Polycythemia Vera Case File
Eugene C. Toy, MD, Gabriel M. Aisenberg, MD
Case 57
A 55-year-old woman comes to the clinic complaining of 6 months of progressive dull headaches and dizziness. She also endorses occasional blurred vision. She has a history of hypertension treated with metoprolol and is otherwise healthy. Her temperature is 99 °F, heart rate is 80 beats per minute (bpm), blood pressure is 110/70 mm Hg, and O2 saturation is 95%. On examination, the patient looks flushed. Her mucous membranes are normal. Her heart and lung examinations are unremarkable, but the liver is palpable 3 cm below the costal margin, and dullness to percussion is noted at the lowest intercostal space in the left axillary line. Though the patient did not notice this, the right leg is swollen compared to
the left one. The neurologic examination is nonfocal; no nystagmus is appreciated. The fundoscopic examination shows bilateral plethora of the retinal veins. The complete blood count reveals a white blood cell (WBC) count of 11,500/mm3, hemoglobin level of 17 g/dL with a hematocrit of 51%, and platelet count of 350,000/mm3.
▶ What is the most likely diagnosis?
▶ What is your next diagnostic step?
▶ What is the next step in therapy?
ANSWERS TO CASE 57:
Polycythemia Vera
Summary: A 55-year-old woman presents with
- Headaches, dizziness, blurred vision
- Congested retinal veins, flushed face, and hepatosplenomegaly
- Right leg swelling
- No hypoxemia
- Hemoglobin level of 17 g/dL with a hematocrit of 51%, all cell lines increased
Most likely diagnosis: Polycythemia vera (PV), with elevated hemoglobin and hematocrit and clinical symptoms of hyperviscosity. Additionally, a deep vein thrombosis (DVT) of the right leg is likely.
Next diagnostic step: Serum erythropoietin (EPO) level, JAK2 mutation testing, peripheral smear to look for blasts, lower extremity duplex scan, and bone marrow biopsy.
Next step in therapy: Low-dose aspirin and therapeutic phlebotomy for PV. Due to thrombus history, can consider hydroxyurea if symptoms not controlled by phlebotomy. Therapeutic anticoagulation for DVT is also important.
ANALYSIS
Objectives
- Recognize the diagnostic criteria for PV. (EPA 1, 3)
- Enumerate basic characteristics of myeloproliferative disorders. (EPA 1)
- Understand alternative reasons for expansion of all lineages of blood cells. (EPA 1, 2)
- Outline the treatment options for PV. (EPA 4)
Considerations
This 55-year-old woman with 6 months of headache, dizziness, and blurry vision is admitted with a DVT of the right leg. Physical examination consists of several signs of hyperviscosity commonly seen in polycythemia, including congested retinal veins, flushed face, hepatosplenomegaly, and right leg swelling. Together with an elevated hemoglobin > 16 g/dL and hematocrit > 49% (criteria for women) with normal oxygen saturation, this scenario points toward one of the myeloproliferative neoplasms (MPNs), namely, PV. Peripheral smear, EPO, and JAK2 mutation should be obtained. A low EPO level would point toward a primary polycythemia as opposed to a secondary polycythemia. JAK2 mutation is positive in nearly all PV patients. A bone marrow biopsy would likely show hypercellularity with trilineage growth. According to the World Health Organization guidelines, the diagnosis of PV requires meeting either all three major criteria (hemoglobin/hematocrit, bone marrow, and JAK2 mutation) or two major criteria and one minor criteria (low EPO). PV is a chronic condition and will require low-dose aspirin and therapeutic phlebotomy to keep hematocrit levels < 45% in men and < 42% in women. A cytoreductive agent such as hydroxyurea can be considered if the patient continues to be symptomatic despite phlebotomy due to her thrombus.
APPROACH TO:
Polycythemia Vera
DEFINITIONS
ERYTHROPOIETIN: Hormone produced by the kidneys that is stimulated by low oxygen levels to produce more RBCs in the bone marrow.
HYPERVISCOSITY SYNDROME: Constellation of symptoms arising from increased blood cellularity, including headache, blurry vision, transient loss of vision, chest pain, abdominal pain, and muscle pain.
MYELOPROLIFERATIVE DISEASE: Group of hematologic disorders characterized by overgrowth of bone marrow cell lines. Includes essential thrombocythemia (ET), PV, and primary myelofibrosis (MF).
POLYCYTHEMIA VERA: Disorder of the bone marrow resulting in overproduction of red blood cells (RBCs).
CLINICAL APPROACH
Pathophysiology
MPNs are a collection of disorders that are caused by the overproliferation of stem cells of the bone marrow, including ET, primary MF, and PV. All three may share the JAK2 mutation, present in about 50% of cases of ET and MF, but in over 95% of PV (Table 57–1). All have increased risk of leukemia. ET is defined by thrombocytosis, which is overproduction of platelets. MF is the replacement of bone marrow by fibrosis. It has characteristic findings on peripheral smear, described as a leukoerythroblastic picture, and commonly associated with teardrop-shaped RBCs, nucleated erythrocytes, and precursors of granulocytes. PV is defined by erythrocytosis, which is overproduction of RBCs, which we explore in more depth in the following sections.
Etiology. PV, the most common of the myelodysplastic disorders, is seen with an elevated hemoglobin and/or hematocrit; it can be initially differentiated as relative polycythemia or absolute polycythemia. When plasma volume is decreased secondary to diuretics or GI losses such as vomiting and diarrhea, hemoglobin and hematocrit (which represent the concentration of RBCs in blood) can be artificially elevated, commonly referred to as hemoconcentration or relative polycythemia. In these cases, once a patient is appropriately fluid resuscitated, hemoglobin and hematocrit are expected to normalize on a repeat CBC. If there is no normalization of hemoglobin/hematocrit or if the clinical picture is suggestive of PV, then absolute polycythemia, characterized by an increase in RBC mass, is suspected.
Absolute polycythemia can then further be divided into two categories, primary or secondary (Table 57–2). Primary polycythemia, caused most commonly by the JAK2 mutation, results in increased RBC mass. Secondary polycythemia is driven by elevated levels of EPO, which is secreted in response to low levels of oxygen, to stimulate RBC production by the bone marrow. Most commonly, secondary polycythemia stems from chronic hypoxia from a cardiac or pulmonary origin, namely, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea (OSA), obesity hypoventilation syndrome (OHS), right-to-left cardiac shunt, high altitude, or even heavy smoking. Performance-enhancing drugs such as anabolic steroids/testosterone, growth hormone, and EPO have started to become a more common cause of polycythemia. Additional causes include EPO-producing tumors, such as hepatocellular carcinoma, renal cell carcinoma, uterine leiomyoma, and adrenal sources such as pheochromocytoma.
Diagnosis. If patient has elevated hemoglobin/hematocrit on complete blood count in the context of normovolemia and normal O2 saturation along with signs and symptoms of PV, then further evaluation with serum EPO level and/or JAK2 V617F mutation is warranted. If the EPO is elevated, then it is secondary polycythemia, most commonly associated with hypoxia. If the EPO is low to normal or if signs/symptoms of PV are seen, then a positive JAK2 mutation is helpful in confirming its diagnosis. A bone marrow biopsy shows hypercellularity with trilineage growth. Diagnostic criteria are shown in Table 57–3.
Clinical Presentation
Many times, patients are asymptomatic, and polycythemia is suspected from an elevated hemoglobin and hematocrit. Other times, patients present with a constellation of symptoms, many of which may be nonspecific. Symptoms commonly associated with PV include night sweats, weight loss, early satiety, gout, pruritis, and erythromelalgia. Pruritis, described by many as itchiness, tingling, or burning after a warm or hot shower, is often one of the chief complaints of a PV patient. Erythromelalgia, which consists of a burning pain, redness, and increased temperature in the hands and feet, is also a classic finding. Patients with PV are known to have an increased risk of thrombosis, whether a DVT, pulmonary embolism (PE), stroke, or arterial thrombus. Physical examination of a PV patient may include a plethora of the retinal veins and face, hepatomegaly, splenomegaly, thrombosis, easy bleeding or bruising, and tophi. If hyperviscosity develops, patients may have fatigue, headache, blurry vision, stroke, and paresthesias.
Treatment
PV is a slowly progressive disease that can develop over decades, so treatment may be indefinite. Overall, there are two main goals: (1) to reduce microvascular symptoms, such as pruritis, erythromelgia, and bleeding; and (2) to reduce thrombotic events.
Low-dose aspirin is recommended for all PV patients unless contraindications are present. Aspirin is particularly useful in reducing pruritis and erythromelalgia. Therapeutic phlebotomy, which decreases risk of thrombotic events by reducing hematocrit and expanding plasma volume, is the centerpiece of PV treatment. Phlebotomy aims to keep hematocrit levels < 45% in men and < 42% in women.
High-risk PV patients are those who are > 60 years old and/or have a history of thrombosis. In these patients, cytoreductive treatment might be useful. Furthermore, treatment may be indicated in low-risk patients with uncontrolled symptoms, increasing platelet counts (especially over 1,000,000/μL) or persistently elevated hematocrit despite phlebotomy. Hydroxyurea, a ribonucleotide reductase inhibitor that disrupts DNA repair to reduce the number of RBCs made by bone marrow, is the first-line cytoreductive agent. Side effects include cytopenia, oral ulcers, and diarrhea. In patients who fail hydroxyurea, ruxolitinib (Jakafi), a JAK inhibitor, is becoming a mainstay in PV treatment. Other cytoreductive agents include interferon alfa or busulfan. Interferon alfa is often used in patients < 40 years and in pregnant patients. Busulfan, an alkylating agent, is tied to many side effects, including cytopenias, pulmonary fibrosis, skin discoloration, and/or leukemia.
Prognosis. All of the MPNs (PV, MF, and ET) can spontaneously progress to acute myeloid leukemia or myelodysplastic syndrome. Of the three, ET is the least likely to progress, while primary MF is the most likely to transform. The 10-year transformation rate is roughly 2% to 5% in ET, 5% to 8% in PV, and 8% to 20% in MF. The median survival times also follow a similar pattern, with average survival being 20 years for ET, 14 years for PV, and 6 years for MF. In PV patients, risk factors that increase risk of transformation to leukemia include age > 60, history of thrombosis, and leukocytosis. In ET, increased age and anemia correlate with risk of fibrotic transformation. Once progression to leukemia and/or blast phase has occurred, treatment includes induction chemotherapy followed by allogenic hematopoietic cell transplantation.
CASE CORRELATION
- See also Case 14 (Pulmonary Embolism) and Case 58 (Sickle Cell Crisis).
COMPREHENSION QUESTIONS
57.1 A 52-year-old man with diabetes and COPD presents to the emergency department for 2 days of poor oral intake due to nausea, vomiting, and diarrhea. Over the past few months, the patient reports worsening fatigue, headaches, shortness of breath, and insomnia. His temperature is 98.7 °F, blood pressure is 130/81 mm Hg, heart rate is 88 bpm, respiratory rate is 12 breaths/min, and oxygen saturation is 94% on room air. His body mass index (BMI) is 40 kg/m2. On physical examination, he is obese, but he has normal cardiac, respiratory, and abdominal examinations. On his CBC, WBC count is 8500/mm3, hemoglobin is 19 g/dL, hematocrit is 54%, and platelet count is 327,000/mm3. Chest x-ray is unremarkable. Which of the following is the next best step in management?
A. Bone marrow biopsy
B. Computed tomography (CT) of the chest
C. Erythropoietin level
D. Phlebotomy
57.2 The patient in Question 57.1 receives 1 L of normal saline and on repeat laboratory work, the WBC count is 7500/mm3, hemoglobin is 19 g/dL, hematocrit is 53%, and platelet count is 315,000/mm3. EPO is elevated. The patient is sent home from the emergency department and returns to his primary care provider’s office for a posthospitalization follow-up. Which of the following is the next best step in management?
A. Bone marrow biopsy
B. JAK2 mutation evaluation
C. Phlebotomy
D. Pulmonary function test
57.3 A 67-year-old woman with a history of asthma and hypertension presents to her primary care provider’s office for 6 months of fatigue, headache, and blurry vision. She reports smoking 1 pack of cigarettes daily and drinking two or three beers each week. She denies use of illicit drugs. Her temperature is 98.3 °F, blood pressure is 140/75 mm Hg, heart rate is 92 bpm, respiratory rate is 13 breaths/min, and oxygen saturation is 95% on room air. The WBC count is 11,500/mm3, hemoglobin is 17 g/dL, hematocrit is 50%, and platelet count is 600,000/mm3. EPO is low. JAK2 mutation is positive. Bone marrow biopsy shows hypercellularity with trilineage growth. Which of the following is the most likely diagnosis?
A. Chronic myelogenous leukemia
B. Essential thrombocythemia
C. Polycythemia vera
D. Primary MF
57.4 A 67-year-old man with a history of systolic heart failure, pulmonary hypertension, left lower extremity DVT, and PV comes to his primary care provider for an annual checkup. The patient is on aspirin, atorvastatin, metoprolol, lisinopril, and therapeutic phlebotomy. He continues to report fatigue, blurry vision, and headache. The physical examination is unremarkable. The WBC count is 11,000/mm3, hemoglobin is 17 g/dL, hematocrit is 48%, and platelet count is 325,000/mm3. Which of the following is the best next step in management?
A. Continue current regimen
B. Start busulfan
C. Start hydroxyurea
D. Start induction chemotherapy
ANSWERS
57.1 C. This male patient’s hemoglobin is > 16.5 g/dL and hematocrit is > 49%, so he meets the criteria for polycythemia. Polycythemia could be primary or secondary due to COPD or volume depletion. The best next step would be to test the EPO levels, as a low level would point to PV and a high level would point to a secondary polycythemia due to hypoxia or volume depletion, especially in the setting of his COPD history. JAK2 mutation is also another test that is performed as part of the diagnostic approach prior to biopsy. Bone marrow biopsy (answer A) and JAK2 evaluation can be obtained later if EPO is low, but a high EPO makes PV unlikely. CT scan of the chest (answer B) would be indicated if the patient had a pulmonary complaint such as chronic cough, but it would not be high yield in this case. Phlebotomy (answer D) can improve the hyperviscosity symptoms of polycythemia, but treatment should be aimed toward finding and treating the underlying cause.
57.2 D. An elevated EPO level points toward a secondary polycythemia, likely due to chronic hypoxia from a pulmonary or cardiac source, so JAK2 mutation (answer B) and bone marrow biopsy (answer A) are not warranted at this time. Due to the patient’s BMI of 40 kg/m2, shortness of breath, and insomnia, pulmonary function tests may reveal the underlying cause of his polycythemia. Phlebotomy (answer C) can improve the hyperviscosity symptoms of polycythemia, but treatment should be aimed toward finding and treating the underlying cause.
57.3 C. This female patient has hemoglobin > 16 g/dL, low EPO, JAK2 mutation, and bone marrow findings suggestive of PV, so she meets not only all three major criteria, but also the minor criteria. Though her platelets are over 450,000/mm3 and JAK2 mutation is positive, which can also be seen in ET, she has classic bone marrow biopsy findings of PV, and ET (answer B) is considered a diagnosis of exclusion. Chronic myelogenous leukemia (answer A) would typically lead to bone marrow infiltration of cancer cells and cause anemia rather than polycythemia. Similarly, primary MF (answer D) is a disorder where fibrous tissue forms in the bone marrow, leading to abnormally shaped RBCs and anemia.
57.4 C. This patient is over the age of 60 and has a history of DVT, so he is considered a high-risk PV patient. Despite being on both aspirin and therapeutic phlebotomy, the patient continues to have a hematocrit > 45%, so adding a cytoreductive agent is recommended. Hydroxyurea is considered first-line treatment. Busulfan (answer B) is another option, but it can cause pulmonary fibrosis and would not be a good option in this patient with pulmonary hypertension. Induction chemotherapy (answer D) would not be needed unless we have confirmed progression to leukemia. Continuing the current regimen (answer A) is not appropriate for this patient, who continues to have an increased hematocrit.
CLINICAL PEARLS
▶ Myeloproliferative neoplasms include ET, primary MF, and PV.
▶ Classic PV findings include pruritis and erythromelalgia.
▶ Hyperviscosity syndrome is characterized by fatigue, headache, blurry vision, transient vision loss, paresthesias, and thrombosis.
▶ Patients with primary polycythemia have low EPO and positive JAK2 mutation.
▶ Those with secondary polycythemia have elevated EPO.
▶ In PV, hemoglobin is > 16.5 g/dL or hematocrit > 49% in men, hemoglobin > 16 g/dL or hematocrit > 48% in women.
▶ Essential thrombocythemia is associated with overproduction of platelets and is a diagnosis of exclusion.
▶ Teardrop cells are commonly seen on peripheral smear of MF.
▶ Mainstays of PV treatment include low-dose aspirin, therapeutic phlebotomy, and addition of cytoreductive agent in higher risk patients.
▶ Ruxolitinib (Jakafi) is a JAK inhibitor.
REFERENCES
Fowlkes S. Myeloproliferative neoplasms (MPNs)—Part 1: An overview of the diagnosis and treatment of the “classical” MPNs. Can Oncol Nurs J. 2018;28(4):262-268.
Spivak JL. Myeloproliferative neoplasms. N Engl J Med. 2017;376:2168-2181.
Spivak JL. Polycythemia. Curr Treat Options Oncol. 2019;19:12.
Tefferi A. Clinical manifestations and diagnosis of polycythemia vera. UpToDate. Waltham, MA: UpToDate; 2019. http://www.update.com/contents/clinical-manifestations-and-diagnosis-of-polycythemia-vera. Accessed June 8, 2019.
Vannucchi AM. How I treat polycythemia vera. Blood. 2014;124:3212-3220.
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