Approach

The diagnosis of PV should be considered in any patient with a history or presentation of bleeding or thrombosis, particularly those who are middle-aged or older (approximately 63% of patients are age ≥60 years at diagnosis).[11]

Diagnostic criteria for PV reported by the World Health Organization (WHO) and International Consensus Classification of myeloid neoplasms and acute leukemias require:​[7]​​​​[8]

  • hemoglobin/hematocrit levels of >16.5 g/dL/49% in men or >16 g/dL/48% in women,

  • bone marrow biopsy showing hypercellularity for age with trilineage proliferation, and

  • presence of a JAK2 mutation associated with PV, or subnormal serum erythropoietin.

Bone marrow biopsy may not be required if there is sustained absolute erythrocytosis (hemoglobin/hematocrit levels >18.5 g/dL/55.5% in men and >16.5 g/dL/49.5% in women) in the presence of both a JAK2 mutation and low serum erythropoietin. See Criteria.

Once a diagnosis of PV is made, it is important to carry out risk assessment to inform prognosis and to guide management.

History and physical exam

A careful history and physical exam should be performed to identify signs and symptoms associated with PV, and to identify possible causes of elevated hemoglobin.

Ask patients about:[13][66][67]

  • Family history of PV, or other hematologic disorder

  • Lifestyle factors (e.g., smoking, alcohol consumption)

  • Comorbid conditions (particularly those associated with cardiovascular risk, such as hypertension, diabetes, hyperlipidemia)

  • Concurrent medications/drugs (prescribed and recreational)

Signs and symptoms

​At initial presentation, 12% to 39% of patients have major thrombosis (e.g., stroke, myocardial infarction, pulmonary embolism, superficial thrombophlebitis, deep vein thrombosis) and 1.7% to 20% have major bleeding.[2][12]​​​​ The skin and mucous membranes are common sites of bleeding; gastrointestinal bleeding is less frequent, but can be severe.[2]​

Other common presenting symptoms or signs include headache, generalized weakness/fatigue, splenomegaly, pruritus (particularly aquagenic), plethora/ruddy cyanosis, and erythromelalgia (tenderness or painful burning and/or redness of fingers, palms, heels, toes, or face/neck).[14][68][69][70]​​​​​​​​​​

Fatigue (in 85% of patients), pruritus (65%), night sweats (49%), and bone pain (43%) were the most commonly reported symptoms in one internet-based survey of patients with PV.[68] In a large international study, palpable splenomegaly, pruritus, and vasomotor symptoms were each present in approximately one third of patients with PV.[14]

Some patients may present with tinnitus, blurry vision, arthralgia, abdominal discomfort, and hyperhidrosis.[13]

Frequently, patients are asymptomatic, and elevated hemoglobin is discovered on a blood count performed for other reasons.

Initial investigations

Initial evaluation in any patient with symptoms or signs suggestive of PV consists of the following blood tests.[71]

  • Complete blood count (including hemoglobin, hematocrit, white blood cell count, platelet count, mean corpuscular volume): an elevated hemoglobin, detected either at initial presentation or incidentally, warrants further investigation. Elevated hemoglobin has good diagnostic sensitivity (with a few exceptions), but poor specificity. Elevated hemoglobin or hematocrit is required for PV diagnosis; both should be examined.[7][8]

  • Peripheral blood smear: in patients with PV, red blood cells (RBCs) are abundant and usually normochromic and normocytic, although iron stores may be depleted leading to hypochromic and microcytic RBCs. A leukoerythroblastic blood smear suggests disease progression.

  • Liver function tests (LFTs): liver function is generally normal in patients with PV. Abnormality of bilirubin, aminotransferases, or alkaline phosphatase should prompt screening for hepatic or portal vein thrombosis.

  • Serum ferritin: performed to screen for iron deficiency if a low mean corpuscular volume is found. Iron deficiency can mask erythrocytosis in a patient with PV.

Features suggestive of PV would be pancytosis (particularly erythrocytosis), splenomegaly, and unexplained iron deficiency.

Investigation for secondary causes

It is critical to rule out secondary causes of erythrocytosis.

  • Chronic hypoxia caused by smoking or lung disease is a common secondary cause.[72][73]​​​ Arterial blood gases can be assessed in equivocal cases.

  • Sleep apnea may be considered as a possible cause. Although unlikely to produce erythrocytosis alone, sleep apnea with underlying lung disease may lead to erythrocytosis.

  • Anabolic steroid or testosterone use can also cause erythrocytosis.[74][75]

Further investigation for a primary hematologic disorder is warranted if secondary causes are ruled out.

Confirming the diagnosis

Molecular testing of blood or bone marrow for Janus kinase 2 (JAK2) V617F mutations is recommended for all patients with suspected MPN.[71] Serum erythropoietin level should be measured.[71]

Presence of both a JAK2 mutation and low serum erythropoietin in a patient with sustained absolute erythrocytosis confirms diagnosis of PV.[7][8]

JAK2 gene mutation testing

The JAK2 V617F mutation is present in approximately 95% of patients with PV.[3][4][5][6]​​​​​​​​ However, this mutation is not specific for PV, as it is found in other MPNs (essential thrombocythemia, primary myelofibrosis), chronic myelomonocytic leukemia, and acute myeloid leukemia.[31][76]​​​​ Furthermore, it is among the most common mutations detected in those with “clonal hematopoiesis of indeterminate potential” who have no particular hematologic phenotype.[77]

Quantitative testing for JAK2 V617F mutant allele burden may add important prognostic information. Patients with a higher JAK2 V617F allele burden appear to be at greater risk for thrombosis and myelofibrotic progression.​[48][49]​​[50]​​

If JAK2 V617F mutation is not detected, a diagnosis of PV is less likely. However, some patients have JAK2 exon 12 mutations (approximately 3% of patients with PV).[28]​ Testing for JAK2 exon 12 mutation should be carried out in patients with suspected PV who are negative for the JAK2 V617F mutation.[71]

Erythropoietin levels

Can be interpreted as follows.

  • Low erythropoietin: strongly suggests PV, although alone it is not diagnostic. Low erythropoietin is also reported in those with primary familial and congenital polycythemia associated with gain-of-function erythropoietin receptor mutations.[78] Referral to a hematologist is appropriate.

  • High erythropoietin: consistent with secondary erythrocytosis.[66] In the absence of an obvious secondary cause of erythrocytosis, patients are screened for erythropoietin-secreting tumors (chest x-ray, abdominal imaging, and brain MRI or CT scan). If the diagnosis is still unclear, referral to a hematologist is appropriate; a primary hematologic disorder is unlikely. 

  • Normal erythropoietin: PV is unlikely but cannot be ruled out. The erythropoietin level returns to normal in some patients with PV after phlebotomy. Referral to a hematologist is indicated.

Budd-Chiari syndrome (BCS)

A significant proportion of patients with BCS (particularly young women) who present with a normal hematocrit and a normal erythropoietin level will eventually develop a PV phenotype.[13][15][65]

The estimated prevalence of myeloproliferative neoplasms (MPNs) in patients with BCS is 30% to 50%; the majority being PV.[65] In this setting, it is reasonable to screen for the JAK2 V617F mutation. If the patient has the mutation, referral to a hematologist is indicated.

Bone marrow biopsy

​Mandated in the diagnostic criteria for PV, unless there is sustained absolute erythrocytosis in the presence of both a JAK2 mutation and low serum erythropoietin.​[7]​​[8][79][80]

Bone marrow biopsy allows for karyotype analysis and assessment of reticulin fibrosis. Abnormal karyotype is a marker of inferior survival in PV.[14]​ Reticulin fibrosis in the marrow at presentation (initial myelofibrosis) correlates with an increased risk of post-PV myelofibrosis.​[8][79]​​[81]

Several histologic features (e.g., increased bone marrow cellularity and increases in all three primary cell lines) may distinguish secondary polycythemia from PV, and discriminate among the various MPNs.[82]​ For example, bone marrow exam is critical for making the distinction between "masked PV" and essential thrombocythemia.[18]​ It can also help distinguish early PV with concomitant thrombocytosis from essential thrombocythemia.[18]

Other tests

Consideration may be given to further testing pending the clinical scenario, or the result of prior studies (e.g., JAK2 V617F mutation testing).[71][76]

Uric acid

Commonly elevated owing to rapid cell turnover from expanded hematopoiesis. Elevated levels predispose to gout and urate kidney stones.

Further mutational testing

Performed to exclude differential diagnoses and for prognostication.[36][83]

Testing for calreticulin (CALR) and thrombopoietin receptor (MPL) mutations can be performed if thrombocytosis is the predominant clinical manifestation, and JAK2 V617F and JAK2 exon 12 testing is negative.[71] A positive CALR or MPL mutation generally excludes PV, and suggests a diagnosis of essential thrombocythemia or primary myelofibrosis.[84][85][86][87]​​​ However, there have been reports of CALR mutations in patients with PV.[88]

Next-generation sequencing assays can test for multiple gene mutations simultaneously (including JAK2, CALR, MPL).[71][76]

Mutations in SRSF2, ASXL1, and IDH2 are associated with inferior overall survival and inferior myelofibrosis-free survival.[36]​​

Cytogenetic and molecular testing: BCR::ABL1

Fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) for BCR::ABL1 (Philadelphia chromosome) should be carried out to exclude chronic myeloid leukemia (CML).[71]​ Prognosis and management of CML differs considerably to that of PV.

Imaging studies

Abdominal imaging may be performed if splenomegaly is suspected but physical exam is equivocal. Ultrasound may be preferred to avoid radiation exposure.

Symptoms suggestive of splanchnic vein thrombosis should also prompt imaging studies.

Patients with PV have a high frequency of thrombosis, in both usual and unusual locations. Vascular imaging (CT scan or MRI) is performed if there are any symptoms or physical exam findings suggestive of thrombosis.

Abdominal vessel thromboses should be ruled out in patients with abnormal liver function tests, recurrent abdominal pain, or evidence of BCS.

Routine screening in asymptomatic patients is not indicated.

Red blood cell (RBC) mass measurement

RBC mass is always elevated in PV. RBC mass measurement may be considered if hemoglobin/hematocrit is equivocal, or affected by certain clinical conditions (e.g., volume overload).[52] This test is not commonly performed, and is no longer included in the WHO diagnostic criteria. However, it may have a role if diagnosis cannot be definitively established by other tests.​​[8]

Masked PV

Some patients may have pathologically and molecularly proven PV, without overt elevations in hemoglobin or hematocrit.[16] This is known as “masked PV” as the diagnosis is not obvious from the patient’s hemoglobin/hematocrit. Masked PV patients are more frequently male and tend to present with higher platelet counts and increased reticulin fibrosis in the bone marrow.[16] Patients experience the same spectrum of complications as with overt PV. However, they have worse survival (particularly among those ages >65 years and those with leukocytosis) and higher rates of progression to myelofibrosis and acute leukemia.[16][17]

Masked PV requires careful pathologic distinction from essential thrombocythemia when accompanied by thrombocytosis.[18] Delayed/missed recognition and a lower intensity of treatment of masked PV may contribute to worse outcomes.[19] High clinical vigilance for a possible PV diagnosis is essential in the presence of suggestive symptoms or complications (e.g., otherwise unexplained thrombosis).[18] 

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