Am Fam Physician. 2021;103(11):680-687
Author disclosure: No relevant financial affiliations.
Polycythemia vera is one of three stem-cell–derived myeloid malignancies commonly known as myeloproliferative neoplasms. It is characterized by erythrocytosis, often with associated leukocytosis and thrombocytosis. It has a significant negative impact on overall mortality and morbidity in the form of arterial and venous clots, symptoms of fatigue and pruritus, and conversion to leukemia and myelofibrosis. The World Health Organization's major diagnostic criteria include an elevated hemoglobin or hematocrit level, abnormal results on bone marrow biopsy, and presence of the Janus kinase 2 genetic mutation, which is present in approximately 98% of cases. The only minor criterion is a subnormal erythropoietin level, which helps differentiate polycythemia vera from common causes of secondary erythrocytosis such as smoking, sleep apnea, and testosterone use. First-line treatments, such as low-dose aspirin and goal-directed phlebotomy to a hematocrit level of less than 45% to reduce thrombotic events, improve quality of life and prolong survival. When indicated, cytoreductive therapy, primarily with hydroxyurea, can be added with consideration of second-line agents such as pegylated interferon-alfa, busulfan, and ruxolitinib, depending on the clinical scenario. Smoking cessation and cardiometabolic disease are modifiable risk factors that should be addressed to reduce the risk of thrombosis. Currently, no medications have been shown to cure the disease or to reduce the risk of conversion to leukemia and myelofibrosis.
Polycythemia vera (PV) is one of three common myeloproliferative neoplasms that will likely be encountered during the career of a primary care physician.1 This article summarizes the best, most recent evidence to guide the diagnosis and treatment of PV.
| Clinical recommendation | Evidence rating | Comments |
|---|---|---|
| All people with polycythemia vera should receive phlebotomy with a goal hematocrit level of less than 45%.18,19 | B | Consistent, low-quality evidence |
| All people who have polycythemia vera without contraindications should take daily low-dose aspirin (40 to 100 mg).21 | B | Limited-quality randomized controlled trials |
| Hydroxyurea is considered first-line cytoreductive therapy, if indicated.20,24 | B | Systematic review and meta-analysis of lower-quality studies |
| Patients with polycythemia vera should be counseled to stop smoking to reduce the risk of thrombosis.39 | B | Systematic review and meta-analysis of cohort studies |
Epidemiology
The annual incidence of PV is 0.01 to 2.61 per 100,000 people, and the prevalence is 0.49 to 46.88 per 100,000.2,3
Median age at diagnosis is 64 years (range = 19 to 95 years), and up to 25% of diagnoses occur before 50 years of age.4,5
Nonmodifiable risk factors for PV include older age, male sex, White race, and European descent.2,6,7
Modifiable risk factors for PV include smoking, obesity, hypertension, diabetes mellitus, and hyperlipidemia.8,9
Diagnosis
Patients who have PV typically present with elevated hemoglobin and hematocrit levels found incidentally or after laboratory evaluation for patients' reported symptoms, physical examination findings, or thrombotic/bleeding events.5,10,11
The differential diagnosis of PV includes other myeloproliferative neoplasms and secondary erythrocytosis from smoking, sleep apnea, and androgen use and, rarely, erythropoietin-producing tumors (Table 1).12
Table 2 presents the 2016 World Health Organization's diagnostic criteria for PV.13 A suggested approach to evaluation is summarized in Figure 1.14
| Primary erythrocytosis |
| 2,3-Bisphosphoglycerate deficiency |
| High oxygen-affinity hemoglobin variants |
| Lindau-von Hippel disease |
| Other myeloproliferative neoplasms (essential thrombocytosis, primary myelofibrosis, chronic myelogenous leukemia, myelodysplastic syndrome) |
| Primary familial and congenital polycythemia (EPOR mutation) |
| Secondary erythrocytosis* |
| Cardiopulmonary disease (chronic hypoxia, left-to-right shunt) |
| Erythropoietin-producing tumors (e.g., hepatocellular carcinoma, renal cell carcinoma, hemangioblastoma, pheochromocytoma, uterine leiomyomata) |
| High-altitude habitat |
| Iatrogenic (testosterone, anabolic steroids, erythropoietin, blood doping) |
| Renal disease (renal artery stenosis, hydronephrosis, transplant) |
| Sleep apnea, obesity-hypoventilation syndrome, pickwickian syndrome |
| Smoking, chronic carbon monoxide poisoning |
| Must meet all three major criteria or the first two major criteria and the minor criterion |
| Major criteria (1) Hemoglobin > 165 g per L (16.5 g per dL) in men or > 160 g per L (16.0 g per dL) in women or Hematocrit > 49% in men or > 48% in women or Increased red blood cell mass (> 25% above normal) (2) Bone marrow with tri-lineage proliferation with pleomorphic mature megakaryocytes* (3) Presence of Janus kinase 2 mutation |
| Minor criterion Subnormal erythropoietin level |
SIGNS AND SYMPTOMS
| Finding | Value |
|---|---|
| Hemoglobin, median in g per L (range) | 184 (18.4 g per dL); (151 [15.1 g per dL] to 265 [26.5 g per dL]) |
| Hematocrit, median (range) | 55% (36% to 78%) |
| Leukocyte count, median × 109 per L (range) | 10.4 (10,400 per μL); (3 [3,000 per μL] to 171.6 [171,600 per μL]) |
| Platelet count, median × 109 per L (range) | 466 (466 × 103 per μL); (7 [7 × 103 per μL] to 2,370 [2,370 × 103 per μL]) |
| Janus kinase 2 mutation presence | 98% of patients |
| Subnormal erythropoietin presence | 81% of patients |
| Symptom/finding | Percentage with finding |
|---|---|
| Fatigue | 91 |
| Insomnia | 68 |
| Pruritus on contact with water | 36 to 68 |
| Concentration problems | 61 |
| Splenomegaly | 36 |
| Erythromelalgia* | 29 |
| Arterial thrombosis | 16 |
| Venous thrombosis | 7.4 |
| Major hemorrhage | 4.2 |
DIAGNOSTIC TESTING
If PV is suspected after an elevated hemoglobin/hematocrit level is found, Janus kinase 2 (JAK2) V617F mutation and erythropoietin testing should be performed.12
Bone marrow biopsy with fluorescence in situ hybridization testing and karyotyping can be helpful to confirm the diagnosis and to stratify risk.12
Treatment
The goals of therapy are to improve survival and to improve quality of life by decreasing hematocrit levels, symptom burden, bleeding, and clotting complications.15
No treatments have been shown to reduce the risk of transformation to leukemia or myelofibrosis. Figure 2 presents a suggested approach to the treatment of PV.12,16,17
PHLEBOTOMY
All patients should receive phlebotomy with a goal hematocrit level of less than 45%.18–20
A randomized controlled trial of 365 patients who had PV with an average age of 65 years showed a decreased incidence of death from cardiovascular events and thrombotic events if phlebotomy was used to keep the hematocrit level at less than 45% vs. 45% to 50% over a median follow-up period of 31 months (1.1 events vs. 4.4 events per 100 person-years; number needed to treat = 30).18
In a retrospective cohort study, 820 predominantly White patients with Medicare, a median age of 77 years, and a low rate of previous thrombosis (13%) were followed for 2.8 years. The study found that phlebotomy used a median of 2.3 times per year was associated with significantly improved survival compared with no phlebotomy (6.3 years vs. 4.5 years). The risk of thrombosis was also significantly lower with phlebotomy use (29% vs. 46%).19
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