 percent in females; serum EPO level was inappropriately normal or increased in all 27 cases in which it was measured. With a median follow-up >2 years, two male patients experienced unstable angina; no other thrombotic events were reported. Discontinuation of the SGLT2 inhibitor led to resolution of erythrocytosis.

The mechanism of erythrocytosis by SGLT2 inhibitors may be due to increased EPO production via hypoxia-induced activation of HIF2a, modulation of iron metabolism through hepcidin, and/or hemoconcentration [15,16].

●Athletic performance enhancers – Polycythemia may be due to autologous blood transfusion ("blood doping"), self-injection of recombinant EPO, or use of androgens or anabolic steroids as a technique for enhancing athletic performance.

●Cobalt – Cobalt toxicity has been associated with polycythemia, but the mechanism is poorly understood [17].

●POEMS syndrome – POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, Skin changes) is a paraneoplastic process that is occasionally associated with polycythemia, but the mechanism is not well understood. (See "POEMS syndrome", section on 'Polycythemia and thrombocytosis'.)

INITIAL EVALUATION — Erythrocytosis may be encountered in the course of evaluating other clinical findings or as an incidental abnormality on a complete blood count (CBC) and differential (algorithm 1). The initial evaluation should enable the clinician to distinguish between relative polycythemia (ie, plasma volume depletion) versus absolute polycythemia (ie, increased red blood cell [RBC] mass). Findings from the initial evaluation, together with the clinical scenario, should direct the subsequent evaluation to establish the underlying diagnosis (table 3), as illustrated by the algorithm. (See 'Clinical scenarios' below.)

Urgency of evaluation — Patients with medical emergencies related to polycythemia (eg, cerebrovascular accident, chest pain) should receive emergency management (eg, hydration, phlebotomy, other measures), as described separately. (See "Polycythemia vera and secondary polycythemia: Treatment and prognosis", section on 'Specific clinical scenarios'.)

For other patients, the urgency of evaluation is related to the level of polycythemia and the presence of findings that suggest the presence of polycythemia vera (PV), another myeloproliferative neoplasm (MPN), or other cancers. As an example, a patient with a hematocrit (Hct) ≥60 and pruritus, erythromelalgia, and abdominal fullness should be evaluated promptly because of likelihood of PV and the substantial risk of associated thrombosis or other complication. Conversely, an asymptomatic adult with an Hct of 50 may be evaluated in days to weeks.

CBC/blood smear — CBC and differential count may demonstrate abnormalities in RBCs alone or may also reveal findings in white blood cells (WBC) and/or platelets. If available, serial CBCs may reveal the rate of rise (or stability) of hemoglobin (Hb) and Hct.

Normal values for Hb and Hct in adults (table 1) and children (table 2) are provided separately. World Health Organization (WHO) criteria for erythrocytosis [1] are:

●Increased hemoglobin – >16.5 g/dL in men or >16.0 g/dL in women

●Increased hematocrit – >49 percent in men or >48 percent in women

Elevation of RBC count alone (ie, not accompanied by increased Hb or Hct) is not a criterion for polycythemia. As an example, an elevated RBC count may be associated with anemia and an increased number of hypochromic, microcytic RBCs, as is typically seen with thalassemia minor. (See "Diagnosis of thalassemia (adults and children)", section on 'CBC and hemolysis testing'.)

The blood smear may reveal increased levels of WBCs, eosinophils, or basophils; immature WBC forms; abnormal appearance or an increased number of platelets; or a leukoerythroblastic picture (ie, teardrop-shaped RBCs with circulating nucleated RBCs and/or immature white cells); such abnormalities may suggest an underlying MPN. (See "Clinical manifestations and diagnosis of polycythemia vera".)

History — The history should evaluate:

●Symptoms that may be caused by the elevated Hb/Hct and/or suggest the presence of PV/MPN [18] include:

•Hyperviscosity symptoms – Chest or abdominal pain, myalgia and weakness, fatigue, headache, blurred vision, transient loss of vision, paresthesias, slow mentation, and/or a sense of depersonalization

•Thrombosis or bleeding – Thromboses at unusual sites (eg, mesenteric, hepatic, portal, or retinal veins; arterial thromboses) or excessive bleeding/bruising

•Symptoms associated with PV – Unexplained fever, sweats, weight loss; pruritus (especially after bathing [aquagenic pruritus]); erythromelalgia (intense, burning pain and/or redness of the extremities); gout; early satiety due to splenomegaly (see "Clinical manifestations and diagnosis of polycythemia vera", section on 'Clinical presentation')

●Additional clues to the underlying disorder, including causes and risk factors for secondary polycythemia (eg, volume depletion, hypoxemia, erythropoietin [EPO]-secreting tumor) include:

•Volume depletion – Use of diuretics, vomiting, diarrhea, anorexia, lightheadedness, and/or orthostatic symptoms

•Cardio-pulmonary disease – Chronic lung disease, dyspnea at rest or with exertion, chronic cough; sleep apnea/hypersomnolence; history of cyanotic heart disease, intracardiac or intrapulmonary shunts; or extensive mucocutaneous telangiectasia (eg, from hereditary hemorrhagic telangiectasia that can be associated with pulmonary arteriovenous malformations) (see "Medical management of cyanotic congenital heart disease in adults" and "Approach to cyanosis in children" and "Approach to cyanosis in the newborn" and "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)")

•Abdomino-pelvic tumor – Unexpected weight loss, hematuria, abdominal/pelvic pain or fullness (which may point to an intra-abdominal EPO-secreting tumor), history of renal transplantation (see 'Tumor-associated polycythemia' above and "Kidney transplantation in adults: Posttransplant erythrocytosis")

●Social history should evaluate:

•Smoking – Cigarette or cigar smoking, including the number smoked and whether the patient inhales

•Carbon monoxide – Exposure to carbon monoxide (CO) from smoking, work (eg, engine exhausts or combustion products, work in underground parking lots or tunnels, employment as an auto mechanic, truck or taxicab driver), hobbies, or home life (eg, home heating devices, faulty venting of furnaces or fireplaces) (see "Carbon monoxide poisoning")

•"Blood doping" – Use of products to improve athletic performance, including androgens (eg, testosterone) or anabolic steroids, self-injection of recombinant erythropoiesis-stimulating agents (eg, epoetin alfa), or transfusion of stored autologous blood

●Family history should examine whether relatives have polycythemic conditions (eg, high oxygen affinity hemoglobinopathies) or documented elevation of Hb or Hct, or other hematologic or systemic syndromes (see 'Familial polycythemia' below)

Physical examination — Physical examination should evaluate manifestations of volume depletion, hyperviscosity, cardio-pulmonary disease, and a possible underlying MPN, including:

●General examination

•Cyanosis in the lips, earlobes and fingers, and clubbing in the nailbeds associated with hypoxia

•Plethoric facies, dilated lingual or retinal veins, or areas of painful erythema may be seen in patients with PV

●Cardiopulmonary – Breathing pattern, other respiratory findings, cardiac murmurs or bruits (eg, from pulmonary arteriovenous shunts or right-to-left cardiac shunts) (see 'Hypoxia/cardiopulmonary disease' below)

●Organomegaly – Hepatomegaly and/or splenomegaly (from PV or another MPN) or other masses that may be associated with or an EPO-secreting tumor (see 'Suspected PV/MPN' below)

Laboratory testing — There is no universal agreement about the essential components of the initial screening evaluation for polycythemia. Our approach is to perform pulse oximetry; measure serum EPO, electrolytes, kidney and liver function tests; and obtain a urinalysis in all patients, unless polycythemia is clearly due to hemoconcentration (ie, volume depletion). We suggest reserving other testing (eg, JAK2 and other gene mutation analysis, bone marrow examination, imaging) for selected patients, as guided by the history, physical examination, initial laboratory studies, and clinical scenario (algorithm 1). (See 'Clinical scenarios' below.)

Some experts suggest obtaining a chest X-ray and testing for JAK2 V617F in the initial evaluation of all patients who do not have apparent relative polycythemia (ie, due to volume contraction).

Pulse oximetry — Pulse oximetry should be performed in all patients with polycythemia, as an initial estimate of tissue oxygenation. Pulse oximetry should be performed at rest and after modest exertion. Interpretation of pulse oximetry results is discussed separately. (See "Pulse oximetry", section on 'Interpreting the results'.)

Hypoxia may suggest the presence of cardiopulmonary disease or other processes as the cause of polycythemia, which should be further evaluated as described below. (See 'Hypoxia/cardiopulmonary disease' below.)

It is important to note that standard pulse oximetry is not an adequate screen for carbon monoxide (CO) exposure, as it does not distinguish carboxyhemoglobin from oxyhemoglobin, as discussed below and separately. (See "Carbon monoxide poisoning", section on 'Diagnosis' and 'Hypoxia/cardiopulmonary disease' below.)

Serum erythropoietin (EPO) — We suggest obtaining serum EPO for all patients, except when the initial evaluation (ie, history and physical examination, serum chemistries) indicates that the elevation of Hb/Hct is due to volume contraction alone (ie, relative polycythemia). Measurement of serum EPO is important for distinguishing between primary (low or absent EPO) and secondary causes of polycythemia (elevated EPO).

An increase of serum EPO indicates either an appropriate physiologic response to hypoxia or the autonomous production of EPO (eg, EPO-secreting tumor). Although EPO levels vary with particular conditions, the degree of elevation does not indicate the underlying cause. Nevertheless, EPO levels are generally highest in congenital heart disease with right-to-left shunting or following renal transplantation [19]. Causes of elevated EPO are described above. (See 'Secondary polycythemia' above.)

A low or absent level of serum EPO in the patient with polycythemia is relatively specific for the diagnosis of PV or other MPN. Exceptions include "blood doping" (autologous transfusion to enhance athletic performance), rare cases of congenital polycythemia due to an activating mutation in the EPO receptor [20-22], and occasional patients with post-renal transplant erythrocytosis [19,23]. (See 'Primary polycythemia' above.)

Other screening labs — Other laboratory studies that are useful in the initial evaluation of patients with polycythemia include:

●Serum chemistries – Serum electrolytes and kidney and liver function tests can indicate volume contraction or organ dysfunction that may be associated with renal disease or an underlying tumor.

●Urinalysis – Hematuria may point to a kidney tumor or other renal abnormalities.

Are JAK2 testing/bone marrow examination required for all? — We suggest not testing for JAK2 mutation and/or bone marrow examination in all patients with polycythemia.

We selectively perform JAK2 mutation testing in the following settings:

●Patients with clinical findings from the history and physical examination that suggest PV or other MPN (eg, pruritus, erythromelalgia, arterial or venous thrombosis, unexplained bleeding/excessive bruising) (see 'Suspected PV/MPN' below)

●Patients with low or normal serum EPO and no evidence of volume contraction (ie, relative polycythemia)

Evaluation of JAK2 mutation testing and other molecular evaluation for PV and MPNs is discussed below and separately. (See 'Suspected PV/MPN' below and "Clinical manifestations and diagnosis of polycythemia vera", section on 'JAK2 mutations'.)

We perform a bone marrow examination only when there is clinical suspicion or molecular evidence for PV or other MPN, as described above. In those settings, bone marrow biopsy is important for evaluation of myelofibrosis, acute myeloid leukemia, or other complications of these disorders. (See 'Suspected PV/MPN' below.)

CLINICAL SCENARIOS — The initial evaluation provides findings that direct further evaluation and enable the clinician to define the underlying cause of erythrocytosis, as described in the sections below. (See 'Initial evaluation' above.)

Resolution of polycythemia — If a repeat complete blood count (CBC) reveals resolution of polycythemia, and no findings from the initial evaluation that suggest polycythemia vera (PV), other myeloproliferative neoplasm (MPN), or other malignancy, no further evaluation is required. In many such cases, the initial evaluation will identify a likely explanation for transient polycythemia. As examples:

●Erythrocytosis resolved after management of dehydration from diarrhea or diuretic use; in this setting, the diagnosis is relative polycythemia due to plasma volume contraction.

●Erythrocytosis resolved in association with improvement of hypoxia after smoking cessation or management of obstructive sleep apnea in a patient with elevated serum erythropoietin (EPO).

Suspected volume depletion — When hemoglobin (Hb) and/or hematocrit (Hct) are elevated due to volume depletion, rather than an increase in RBC mass, the patient is considered to have relative polycythemia. In this setting, evaluation and management are primarily focused on identifying the underlying cause, managing symptoms, and correcting volume depletion, fluid loss, and associated electrolyte abnormalities.

Identification of volume depletion is generally based on the initial clinical evaluation, because direct methods for estimating blood volume are not widely available. Examples of clinical findings that suggest volume depletion are thirst, postural dizziness, loss of skin turgor, orthostatic hypotension, and elevated blood urea nitrogen (BUN)/creatinine, but these findings are not always reliable in older individuals. Clinical evaluation of volume depletion is discussed separately. (See "Etiology, clinical manifestations, and diagnosis of volume depletion in adults", section on 'Clinical manifestations'.)

When volume depletion is suspected as the cause of relative polycythemia, a repeat CBC after fluid restoration or reduction of diuretics should reveal improvement in Hb/Hct. No further evaluation is required if polycythemia resolved and the initial clinical evaluation did not reveal findings associated with PV/MPN (eg, constitutional symptoms, pruritus, erythromelalgia, splenomegaly, or thromboses) or other cancer. (See 'History' above.)

In this setting, symptoms and complications are more commonly associated with volume depletion than with the level of Hb/Hct. Consequently, a balance should be struck between the patient's overall condition (eg, fluid status) and a desire to normalize hematologic values. However, if polycythemia persists after restoration of clinical euvolemia, the clinician should remain suspicious that other causes are contributing to erythrocytosis.

There is controversy regarding the existence of a distinct entity called Gaisböck's syndrome (also referred to as spurious polycythemia or stress polycythemia) [4-6]. Classically, this was described as polycythemia in anxious patients with hypertension, no splenomegaly, and reduced plasma volume. However, hypertension with diuretic use and smoking may account for the relative polycythemia in many of these individuals. Smoking should be discontinued in all such patients.

Volume contraction contributes to polycythemia in smokers. A clue to the presence of smoking-related polycythemia is a reduction in Hct by ≥4 percent within a few days of smoking cessation [2].

Although this testing is no longer widely available, the RBC mass can be determined directly by infusion of the patient's own RBCs labeled with a radioactive isotope (eg, Tc99m, Cr51), while the plasma volume is simultaneously and directly determined following infusion of isotopically-labeled human albumin [24-27]. Similar methods have been developed using non-radioactive labels (eg, carbon monoxide, biotin) [28,29].

Elevated serum EPO — Serum EPO may be elevated as an appropriate physiologic response to hypoxia or because of inappropriate, autonomous production of EPO (eg, EPO-secreting tumor). Distinguishing between these causes for elevated EPO is based on findings from the history and physical examination and the results of pulse oximetry, as described below.

Hypoxia/cardiopulmonary disease — A cardiopulmonary cause for secondary polycythemia is diagnosed by the clinical evaluation together with hypoxia and elevated serum EPO. Management should focus on improving the underlying cause of hypoxia.

●Investigating the cause – Clinical findings that suggest a cardiopulmonary cause for polycythemia include dyspnea, cough, cyanosis, symptoms associated with obstructive sleep apnea (OSA; eg, snoring, wake-time sleepiness, nocturnal choking or gasping), cyanotic heart disease, intracardiac or intrapulmonary shunts, and extensive mucocutaneous telangiectasia (suggestive of hereditary hemorrhagic telangiectasia; HHT). (See 'History' above.)

In-laboratory or home sleep apnea testing should be performed if the clinical history suggests OSA, as described separately.

Hypoxia may also be related to residence at high altitude or chronic carbon monoxide (CO) exposure. Carboxyhemoglobin should be measured in patients with a substantial smoking history or potential chronic exposure to CO, because standard pulse oximetry, which does not distinguish between carboxyhemoglobin and oxyhemoglobin, is not sufficient to diagnose CO toxicity. Levels of carboxyhemoglobin ≥5 percent strongly suggest polycythemia caused by CO poisoning; this diagnosis is confirmed if Hb/Hct normalize within two to three months after cessation of exposure [2,3]. Other aspects of the clinical presentation and diagnosis of chronic CO toxicity are presented separately. (See "Carbon monoxide poisoning".)

In children and in adults, congenital cyanotic heart disease may cause secondary polycythemia. Evaluation and management of such disorders are described separately. (See "Approach to cyanosis in the newborn" and "Approach to cyanosis in children" and "Medical management of cyanotic congenital heart disease in adults".)

●Management – Management is based on correcting or improving the underlying cause of hypoxia. Examples include supplemental oxygen and/or bronchodilators for lung disease, techniques for improving OSA, and repair of cardiac or pulmonary shunts. Smoking should be discontinued and exposure to CO eliminated.

Because erythrocytosis caused by cardiopulmonary disease is an appropriate response to tissue hypoxia, attempts to reduce RBC mass by phlebotomy may exacerbate tissue hypoxia. Consequently, phlebotomy is not often utilized unless there is extreme elevation of Hct (eg, ≥65 percent) or symptoms attributable to increased blood volume/hyperviscosity (eg, fatigue, headache, blurred vision, transient loss of vision, paresthesias, slow mentation).

Management of secondary erythrocytosis is discussed separately. (See "Polycythemia vera and secondary polycythemia: Treatment and prognosis", section on 'Secondary polycythemia'.)

Other causes of EPO elevation — Other causes of erythrocytosis should be considered if serum EPO is elevated, but clinical evaluation and pulse oximetry do not suggest a cardiopulmonary cause (as described above). The evaluation should seek to distinguish between renal causes for elevated EPO (eg, renal artery stenosis, post-renal transplantation) versus autonomous production by an EPO-secreting tumor.

Findings from the initial clinical evaluation that might suggest an EPO-producing tumor include abdominal pain or fullness, menorrhagia, constitutional symptoms, unexplained weight loss, neurologic abnormalities, or hematuria. Erythrocytosis in the setting of significant menorrhagia may be a clue to fibroids as the source of elevated EPO. Further diagnostic testing for an EPO-producing tumor should include CT (computerized tomography) of the abdomen and pelvis, CT or MRI (magnetic resonance imaging) of the brain, or other imaging modality. Cancer diagnosis generally requires a biopsy of the suspected mass. (See 'Tumor-associated polycythemia' above.)

The diagnostic evaluation for renal artery stenosis or other renal disease as a cause of elevated EPO is guided by the clinical setting and presence of hypertension, renal insufficiency, or abnormal urinalysis, as described separately. (See "Establishing the diagnosis of renovascular hypertension", section on 'Selecting a diagnostic test'.)

Suspected PV/MPN — PV should be suspected in patients with MPN-related symptoms (eg, headache, dizziness, visual disturbances, pruritus, early satiety) or complications (eg, thrombosis, bleeding); a blood smear that reveals leukocytosis, increased levels of eosinophils or basophils, immature white blood cell forms, an increased number or abnormal appearance of platelets, or a leukoerythroblastic picture; or polycythemia in association with low or absent EPO. Evaluation for PV requires molecular testing (eg, for JAK2 mutation) and bone marrow examination.

Diagnosis of PV, according to World Health Organization criteria (table 4), is based on elevation of Hb/Hct, a bone marrow biopsy that shows hypercellularity with panmyelosis, and JAK2 V617F or JAK2 exon 12 mutation. Further details of the diagnostic evaluation of PV are presented separately. (See "Clinical manifestations and diagnosis of polycythemia vera", section on 'Diagnosis'.)

Polycythemia may also be a manifestation of essential thrombocythemia (ET), primary myelofibrosis, or chronic myeloid leukemia. Distinguishing PV from ET or other MPN may be difficult at times, as described separately. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Differential diagnosis'.)

Familial polycythemia — Familial polycythemia should be suspected when the onset of polycythemia is in childhood or there is a positive family history of polycythemia.

Laboratory investigation usually begins with the determination of the oxygen pressure at 50 percent Hb saturation (P₅₀) (figure 2). A low P₅₀ suggests a high oxygen affinity hemoglobinopathy, congenital methemoglobinemia, bisphosphoglyceromutase deficiency, or other rare conditions. (See "Hemoglobin variants that alter hemoglobin-oxygen affinity" and "Molecular pathogenesis of congenital erythrocytoses and polycythemia vera".)

A normal P₅₀ in a patient with a familial polycythemia may be caused by a variety of rare syndromes caused by inherited (germline) mutations [30]. Examples include primary familial and congenital polycythemia, which may be caused by an activating mutation of the EPO-receptor (EPOR) or other mutations; Chuvash polycythemia, caused by variants or deletions of VHL; or other genetic disorders, as described separately. (See "Molecular pathogenesis of congenital erythrocytoses and polycythemia vera" and "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myeloproliferative neoplasms".)

SUMMARY

●Definition – Erythrocytosis (also called polycythemia) describes an increased hemoglobin (Hb) concentration and/or hematocrit (Hct) in blood. Polycythemia can be due to an increased red blood cell (RBC) mass and/or hemoconcentration (decreased plasma volume). (See 'Terminology' above.)

Thresholds for erythrocytosis:

•Adults – (table 1):

-Males – Hb >16.5 g/dL or Hct >49 percent

-Females – Hb >16.0 g/dL or Hct >48 percent

•Children – Normal values vary with age and sex (table 2)

●Physiology of erythropoiesis – Erythropoietin (EPO) is the primary driver of RBC mass; 90 percent of circulating EPO is produced by the kidneys in response to hypoxia. (See 'Physiology of erythropoiesis' above.)

●Initial evaluation – Initial evaluation for erythrocytosis (algorithm 1) should distinguish volume contraction from increased RBC mass, based upon (see 'Initial evaluation' above):

•History and physical examination

•Complete blood count (CBC) and differential count

•Serum electrolytes and kidney function tests

●Status after achieving euvolemia – Volume-depleted patients should be volume repleted, with further evaluation guided by the resultant level of Hb/Hct.

•Normalization with euvolemia – For Hb/Hct that normalizes after volume repletion (ie, relative polycythemia), no further evaluation for polycythemia is needed. (See 'Relative polycythemia' above.)

•Persistent polycythemia – For polycythemia that persists after correction of volume loss (ie, absolute polycythemia), we obtain:

-Pulse oximetry

-Serum EPO

●Clinical scenarios – Results from pulse oximetry and serum EPO guide further evaluation and likely diagnoses (table 3) (see 'Clinical scenarios' above):

•Decreased O₂ saturation and/or elevated EPO – Hypoxia or elevated EPO indicates secondary polycythemia; possible causes include (table 3):

-Hypoxia/cardiopulmonary causes – Chronic lung disease, right-to-left cardiac shunt, sleep apnea, high altitude, carbon monoxide poisoning, and other disorders that cause hypoxia and elevated EPO

-Kidney-associated – Elevated EPO due to renal artery stenosis or post-kidney transplantation

-Miscellaneous causes – SGLT2 (sodium-glucose cotransporter-2) inhibitors, EPO-producing tumors, blood-doping

•Adequate O₂ saturation and low or normal EPO – These patients should be evaluated for polycythemia vera (PV) and other myeloproliferative neoplasms (MPNs). Testing should begin with JAK2 V617F; if negative, the evaluation should include other mutations of JAK2, MPL, CALR, and BCR::ABL1 and may include bone marrow examination. Evaluation and diagnostic criteria for PV and other MPNs are presented separately. (See "Clinical manifestations and diagnosis of polycythemia vera" and "Overview of the myeloproliferative neoplasms" and "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

Testing for rare inherited mutations of Hb or metabolic disorders should be considered if an MPN is not found.

ACKNOWLEDGMENT — The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.