Diagnostic Approach To The Patient With Polycythemia

04/12/2018 Diagnostic approach to the patient with polycythemia - UpToDate
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Diagnostic approach to the patient with polycythemia
Author: Ayalew Tefferi, MD

Section Editor: Stanley L Schrier, MD
Deputy Editor: Alan G Rosmarin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2018. | This topic last updated: Nov 06, 2018.
INTRODUCTION — 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 polycythemia 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 polycythemia:
● Polycythemia – Polycythemia (erythrocytosis) is an abnormal elevation of hemoglobin (Hgb) 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 Hgb 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 hematology instrumentation", section on 'Definitions of hematology parameters'.)
PHYSIOLOGY OF ERYTHROPOIESIS — 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
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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 (Hgb) 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 polycythemia 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 polycythemia 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 polycythemia (algorithm 1) 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), which are discussed separately. (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, and other rare conditions (table 3), which are discussed separately. (See "Genetic disorders of
hemoglobin oxygen affinity" and "Molecular pathogenesis of congenital polycythemic disorders 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 polycythemia 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, polycythemia 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).
Polycythemia 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 "Erythrocytosis following renal
transplantation".)
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:
● Polycythemia 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 leiomyomas (fibroids): Epidemiology, clinical features, diagnosis, and natural history".)
Other causes — Occasionally, polycythemia may be due to other, miscellaneous causes. As examples, 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 toxicity has been associated with polycythemia, but the mechanism is poorly understood [14]. POEMS syndrome is
occasionally associated with polycythemia, but the mechanism is not well understood. (See "POEMS syndrome", section on
'Hematologic features'.)
INITIAL EVALUATION — Polycythemia may be encountered in the course of evaluating other clinical findings or as an
incidental abnormality on a complete blood count (CBC) and differential. The initial evaluation should enable the clinician to
distinguish between relative polycythemia (ie, plasma volume depletion) versus absolute polycythemia (ie, increased 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 (algorithm 1). (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
"Prognosis and treatment of polycythemia vera", 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 (Hgb)
and Hct.
Normal values for Hgb and Hct in adults (table 1) and children (table 2) are provided separately. World Health Organization
(WHO) criteria for polycythemia [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 Hgb 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 "Clinical manifestations and diagnosis of the thalassemias", section on 'CBC
and routine laboratory studies'.)
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; 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 Hgb/Hct and/or suggest the presence of PV/MPN [15] 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);
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, 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 "Overview of 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 "Erythrocytosis following renal transplantation")
● Social history should evaluate:
• Cigarette or cigar smoking, including the number smoked and whether the patient inhales
• 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")
• 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 Hgb 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), 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. (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 Hgb/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 [16]. 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 [17-19], and occasional patients with post-renal transplant
erythrocytosis [16,20]. (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 exam 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 polycythemia, 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:
● Polycythemia resolved after management of dehydration from diarrhea or diuretic use; in this setting, the diagnosis is
relative polycythemia due to plasma volume contraction.
● Polycythemia resolved in association with improvement of hypoxia after smoking cessation or management of obstructive
sleep apnea in a patient with elevated serum EPO.
The urgency of evaluation and repeat CBC is discussed above. (See 'Urgency of evaluation' above.)
Suspected volume depletion — When hemoglobin (Hgb) 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 Hgb/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
Hgb/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 [21-24]. Similar methods have been developed using non-radioactive
labels (eg, carbon monoxide, biotin) [25,26].
Elevated serum EPO — Serum erythropoietin (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.
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.
(See "Overview of obstructive sleep apnea in adults" and "Overview of obstructive sleep apnea in adults", section on
'Diagnosis'.)
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 Hgb/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 "Overview of cyanosis in the newborn" and "Approach to cyanosis in children"
and "Medical management of cyanotic congenital heart disease in adults".)
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 polycythemia 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). In such settings, cautious phlebotomy (eg,
removal of 250 mL replaced with an equal volume of crystalloid) to reduce Hct to 55 to 60 percent may provide relief of these
symptoms; however, reduction of Hct to <55 percent range is likely to exacerbate dyspnea or other hypoxic symptoms.
Other causes of EPO elevation — Other causes of polycythemia 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 Hgb/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 "Diagnosis and
clinical manifestations 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 Hgb saturation (P50)
(figure 2). A low P50 suggests a high oxygen affinity hemoglobinopathy, congenital methemoglobinemia,
bisphosphoglyceromutase deficiency, or other rare conditions. (See "Genetic disorders of hemoglobin oxygen affinity" and
"Molecular pathogenesis of congenital polycythemic disorders 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 [27]. 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 polycythemic disorders
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 disorders".)
SUMMARY
● Polycythemia refers to an increased hemoglobin (Hgb) concentration (>16.5 g/dL in men or >16.0 g/dL in women) and/or
hematocrit (Hct; >49 percent in men or >48 percent in women) in peripheral blood. Red blood cell (RBC) parameters vary
with age, and normal values for adults (table 1) and children (table 2) are presented in the accompanying tables. (See
'Terminology' above.)
Hgb and Hct are affected by the total RBC mass and the plasma volume. As a consequence, polycythemia may be
caused by either a decrease in plasma volume without an increase of the RBC mass (ie, relative polycythemia) or by an
increase in RBC mass (ie, absolute polycythemia).
● In normal physiology, erythropoietin (EPO) is the primary driver of RBC mass. Ninety percent of circulating EPO in
humans is produced by the kidneys in response to hypoxia. (See 'Physiology of erythropoiesis' above.)
● Absolute polycythemia (increased RBC mass) may be caused by autonomous production of RBCs (primary polycythemia)
or by an appropriate physiologic response to elevated serum EPO (secondary polycythemia). Causes of absolute
polycythemia (table 3) vary by patient population and clinical setting and include:
• Primary polycythemia from polycythemia vera (PV), other myeloproliferative neoplasms (MPN), or a variety of
inherited conditions. (See 'Primary polycythemia' above.)
• Secondary polycythemia may be due to systemic hypoxia from cardiopulmonary disease (eg, chronic pulmonary
disease, cyanotic heart disease, obstructive sleep apnea), high altitude, chronic carbon monoxide exposure, or from
kidney-related processes (eg, renal artery stenosis, post-kidney transplantation). (See 'Hypoxia-associated
polycythemia' above.)
Secondary polycythemia may also be caused by autonomous production of EPO (ie, independent of oxygen sensing)
by a variety of tumors and can cause paraneoplastic polycythemia. (See 'Tumor-associated polycythemia' above.)
• Miscellaneous causes of polycythemia include "blood doping" and other approaches for enhancing athletic
performance, and cobalt toxicity. (See 'Other causes' above.)
● Polycythemia may be encountered as an incidental abnormality on a complete blood count (CBC) and differential or in the
course of evaluating other clinical findings. The urgency of evaluation is influenced by the presence of medical
emergencies related to polycythemia (eg, cerebrovascular accident, chest pain), the level of Hgb/Hct, and symptoms or
signs that suggest PV or other MPN. (See 'Urgency of evaluation' above.)
● The initial evaluation of polycythemia (algorithm 1) should include a CBC and review of the blood smear, history and
physical examination, pulse oximetry, measurement of serum EPO, and selected chemistry tests. (See 'Initial evaluation'
above.)
It is not necessary to perform pulse oximetry and measurement of serum EPO when polycythemia appears to be due to
volume depletion alone (hemoconcentration), and/or Hgb/Hct normalize with fluid restoration. (See 'Resolution of
polycythemia' above.)
We suggest not performing JAK2 mutation analysis or bone marrow examination in the initial evaluation of all patients,
unless clinical findings suggest PV (eg, pruritus, erythromelalgia, constitutional symptoms, abdominal fullness) or serum
EPO is low or absent. (See 'Are JAK2 testing/bone marrow exam required for all?' above.)
● Further diagnostic evaluation of polycythemia is guided by results from the initial evaluation and by the clinical scenario,
as described above. (See 'Clinical scenarios' above.)
REFERENCES
1. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition, Swerdlow SH, Campo E,
Harris NL, et al. (Eds), International Agency for Research on Cancer (IARC), Lyon 2017.
2. Smith JR, Landaw SA. Smokers' polycythemia. N Engl J Med 1978; 298:6.
3. Aitchison R, Russell N. Smoking--a major cause of polycythaemia. J R Soc Med 1988; 81:89.
4. LAWRENCE JH, BERLIN NI. Relative polycythemia; the polycythemia of stress. Yale J Biol Med 1952; 24:498.
5. Berlin NI, Wasserman LR. Polycythemia vera: a retrospective and reprise. J Lab Clin Med 1997; 130:365.
6. Brown SM, Gilbert HS, Krauss S, Wasserman LR. Spurious (relative) polycythemia: a nonexistent disease. Am J Med
1971; 50:200.
7. Weaver LK. Clinical practice. Carbon monoxide poisoning. N Engl J Med 2009; 360:1217.
8. Kew MC, Fisher JW. Serum erythropoietin concentrations in patients with hepatocellular carcinoma. Cancer 1986;
58:2485.
9. Da Silva JL, Lacombe C, Bruneval P, et al. Tumor cells are the site of erythropoietin synthesis in human renal cancers
associated with polycythemia. Blood 1990; 75:577.
10. Wiesener MS, Seyfarth M, Warnecke C, et al. Paraneoplastic erythrocytosis associated with an inactivating point
mutation of the von Hippel-Lindau gene in a renal cell carcinoma. Blood 2002; 99:3562.
11. Yoshida M, Koshiyama M, Fujii H, Konishi M. Erythrocytosis and a fibroid. Lancet 1999; 354:216.
12. Suzuki M, Takamizawa S, Nomaguchi K, et al. Erythropoietin synthesis by tumour tissues in a patient with uterine myoma
and erythrocytosis. Br J Haematol 2001; 113:49.
13. LevGur M, Levie MD. The myomatous erythrocytosis syndrome: a review. Obstet Gynecol 1995; 86:1026.
14. Paustenbach DJ, Tvermoes BE, Unice KM, et al. A review of the health hazards posed by cobalt. Crit Rev Toxicol 2013;
43:316.
15. Keohane C, McMullin MF, Harrison C. The diagnosis and management of erythrocytosis. BMJ 2013; 347:f6667.
16. Gaston RS, Julian BA, Curtis JJ. Posttransplant erythrocytosis: an enigma revisited. Am J Kidney Dis 1994; 24:1.
17. Gregg XT, Prchal JT. Erythropoietin receptor mutations and human disease. Semin Hematol 1997; 34:70.
18. Arcasoy MO, Degar BA, Harris KW, Forget BG. Familial erythrocytosis associated with a short deletion in the
erythropoietin receptor gene. Blood 1997; 89:4628.
19. Kralovics R, Indrak K, Stopka T, et al. Two new EPO receptor mutations: truncated EPO receptors are most frequently
associated with primary familial and congenital polycythemias. Blood 1997; 90:2057.
20. Brox AG, Mangel J, Hanley JA, et al. Erythrocytosis after renal transplantation represents an abnormality of insulin-like
growth factor-I and its binding proteins. Transplantation 1998; 66:1053.
21. Pearson TC, Messinezy M. Investigation of patients with polycythaemia. Postgrad Med J 1996; 72:519.
22. Bernard PJ. Measurement of red-cell and plasma volumes. Nouv Rev Fr Hematol 1994; 36:155.
23. Fairbanks VF, Klee GG, Wiseman GA, et al. Measurement of blood volume and red cell mass: re-examination of 51Cr
and 125I methods. Blood Cells Mol Dis 1996; 22:169.
24. Holme S, Elfath MD, Heaton A, et al. Prediction of red cell and blood volumes distribution by various nomograms: do
current nomograms overestimate? Transfusion 2008; 48:910.
25. Schmidt W, Prommer N. The optimised CO-rebreathing method: a new tool to determine total haemoglobin mass
routinely. Eur J Appl Physiol 2005; 95:486.
26. Mock DM, Matthews NI, Strauss RG, et al. Red blood cell volume can be independently determined in vitro using sheep
and human red blood cells labeled at different densities of biotin. Transfusion 2009; 49:1178.
27. Prchal JT, Sokol L. "Benign erythrocytosis" and other familial and congenital polycythemias. Eur J Haematol 1996;
57:263.
Topic 7075 Version 21.0
GRAPHICS
Normal values for red blood cell parameters in adults
RBC parameter Men Women
Hemoglobin, g/dL 15.7 (14.0 to 13.8 (12.3 to

17.5) 15.3)
Hematocrit, percent 46 (42 to 50) 40 (36 to 45)
RBC count, million/microL 5.2 (4.5 to 5.9) 4.6 (4.1 to 5.1)
Reticulocyte count, cells/microL 20,000 to 20,000 to

110,000 110,000
Reticulocyte percentage 1.6 ± 0.5 1.4 ± 0.5
Mean corpuscular volume (MCV), femtoliters (fL) 88 (80 to 96) 88 (80 to 96)
Mean cell hemoglobin (MCH), pg/RBC 30 (28 to 33) 30 (28 to 33)
Mean cell hemoglobin concentration (MCHC), g/dL of RBC 34 (33 to 36) 34 (33 to 36)
Red cell distribution width (RDW), CV, percent 13 (12 to 15) 13 (12 to 15)
Values represent the mean and reference intervals (normal range, based on nonparametric 95% confidence interval) for each sex.
Reference ranges may vary slightly in different laboratories. There are no sex differences in absolute reticulocyte count, MCV, MCH,
MCHC, or RDW. Values for children are presented separately in UpToDate. Refer to UpToDate topics on anemia for further details.
RBC: red blood cell; CV: coefficient of variation method.
Adapted with permission from: Williams' Hematology, 7th ed, Lichtman MA, Beutler E, Kipps TJ, et al. (Eds), McGraw-Hill, New York 2006, p.
12. Copyright © 2006 McGraw-Hill Education. McGraw-Hill Education makes no representations or warranties as to the accuracy of any
information contained in the McGraw-Hill Education Material, including any warranties of merchantability or fitness for a particular purpose. In
no event shall McGraw-Hill Education have any liability to any party for special, incidental, tort, or consequential damages arising out of or in
connection with the McGraw-Hill Education Material, even if McGraw-Hill Education has been advised of the possibility of such damages.
Graphic 64238 Version 7.0
https://www.uptodate.com/contents/diagnostic-approach-to-the-patient-with-polycythemia/print?csi=560d9be4-261b-4c15-b99e-296d39e828b5… 10/17
Hemoglobin, hematocrit, red blood cells, mean corpuscular volume, and white blood cells in
children 1 to 14 years of age, by age group and sex: The Third National Health and Nutrition
Examination Survey (1988 to 1991)
Male* (n = 5070) Female* (n = 5175)

Characteristic
Mean SD 95% CI Mean SD 95% CI
Hemoglobin, g/dL ¶
1 to 2 years 12.01 0.82 10.37 13.65 12.02 0.8 10.42 13.62
3 to 5 years 12.35 0.77 10.81 13.89 12.39 0.77 10.85 13.93
6 to 8 years 12.88 0.8 11.28 14.48 12.82 0.77 11.28 14.36
9 to 11 years 13.28 0.84 11.6 14.96 13.1 0.78 11.54 14.66
12 to 14 years 14.14 1.08 11.98 16.3 13.29 1 11.29 15.29
15 to 19 years 15.07 1.03 13.01 17.13 13.15 1 11.15 15.15
Hematocrit, percent
1 to 2 years 36 2 32 40 36 2 32 40
3 to 5 years 37 2 33 41 37 2 33 41
6 to 8 years 38 2 34 42 38 2 34 42
9 to 11 years 39 2 35 43 39 2 35 43
12 to 14 years 42 3 36 48 40 3 34 46
15 to 19 years 45 3 39 51 39 3 33 45
Red blood cells, 10 12 cells per liter
1 to 2 years 4.55 0.34 3.87 5.23 4.5 0.34 3.82 5.18
3 to 5 years 4.51 0.34 3.83 5.19 4.49 0.32 3.85 5.13
6 to 8 years 4.6 0.29 4.02 5.18 4.56 0.31 3.94 5.18
9 to 11 years 4.71 0.32 4.07 5.35 4.62 0.3 4.02 5.22
12 to 14 years 4.93 0.39 4.15 5.71 4.59 0.32 3.95 5.23
15 to 19 years 5.06 0.37 4.32 5.8 4.47 0.35 3.77 5.17
Mean corpuscular volume (femtoliters)
1 to 2 years 79.2 4.5 70.2 88.2 79.8 4.5 70.8 88.8
3 to 5 years 81.8 4.3 73.2 90.4 82.3 4 74.3 90.3
6 to 8 years 83.2 4 75.2 91.2 83.6 3.6 76.4 90.8
9 to 11 years 83.9 3.7 76.5 91.3 84.2 3.9 76.4 92
12 to 14 years 85.3 4 77.3 93.3 86.2 4.2 77.8 94.6
15 to 19 years 88.3 3.9 80.5 96.1 87.8 4.7 78.4 97.2
White blood cells, 10 9 cells per liter
1 to 2 years 8.74 2.53 3.68 13.8 8.66 2.41 3.84 13.48
3 to 5 years 7.68 2.26 3.16 12.2 7.9 2.12 3.66 12.14
6 to 8 years 7.45 2.02 3.41 11.49 7.63 2.1 3.43 11.83
9 to 11 years 7.01 2.07 2.87 11.15 7.2 1.98 3.24 11.16
12 to 14 years 7.02 2.07 2.88 11.16 7.3 2.06 3.18 11.42
15 to 19 years 7.15 2.11 2.93 11.37 7.58 2.18 3.22 11.94
The 95% confidence interval (+/– 2 SD) defines the normal range, and corresponds to the 2.5 th through 97.5 th percentiles.
SD: standard deviation; 95% CI: 95 percent confidence interval.

* Includes all race/ethnic groups.
¶ Hemoglobin is sometimes reported as grams/liter (g/L), in which case the values are 10 times those reported as g/dL (13.5 g/dL = 135
g/L).
Adapted from: Hollowell JG, van Assendelft OW, Gunter EW, et al. Hematological and iron-related analytes-reference data for persons aged 1
year and over: United States, 1988-94. Vital Health Stat 2005; 11:1.
Causes of polycythemia
Relative polycythemia
Volume contraction (eg, diuretics, vomiting, diarrhea, smoking)
Absolute polycythemia
Primary polycythemia
Inherited (germline mutations)
Primary familial and congenital polycythemia (eg, EPOR mutation)
Chuvash polycythemia/VHL mutation
Congenital methemoglobinemia
High oxygen affinity hemoglobin
Bisphosphoglyceromutase (BPGM) mutation
Other mutations (eg, prolyl hydroxylase 2/EGLN1, HIF-2alpha/EPAS1)
Acquired (somatic mutations)
Polycythemia vera (JAK2 mutation)
Other myeloproliferative neoplasms (eg, JAK2, MPL, CALR mutations)
Secondary polycythemia (elevated serum erythropoietin [EPO])
Hypoxia/cardiopulmonary-associated
Chronic pulmonary disease
Right-to-left cardiac shunts
Sleep apnea
Obesity hypoventilation syndrome (Pickwickian syndrome)
High altitude
Chronic carbon monoxide poisoning (including heavy smoking)
Kidney-associated causes
Following renal transplantation
Others (eg, renal artery stenosis, cysts, hydronephrosis)
Autonomous EPO production
EPO-producing tumors (eg, hepatocellular carcinoma, renal cell carcinoma, hemangioblastoma, pheochromocytoma, uterine
leiomyomata)
Other causes
Athletic performance enhancing agents (eg, recombinant erythropoiesis stimulating agents, autologous transplantation ["blood
doping"], androgens or anabolic steroids)
Cobalt toxicity
POEMS syndrome
Serum erythropoietin levels in anemia
This graph indicates the exponential relationship between serum erythropoietin

levels (EPO, milliUnits/mL, logarithmic scale) and venous hematocrit (percent,
linear scale) in normal and anemic subjects without renal or chronic diseases.
EPO was assayed by either bioassay or radioimmunoassay.
Data from: Erslev AJ, Wilson J, Caro J. Erythropoietin titers in anemic, nonuremic
patients. J Lab Clin Med 1987; 109:429.
Evaluation of the patient with polycythemia
This algorithm presents our approach to polycythemia in men (Hgb >16.5 g/mL or Hct >49%), women (Hgb >16 g/mL or Hct >48%),
and children (age-based). It should be used in conjunction with UpToDate content on the evaluation of polycythemia and
myeloproliferative neoplasms.
EPO: erythropoietin; PV: polycythemia vera; MPN: myeloproliferative neoplasm; CT: computed tomography; MRI: magnetic resonance imaging;
RAS: renal artery stenosis; Hgb: hemoglobin; Hct: hematocrit.
* PV should be suspected in patients with MPN-related symptoms (eg, headache, dizziness, visual disturbances, pruritus, early satiety) or
complications (eg, thrombosis, bleeding), or 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.
¶ Diagnosis of polycythemia due to carbon monoxide toxicity is confirmed if Hgb/Hct normalize in two to three months after cessation of exposure.
WHO diagnostic criteria polycythemia vera
Major criteria
1. Hemoglobin >16.5 g/dL in men
Hemoglobin >16.0 g/dL in women
or,
Hematocrit >49% in men
Hematocrit >48% in women
or,
Increased red cell mass*
2. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid,
granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)
3. Presence of JAK2 V617F or JAK2 exon 12 mutation
Minor criterion
1. Subnormal serum erythropoietin level
Diagnosis of PV requires meeting either all 3 major criteria, or the first 2 major criteria and the minor criterion ¶
MF: myelofibrosis; PV: polycythemia vera; WHO: World Health Organization

* More than 25% above mean normal predicted value.
¶ Criterion number 2 (bone marrow biopsy) may not be required in cases with sustained absolute erythrocytosis: hemoglobin levels >18.5
g/dL in men (hematocrit, 55.5%) or >16.5 g/dL in women (hematocrit, 49.5%) if major criterion 3 and the minor criterion are present.
However, initial myelofibrosis (present in up to 20% of patients) can only be detected by performing a bone marrow biopsy; this finding may
predict a more rapid progression to overt myelofibrosis (post-PV MF).
Republished with permission of the American Society of Hematology, from Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the
World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391. Copyright © 2016; permission
conveyed through Copyright Clearance Center, Inc.
Oxyhemoglobin dissociation curve
Depicted here is the oxyhemoglobin dissociation curve for normal adult hemoglobin
(hemoglobin A, solid line). Note that at a partial pressure of oxygen of 27 mmHg on the
X axis, hemoglobin is 50% saturated with oxygen (the P50 is 27 mmHg), and at an
arterial partial pressure of oxygen of 100 mmHg, hemoglobin is 100% saturated. At the
typical mixed venous oxygen tension of approximately 40 mmHg, the oxygen
saturation of hemoglobin is approximately 75%. Shifting the curve to the right (red
line) can reduce oxygen saturation to 50 to 60% for the partial oxygen pressure of 40
mmHg, meaning that less oxygen is bound to hemoglobin and more oxygen is delivered
to the tissues. The opposite occurs with left shifts (blue line). A high proportion of fetal
hemoglobin, which has high oxygen affinity, shifts this curve to the left in newborns.
The effect of right- or left-shifting of the curve is most pronounced at low partial
pressures of oxygen.
Contributor Disclosures
Ayalew Tefferi, MD Nothing to disclose Stanley L Schrier, MD Nothing to disclose Alan G Rosmarin, MD Nothing to
disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting
through a multi-level review process, and through requirements for references to be provided to support the content.
Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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Author: Ayalew Tefferi, MD

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

● 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

History — The history should evaluate:

● Social history should evaluate:

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

We selectively perform JAK2 mutation testing in the following settings:

increase in RBC mass (ie, absolute polycythemia).

Topic 7075 Version 21.0

Normal values for red blood cell parameters in adults

RBC parameter Men Women

Hemoglobin, g/dL 15.7 (14.0 to 13.8 (12.3 to

Hematocrit, percent 46 (42 to 50) 40 (36 to 45)

RBC count, million/microL 5.2 (4.5 to 5.9) 4.6 (4.1 to 5.1)

Reticulocyte count, cells/microL 20,000 to 20,000 to

Reticulocyte percentage 1.6 ± 0.5 1.4 ± 0.5

Mean cell hemoglobin (MCH), pg/RBC 30 (28 to 33) 30 (28 to 33)

RBC: red blood cell; CV: coefficient of variation method.

Graphic 64238 Version 7.0

Male* (n = 5070) Female* (n = 5175)

1 to 2 years 12.01 0.82 10.37 13.65 12.02 0.8 10.42 13.62

3 to 5 years 12.35 0.77 10.81 13.89 12.39 0.77 10.85 13.93

6 to 8 years 12.88 0.8 11.28 14.48 12.82 0.77 11.28 14.36

9 to 11 years 13.28 0.84 11.6 14.96 13.1 0.78 11.54 14.66

12 to 14 years 14.14 1.08 11.98 16.3 13.29 1 11.29 15.29

15 to 19 years 15.07 1.03 13.01 17.13 13.15 1 11.15 15.15

Red blood cells, 10 12 cells per liter

1 to 2 years 4.55 0.34 3.87 5.23 4.5 0.34 3.82 5.18

3 to 5 years 4.51 0.34 3.83 5.19 4.49 0.32 3.85 5.13

6 to 8 years 4.6 0.29 4.02 5.18 4.56 0.31 3.94 5.18

9 to 11 years 4.71 0.32 4.07 5.35 4.62 0.3 4.02 5.22

12 to 14 years 4.93 0.39 4.15 5.71 4.59 0.32 3.95 5.23

15 to 19 years 5.06 0.37 4.32 5.8 4.47 0.35 3.77 5.17

Mean corpuscular volume (femtoliters)

1 to 2 years 79.2 4.5 70.2 88.2 79.8 4.5 70.8 88.8

3 to 5 years 81.8 4.3 73.2 90.4 82.3 4 74.3 90.3

6 to 8 years 83.2 4 75.2 91.2 83.6 3.6 76.4 90.8

9 to 11 years 83.9 3.7 76.5 91.3 84.2 3.9 76.4 92

12 to 14 years 85.3 4 77.3 93.3 86.2 4.2 77.8 94.6

15 to 19 years 88.3 3.9 80.5 96.1 87.8 4.7 78.4 97.2

White blood cells, 10 9 cells per liter

1 to 2 years 8.74 2.53 3.68 13.8 8.66 2.41 3.84 13.48

3 to 5 years 7.68 2.26 3.16 12.2 7.9 2.12 3.66 12.14

6 to 8 years 7.45 2.02 3.41 11.49 7.63 2.1 3.43 11.83

9 to 11 years 7.01 2.07 2.87 11.15 7.2 1.98 3.24 11.16

12 to 14 years 7.02 2.07 2.88 11.16 7.3 2.06 3.18 11.42

15 to 19 years 7.15 2.11 2.93 11.37 7.58 2.18 3.22 11.94

SD: standard deviation; 95% CI: 95 percent confidence interval.

Graphic 57465 Version 13.0

Inherited (germline mutations)

Primary familial and congenital polycythemia (eg, EPOR mutation)

Chuvash polycythemia/VHL mutation

High oxygen affinity hemoglobin

Bisphosphoglyceromutase (BPGM) mutation

Other mutations (eg, prolyl hydroxylase 2/EGLN1, HIF-2alpha/EPAS1)

Acquired (somatic mutations)

Polycythemia vera (JAK2 mutation)

Other myeloproliferative neoplasms (eg, JAK2, MPL, CALR mutations)

Secondary polycythemia (elevated serum erythropoietin [EPO])