Polycythemia Vera


Continuing Education Activity

Polycythemia vera is a myeloproliferative disorder associated with a JAK2 kinase mutation that causes the neoplastic proliferation of the hematopoietic progenitor cells. It causes elevated red blood cell production along with secondary white blood cell and platelet production. Disease complications are associated with increased blood viscosity, including thromboses. This activity reviews the evaluation and treatment of polycythemia vera and the role of the interprofessional team in managing this condition.

Objectives:

  • Identify the etiology of polycythemia vera.
  • Describe the presentation of polycythemia vera.
  • Outline treatment recommendations for polycythemia vera.
  • Review the importance of collaboration among specialties to achieve correct diagnosis and management to improve outcomes in patients with polycythemia vera.

Introduction

Polycythemia vera (PV) is a myeloproliferative neoplastic disorder involving uncontrolled red blood cell production resulting in elevated red blood cell (RBC) mass. There is often concurrent stimulation of myeloid and megakaryocytic lineages leading to increased white blood cell and platelet production, respectively. The current understanding of pathophysiology involves increased sensitivity to growth factors due to an abnormal hematopoietic cell clone. Signs and symptoms, including headache, dizziness, claudication, thrombosis, are a consequence of increased blood viscosity.

Etiology

The etiology of the disease process appears to be neoplastic proliferation. There is a signaling defect leading to an abnormal response to growth factors, and the abnormal clonal line interferes with normal lineage proliferation. The Janus kinase-2 (JAK2) gene involved with intracellular signaling is mutated in 90% of cases of PV.[1]

Epidemiology

Polycythemia vera can affect all ethnic groups with no sex predilection, although there are slightly more cases in men than women.[2] It can occur in all age groups, but the median age of diagnosis is 60.[3] PV affects 0.6 to 1.6 per million people in the United States. There are fewer incidences in Japan than in the United States or Europe.[4]

Pathophysiology

JAK2 kinase mutation likely leads to the signaling derangements resulting in Polycythemia vera. A valine to phenylalanine substitution at position 617 of the JAK2 gene, or JAK2V617F, leads to constitutively active cytokine receptors.[5] This mutation is observed in over 90% of patients with PV, as well as 50% to 60% of primary myelofibrosis and 50% of essential thrombocythemia.[1][6] This process leads to increased production of RBCs and platelets with associated complications of thrombosis and bleeding.

Histopathology

Peripheral blood smear findings can be different based on the stage of the disease. In pre-polycythemia and overt polycythemia, normochromic and normocytic red blood cells are seen. A hypochromic and microcytic pattern can accompany concomitant iron deficiency. Platelets and white blood cells can also be elevated. Leukocytosis, predominantly with neutrophils, can be seen without blast activity. In the post-polycythemic stage, myelofibrosis develops with teardrop red blood cells, poikilocytosis, and circulating nucleated red cells.

Bone marrow sampling typically shows hypercellularity with panproliferation. Again, histopathology is dependent on the stage of the disease. Erythrocytosis is seen with pre-polycythemia, increased red cell mass in overt polycythemia, and increased reticulin deposition in post-polycythemia with fibrosis, ineffective production, and extramedullary hematopoiesis.[7]

History and Physical

Symptoms are related to hyperviscosity and thrombosis, impairing oxygen delivery. Physical complaints can include fatigue, headache, dizziness, tinnitus, vision changes, insomnia, claudication, pruritus, gastritis, and early satiety. Aquagenic pruritus, which occurs during or after a hot shower, is a complaint in 40% of patients.[8][9] The mechanism is likely from mast cell and basophil degranulation, causing a histamine surge. In a 2013 study with 1545 patients, pruritis was associated with better survival.[10] Erythromelalgia is burning pain in the hands and feet with erythema or pallor. This can be seen in PV or essential thrombocythemia and responds well to low-dose aspirin.[11] Bleeding and thrombotic complications are each observed in 1% of patients.  Bleeding events can include epistaxis, gum bleeding, and gastrointestinal (GI) bleeding.  Thrombotic events can include deep venoust thrombosis (DVT), pulmonary ebmolism (PE), Budd-Chiari syndrome, splanchnic vein thrombosis, stroke, and arterial thrombosis.[12] Early satiety occurs from impaired gastric filling due to splenomegaly. GI discomfort and peptic ulcer disease are common, likely from increased histamine from basophils and increased viscosity in gastrointestinal blood supply.[13] 

On physical exam, patients can display plethora and flushing of the face and palms, conjunctival injection, and skin excoriation from pruritus. Splenomegaly and hepatomegaly are also often observed.[14]

Evaluation

In the 1970s, the Polycythemia Vera Study Group (PVSG) set the first diagnostic criteria for PV. The diagnosis can be made if all three category A criteria are met, or if A1, A2, and 2 from category B are met.[15] 

Category A

  • Total red blood cell mass ≥36 mL/kg in males or ≥32 mL/kg in females
  • Arterial oxygen saturation ≥92%
  • Splenomegaly

Category B

  • Platelets >400,000/microliter
  • White blood cell count >12,000/microliter
  • Leukocyte alkaline phosphatase (ALP) >100 U/L
  • Serum vitamin B12 >900 pg/mL or binding capacity >2200 pg/mL

Measuring the red blood cell mass requires labeling with the 51Cr isotope, which is no longer readily available. Therefore, the PVSG guidelines have fallen out of favor, and the World Health Organization (WHO) published revised guidelines for diagnosing PV in 2016. These criteria are composed of three major and one minor criterion. Diagnosis can be made if all 3 major or 2 major and minor criteria are met.[16] 

Major

  • Hg >16.5 g/dL or Hct >49% in men, Hg >16 g/dL or Hct >48% in women; or red blood cell mass >25% above mean normal predicted
  • 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 V617For JAK2 exon 12 mutation

Minor

  • Serum erythropoietin level below the reference range for normal

These criteria should only be applied for diagnosis after secondary causes of polycythemia have been ruled out.

Treatment / Management

There is no cure for polycythemia vera; goals of treatment are aimed at symptom relief and reducing the risk of disease complications, including thrombosis, bleeding, and hematologic transformation. There are currently no means for preventing transformation into myelofibrosis or acute leukemia/myelodysplastic syndrome, but there are known agents to avoid that can increase this risk.[17] 

Patients under the age of 60 without a history of thrombotic events are considered low risk and treatment recommendations include:

  • Phlebotomy, target hematocrit to less than 45%
  • Daily low-dose aspirin, if no contraindications
  • Treat aspirin refractory symptoms
  • Optimizing cardiovascular (CV) health such as weight loss, exercise, tobacco cessation, blood pressure control.

Patients 60 years of age or older and/or have a history of thrombosis are considered high risk, and recommendations are the same as for low-risk patients with the addition of cytoreductive therapy (hydroxyurea, interferon, busulfan) and treating disease-specific complications.[17][18]

Differential Diagnosis

Primary polycythemia vera must demonstrate increased production in all three cell lines to make the diagnosis. Increased red blood cell mass alone is not enough for diagnosis because other conditions such as chronic hypoxia and erythropoietin-secreting tumors can lead to polycythemia. Secondary polycythemia (from hypoxia or smoking) is much more common than primary PV and must be ruled out before the diagnosis of primary PV can be made.[3]  A rare mutation of the EPO receptor can mimic the basic presentation of PV, including increased red cell mass and decreased EPO. However, the mechanism is an over-sensitive receptor to EPO rather than EPO independence.[19][20] Isolated granulocytosis can occur from infections or leukemoid reactions. Thrombocytosis alone can result from bleeding or iron deficiency.

Differential diagnoses to consider include essential thrombocythemia, chronic myelogenous leukemia, agnogenic myeloid metaplasia, chronic myelogenous leukemia, primary myelofibrosis, and secondary polycythemia.

Surgical Oncology

Splenectomy may be appropriate in the setting of painful splenomegaly or recurrent splenic infarcts.

Budd-Chiari syndrome,  or hepatic venous outflow thrombosis, is a potential complication requiring surgical intervention such as transjugular intrahepatic portosystemic shunt (TIPS), portocaval shunt, mesocaval shunt, portocaval/cavoatrial shunt, or mesoatrial shunt.[21]

Treatment Planning

Each unit of phlebotomized blood (500 mL) should drop the hematocrit by 3% in an average-sized adult. Men may tolerate up to the removal of 1.5 to 2 units a week. Whereas women, the elderly, those who weigh less than 50 kg or those with CV disease may only tolerate removal of 0.5 units a week. The goal of phlebotomy is to deliberately induce an iron-deficient state, which will, to some degree, limit the marrow's capacity for erythropoiesis; therefore, patients should not take iron supplements. Patients with hematocrits maintained at <45% have significantly fewer cardiovascular and thrombotic events compared to when the goal hematocrit is 50%.[22] 

Low dose aspirin (40 mg to 100 mg) once or twice daily should be given, if no contraindications, to lower thrombotic risk.[23] Patients with platelets greater than 1 million/microliter can have increased bleeding risk due to acquired von Willebrand disease and therefore, should not be placed on aspirin.[18] 

In high-risk patients, cytoreductive therapy is recommended in addition to phlebotomy and aspirin. The first-line agent is hydroxyurea (HU) due to its safety profile, cost, and efficacy.[24] Initial dosing is 15 mg/kg of actual body weight per day divided into twice-daily dosing. The goal is to reduce platelets to 100,000 to 400,000/microliter without excessive neutropenia and anemia. Dosing should not be adjusted more frequently than once weekly because it takes three to five days for a dose modification to achieve therapeutic effect. Patients failing hydroxyurea therapy or are intolerant may try pegylated interferon or busulfan. Other alternatives include ruxolitinib, anagrelide, pipobroman, and radioactive phosphorus.

To manage pruritus, initial treatment should include antihistamines and SSRIs. If ineffective, INF-a can be attempted, followed by JAK2 inhibitors for highly resistant cases.[17]

Toxicity and Side Effect Management

Older patients and those with cardiovascular disease should have a smaller volume of blood removed during phlebotomy sessions to minimize orthostatic effects. Normal saline may be given post phlebotomy to replace the volume lost. Patients should be educated to stay well-hydrated and limit aggressive physical activity within the first 24 hours of phlebotomy.

Higher dose aspirin (>100 mg/day) is associated with an increased risk of bleeding, and 900 mg daily is associated with a high rate of gastrointestinal bleeding.[25][23][26]

Adverse effects of hydroxyurea include cytopenias, oral ulcers, GI upset, peripheral neuropathy, and rare but severe pulmonary toxicity. If HU is not tolerated, cytoreductive therapy should be changed to other agents listed above.

Prognosis

The average survival of untreated PV is 18 months, whereas median survival is 14 years overall and 24 years if younger than 60 for those undergoing treatment.[17][18][27][18]

Complications

Polycythemia vera related complications and mortality are related to thrombosis, hemorrhage, peptic ulcer disease, myelofibrosis, acute leukemia, or myelodysplastic syndrome (MDS).

Thrombosis is a major complication of PV, and current treatment recommendations are aimed at minimizing these risks. In the setting of a first thrombotic event, an appropriate dose and length of anticoagulation are recommended. There is currently no difference in treatment recommendations for patients with underlying PV.[28] 

Bleeding is another common complication of the disease process, but major bleeding is rare. The risk for bleeding increases with severe thrombocytosis and high-dose aspirin (>100 mg/day) or anticoagulation.[25] 

Myelofibrosis worsens with the progression of the disease. Recommended treatment for secondary myelofibrosis is the same as primary myelofibrosis. Transformation to myelodysplasia and acute leukemia yields poor prognosis. Treatment is the same as primary MDS and acute myeloid leukemia (AML).

Consultations

It is recommended that a hematologist be involved in the care of patients with polycythemia vera.

Deterrence and Patient Education

Polycythemia vera is a condition where the bone marrow goes into “overdrive” and makes too many red blood cells, along with too many white blood cells and platelets. This can put you at risk for life-threatening blood clots, bleeding, and certain blood cancers. It is, therefore, important to have frequent follow up with a hematologist for close monitoring and treatment to lower these risks. Treatment options include phlebotomy, daily aspirin, and certain medications to suppress the bone marrow.

Enhancing Healthcare Team Outcomes

Polycythemia vera may initially present with vague symptoms including headache, dizziness, fatigue, insomnia, GI complaints, pruritus, etc., and patients may initially bring this to the attention of the general practitioner. A combination of these symptoms, along with abnormal hematologic labs, warrants a referral to a hematologist for further workup for the underlying condition. Early diagnosis and treatment of PV can increase survival by decreasing morbidity from disease complications.


Article Details

Article Author

Xiao Lu

Article Editor:

Richard Chang

Updated:

5/13/2020 7:51:25 PM

PubMed Link:

Polycythemia Vera

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