Version May 2024
INTRODUCTION — Polycythemia vera (PV) is a BCR::ABL1-negative myeloproliferative neoplasm characterized by excessive, clonal proliferation of erythroid cells. PV is clinically manifested as an elevated red blood cell mass that is often accompanied by troublesome pruritus, erythromelalgia (burning pain in feet or hands), and abdominal pain/fullness from splenomegaly. PV is associated with an increased risk for thromboembolic events, leukemic transformation, and/or myelofibrosis.
Secondary polycythemia refers to erythrocytosis (ie, elevated hematocrit) associated with intravascular volume contraction, elevated serum erythropoietin (eg, due to hypoxia, renal artery stenosis, certain tumors), rare inherited disorders, and other conditions (table 1).
This topic discusses treatment and prognosis of PV and secondary polycythemia.
Discussed separately are:
●Evaluation of the patient with erythrocytosis. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia".)
●Clinical presentation and diagnosis of PV. (See "Clinical manifestations and diagnosis of polycythemia vera".)
OVERVIEW OF POLYCYTHEMIA VERA — It is important to distinguish PV from secondary polycythemia. Evaluation of erythrocytosis and diagnosis of PV are discussed separately. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia".)
PV is a BCR::ABL1-negative myeloproliferative neoplasm with a less favorable prognosis than essential thrombocythemia but a more favorable prognosis than primary myelofibrosis [1]. Survival in patients with PV is generally measured in years to decades.
●Symptoms – Patients with PV may be asymptomatic at presentation, or they may experience a range of troublesome symptoms. Common symptoms in patients with PV include [1]:
•Vasomotor disturbances – Manifestations include headache, lightheadedness, visual symptoms, chest pain, and paresthesias.
•Erythromelalgia – Erythromelalgia is a pathognomonic vasomotor symptom characterized by burning pain in the feet or hands accompanied by erythema, pallor, or cyanosis (picture 1).
•Pruritus – Pruritus occurs in most patients with PV, and it is often exacerbated by bathing (so-called aquagenic pruritus), especially with hot water.
•Splenomegaly – Approximately one-third of patients present with splenomegaly, which may cause pain, abdominal fullness, or anorexia.
•Constitutional symptoms – Fever or sweating is experienced by 10 to 20 percent of patients.
•Thromboses – Superficial thrombophlebitis is common, but one-quarter of patients with PV will experience major arterial or venous thrombosis.
•Bleeding – Minor mucocutaneous bleeding is common, but less than 5 percent of patients present with a major hemorrhage.
Patients with bleeding or a platelet count >1000 x 109/L (>1,000,000/microL) should be evaluated for acquired von Willebrand syndrome, as discussed below. (See 'Acquired von Willebrand syndrome' below.)
PRETREATMENT EVALUATION — History and physical examination should document polycythemia-associated findings. Laboratory studies are used to assess hematologic findings and organ dysfunction that may influence management.
Clinical — History and physical examination evaluate symptoms and complications associated with polycythemia and comorbid conditions that may exacerbate them.
●History – History should include the following:
•Presence and severity of pruritus, acrocyanosis, vasomotor symptoms (eg, headaches, dizziness, paresthesias, visual disturbances, erythromelalgia), and cutaneous ulcers.
•Venous thrombosis, including deep venous thrombosis in extremities, pelvic, mesenteric, hepatic, or portal veins; arterial thrombosis in extremities, cerebral, coronary, or ophthalmic arteries; and first trimester spontaneous abortion.
•Bleeding, including mucosal bleeding, epistaxis, gastrointestinal or urogenital hemorrhage, deep hematoma, hemarthrosis, and other bleeding/bruising.
•Cardiovascular risk factors, including hypertension, diabetes mellitus, active tobacco use, and hyperlipidemia.
●Physical examination – Evaluation of spleen and liver size and evidence of bleeding/bruising.
Laboratory studies — Blood tests include:
●Hematology – Complete blood count with leukocyte differential and review of a blood smear.
For patients with clinical bleeding or platelet count >1000 x 109/L (>1,000,000/microL), ristocetin cofactor activity should be measured. Patients with ristocetin cofactor activity <30 percent are diagnosed with acquired von Willebrand syndrome. (See 'Acquired von Willebrand syndrome' below.)
●Serum chemistries – Electrolytes and liver and renal function tests.
●Molecular testing – If not previously performed, test for JAK2 V617F and, if negative, test for mutations of JAK2 exon 12.
If a bone marrow biopsy was not previously done, it should be performed to assess reticulin fibrosis, the percentage of CD34-positive cells, and karyotype. Diagnosis of PV is discussed separately. (See "Clinical manifestations and diagnosis of polycythemia vera", section on 'Bone marrow aspiration and biopsy'.)
RISK STRATIFICATION — Thrombotic events are the leading cause of preventable death in PV, and as such, they affect overall survival and contribute to other PV-associated complications. (See 'Prognosis' below.)
Management of PV is guided by the risk for thrombosis, as follows:
●Low risk – Age ≤60 years and no history of thrombosis
●High risk – Age >60 years or history of thrombosis
ALL PATIENTS — The mainstays of treatment for all patients with PV are control of red blood cell (RBC) mass, symptom control, and prevention of PV-associated complications.
Our approach to management of PV is consistent with guidelines and expert opinion from European LeukemiaNet and the United States National Comprehensive Cancer Center Network [2-4].
Regardless of thrombotic risk, all patients with PV require the following:
●Control red blood cell mass – Phlebotomy and/or cytoreductive therapy. (See 'Hematocrit target' below.)
●Symptom relief – Aspirin and/or cytoreductive therapy. (See 'Low-dose aspirin' below and 'Choice of cytoreductive agent' below.)
●Prevent complications – Reduce cardiovascular (CV) risk factors and use cytoreductive therapy in selected cases. (See 'Reduce cardiovascular risk factors' below.)
Hematocrit target — For all patients with PV, we recommend maintaining the hematocrit (Hct) at <45 percent rather than higher targets based on prolonged survival and reduction of thrombotic events.
Some experts suggest a Hct target of <42 percent in females. We consider this acceptable if it more effectively controls symptoms in a patient that persist at 45 percent Hct. A lower Hct target is also acceptable in pregnant patients because the increase in plasma volume in the second and third trimesters of pregnancy may mask an increased RBC mass, as discussed below. (See 'Pregnancy' below.)
Hct control is initially achieved using periodic therapeutic phlebotomy, which reduces the RBC mass and induces iron deficiency. (See 'Therapeutic phlebotomy' below.)
For patients with high-risk PV, cytoreductive therapy is used to complement or substitute for therapeutic phlebotomy. (See 'High-risk PV' below.)
The goal of maintaining the Hct at <45 percent is based on the following studies:
●The phase 3 Cytoreductive Therapy in PV (CYTO-PV) trial reported that maintaining the target Hct at <45 percent reduced deaths from CV causes or major thrombotic events compared with a target Hct of 45 to 50 percent [5]. The trial randomly assigned 365 adults with PV to more intensive treatment (target Hct <45 percent) versus less intensive treatment (target Hct 45 to 50 percent); control of Hct could be achieved by phlebotomy, hydroxyurea, or both. With a median follow-up of 31 months, patients who received less intensive Hct control experienced more deaths from CV causes or major thrombotic events (10 versus 3 percent; hazard ratio [HR] 3.91 [95% CI 1.45-10.53]) and shorter time to such events (HR 3.9 [95% CI 1.5-10.5]). There was no difference between the trial arms in bleeding or progression to myelofibrosis, acute myeloid leukemia, or myelodysplastic syndromes/neoplasms.
●Use of phlebotomy or hydroxyurea to control Hct was associated with improved survival and a decreased risk of thrombosis in 820 older adults with PV (median age 77 years) in the US SEER (Surveillance, Epidemiology, and End Results) database [6]. This population-based study did not report individual patient's Hct levels, but less than two-thirds of patients with PV received phlebotomy or hydroxyurea. The median overall survival (OS) was 6.29 years for phlebotomy users versus 4.50 years for phlebotomy nonusers, and phlebotomy was associated with reduced risk of death (HR 0.65 [95% CI 0.51-0.81]). The median OS was 6.02 years for hydroxyurea users versus 5.25 years for hydroxyurea nonusers. Thrombosis risk was decreased by either phlebotomy (29.3 percent of patients versus 46 percent; HR 0.52 [95% CI 0.42-0.66]) or hydroxyurea (27.6 versus 45.4 percent).
Low-dose aspirin — For all patients with PV, we suggest treatment with low-dose daily aspirin based on its efficacy for alleviating microvascular symptoms, reducing deaths from CV and thromboembolic causes, and safety.
Aspirin should be used with caution in patients with acquired von Willebrand syndrome. (See 'Acquired von Willebrand syndrome' below.)
●Administration – Low-dose aspirin refers to doses of 40 to 100 mg per day.
We favor twice-daily dosing with the total dose ≤100 mg/day, but once-daily dosing is also acceptable.
There is no persuasive evidence that twice-daily dosing more effectively controls vasomotor symptoms or reduces thrombotic risk. Some patients who have persistent vasomotor symptoms while taking single-daily low-dose aspirin respond better to twice-daily low-dose aspirin. A meta-analysis of seven randomized trials (379 patients) reported that twice-daily low-dose aspirin was more effective that once-daily dosing for reducing serum thromboxane B2 levels [7].
●Toxicity – Low-dose aspirin is well-tolerated and has no major adverse effects (AEs).
Higher doses of aspirin (eg, 900 mg/day) were associated with increased incidence of gastrointestinal hemorrhage when combined with dipyridamole in patients with PV [8,9].
●Outcomes – Treatment with low-dose aspirin in PV is supported by the following trials:
•Low-dose aspirin achieved a reduction in the combined endpoint of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from CV causes in the phase 3 ECLAP (European Collaboration on Low-Dose Aspirin in Polycythemia Vera) trial [10]. Among 518 patients with PV who were randomly assigned to aspirin 100 mg daily versus placebo, the combined endpoint was lower in patients treated with aspirin (3.2 versus 7.9 percent; relative risk [RR] 0.40 [95% CI 0.18–0.91]). There was no effect of aspirin on OS, CV mortality, or major bleeding episodes.
•A phase 3 trial that randomly assigned 112 patients with PV to either aspirin or placebo reported that aspirin was well-tolerated, not associated with increased bleeding, and completely inhibited platelet cyclooxygenase activity [11].
Symptom control — Aquagenic pruritus and erythromelalgia are prominent symptoms for many patients with PV. (See 'Overview of polycythemia vera' above.)
Management of these symptoms includes the following.
●Pruritus – Management of pruritus should begin with avoidance of precipitating exposures (eg, attention to temperature of the environment and the water used for bathing; adding laundry starch to bath water; drying the skin by patting, rather than rubbing), moisturizing cream, and antihistamines. General approaches to the management of pruritus are provided separately. (See "Pruritus: Therapies for localized pruritus".)
Low-dose aspirin is generally effective for alleviating pruritus. For pruritus that is resistant to low-dose aspirin, the addition of alternative antiplatelet agents (clopidogrel 75 mg per day) may be effective.
Cytoreductive therapy using hydroxyurea, interferon alfa, or ruxolitinib and narrow band ultraviolet B (UVB) phototherapy are also effective for controlling pruritus [12-14].
●Erythromelalgia – Erythromelalgia typically responds well to low-dose aspirin. Erythromelalgia that is unresponsive to aspirin should be treated with cytoreductive agents. (See 'Choice of cytoreductive agent' below.)
Reduce cardiovascular risk factors — All patients with PV should be counseled to stop smoking and to control blood pressure, weight, and cholesterol/lipids to lessen the risk of CV events.
Management of CV risk factors is discussed separately. (See "Overview of primary prevention of cardiovascular disease".)
LOW-RISK PV — Low-risk PV describes PV in patients ≤60 years with no history of thrombosis. (See 'Risk stratification' above.)
Initial management — For patients with low-risk PV, we suggest low-dose aspirin plus periodic phlebotomy to control hematocrit (Hct) rather than cytoreductive therapy. This suggestion is based on avoidance of adverse effects (AEs) associated with cytoreduction.
Some experts favor treatment with low-dose aspirin plus pegylated interferon alfa (IFNa) in patients with low-risk PV to lessen the burden of phlebotomy, treat aspirin-resistant symptoms, control splenomegaly, and/or enable repletion of iron stores in patients with iron deficiency-related symptoms. Preliminary results from the randomized phase 2 Low-PV study (described below) [15] provide support for this judgment, but we await longer-term outcomes.
Management of patients with low-risk PV includes:
●Hematocrit control – Therapeutic phlebotomy or IFNa is used to manage Hct, as discussed above. (See 'Hematocrit target' above.)
•The phase 2 Low-PV study tested IFNa versus phlebotomy, but the data safety monitoring board stopped patient enrollment after 12 months based on IFNa efficacy and safety [15]. Patients (18 to 60 years) with low-risk PV were randomly assigned to standard therapy (phlebotomy plus low-dose aspirin; 63 patients) versus IFNa plus standard therapy (64 patients). Planned interim analysis reported that IFNa achieved a higher response rate (ie, Hct <45 percent without progressive disease) than standard therapy (84 versus 60 percent); 13 percent of patients treated with only phlebotomy experienced progressive thrombocytosis. IFNa response was accompanied by improvements in platelet and leukocyte counts, splenomegaly, symptoms, and reduced JAK2 V617F allele burden.
During the 24-month study period of Low-PV, treatment-attributed AEs occurred in 55 percent of patients treated with IFNa and in 6 percent in the standard treatment arm [15]. The most frequent grade 3 AE in the IFNa arm was neutropenia (8 percent of patients), while 4 percent of patients in the standard treatment arm experienced grade 3 skin symptoms; there were no grade 4 AEs in either arm. Follow-up of patients in Low-PV will continue for two additional years. We await longer follow-up and assessment of quality of life before routinely implementing IFNa treatment for patients with lower-risk PV.
•A randomized trial [5] and a retrospective analysis [6] that demonstrated the benefit of phlebotomy for reducing thrombotic risk in patients with PV are discussed above. (See 'Hematocrit target' above.)
Therapeutic phlebotomy and treatment with IFNa are discussed below. (See 'Therapeutic phlebotomy' below and 'Pegylated interferon' below.)
●Low-dose aspirin – Aspirin can alleviate symptoms and reduce thrombotic risk in patients with low-risk PV.
Treatment with low-dose aspirin is discussed above. (See 'Low-dose aspirin' above.)
Aspirin should be used with caution in patients with acquired von Willebrand syndrome, as discussed below. (See 'Acquired von Willebrand syndrome' below.)
Management of aspirin-resistant symptoms is discussed below. (See 'Persistent symptoms' below.)
●Symptom control – Low-dose aspirin effectively relieves pruritus and erythromelalgia in many patients with low-risk PV. Adjunctive treatments for symptom control are discussed above. (See 'Symptom control' above.)
●Cardiovascular risk factors – Smoking cessation, blood pressure control, and other approaches for primary prevention of cardiovascular complications are discussed separately. (See "Overview of primary prevention of cardiovascular disease".)
Persistent symptoms — For low-risk patients who tolerate phlebotomy poorly or have uncontrolled PV-associated symptoms, splenomegaly, or other cytoses, we treat with cytoreduction, as described below. (See 'Choice of cytoreductive agent' below.)
HIGH-RISK PV — High-risk PV includes patients >60 years and those with a history of thrombosis.
Initial treatment — Treatment of high-risk PV includes a cytoreductive agent plus low-dose aspirin. Selection of a cytoreductive agent is discussed below. (See 'Choice of cytoreductive agent' below.)
Cytoreduction in patients with high-risk PV has been standard care for decades. No randomized trials have directly compared cytoreduction versus phlebotomy for hematocrit (Hct) control in patients with high-risk PV. Preliminary results from a randomized phase 2 study that compared phlebotomy versus interferon alfa (IFNa) in patients with low-risk PV are discussed above [15], but patients with high-risk PV have greater thrombotic risk and inferior survival. (See 'Initial management' above.)
Agents that are associated with increased leukemogenic and/or carcinogenic potential (eg, chlorambucil, 32P, pipobroman) should be avoided [16-19], except in very limited circumstances. (See 'Older/frail patients' below.)
Initial treatment of patients with high-risk PV involves:
●Phlebotomy – Therapeutic phlebotomy is performed until the Hct is adequately controlled with a cytoreductive agent. Therapeutic phlebotomy is discussed below. (See 'Therapeutic phlebotomy' below.)
●Low-dose aspirin – Aspirin can alleviate symptoms and reduce thrombotic risk, but it should be used with caution in patients with acquired von Willebrand syndrome. (See 'Acquired von Willebrand syndrome' below.)
●Symptom control – Adjunctive treatments for symptom control are discussed above. (See 'Symptom control' above.)
●Cardiovascular risk factors – Control of cardiovascular (CV) risk factors includes smoking cessation, blood pressure control, and other measures. (See 'Reduce cardiovascular risk factors' above.)
●Venous thrombosis – Patients with PV and a prior venous thrombosis should be treated with a cytoreductive agent plus systemic anticoagulation.
Systemic anticoagulation for treatment of venous thrombosis is discussed separately. (See "Venous thromboembolism: Anticoagulation after initial management".)
Choice of cytoreductive agent — The choice of cytoreductive agent is guided by the potential for pregnancy.
No potential for pregnancy — For cytoreductive treatment of high-risk PV in patients with no potential for pregnancy, we suggest low-dose aspirin plus either hydroxyurea or IFNa.
The choice of hydroxyurea versus IFNa is individualized based on route of administration, toxicity, convenience, cost, and personal preference. These agents have similar efficacy for Hct control and symptom relief.
Considerations for selecting a cytoreductive agent include:
●Hydroxyurea is an inexpensive and well-tolerated oral medication. Although some fear potential leukemogenicity with long-term use, there is no evidence that hydroxyurea is associated with an increased risk of leukemia in patients with PV [20] or essential thrombocythemia [21]. (See 'Hydroxyurea' below.)
●Pegylated IFNa, which has largely replaced nonpegylated forms, is associated with mild to moderate adverse effects (AEs), but some favor IFNa because it is associated with molecular remission in a subset of patients, as discussed below. (See 'Pegylated interferon' below.)
Two randomized trials found that hydroxyurea and IFNa achieved similar outcomes in patients with PV.
●A phase 3 trial (MPD-RC 112) reported similar rates of complete response (CR) with hydroxyurea versus pegylated IFNa for patients with PV or essential thrombocythemia (ET), but the trial closed early due to lack of availability of IFNa [22]. The trial accrued 168 patients (87 with PV, 81 patients with ET) among 300 planned enrollments. Among the patients with PV, high-risk features were present in 82 percent, and one-half required phlebotomy within six months prior to enrollment. The primary trial endpoint of MPD-RC 112 was CR, which for patients with PV was defined as Hct <45 percent without phlebotomy, platelet count <400 x 109/L, white blood cell (WBC) count <10 x 109/L, resolution of splenomegaly, and control of disease-related symptoms (microvascular disturbances, headache, and pruritus). Preliminary results of MPD-RC 112 included:
•Patients with PV – IFNa more effectively controlled Hct without phlebotomy at 12 months (65 versus 43 percent).
•Entire enrolled population (PV plus essential thrombocythemia) – There was no difference in CR at 12 months (30 percent with hydroxyurea and 28 percent with polyethylene glycol), 24 months, or 36 months. IFNa more effectively reduced median JAK2 V617F variant allele frequency (VAF), which consistently declined through month 24 with IFNa; JAK2 V617F VAF increased after month 12 for patients treated with hydroxyurea.
•Adverse effects – Complication-free survival did not differ between trial arms, but the number of thrombotic events and disease progression was small. AEs occurred in 28 percent of patients treated with hydroxyurea and in 46 percent with IFNa [22]. Mucositis and anorexia were more common with hydroxyurea, whereas leukopenia, flu-like symptoms, injection site reactions, elevated liver function tests (LFTs), and depression occurred more frequently with IFNa.
●The phase 3 PROUD/CONTINUATION-PV trial reported similar outcomes for patients with PV who were randomly assigned to hydroxyurea versus pegylated IFNa [23]. Among 302 patients in PROUD-PV, 12-month CR rates were similar (21 percent with IFNa and 28 percent with hydroxyurea). Among 171 patients who continued therapy in an extension study (CONTINUATION-PV), control of blood counts without phlebotomy occurred in 56 percent of patients treated with IFNa and in 44 percent for patients treated with hydroxyurea. However, responses in this study did not include symptoms, bone marrow histopathology, or cytogenetics. Reduction and progressive decline of JAK2 V617F VAF was seen with IFNa but not with hydroxyurea. There was no difference in thrombotic events or disease progression. The most common grade ≥3 AEs were elevated LFTs (<10 percent with IFNa) and cytopenias (<10 percent with hydroxyurea). One patient receiving hydroxyurea died with acute leukemia.
Potential for pregnancy — For cytoreduction in patients with the potential to become pregnant, we suggest low-dose aspirin plus IFNa based on efficacy and safety of IFNa in this setting. Hydroxyurea is contraindicated in pregnant patients.
Outcomes with IFNa treatment in patients with high-risk PV are discussed above. (See 'No potential for pregnancy' above.)
Other aspects of PV management in pregnant patients are discussed below. (See 'Pregnancy' below.)
MONITORING — Patients are monitored for control of hematocrit (Hct), symptoms, and treatment complications.
Response assessment — Response to therapy should be monitored by blood counts and periodic clinical evaluation of symptoms. The frequency of monitoring is guided by the patient's clinical status and the nature of treatment.
Treatment failure is defined as the inability of cytoreductive therapy to maintain Hct <45 percent (with or without ongoing phlebotomy) without causing severe cytopenias or inadequate control of PV-associated symptoms.
We do not perform routine bone marrow examinations or measurement of JAK2 V617F allele burden outside of a clinical trial. However, bone marrow examination should be performed if there is an unexpected change in blood counts or other evidence of disease transformation. (See 'Disease progression' below.)
Response criteria that were developed for clinical trials by the European LeukemiaNet and the International Working Group-Myeloproliferative Neoplasms Research and Treatment are applicable to the clinical management of PV, as follows [24,25]:
●Complete response
•Resolution of disease signs and improved symptoms (10-point decrease in the myeloproliferative neoplasms symptom assessment total symptom score [MPN-SAF TSS]) for at least 12 weeks.
•Normalization of peripheral blood counts (white blood cell count ≤10,000/microL, platelets ≤400,000/microL, Hct <45 percent without phlebotomy) for at least 12 weeks.
•Absence of vascular events and disease progression.
•Disappearance of bone marrow histologic abnormalities.
●Partial response – The first three criteria of complete response (CR) are achieved in the absence of bone marrow histologic remission.
●No response – Any response that does not satisfy criteria for PR.
●Progressive disease – Transformation to post-PV myelofibrosis, myelodysplastic neoplasm/syndrome, or acute leukemia.
Follow-up — The frequency of follow-up visits is influenced by the severity of symptoms, disease complications, type of treatment, and concerns of the patient or clinician.
●Low-risk PV – Patients who are treated with low-dose aspirin only may require only annual or semiannual visits.
●High-risk PV – Patients treated with cytoreductive therapy and/or systemic anticoagulation are seen based on the treatment response and stability of blood counts and anticoagulation.
RESISTANCE OR INTOLERANCE TO CYTOREDUCTION — For patients with PV that is refractory to cytoreductive therapy or who are intolerant of initial treatment, we suggest changing the cytoreductive agent.
Response assessment is discussed above. (See 'Response assessment' above.)
The choice of cytoreductive agent is guided by the previous agent:
●Prior hydroxyurea – We suggest interferon alfa (IFNa) to avoid adverse effects associated with other treatment options.
For patients who are transitioning to pegylated IFNa while receiving hydroxyurea, IFNa should be started at 50 mcg subcutaneously once every two weeks (in combination with hydroxyurea). The dose is increased by 50 mcg every two weeks to a maximum of 500 mcg until hematologic parameters are stabilized. The total biweekly dose of hydroxyurea is reduced by 20 to 40 percent every two weeks during weeks 3 to 12 and discontinued by week 13.
IFNa administration is discussed below. (See 'Pegylated interferon' below.)
●Prior interferon alfa – For an inadequate response/intolerance to IFNa, we suggest hydroxyurea unless there is a contraindication, such as pregnancy.
If neither hydroxyurea nor IFNa was effective, tolerated, or cannot be given safely, other options, such as ruxolitinib or busulfan, are discussed below. (See 'Ruxolitinib' below and 'Busulfan' below.)
SPECIFIC CLINICAL SCENARIOS — Management must be tailored for patients with specific complications of PV (eg, thrombosis, leukemic transformation).
Acquired von Willebrand syndrome — Acquired von Willebrand syndrome (aVWS) should be suspected in patients with PV who have bleeding and/or >1000 x 109 platelets/L (>1,000,000/microL).
●Diagnosis – Diagnosis of aVWS is based on ristocetin cofactor activity <30 percent. (See "Acquired von Willebrand syndrome", section on 'Diagnostic evaluation'.)
aVWS is thought to be caused by adsorption of von Willebrand factor to the expanded population of platelets or by increased proteolysis from platelet proteases.
●Management – Aspirin should be used with caution, or not at all, in patients with aVWS.
We consider a single daily treatment of ≤100 mg acceptable in patients with aVWS who have no bleeding history, especially if ristocetin cofactor activity is >20 percent [1].
For patients with low-risk PV who cannot take aspirin, cytoreductive therapy can be used to control vasomotor symptoms and reduce thrombotic risk, as described above. (See 'High-risk PV' above.)
Thrombosis — Thromboembolic events are the major cause of morbidity and mortality in PV. Approximately one-quarter of patients with PV will experience thrombotic complications within 20 years [26].
Prevention of thrombotic complications, maintaining hematocrit (Hct) <45 percent, low-dose aspirin, and/or cytoreductive agents are discussed above. (See 'All patients' above.)
●Venous thrombosis – Patients with PV and venous thrombotic events should be treated with appropriate doses and intensity of anticoagulation, but no randomized studies have examined the optimal duration of anticoagulation in a patient with PV and a first episode of venous thromboembolism [27-29].
General management of venous thromboembolism is discussed separately. (See "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Anticoagulation after initial management".)
●Arterial thrombosis – Patients with PV and acute arterial thrombotic events (eg, cerebrovascular accidents, myocardial infarction, limb ischemia) should be treated as described separately. (See "Initial assessment and management of acute stroke" and "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department".)
Pregnancy — Pregnant patients with PV are at an increased risk for hypertension, thromboses, and other complications of pregnancy. We do not consider pregnancy to be contraindicated in patients with PV.
Hydroxyurea, alkylating agents, and warfarin are contraindicated in pregnant patients because of potential teratogenicity.
●Management – Guided by thrombotic risk (see 'Risk stratification' above):
•Low-risk PV – Management of low-risk PV is based on therapeutic phlebotomy and low-dose aspirin, as discussed above. (See 'Low-risk PV' above.)
Some experts favor a lower target Hct (eg, <42 percent) in pregnant patients because increased plasma volume in the second and third trimesters may mask an elevated red blood cell mass [30]. The European LeukemiaNet suggested a target Hct in the pregnant patient of <45 percent or the normal midgestation Hct range, whichever is lower [31].
•High-risk PV – For pregnant patients with high-risk PV, we suggest low-dose aspirin plus interferon alfa (IFNa) rather than aspirin alone.
Hydroxyurea and alkylating agents are contraindicated in pregnant patients.
●Thrombosis – Pregnant patients with PV are at an increased risk for thromboses.
•Acute thrombosis – Management of venous thromboembolism in a pregnant patient is discussed separately. (See "Venous thromboembolism in pregnancy and postpartum: Treatment".)
•Prophylaxis – A decision to use prophylaxis should be individualized and made jointly with the patient. No published studies have tested the safety and utility of thrombosis prophylaxis in pregnant patients with PV.
-No prior thrombosis – We do not routinely offer prophylaxis to pregnant patients with no prior thrombosis.
-History of thrombosis – For pregnant patients with a history of venous thrombosis, we consider prophylaxis using low molecular weight heparin (LMWH).
Some experts routinely administer LMWH throughout pregnancy and for six weeks after delivery in patients with a prior major thrombotic complication [31-33].
Use of LMWH in pregnant patients is discussed separately. (See "Venous thromboembolism in pregnancy: Prevention".)
There is an increased risk for miscarriages and other complications of pregnancy (eg, abruptio placentae, pre-eclampsia, intrauterine growth retardation) in patients with PV and other myeloproliferative neoplasms [34-36]. However, there are only limited data regarding the occurrence and outcomes of pregnancy in PV patients. A meta-analysis reported that aspirin and IFNa were associated with reduced rates of pregnancy loss in pregnant patients [37].
Disease progression — PV can progress to myelofibrosis (MF), myelodysplastic syndromes/neoplasms (MDS), or acute myeloid leukemia (AML).
●Myelofibrosis – Progression to MF (ie, secondary MF) is one of the most common complications of PV.
Treatment of post-PV secondary MF is discussed separately. (See "Myelofibrosis (MF): Management of primary MF and secondary MF".)
●Myelodysplastic syndromes/neoplasms or acute myeloid leukemia – Prognosis of patients who develop post-PV MDS or AML is generally poor.
Management of secondary MDS and AML are discussed separately. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis" and "Overview of the treatment of myelodysplastic syndromes".)
The best outcomes are seen in patients with complete remission who undergo allogeneic hematopoietic cell transplantation. (See "Overview of the myeloproliferative neoplasms", section on 'Treatment of MPN-associated acute leukemia'.)
Older/frail patients — The risk of thrombosis greatly exceeds the risk of hematologic transformation to MF or AML/MDS in patients of advanced age (eg, >80 years) or limited life expectancy.
In addition to hydroxyurea, the relative ease of treatment with alkylating agents (eg, busulfan, cyclophosphamide) makes them acceptable agents in frail patients or in patients with limited life expectancy (eg, <3 years).
TREATMENTS — Treatments for PV can control symptoms, reduce the risk of thrombotic and cardiovascular (CV) complications, and prolong survival, but they do not prevent hematologic transformation.
Therapeutic phlebotomy — Phlebotomy is the first and fastest method for controlling red blood cell mass in patients with PV.
A standard one-unit phlebotomy (eg, 500 mL) typically reduces the hematocrit (Hct) by three percentage points in an adult. Patients should be encouraged to maintain hydration and avoid vigorous exercise within 24 hours of phlebotomy.
Most males tolerate removal of 1.5 to 2 units per week, whereas some females, older adults, and those with low body mass (eg, <50 kg) or cardiopulmonary disease may only tolerate removal of 0.5 units per week (eg, 7 mL/kg). Since phlebotomy controls polycythemia by producing a state of absolute iron deficiency, iron supplementation should not be given.
The role of therapeutic phlebotomy in patients with secondary polycythemia is discussed below. (See 'Secondary polycythemia' below.)
Hydroxyurea — Hydroxyurea (hydroxycarbamide) is an inexpensive oral agent with a favorable toxicity profile that interferes with deoxyribonucleic acid (DNA) repair by inhibiting ribonucleotide reductase.
Hydroxyurea has been widely adopted as the initial cytoreductive treatment for PV despite a limited base of evidence.
●Administration – Hydroxyurea 500 mg twice daily by mouth is the typical starting dose (table 2).
Dosing should be based on 15 to 20 mg/kg per day, using the patient's actual body weight. The dose should be reduced in the setting of renal impairment, but it does not require adjustment for liver impairment.
The dose of hydroxyurea should be adjusted to achieve a platelet count between 100,000 to 400,000/microL and to limit neutropenia and anemia. Dose adjustments should not be made more than once per week because it generally takes at least three to five days for the effect of hydroxyurea to be seen.
●Toxicity – Adverse effects (AEs) include cytopenias, mucocutaneous ulcers, diarrhea, and peripheral neuropathy. Skin cancer, potential teratogenicity, and rare cases of severe (including fatal) pulmonary toxicity have been reported [38]. Macrocytosis/megaloblastic erythrocytosis is expected because of its mechanism of action.
Hydroxyurea is not associated with an increased risk of leukemic transformation or myelofibrosis (MF) in patients with PV. Studies that addressed potential leukemogenicity of hydroxyurea include:
•Single-agent hydroxyurea was not associated with an increased risk of leukemic transformation (median follow-up of 6.9 years) in a multivariate analysis of 1545 patients with PV [16].
•Estimates of leukemic transformation in patients treated with hydroxyurea have ranged from 1 to 17 percent, with the lower values generally obtained at shorter follow-up times [17,39-47]. However, rates approached 30 percent when hydroxyurea was combined with other agents [47-51].
●Outcomes – Hydroxyurea is associated with a complete response (CR; ie, control of blood counts without phlebotomy) in nearly one-half of patients with PV, based on clinical trials that compared hydroxyurea with interferon alfa (IFNa), as described above. (See 'High-risk PV' above.)
Most data for use of hydroxyurea in PV are extrapolated from randomized trials in essential thrombocythemia (ET), but studies that compared hydroxyurea with other approaches for patients with PV include:
•A population-based study that reported longer survival and fewer thrombotic events in patients with PV who were treated with hydroxyurea compared with no hydroxyurea [6] is discussed above. (See 'Hematocrit target' above.)
•A study by the Polycythemia Vera Study Group reported fewer thrombotic events in 51 patients treated with hydroxyurea (10 percent) compared with 33 percent in 134 historical controls treated with phlebotomy alone [42].
•Two European trials that randomly assigned nearly 600 patients to hydroxyurea versus the alkylating agent, pipobroman, reported no significant difference in thrombotic events but higher rates of leukemic transformation with pipobroman [17,44].
Approximately 10 percent of patients develop resistance to hydroxyurea, based on European LeukemiaNet criteria [24]. Treatment failure is defined above. (See 'Response assessment' above.)
Pegylated interferon — IFNa is a pharmaceutical product obtained from human leukocytes that contains several naturally occurring subtypes of IFN alpha, a naturally occurring biologic response modifier that has antiangiogenic, antiproliferative, proapoptotic, immunomodulatory, and differentiating properties [52,53].
Pegylated IFNa provides a more favorable toxicity profile than conventional IFNa, and its prolonged activity is compatible with once-weekly dosing.
●Administration – Pegylated IFNa 100 mcg is given subcutaneously once every two weeks, and the dose is increased by 50 mcg every two weeks to a maximum of 500 mcg until hematologic parameters are stabilized (ie, Hct <45 percent, platelets <400,000/microL, and leukocytes <10,000/microL).
The two-week dosing interval of pegylated IFNa should be maintained for at least one year. After one year of hematologic stability on a stable dose, the dosing interval can be increased to once every four weeks.
If pegylated IFNa is not available, the usual starting dose of nonpegylated IFNa is 3 million units subcutaneously three times per week.
Administration of pegylated IFNa for patients with an inadequate response or intolerance to hydroxyurea is discussed above. (See 'Resistance or intolerance to cytoreduction' above.)
Pegylated IFNa is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treatment of adults with PV.
●Outcomes – Treatment with pegylated IFNa is associated with CR in at least one-half of patients with PV. A potential advantage of IFNa is its association with molecular responses in PV, but the relevance of molecular remissions to long-term rates of thrombotic events and mortality is currently uncertain [54-57].
Randomized clinical trials that compared AEs and outcomes with IFN versus hydroxyurea for PV are described above. (See 'High-risk PV' above.)
Other studies of IFNa in patients with PV include:
•In a phase 2 study of pegylated IFNa, 35 of 37 evaluable patients achieved CR, and 7 of those 35 patients achieved complete molecular remission (ie, undetectable JAK2 V617F) [54]. Responses were durable, and 35 patients remained in CR at one year. Only three patients stopped treatment during the first year because of side effects.
•In a study of 43 patients with advanced PV, most patients were treated with IFNa 45 to 90 mcg/week [55,58]. With a median follow-up of 42 months, the CR rate was 76 percent, including a 19 percent complete molecular response. Most patients who received these doses had only grade 1 or 2 AEs, but the planned dose of 450 mcg/week was poorly tolerated.
•Treatment with pegylated IFNa in 50 patients with hydroxyurea-refractory PV was associated with a 60 percent overall response (including 22 percent CR) at 12 months [59]. Grade ≥3 toxicity included cytopenias, myalgia/arthralgia, depression, dyspnea, and headache (all of which were reported in <10 percent of patients); 14 percent discontinued therapy for treatment-related AEs.
Management of patients with an inadequate response or intolerance to IFNa is discussed above. (See 'Resistance or intolerance to cytoreduction' above.)
Ruxolitinib — Ruxolitinib is a Janus associated kinase inhibitor (JAKi) that can control PV-associated symptoms, but its long-term effects on PV are uncertain, and it has not been shown to reduce the malignant clone or disease progression.
We generally offer ruxolitinib to patients with PV only for symptomatic splenomegaly or severe pruritus that failed to respond adequately to hydroxyurea and IFNa.
Discontinuation of ruxolitinib can be associated with a relapse of disease-related symptoms and/or clinical findings suggestive of systemic inflammatory response syndrome (eg, fever, hypotension, hypoxia) that may require resumption of ruxolitinib and/or other medical management. (See "Myelofibrosis (MF): Management of primary MF and secondary MF", section on 'Ruxolitinib'.)
●Administration – Ruxolitinib is given orally at doses up to 20 mg twice daily, and dosing is adjusted for efficacy and tolerance.
Dose adjustments are required for impaired renal and hepatic function and for patients taking strong inhibitors of CYP3A4 (table 3).
Ruxolitinib is approved by the FDA for treatment in patients with hydroxyurea-resistant PV or intolerance to hydroxyurea. It is approved by the EMA for post-PV MF.
●Toxicity – Patients should be counseled about the ruxolitinib withdrawal syndrome before starting on therapy.
AEs include cytopenias; dizziness, headache, and fatigue (in approximately 15 percent of patients); bruising; elevated serum cholesterol; and viral, bacterial, mycobacterial, and fungal infections.
●Outcomes – An open-label trial (RESPONSE) evaluated ruxolitinib in 222 patients with PV who were either resistant to (46 percent) or intolerant of hydroxyurea (54 percent) [60,61]. Patients were randomly assigned to receive ruxolitinib 10 mg twice daily or best available therapy (BAT), which included hydroxyurea, IFNa or pegylated IFNa, anagrelide, other therapy, or observation. An important limitation of this trial was the widespread use of hydroxyurea for those assigned to BAT, despite documented resistance or intolerance to this agent. Other concerns include the choice of clinical endpoints (rather than reduction of thrombotic complications and disease transformation) and the open-label design (which might affect subjective measures of symptom assessment).
Compared with BAT, ruxolitinib was more effective for reducing the number of patients who needed phlebotomy (20 versus 62 percent, respectively), patients who required ≥2 phlebotomy sessions (7 versus 34 percent), thromboembolic events in the first 32 weeks (one versus six events), controlling PV-related symptoms (ie, fatigue, itching, night sweats; 49 versus 5 percent), and reducing spleen size (38 versus 1 percent) [60]. In a preplanned analysis of outcomes after all patients completed 80 weeks of therapy or discontinued treatment, most patients assigned to ruxolitinib remained on therapy (83 percent), while 88 percent on BAT crossed over to ruxolitinib. Ruxolitinib adequately and durably controlled Hct in 89 percent of patients. Ruxolitinib was associated with an increased rate of herpes zoster infection (5.3 per 100 patient-years of exposure versus none) and nonmelanoma skin cancer (4.4 versus 2.7 cases per 100 patient-years of exposure) [61]. Estimated rates of long-term PV-associated complications did not appear to be increased, but the number of events was small.
Ruxolitinib for treatment of MF is discussed separately. (See "Myelofibrosis (MF): Management of primary MF and secondary MF", section on 'Ruxolitinib'.)
Busulfan — Busulfan is an alkylating agent that can be used as a second-line agent for treatment of older patients (eg, ≥60 years) who were intolerant of or did not respond adequately to hydroxyurea and IFNa.
Busulfan was widely used to treat PV for decades, but it fell out of favor because of long-lasting cytopenias, marrow aplasia, skin pigmentation, pulmonary fibrosis, and/or leukemia [20].
●Administration – We begin treatment with busulfan 2 to 4 mg/day by mouth.
Dose adjustment can be made based on weekly monitoring of complete blood counts [62]:
•For <200,000 platelets/microL or white blood cell (WBC) count <5000/microL, the dose should be reduced to 2 mg/day.
•For <100,000 platelets/microL or <3000 WBC/microL, the dose is temporarily withheld.
●Toxicity – Busulfan can cause persistent cytopenias and skin pigmentation.
●Outcomes – Busulfan appears to be leukemogenic only when used in combination with other agents and not when used alone [16]. Long-lasting cytopenias may be lessened by use of lower doses given for shorter periods of time.
Other agents — Other agents have limited roles for treatment of PV.
●Pipobroman – Pipobroman is an alkylating agent that is available in Europe. In a French study, 292 patients with PV under the age of 65 were randomly assigned to treatment with hydroxyurea or pipobroman [44]. At a median follow-up of 16.3 years, treatment with pipobroman resulted in a shorter median survival (15 versus 20 years) and a doubling of the incidence of transformation to acute myeloid leukemia/myelodysplastic syndromes/neoplasms [17].
●Anagrelide – Anagrelide is approved for use in ET, where it can reduce the platelet count. It is not suggested for treatment of PV because it has been associated with an increased risk of arterial thrombosis, major bleeding, and fibrotic progression [63]. (See "Essential thrombocythemia: Treatment and prognosis", section on 'Anagrelide'.)
PROGNOSIS — Older age, control of hematocrit (Hct), leukocytosis, and thrombosis are important prognostic factors for outcomes in patients with PV.
●Survival – Median overall survival (OS) is at least 13 years in patients who receive treatment for PV, but this is lower than the age- and sex-matched normal population [16,39,64,65].
•A prospective study of 1638 patients reported that the overall mortality rate was 3.7 deaths per 100 persons/year [40]. Cardiovascular (CV) mortality, solid tumors, and hematologic transformation accounted for 45, 20, and 13 percent of the deaths, respectively.
•A study of 226 patients reported that treatment of PV is associated with 10-year projected rates for survival, leukemic transformation, and fibrotic progression of >75 percent, <5 percent, and <10 percent, respectively [66].
Adverse risk factors for survival of patients with PV include age ≥65 years, leukocytosis, thrombosis at diagnosis, and abnormal karyotype:
•Registry data from 327 patients with PV reported the median age at death was 81 years [67]. Causes of death included thrombotic events (21 percent), secondary acute myeloid leukemia (AML; 17 percent), solid tumors (17 percent), and chronic heart failure (15 percent). Patients <65 years at diagnosis had a 17.5-year median OS compared with 6.5 years for patients ≥65 years. Survival rates after 5, 10, and 20 years of PV were 93, 72, and 46 percent, respectively. Age >70 years, white blood cell (WBC) count >13,000 cells/microL (>13 x 109/L), and thrombosis at diagnosis were predictors of inferior survival in a multivariate analysis. With a median follow-up of 11 years, OS in patients with none, one, or two to three of these risk factors at diagnosis was 84, 59, and 26 percent.
•A prospective study of 1638 patients reported that the overall mortality rate was 3.7 deaths per 100 persons/year [40]. CV mortality, solid tumors, and hematologic transformation accounted for 45, 20, and 13 percent of the deaths, respectively.
•A study of 226 patients reported that treatment of PV was associated with 10-year projected rates for OS, leukemic transformation, and fibrotic progression of >75, <5, and <10 percent, respectively [66].
•Age ≥60 years, ≥15,000 WBC/microL, and arterial thrombosis at diagnosis were independent predictors of inferior survival in multivariate analysis in a study of 459 patients with PV [68].
•Abnormal karyotype (eg, +9, +8, 20q-), which is seen in approximately 20 percent of patients with PV, is associated with inferior survival [69,70].
●Thrombosis – Thromboembolic events are the major cause of morbidity and mortality in PV.
Older age and prior thrombosis are strong predictors of thromboembolic risk in patients with PV; leukocytosis and thrombocytosis are less conclusively associated with vascular events in PV. Reduced thrombotic risk is associated with maintaining Hct <45 percent, as discussed above. (See 'Hematocrit target' above.)
•Age ≥65 years and previous thrombosis were powerful predictors of recurrent thrombosis and CV events in large studies of patients with PV [40,64]. The annual incidence of thrombosis in PV ranged from 1.8 percent in patients <40 years of age to 5.1 percent in those >70 years [64]. For perspective, the 5.1 percent risk in older patients is similar to the annual stroke risk of a 75-year-old person with atrial fibrillation and a prior thromboembolic event (5.3 percent) or to the annual CV risk of a 75-year-old smoker with hypertension and diabetes (5.6 percent).
•JAK2 V617F allele burden has been variably associated with an increased thrombotic risk [71,72].
•Some studies reported that leukocytosis is associated with vascular events in PV [68,73-75]. One study reported that the frequency of vascular occlusive episodes was 1.5 times higher in patients with a platelet count >400,000/microL, although neither the degree of thrombocytosis nor the presence of platelet function abnormalities has been consistently correlated with thrombotic risk [41,76,77].
Other risk factors for arterial thrombosis include hypertension, hyperlipidemia, and diabetes [78-80].
Thrombocytosis, per se, has not been correlated with an increased risk of thrombosis in PV [16,81]. Major hemorrhage has also been associated with an increased risk for venous thrombosis [79].
●Disease progression – A major cause of death in PV is disease transformation to post-PV myelofibrosis (MF) and/or evolution to AML/myelodysplastic syndromes/neoplasms (MDS).
A large prospective study reported that the rate of such hematologic complications was 1.3 episodes per 100 patient-years (21 cases of AML, 1 case of myelodysplasia, and 38 cases of MF among 1638 patients) [40].
•Secondary myelofibrosis – Post-PV MF occurs in 12 to 21 percent of patients with PV [39].
Median survival was 5.7 years among 68 patients who developed post-PV MF [82]. In a multivariate analysis, adverse risk factors for survival after the onset of post-PV secondary MF included hemoglobin <10 g/dL, >30,000 WBC/microL, and <100,000 platelets/microL. For patients with none, one, two, or all three adverse risk factors during their disease course, median survivals were >108, 51, 15, and 3 months, respectively.
The Dynamic International Prognostic Scoring System (DIPSS) and DIPSS Plus for primary myelofibrosis (table 4) may be useful for defining prognosis in secondary MF [83]. Risk factors that are associated with an increased risk for progression to MF include disease duration, age, and WBC count [40,68,82].
Other factors that have been reported to be associated with a higher risk for development of post-PV secondary MF include homozygosity for the JAK2 V617F, elevated serum lactate dehydrogenase, and grade ≥2 bone marrow fibrosis at presentation [71,84-89].
•Acute myeloid leukemia or myelodysplastic syndromes/neoplasms – Transformation to AML or MDS is a major cause of death in PV.
-Incidence and onset – In a large international study, 7 percent of patients with PV developed AML or MDS within 20 years [39]. Secondary AML developed in 3.2 percent of 1545 patients with PV after a median of 10.8 years from diagnosis. The cumulative risks of secondary AML were 2.3, 5.5, and 7.9 percent at 10, 15, and 20 years, respectively (figure 1) [16].
-Risk factors – Older age and treatment with cytoreductive agents other than hydroxyurea and interferon were associated with an increased risk of secondary myeloid malignancies [20,40]. The relative risk (RR) for age >70 years was 4.3 to 5, and the RR for treatments other than hydroxyurea and interferon was 5.5 to 11.
In one study, the incidence of secondary leukemia was related to the type of treatments for PV [68]. The risk was 2.4 percent in patients treated with no cytoreductive therapy, interferon, or anagrelide; 4 percent in those treated with hydroxyurea; 12 percent with another cytotoxic single agent; and 17 percent with ≥2 cytotoxic agents [68].
Another study reported the hazard ratio (HR) for post-PV secondary leukemia compared with single-agent hydroxyurea or busulfan as pipobroman only (HR 3.9), pipobroman plus either hydroxyurea or busulfan (HR 4.1), and 32P or chlorambucil (HR 4.8) [16].
Prognosis for post-PV secondary AML is grim [90-92]. In a study of 74 cases, the median OS was five months from the time of blastic transformation [92]. Complete remissions were noted in approximately one-half of the patients treated with induction chemotherapy, but remissions were not durable, and the median progression-free survival was five months. Long-term survival was seen only in patients who received allogeneic hematopoietic cell transplantation as initial therapy or during first remission.
SECONDARY POLYCYTHEMIA — Secondary polycythemia refers to an increase of red blood cell (RBC) mass caused by elevated serum erythropoietin (EPO; eg, hypoxia, renal artery stenosis, certain tumors), rare inherited conditions, and other causes (table 1).
●Diagnosis – Evaluation and diagnosis of secondary polycythemia are discussed separately. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia", section on 'Secondary polycythemia'.)
●Management – For patients with secondary polycythemia, the focus of management is amelioration of the underlying cause and contributing factors to alleviate symptoms and reduce the risk of thrombosis [93].
For patients who remain symptomatic, we empirically employ cautious phlebotomy (without a specified hematocrit [Hct] target) rather than cytoreduction.
•Lessen contributing factors – Remediable causes of secondary polycythemia should be addressed whenever possible.
Examples include improving oxygenation in patients with pulmonary or heart disease, providing continuous positive airway pressure for obstructive sleep apnea, correcting renal artery stenosis, removing EPO-producing tumors, considering angiotensin converting enzyme inhibitors for postrenal transplant syndrome, and re-evaluating the need for drugs that may be causing erythrocytosis.
All patients with secondary polycythemia should be encouraged to discontinue smoking.
•Symptom relief – For patients with symptomatic secondary polycythemia, we suggest empiric, cautious therapeutic phlebotomy rather than cytoreductive therapy.
There is no specific target Hct for patients with secondary polycythemia. Rather, cautious phlebotomy (eg, removal of 250 mL blood, replaced by an equal volume of crystalloid) may be evaluated for symptom relief; however, reduction to Hct <55 percent is likely to exacerbate dyspnea or other hypoxic symptoms.
Therapeutic phlebotomy is discussed above. (See 'Therapeutic phlebotomy' above.)
•Thrombosis prophylaxis – There is no persuasive evidence that prophylactic phlebotomy or cytoreduction reduces the risk of thrombosis in patients with secondary polycythemia.
We offer once-daily low-dose aspirin to patients with cardiovascular risk factors, twice-daily low-dose aspirin for patients with a history of arterial thrombosis, and systemic anticoagulation for those with a history of venous thromboembolism. (See 'Low-dose aspirin' above.)
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 5th to 6th 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 10th to 12th 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 AND RECOMMENDATIONS
●Description – Polycythemia vera (PV) is a BCR::ABL1-negative myeloproliferative neoplasm characterized by an increased red blood cell (RBC) mass and increased risk for thrombosis, leukemic transformation, and/or myelofibrosis (MF). (See 'Overview of polycythemia vera' above.)
Secondary polycythemia is an increase of RBC mass caused by hypoxia, elevated serum erythropoietin, and other causes (table 1). (See 'Secondary polycythemia' above.)
●Pretreatment evaluation – Evaluate vasomotor symptoms, thrombosis, splenomegaly, cardiovascular risk factors, and blood counts.
For patients with bleeding or platelets >1000 x 109/L (1,000,000/microL), test for acquired von Willebrand syndrome (aVWS). (See 'Acquired von Willebrand syndrome' above.)
●Risk stratification – Risk is based on age >60 years and/or prior thrombosis. (See 'Risk stratification' above.)
●Management
•All patients – All patients with PV require the following (see 'All patients' above):
-Hematocrit control – For nonpregnant patients, we recommend maintaining hematocrit (Hct) <45 percent rather than higher targets (Grade 1B). Some experts suggest a Hct target of <42 percent in females, which is acceptable if it more effectively controls symptoms that persist at 45 percent. (See 'Hematocrit target' above.)
-Low-dose aspirin – We suggest low-dose aspirin (Grade 2C), to alleviate vasomotor symptoms and reduce thrombosis risk. Aspirin may be taken either twice daily or once daily, but we limit the total daily dose to ≤100 mg. (See 'Low-dose aspirin' above.)
Aspirin should be used with caution in patients with aVWS and bleeding. (See 'Acquired von Willebrand syndrome' above.)
-Symptom control – Adjunctive treatments for pruritus and erythromelalgia are discussed above. (See 'Symptom control' above.)
-Reduce cardiovascular risk factors – Stop smoking and control blood pressure, weight, and cholesterol/lipids.
•Low-risk PV – For low-risk PV, we suggest low-dose aspirin plus periodic phlebotomy to control Hct rather than cytoreductive therapy (Grade 2C). (See 'Low-risk PV' above.)
•High-risk PV – Choice of treatment is based on:
-No potential for pregnancy – We suggest low-dose aspirin plus either hydroxyurea or interferon alfa (IFNa) for cytoreduction rather than aspirin alone (Grade 2C). (See 'No potential for pregnancy' above.)
-Potential for pregnancy – We suggest low-dose aspirin plus IFNa rather than aspirin alone (Grade 2C). Hydroxyurea is contraindicated in pregnancy. (See 'Potential for pregnancy' above.)
●Response assessment – Based on symptoms, blood counts, vascular events, and disease progression; histologic and molecular responses are not routinely required. (See 'Response assessment' above.)
●Resistance/intolerance. (See 'Resistance or intolerance to cytoreduction' above.)
•For resistance/intolerance to hydroxyurea, we suggest IFNa (Grade 2C).
•For resistance/intolerance to IFNa, we suggest hydroxyurea (Grade 2C).
•Alternative treatments for patients with resistance/intolerance to both hydroxyurea and IFNa are described above. (See 'Treatments' above.)
●Pregnancy – Management is guided by thrombotic risk (see 'Pregnancy' above):
•Low risk – We suggest treatment with phlebotomy and aspirin rather than IFNa and aspirin (Grade 2C). A target of Hct <42 percent may be appropriate in pregnant patients because increased plasma volume in the second and third trimesters may mask an increased RBC mass. (See 'Low-risk PV' above.)
•High risk – We suggest low-dose aspirin plus IFNa rather than aspirin alone (Grade 2C).
●Secondary polycythemia – For secondary polycythemia, we seek to ameliorate the underlying cause and contributing factors. (See 'Secondary polycythemia' 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.
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