Clinical manifestations and diagnosis of polycythemia vera

INTRODUCTION — Polycythemia vera (PV, polycythemia rubra vera, maladie de Vaquez) is one of the chronic myeloproliferative neoplasms (MPNs), which are collectively characterized by clonal proliferation of myeloid cells with variable morphologic maturity and hematopoietic efficiency. PV is distinguished clinically from the other MPNs by the presence of an elevated red blood cell mass. However, an increased red blood cell mass alone is insufficient to establish the diagnosis, since this is also observed in conditions associated with chronic hypoxia and with erythropoietin-secreting tumors (table 1). (See "Overview of the myeloproliferative neoplasms".)

The clinical manifestations and diagnosis of PV will be discussed here. The prognosis and treatment of PV and the overall approach to the patient with polycythemia are discussed separately. (See "Polycythemia vera and secondary polycythemia: Treatment and prognosis" and "Diagnostic approach to the patient with erythrocytosis/polycythemia".)

EPIDEMIOLOGY — PV occurs in all populations, and all ages, including early adulthood and occasionally in children and adolescents [1-3]. The median age at diagnosis is approximately 60 years [4,5]. Approximately one-quarter of cases present before age 50 years and one-tenth before age 40 years.

The incidence of PV in Olmsted County, Minnesota, during the period from 1935 through 1989, was estimated to be 1.9/100,000 per year, approximately one-half that for multiple myeloma in the same population [6]. The incidence of PV is slightly higher in men than women (2.8 versus 1.3 cases/100,000 per year) and is highest for men aged 70 to 79 years (24 cases/100,000 persons per year) [6]. The incidence is lower in Japan than in the United States and Europe [7].

While there is no known familial disposition to PV, rare families have been described in which multiple members develop myeloproliferative neoplasms, including PV [8]. Studies of these families suggest the presence of an autosomal dominant mutation that may predispose to acquisition of a secondary somatic mutation such as a JAK2 mutation.

Exposure to ionizing radiation and toxins (eg, benzene) has been suggested as a risk factor, although the vast majority of patients presenting with PV have no evidence of risk exposure.

CLINICAL PRESENTATION

Overview of signs and symptoms — Most patients with PV are discovered incidentally when an elevated hemoglobin or hematocrit is noted on a complete blood count obtained for some other reason. Others present with disease-related symptoms (eg, headache, dizziness, visual disturbances, pruritus, early satiety) or complications (eg, thrombosis, bleeding) (table 2).

An analysis of 1545 patients with World Health Organization (WHO)-defined PV collected by the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) noted the following findings prior to or at diagnosis [5]:

●Hemoglobin – median 18.4 g/dL, range 15.1 to 26.5 g/dL

●Hematocrit – median 55 percent, range 36 to 78 percent

●Leukocyte count – median 10,400/microL, range 3000 to 172,000/microL

●Platelet count – median 466,000/microL, range 70 to 2,370,000/microL

●Elevated lactate dehydrogenase – 50 percent

●Hypertension – 46 percent

●Palpable spleen – 36 percent

●Pruritus – 36 percent

●Vasomotor symptoms (eg, erythromelalgia) – 29 percent

●Arterial thrombosis – 16 percent

●Venous thrombosis – 7 percent

●Major hemorrhage – 4 percent

Other physical findings that suggest a diagnosis of PV include the following:

●Injection of the conjunctival small vessels and/or engorgement of the veins of the optic fundus

●Facial plethora (ruddy cyanosis)

●Hepatomegaly in a minority of cases

●Excoriation of the skin, which might be extensive, suggesting the presence of severe pruritus, a common complaint in PV

●Stigmata of a prior arterial or venous thrombotic event (eg, stroke, deep vein thrombosis, superficial thrombophlebitis)

●Gouty arthritis and tophi

Patient questionnaires have also reported mild nonspecific complaints in the majority of patients including fatigue, early satiety, abdominal discomfort, headache, difficulty concentrating, dizziness, numbness, insomnia, sad mood, sexual problems, excessive sweating, itching, and impaired quality of life [9,10]. In one study, a more severe total symptom burden similar to that of patients with primary myelofibrosis was seen in patients with splenomegaly and those requiring phlebotomy and/or hydroxyurea [11]. These results illustrate the variability of total symptom burden and suggest that splenomegaly is a marker of more severely symptomatic disease.

Pruritus — Pruritus following a warm bath or shower (aquagenic pruritus) is characterized by strong sensations in the skin following contact with water without visible changes in the skin [12-14]. Aquagenic pruritus is often the chief complaint of a patient with PV, has been described as "unbearable" in 15 percent of those with this symptom, and may be present for many years before the diagnosis of PV is made.

In a questionnaire completed in 441 patients with PV, 301 (68 percent) of which had aquagenic pruritus, the following information was obtained [14]:

●Symptoms were described as itching, tickling, stinging, or burning in 72, 21, 31, and 18 percent, respectively.

●Almost one-half of the respondents noted that warm water caused stronger symptoms than cold water, while 38 percent noted no difference between the two.

●In 78 percent, symptom onset was within less than 10 minutes after water contact.

●The most commonly involved symptomatic areas were the chest, back, medial side of the arms, and ventral side of the legs.

●Aquagenic pruritus was present, on average, approximately three years before the diagnosis of PV was made and was the basis for suspecting the diagnosis of PV in 15 percent.

This complaint was present in 31 percent of patients with PV seen at the Mayo Clinic, where, for unexplained reasons, it was associated with a significantly lower incidence of arterial thrombosis [15].

The cause of pruritus in PV is unclear. It has been suggested that mast cell degranulation, with release of histamine, fibrinolytic factors, prostaglandins, or interleukin-31, may play a role [16-19]. An alternative hypothesis is that the release of adenosine diphosphate from red cells or catecholamines from adrenergic vasoconstrictor nerves when the skin is cooled down might cause platelet aggregation in skin vessels, with local production of pruritogenic factors, such as prostaglandins [18]. The observation that aspirin can relieve pruritus in at least some patients is compatible with an important role for prostaglandins [18].

Erythromelalgia — Erythromelalgia, or burning pain in the feet or hands accompanied by erythema, pallor, or cyanosis, in the presence of palpable pulses (picture 1) was seen in 29 percent of patients with WHO-defined PV in one series [5]. Erythromelalgia and the associated symptom of acral paresthesias, both of which can be considered to be forms of dysesthesia, are considered to be pathognomonic microvascular thrombotic complications in PV and essential thrombocythemia and are associated with platelet counts usually >400,000/microL [20,21]. These symptoms respond dramatically to aspirin in low doses or to reduction of the platelet count to normal with low-dose myelosuppressive agents [20-22]; they may be related to abnormal arachidonic acid metabolism in PV platelets [22]. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Vasomotor symptoms'.)

Thrombosis and hemorrhage — Patients with PV have an increased risk of thrombosis (eg, cerebrovascular event, myocardial infarction, superficial thrombophlebitis, deep vein thrombosis, pulmonary embolus) and hemorrhage. In a large international study, an arterial thrombotic complication, venous thrombosis, or major hemorrhage was noted prior to or at the time of diagnosis in 16, 7, and 4 percent of patients with PV as defined by the WHO [5].

Although the mechanisms involved in this hypercoagulable state are unclear, abnormalities in blood viscosity, platelets, and leukocytes have been implicated [23]. Major thrombotic events can occur in patients who otherwise have few clinical and laboratory features of PV. Examples include the Budd-Chiari syndrome and portal, splenic, or mesenteric vein thrombosis [24], in whom the ensuing portal hypertension and hypersplenism may mask the increase in blood cell counts [25-30]. PV should be suspected in patients with these diagnoses, particularly women under the age of 45. (See "Etiology of the Budd-Chiari syndrome", section on 'Myeloproliferative disorders'.)

In some patients with PV and platelet counts >1 million/microL, acquired von Willebrand disease may be present, likely due to increased binding of large von Willebrand factor multimers to the platelets and their removal from the plasma. Such patients may have increased bleeding, especially when treated with aspirin. (See "Acquired von Willebrand syndrome".)

Transient visual disturbance — Transient visual disturbances (eg, transient ocular blindness [amaurosis fugax], scintillating scotomata, ophthalmic migraine) can occur in PV, similar to those seen in patients with essential thrombocythemia [31].

In one study of 374 patients with PV, 53 presented with visual disturbance as an initial symptom [32]. Fluorescein angiography in the 21 patients who presented with transient ocular blindness indicated significantly delayed choroidal and retinal blood flow when compared with results obtained in 30 non-PV control patients. On multivariate analysis, an increased hematocrit was the only parameter significantly correlated with reduced choroidal and retinal blood flow. Treatment of these 21 patients with phlebotomy and hydroxyurea to reduce their hematocrit to less than 50 percent resulted in significant improvement in choroidal and retinal blood flow and a reduction in the subsequent incidence of transient blindness. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Vasomotor symptoms'.)

Gastrointestinal symptoms — Gastrointestinal complaints are common in PV, with a high incidence of epigastric distress, history of peptic ulcer disease, and gastroduodenal erosions on upper endoscopy [33]. These have been attributed to alterations in gastric mucosal blood flow due to altered blood viscosity, and/or increased histamine release from tissue basophils, although one study has indicated a high incidence of positivity for infection with Helicobacter pylori [33].

PATHOLOGIC AND LABORATORY FEATURES — Most patients with PV are discovered incidentally when an elevated hemoglobin or hematocrit is noted on a complete blood count obtained for some other reason. In one series of patients with World Health Organization (WHO)-defined PV, the following laboratory findings were noted [5]:

●Hemoglobin >18.5 g/dL – 73 percent

●Total white blood cell (WBC) count >10,500/microL – 49 percent

●Platelet count >450,000/microL – 53 percent; platelet count >1 million/microL – 4 percent

●Leukoerythroblastic blood smear – 6 percent

●Elevated serum lactate dehydrogenase – 50 percent

●JAK2 mutation positivity – 98 percent

●Abnormal karyotype – 12 percent

●Subnormal serum erythropoietin level – 81 percent

●Endogenous erythroid colony formation – 73 percent

These findings are described in more detail in the following sections.

Peripheral blood smear — The findings in the peripheral blood differ depending upon the stage of disease at the time of diagnosis.

In the prepolycythemic and overt polycythemic stages, the peripheral blood usually has an excess of normochromic, normocytic red blood cells. Hypochromic, microcytic red cells may be present if there is concomitant iron deficiency. Thrombocytosis is common (median platelet count 466,000/microL, range 70 to 2,370,000/microL) and approximately 15 percent of cases may mimic essential thrombocytosis [5]. Leukocytosis is also seen in the absence of fever or infection (median WBC count 10,400/microL, range 3000 to 172,000/microL). However, the total WBC count may not accurately reflect disease activity, since neutrophils and not lymphocytes or monocytes are increased in PV. While immature cells may be seen, blasts are not a characteristic feature.

In contrast, a leukoerythroblastic picture develops in the postpolycythemic myelofibrosis stage with teardrop-shaped red blood cells (dacryocytes), poikilocytosis, and circulating nucleated red cells. (See "Clinical manifestations and diagnosis of primary myelofibrosis".)

Bone marrow aspiration and biopsy

Morphology — Bone marrow biopsy classically shows hypercellularity for age and trilineage growth with prominent erythroid, granulocytic, and megakaryocytic proliferation [34]. The findings on bone marrow examination change as the disease evolves from a prodromal prepolycythemia phase with borderline to mild erythrocytosis to an overt polycythemic phase with increased red cell mass to a "spent" or postpolycythemic myelofibrosis with cytopenias, ineffective erythropoiesis, fibrosis, extramedullary hematopoiesis, and hypersplenism.

Although the Polycythemia Vera Study Group (PVSG) did not include specific bone marrow findings as either major or minor criteria for diagnosis, 281 pretreatment bone marrow biopsies were obtained in the first PVSG study and the following observations were noted [35]:

●The most common abnormality was the absence of stainable iron in 94 percent

●Cellularity varied from 36 to 100 percent (mean 82 percent, normal 35 to 50 percent)

●The numbers of megakaryocytes and amount of reticulin were variable, although both were generally increased

Bone marrow biopsy findings are a major criterion in the WHO diagnostic criteria. In a study of 526 subjects who met the WHO criteria for the diagnosis of PV, 74 (14 percent) displayed minor (grade 1) reticulin fibrosis on their initial bone marrow examination, and only two showed higher grade fibrosis [36]. Presenting clinical and laboratory characteristics, including JAK2 V617F allele burdens, between patients with and without fibrosis were generally similar, although palpable splenomegaly was significantly more common in those with fibrosis. While there was no difference between the two patient groups in terms of overall or leukemia-free survival, those with fibrosis were significantly more prone to develop post-PV myelofibrosis (2.2 versus 0.8 per 100 patient-years) and significantly less prone to experience thrombosis during their clinical course (1.1 versus 2.7 per 100 patient-years).

Clonal markers — Bone marrow examination can also be used to identify clonal markers that have been associated with PV, such as karyotypic changes and, in women, X-linked inactivation patterns or restriction length polymorphisms. These clonal features initially helped to establish the malignant character of PV but are not incorporated into diagnostic criteria.

Deletion of the long arm of chromosome 20, trisomy for chromosomes 8 or 9, or loss of heterozygosity on the short arm of chromosome 9 are found in up to 30 percent of previously untreated patients with PV [37-42]. Of interest, chromosome 9p24 houses the JAK2 gene, which carries a somatic point mutation in virtually all patients with PV (see 'JAK2 mutations' below).

JAK2 mutations — When sensitive quantitative assays are employed, 95 to 100 percent of patients with PV have a JAK2 (Janus kinase 2) mutation involving either exon 14 or 12 [5,43-48].

Exon 14 mutation — In multiple studies, 95 to 97 percent of patients with PV have the V617F mutation in exon 14 of the JAK2 gene, which is absent in normal subjects as well as those with secondary polycythemia. Thus, this mutation, when present, enables one to distinguish patients with PV from those with secondary polycythemia [49-51]. The finding of the JAK2 V617F mutation is not specific for PV, since it is also present in a substantial proportion of patients with essential thrombocythemia (ET) as well as primary myelofibrosis. (See "Overview of the myeloproliferative neoplasms", section on 'JAK2 mutations'.)

In a study of 63 patients with PV evaluated at the Mayo Clinic, the JAK2 mutation was present in 58 (92 percent); 45 and 13 were heterozygous or homozygous for this mutation in peripheral blood granulocytes, respectively [52]. A comparison between the heterozygotes and homozygotes did not reveal significant differences with regard to duration of disease or incidence of thrombosis or bleeding. However, homozygotes had higher hemoglobin levels, a greater incidence of pruritus, a higher rate of fibrotic transformation, and higher PRV-1 transcript levels in peripheral blood granulocytes than the heterozygotes.

In other studies, high levels of this mutation were found to correlate with higher granulocyte counts [53-55], potentially linking this mutation to the higher incidence of thrombosis seen in PV patients with leukocytosis [56]. (See "Polycythemia vera and secondary polycythemia: Treatment and prognosis".)

A higher rate of homozygous JAK2 V617F mutations may be present when testing is performed in erythroid burst-forming units (BFU-Es) rather than peripheral blood granulocytes. In one report using this technology, homozygous JAK2 V617F mutations were found in all 17 patients with PV, both patients with ET after polycythemic transformation, and none of the 15 patients with ET alone [57].

Exon 12 mutations — In one study, four different mutations in exon 12 of the JAK2 gene were found in 10 of 11 patients clinically diagnosed as having PV who had tested negative for the exon 14 V617F mutation [43]. The mutations were frequently present at low levels in granulocyte DNA but were readily identifiable in clonally derived erythropoietin-independent erythroid colonies. When transduced into BaF3/EpoR cells, all four JAK2 exon 12 mutations caused growth factor hypersensitivity and activated biochemical pathways associated with erythropoietin signaling.

In a second report of 114 patients fulfilling the PVSG diagnostic criteria for PV, 111 ultimately tested positive for the exon 14 V617F mutation (97 percent); a JAK2 exon 12 mutation was present in the remaining three subjects (3 percent), suggesting that either an exon 14 or 12 JAK2 mutation is present in virtually all patients with PV [48,58,59].

A third study reported on 106 patients with PV and exon 12 mutations, in which 17 different mutations were identified [60]. Irrespective of the mutation, two-thirds had isolated erythrocytosis, with the remainder having erythrocytosis plus leukocytosis and/or thrombocytosis. The panmyelosis observed in the bone marrow of most patients with PV is typically absent in those with exon 12 mutations. Compared with JAK2 V617F-positive PV patients, those with exon 12 mutations had similar incidences of thrombosis, myelofibrosis, leukemia, and death [47,60].

Exon 12 mutations were not found in granulocyte DNA in any of 55 patients with V617F-positive PV, any of 25 patients with V617F-negative ET, or any of 12 patients with V617F-negative primary myelofibrosis [43]. However, exon 12 mutations have been found in patients with myeloproliferative disorders presenting with isolated erythrocytosis, familial PV, and, in two cases, splanchnic vein thrombosis [61,62].

Serum erythropoietin — Patients with PV usually have low serum erythropoietin (EPO) concentrations [63-67]. While low EPO levels are highly specific for PV, levels above normal are unusual and suggest secondary erythrocytosis, with a specificity of 98 percent [68]. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia".)

In two studies, for example, serum EPO levels in 42 patients with PV were compared with control subjects with other causes of polycythemia (eg, hypoxia) [63,68]. The sensitivity and specificity of serum EPO levels below the reference range of normal for the diagnosis of PV (using the polycythemia vera study group criteria as the gold standard) were 64 and 92 to 99 percent, respectively. The sensitivity increased to 72 percent in patients who were tested on two occasions, as low serum EPO values were noted on a repeat study in some patients with normal levels on the initial examination. The serum EPO concentration remained low even when the red cell mass was normalized following phlebotomy. Accordingly, most of the newer diagnostic criteria for PV have included a low serum EPO level. (See 'Diagnostic criteria' below.)

Increased red blood cell mass — Red blood cell mass (RCM) can be measured directly using isotope dilution methodology, but this technique is no longer available in many locations. Instead, most clinicians use the hemoglobin concentration to estimate the RCM such that a hemoglobin >18.5 g/dL in men or >16.5 g/dL in women is considered a measure of elevated RCM.

Direct determination of the RCM is prone to error and has suboptimal sensitivity [69,70]. In the original PVSG diagnostic criteria, RCM cutoffs (RCM, >36 mL/kg in men and >32 mL/kg in women) were set at approximately 10 to 20 percent above the upper limits of normal and were deliberately chosen to reject patients with relatively early or inactive disease. However, this specific PVSG research protocol requirement did not apply to the general clinical setting, in which it may be preferable to include a broader range of patients. As a result, two revised approaches have been proposed:

The International Council for Standardization in Hematology (ICSH) recommended that blood volumes be calculated in terms of body surface area, since normalization of blood volume to total body weight is less accurate in obese patients [71]. Historically, RCM, normalized to body surface area, was considered elevated if it was more than 25 percent above the mean expected value [72].

It has been our experience, and that of others, that the majority of female patients with a hemoglobin concentration >16.5 g/dL (or hematocrit [Hct] above 50 percent) and all male patients with a hemoglobin concentration >18.5 g/dL (or Hct above 56 percent) have an increased RCM [69,73]. Slightly different cutoff values were found in reports from Belgium and Sweden (Hct greater than 55 [74] or 60 percent [75] in women and greater than 60 percent in men [74,75]).

Endogenous erythroid colony formation — A common feature of several myeloproliferative neoplasms is the demonstration, using in vitro culture techniques, of the formation of erythroid colonies in the absence of added (exogenous) erythropoietin (ie, endogenous erythroid colonies [EEC]). However, the measurement of EEC is not a standard test and is available only in a limited number of research laboratories that are especially interested in PV and hematopoiesis.

The presence of EEC strongly supports the diagnosis of PV if other criteria are present. One study, for example, evaluated EEC formation in 89 patients with various forms of polycythemia [76]. EEC formation was found in 100 percent of PV patients with no prior cytotoxic chemotherapy, 50 percent of PV patients with prior cytotoxic therapy, and in no patient with secondary polycythemia.

Thus, in polycythemic patients who have not had prior cytotoxic chemotherapy, the sensitivity and specificity of EEC formation for the diagnosis of PV is approximately 100 percent. This observation has been confirmed in other series [77,78].

DIAGNOSIS

When to suspect the diagnosis — PV should be suspected in any patient with an increased red blood cell mass or increased hemoglobin/hematocrit and an arterial oxygen saturation >92 percent. To be considered for the diagnosis, men should have a hemoglobin level of at least 16.5 g/dL or a hematocrit level of ≥49 percent, and women should have a hemoglobin level of at least 16 g/dL or a hematocrit level of ≥48 percent. PV should also be suspected in patients with the Budd-Chiari syndrome and portal, splenic, or mesenteric vein thrombosis, particularly women under the age of 45. In this setting, the ensuing portal hypertension and hypersplenism may mask the increase in blood cell counts. Additional evidence suggesting the diagnosis of PV includes the following (see 'Clinical presentation' above):

●Splenomegaly

●Thrombocytosis and/or leukocytosis

●Thrombotic complications

●Erythromelalgia or aquagenic pruritus

●Microvascular symptoms (eg, headaches, paresthesias)

Diagnostic evaluation — The initial evaluation of a patient with suspected PV depends at least partially upon the initial presentation and whether the patient has asymptomatic, isolated erythrocytosis or has other signs/symptoms of a myeloproliferative disorder (eg, elevated white cell or platelet count) (algorithm 1). (See "Diagnostic approach to the patient with erythrocytosis/polycythemia".)

●If the only indication of PV is an elevated hemoglobin concentration or hematocrit, a complete blood count should be repeated. Further testing is unnecessary if the hemoglobin/hematocrit returns to normal.

●If the hemoglobin/hematocrit remains elevated or if the patient has other signs/symptoms of a myeloproliferative disorder, the evaluation should include a serum erythropoietin (EPO) level and peripheral blood mutation screening for JAK2 V617F. (See 'JAK2 mutations' above and 'Serum erythropoietin' above.)

●Patients with a normal or elevated EPO level and no JAK2 V617F mutation do not have PV. Further evaluation is directed at other causes of polycythemia.

●Patients with a sustained elevation of hemoglobin/hematocrit, a subnormal serum EPO level, and a JAK2 V617F mutation meet the diagnostic criteria for PV. A bone marrow aspiration and biopsy is not required in such patients unless there is reason to suspect disease evolution (eg, leukoerythroblastic blood smear).

●Patients with a subnormal serum EPO level who do not have a JAK2 V617F mutation should have peripheral blood mutation screening for exon 12 mutations. Identification of an exon 12 mutation in this setting confirms PV. If an exon 12 mutation is not identified, a bone marrow aspiration and biopsy should be performed. (See 'Exon 12 mutations' above and 'Morphology' above.)

●Serum EPO levels should be repeated in patients with a single normal test; the second value will be low in more than one-quarter of these patients [63].

●Patients with nondiagnostic bone marrow studies and/or absence of a JAK2 mutation should have repeat measurement of the hemoglobin or hematocrit and serum EPO concentrations in three months. A diagnosis other than PV should be entertained in such patients.

Diagnostic criteria — The diagnostic criteria for PV have evolved over the years. We generally agree with and use the World Health Organization (WHO) criteria (table 3). (See 'WHO criteria' below.)

Diagnostic criteria for PV require the following be met:

●Demonstration of an increased red blood cell mass as determined either by blood volume studies or the presence of a very much increased hemoglobin concentration or elevated hematocrit

●Disorders causing secondary erythrocytosis are absent, including hypoxia, familial polycythemic disorders, high-affinity hemoglobins, truncated EPO receptor, and inappropriate EPO production by tumor

Some patients with PV may not fulfill the WHO criterion of an increased hemoglobin/hematocrit or increased red cell mass because of a prior bleeding episode. This has been called "bled-down" PV if they otherwise meet the major and minor criteria for this diagnosis. Such patients may be incorrectly diagnosed as having iron deficiency or essential thrombocythemia since their high platelet counts, low red blood cell indices, and low serum ferritin concentrations may be the most striking features.

When blood volume measurements are either unavailable or not performed, some patients with a simultaneous increase in red cell mass and plasma volume due to an increase in splenic size may not have an elevated hemoglobin/hematocrit [79]. Such patients have been termed "masked" PV [80-82].

Patients with the Budd-Chiari syndrome often present without classical features of PV and may not fulfill the WHO criteria. The diagnosis can be suspected because many are positive for the JAK2 mutation. (See "Etiology of the Budd-Chiari syndrome", section on 'Myeloproliferative disorders'.)

WHO criteria — We generally use the 2016 WHO criteria for the diagnosis of PV, which includes the following (table 3) [83-88]:

Major criteria

●Increased hemoglobin level (>16.5 g/dL in men or >16.0 g/dL in women), hematocrit (>49 percent in men or >48 percent in women), or other evidence of increased red cell volume

●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)

●JAK2 V617F or JAK2 exon 12 mutation

Minor criterion

●Serum erythropoietin level below the reference range for normal

The diagnosis of PV requires the presence of all three major criteria or the presence of the first two major criteria together with the minor criterion. These diagnostic criteria should be applied only to patients who have undergone the appropriate diagnostic evaluation to exclude secondary causes of polycythemia. The second major criterion may not be required in cases with sustained absolute erythrocytosis (hemoglobin >18.5 g/dL or hematocrit >55.5 percent in men; hemoglobin >16.5 g/dL or hematocrit >49.5 percent in women) if the third major criterion and the minor criterion are present. While this may permit the avoidance of a bone marrow evaluation for diagnostic purposes in some patients, the detection of myelofibrosis in the bone marrow at the time of diagnosis has prognostic value. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia" and "Polycythemia vera and secondary polycythemia: Treatment and prognosis", section on 'Prognosis'.)

British Committee for Standards in Hematology criteria — Criteria for the diagnosis of PV according to the British Committee for Standards in Hematology are similar to those of the WHO criteria, with the exception that they are based upon an elevated hematocrit (>52 percent in men, >48 percent in women), rather than an elevated hemoglobin [89,90].

DIFFERENTIAL DIAGNOSIS — Diagnostic possibilities in a patient who has fulfilled the diagnostic criteria for PV are vanishingly small and are likely confined to patients with one of the other JAK2 mutation-positive myeloproliferative neoplasms (ie, essential thrombocythemia, primary myelofibrosis) who have an unrelated secondary cause for polycythemia (table 1). (See 'Secondary polycythemia' below.)

Essential thrombocythemia — When blood volume measurements are either unavailable or not performed, some patients with a simultaneous increase in red cell mass and plasma volume due to an increase in splenic size may not have an elevated hemoglobin/hematocrit [79]. Such patients have been termed "masked" PV if they otherwise meet the major and minor criteria for the diagnosis of PV [80-82].

Distinguishing patients with masked PV from those with essential thrombocythemia may be difficult (table 4). (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia".)

A comparison of hematocrit or hemoglobin values in 257 patients with WHO-defined PV, 140 patients with masked PV, and 397 patients with essential thrombocythemia (ET) has suggested that the best cut-offs to distinguish masked PV from ET are the following [82]:

●For hemoglobin – >16.5 g/dL in men and >16.0 g/dL in women

●For hematocrit – >49 percent in men and >48 percent in women

The differential diagnosis for a patient with polycythemia but without the other major or minor Polycythemia Vera Study Group (PVSG), World Health Organization (WHO), or British Committee for Standards in Hematology (BCSH) criteria is discussed separately. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia".)

EPO receptor mutations — A rare disorder that can mimic the basic findings of PV (ie, increased RCM with low serum erythropoietin [EPO]) is an activating mutation in the EPO receptor [91-93]. Patients with this disorder may also have endogenous erythroid colony formation [76]. However, colony growth in these patients can be distinguished from true PV because the colonies demonstrate in vitro EPO hypersensitivity rather than EPO independence [91-93]. A positive family history, early age at disease onset, and the lack of PV-associated clinical findings should provide adequate information to distinguish this familial disorder from PV.

Secondary polycythemia — Because secondary causes of an elevated red cell mass (RCM) are much more common than PV, the diagnostic criteria should only be applied to populations in which other causes have been excluded. It has been estimated that the practicing hematologist sees 10 cases of relative or secondary polycythemia for every new patient with PV [4].

Since splenomegaly, leukocytosis, and thrombocytosis are common to all of the chronic myeloproliferative neoplasms (table 5), a patient with chronic myeloid leukemia, essential thrombocythemia, or primary myelofibrosis who has an elevated hematocrit for another reason (eg, hypoxia, smoking) may be falsely diagnosed as having PV. This is an important distinction clinically because each of these disorders is treated in a different manner.

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Polycythemia vera (PV) (The Basics)")

SUMMARY

●Definition – Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by autonomous overproduction of red blood cells (RBCs) that is clinically manifested by elevated hemoglobin (Hb)/hematocrit (Hct), with or without an elevated white blood cell (WBC) and/or platelet count. PV can evolve into myelofibrosis or acute myeloid leukemia (AML).

●Presentation – The most prominent symptoms of PV (table 2) are related to increased blood viscosity and may include venous or arterial thrombosis (eg, deep vein thrombosis, myocardial infarction or ischemia, cerebrovascular accident), pruritus, erythromelalgia (ie, burning pain in hands or feet (picture 1)), facial plethora, visual disturbance, and/or headache. Other patients are detected by isolated laboratory abnormalities. (See 'Clinical presentation' above.)

●Evaluation – Evaluation of suspected PV includes (algorithm 1):

•Clinical – History of thromboembolic or cardiovascular events, constitutional symptoms (fever, sweats, weight loss), pruritus, erythromelalgia, cardiovascular risk factors, abdominal fullness and examination for splenomegaly, thromboses, or bruising.

•Laboratory – Laboratory studies include (see 'Pathologic and laboratory features' above):

-Complete blood count (CBC) with differential count

-Blood smear

-Testing for JAK2 V617F in blood

-Serum erythropoietin (EPO)

•Bone marrow examination – Microscopy and cytogenetics. (See 'Bone marrow aspiration and biopsy' above.)

●Diagnosis – PV should be suspected in a patient with increased Hb/Hct with adequate arterial oxygen saturation, especially if accompanied by thromboembolic events, splenomegaly, or constitutional symptoms (algorithm 1). (See 'When to suspect the diagnosis' above.)

Diagnosis of PV requires all three major criteria or the first two major criteria plus the minor criterion (table 3):

•Major criteria

-Increased RBC mass – Elevated Hb (>16.5 g/dL in men or >16.0 g/dL in women) or elevated Hct (49 percent in men, >48 percent in women).

-Bone marrow biopsy – Age-adjusted hypercellularity with panmyelosis (ie, increased erythroid, granulocytic, and megakaryocytic growth) and pleomorphic, mature megakaryocytes. Later phases of PV may exhibit variable levels of erythroid cellularity and/or increased fibrosis.

-JAK2 mutation – JAK2 V617F or exon 12 mutation.

•Minor criterion – Subnormal serum EPO

●Differential diagnosis – PV must be distinguished from (see 'Differential diagnosis' above):

•Relative polycythemia – Elevated Hb/Hct due to intravascular volume contraction. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia", section on 'Relative polycythemia'.)

•Secondary polycythemia – Hypoxia and/or elevated EPO due to cardiovascular, lung disease, kidney disorders, EPO-producing tumors, as described separately. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia", section on 'Secondary polycythemia'.)

•Other MPNs – Essential thrombocythemia, chronic myeloid leukemia, primary myelofibrosis. (See 'Essential thrombocythemia' above.)

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.