Polycythemia vera is a chronic myeloproliferative neoplasm characterized by an increase in morphologically normal red cells (its hallmark), but also white cells and platelets. There is a risk of progression to myelofibrosis or acute myeloid leukemia. Untreated, there is an increased risk of bleeding and arterial or venous thrombosis. Common manifestations include splenomegaly, macrovascular and microvascular events (eg, transient ischemic attacks, erythromelalgia, ocular migraine), and aquagenic pruritus (itching triggered by exposure to hot water). Diagnosis is made by complete blood count, testing for JAK2 or rarely CALR mutations, and clinical criteria. Treatment involves phlebotomy, low-dose aspirin, ruxolitinib, interferon, and rarely stem cell transplantation.mutations, and clinical criteria. Treatment involves phlebotomy, low-dose aspirin, ruxolitinib, interferon, and rarely stem cell transplantation.
(See also Overview of Myeloproliferative Neoplasms.)
Polycythemia vera is the most common of the myeloproliferative neoplasms; its incidence in the United States is estimated to be 1.97/100,000 (1), with incidence increasing with age. The mean age at diagnosis is approximately 60 years, but it occurs much earlier in women, who may present in their second and third decades, often with the Budd-Chiari syndrome.
Approximately 10 to 15% of patients eventually develop myelofibrosis and bone marrow failure (2). Acute leukemia occurs spontaneously in approximately 1.5 to 7% of patients (3).
General references
1. Shallis RM, Wang R, Davidoff A, et al. Epidemiology of the classical myeloproliferative neoplasms: The four corners of an expansive and complex map. Blood Reviews. 2020;42:100706. doi.org/10.1016/j.blre.2020.100706
2. Tremblay D, Kremyanskaya M, Mascarenhas J, et al. Diagnosis and Treatment of Polycythemia Vera: A Review. JAMA. 2025;333(2):153-160. doi:10.1001/jama.2024.20377
3. Spivak JL. Myeloproliferative Neoplasms. N Engl J Med. 2017;376(22):2168-2181. doi:10.1056/NEJMra1406186
Pathophysiology of Polycythemia Vera
Polycythemia vera is a panmyelosis, which is a condition characterized by increased production of all 3 peripheral blood components (red blood cells [RBCs], white blood cells [WBCs], and platelets). Increased production confined to the RBC line is termed erythrocytosis. Isolated erythrocytosis may occur with polycythemia vera but is more commonly due to other causes (see secondary erythrocytosis). In polycythemia vera, RBC production proceeds independently of the serum erythropoietin level, which is usually low but can be normal. However, because the thrombopoietin receptor is the only growth factor receptor in hematopoietic stem cells, thrombocytosis can occur before erythrocytosis.
Extramedullary hematopoiesis may occur in the spleen, liver, and other sites that support blood cell formation. In polycythemia vera, in contrast to secondary erythrocytosis, the red cell mass increase is often initially masked by an increase in the plasma volume that leaves the hematocrit in the normal range. This is particularly the case in women, who can present with hepatic vein thrombosis and a normal hematocrit.
In polycythemia vera, iron absorption is increased due to suppression of hepcidin production. In the presence of iron deficiency of any kind,red blood cells become increasingly smaller (microcytosis) because the red cell hemoglobin concentration (MCHC) is defended at the expense of red cell volume (mean corpuscular volume [MCV]). Thus, microcytic erythrocytosis is a hallmark of patients with polycythemia vera. Importantly, the hemoglobin level is a less accurate measurement of erythropoiesis than the red cell count or the hematocrit. Bone marrow iron stores can be misleading since the bulk of the iron in the body is in the red cell mass.
Eventually, approximately 10 to 15% of patients progress to a syndrome similar to primary myelofibrosis but with better survival in the absence of anemia.
Transformation to acute leukemia is rare and may take many years to develop. The risk of transformation is increased with exposure to alkylating agents, such as chlorambucil and busulfan, radioactive phosphorus (mostly of historic significance), and hydroxyurea. Acute leukemia is more common in men, particularly after age 60.is rare and may take many years to develop. The risk of transformation is increased with exposure to alkylating agents, such as chlorambucil and busulfan, radioactive phosphorus (mostly of historic significance), and hydroxyurea. Acute leukemia is more common in men, particularly after age 60.
Genetic basis
Polycythemia vera is caused by a mutation in a hematopoietic stem cell.
Mutations in the Janus kinase 2 (JAK2) gene are responsible in most cases of polycythemia vera. JAK2 is a member of the class I type of tyrosine kinase family of enzymes and is involved in signal transduction for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor (G-CSF) receptors. Specifically, the JAK2V617F exon14 mutation is present in 90% of patients, and the JAK2 exon12 mutations are present in 5% of patients with polycythemia vera. Calreticulin (CALR) mutations have been found rarely in patients with polycythemia vera who lack a JAK2 mutation, and lymphocytic adaptor protein (LNK) mutations have been found in patients with isolated erythrocytosis. These mutations lead to sustained activation of JAK2 kinase, which causes excess blood cell production independent of erythropoietin.
Complications
Complications of polycythemia vera include:
Thrombosis
Bleeding
In polycythemia vera, the blood volume expands, and the increased number of RBCs can cause hyperviscosity. Hyperviscosity predisposes to macrovascular thrombosis, resulting in stroke, deep venous thrombosis, myocardial infarction, retinal artery or retinal vein occlusion, splenic infarction (often with a friction rub), or, particularly in women, the Budd-Chiari syndrome. Microvascular events (eg, transient ischemic attack, erythromelalgia, ocular migraine) also may occur.
Platelets may function abnormally if the platelet count is > 1,000,000 platelets/mcL (> 1000 × 109/L) due to acquired deficiency of von Willebrand factor because the platelets adsorb and proteolyze high molecular weight von Willebrand multimers. This acquired von Willebrand disease predisposes to increased, but not spontaneous, bleeding.
Increased cell turnover may cause hyperuricemia, increasing the risk of gout and urate kidney stones. Patients with polycythemia vera are prone to acid peptic disease due to Helicobacter pylori infection.
Symptoms and Signs of Polycythemia Vera
Polycythemia vera itself is often asymptomatic, but eventually the increased red cell volume and viscosity cause weakness, headache, light-headedness, visual disturbances, fatigue, and dyspnea. Pruritus often occurs, particularly after a hot bath or shower (aquagenic pruritus) and may be the earliest symptom. The face may be plethoric and the retinal veins engorged. The palms and feet may be red, warm, and painful, sometimes with digital ischemia (erythromelalgia). Over 30% of patients have splenomegaly.
Thrombosis may cause symptoms in the affected site (eg, neurologic deficits with stroke or transient ischemic attack; leg pain, swelling, or both with lower extremity thrombosis; unilateral vision loss with retinal vascular occlusion).
Bleeding, typically from the gastrointestinal tract, occurs in approximately 10% of patients.
Hypermetabolism can cause low-grade fevers and weight loss. Hypermetabolism and splenomegaly suggest progression to secondary myelofibrosis, which is clinically indistinguishable from primary myelofibrosis but has a better prognosis.
Diagnosis of Polycythemia Vera
Complete blood count (CBC) and blood smear analysis
Sequential testing for JAK2 mutations, CALR mutations, or LNK mutations
Red blood cell (RBC) mass determination, if available
Polycythemia vera is often first suspected because of an abnormal CBC (eg, hemoglobin > 16.5 g/dL [> 165 g/L] in men or >16.0 g/dL [> 160 g/L] in women). However, hemoglobin and hematocrit levels may be misleading. The hematocrit may be normal because of plasma volume expansion, and the hemoglobin may be normal if there is concurrent iron deficiency. Thus, an elevated red cell count is the most useful measure of erythrocytosis (see figure Algorithm for the Diagnosis of Erythrocytosis).
Algorithm for the Diagnosis of Erythrocytosis
* Some patients with obstructive sleep apnea will have normal oxygen saturation when seen in the office. † A homozygous mutation in the EGLN1 gene leads to Chuvash polycythemia. ‡ EGLN1 is a protein encoded by the EPAS1 gene. § EPAS1 (also known as hypoxia-inducible factor-2alpha [HIF-2alpha]) is a protein encoded by the gene. EGLN1 = egl-9 family hypoxia inducible factor 1; EPAS1 = endothelial PAS domain-containing protein 1; VHL = von Hippel-Lindau. Data from Spivak JL, Silver RT. The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: an alternative proposal. Blood. 2008;112(2):231-239. doi:10.1182/blood-2007-12-128454 |
Along with erythrocytosis, the neutrophil and platelet counts are usually, but not invariably, increased. Polycythemia vera can present with thrombocytosis alone due to masked erythrocytosis or because thrombocytosis occurs before erythrocytosis.
In patients with only an elevated hematocrit, polycythemia vera may be present, but secondary erythrocytosis, a much more common cause of elevated hematocrit, must be considered first. Polycythemia vera should always be considered in patients with a normal hematocrit but microcytic erythrocytosis; this combination of findings is a hallmark of polycythemia vera.
Polycythemia vera may also be suspected based on clinical findings, including thrombosis in an unusual site, such as Budd-Chiari syndrome in women or portal vein thrombosis in men.
The challenge in diagnosing polycythemia vera is that several other myeloproliferative neoplasms can have the same genetic mutations and bone marrow findings. Although the hallmark of polycythemia vera is erythrocytosis, some patients present with isolated leukocytosis or isolated thrombocytosis and do not initially manifest an elevated hematocrit level. Myeloproliferative neoplasms can evolve over time and even primary myelofibrosis can transform into polycythemia vera.
Patients suspected of having polycythemia vera should have testing for JAK2V617Fexon 14 and JAK2 exon12 mutations. If these results are negative, testing for CALR and LNK mutations is performed. The presence of a known causative mutation in a patient with isolated erythrocytosis is strongly suggestive of polycythemia vera. If erythrocytosis is not clearly present, direct measurement of red cell mass and plasma volume is performed (eg, with chromium-labeled RBCs and 131-labeled albumin, although this test is usually available only at specialized centers) to help differentiate between true and relative polycythemia and between polycythemia vera and other myeloproliferative disorders (which do not have an increased red cell mass). If erythrocytosis is present but secondary causes have not been excluded, serum erythropoietin level should be measured. Patients with polycythemia vera typically have low or low-normal serum erythropoietin levels; elevated levels suggest secondary erythrocytosis.
Bone marrow aspirate and biopsy are not diagnostic of polycythemia vera. When performed, bone marrow aspirate and biopsy typically shows panmyelosis, large and clumped megakaryocytes, and sometimes an increase in reticulin fibers. However, no bone marrow findings absolutely differentiate polycythemia vera from other disorders of excessive erythrocytosis (eg, congenital familial polycythemia) or from other myeloproliferative neoplasms, of which polycythemia vera is the most common.
Acquired von Willebrand disease (as a cause of bleeding) may be diagnosed by showing decreased plasma von Willebrand factor antigen using the ristocetin cofactor assay.
Nonspecific laboratory abnormalities that may occur in polycythemia vera due to increased production of transcobalamin include elevated vitamin B12 and B12-binding capacity, hyperuricemia and hyperuricosuria (present in ≥ 30% of patients), and decreased expression of MPL (the receptor for thrombopoietin) in megakaryocytes and platelets. These tests are not needed for diagnosis.
Treatment of Polycythemia Vera
Phlebotomy
Possibly aspirin therapy
Possibly targeted therapy with ruxolitinib or peginterferonPossibly targeted therapy with ruxolitinib or peginterferon
Therapy must be individualized according to age, sex, medical status, clinical manifestations, and hematologic findings (1). However, previous criteria used to stratify treatment by high- or low-risk classification such as age and extreme thrombocytosis (1,000,000 platelets/mcL [1000 × 109/L]) have not been prospectively validated and are not recommended to guide therapy. The quantitative JAK2 V617F mutation allele burden is a useful indicator. Generally, when this allele burden is less than 50%, patients tend to have an indolent disease.
Although very high leukocyte counts (> 30,000/mcL [> 30 × 109/L]) have been correlated with disease acceleration, there is no evidence that lowering the leukocyte count with chemotherapy prolongs survival. In fact, the polycythemia vera hematopoietic stem cell is resistant to conventional chemotherapy, and lowering the leukocyte or platelet count to normal does not prevent thrombosis if the red cell mass is not normalized by phlebotomy.
Phlebotomy
Phlebotomy is the mainstay of therapy. The targets for phlebotomy are a hematocrit < 45% in men and < 42% in women. A randomized trial showed that patients randomized to a hematocrit < 45% had a significantly lower rate of cardiovascular death and thrombosis than did those with a target hematocrit of 45 to 50% (2). In pregnancy, the hematocrit level should be lowered to < 35%; the fetus will always get sufficient iron.
Initially, 500 mL of blood is removed every other day. Less blood is removed (ie, 200 to 300 mL twice a week) from older patients and from patients with cardiac or cerebrovascular disorders. Once the hematocrit is below the target value, it is checked monthly and maintained at this level by additional phlebotomies as needed. If necessary, intravascular volume can be maintained with crystalloid or colloid solution.
Platelets may increase as a result of phlebotomy, but this increase is small and transient, and a gradual increase in the platelet count as well as the leukocyte count is a feature of polycythemia vera and requires no therapy in patients without symptoms.
In patients treated only with phlebotomy, the phlebotomy requirement will eventually diminish. This is not a sign of marrow failure (ie, the so-called spent phase) but rather is due to an expansion of plasma volume.
Hepcidin mimetics such as rusfertide are being studied (3). These agents are used to prevent iron absorption, which is increased in polycythemia vera. They may obviate the need for additional phlebotomy once body iron stores are depleted by phlebotomy. Results from the VERIFY trial have shown that rusfertide reduces the number of required phlebotomies with better hematocrit control and some improvement in symptoms compared to other therapies (4).
Aspirin
Aspirin alleviates symptoms of microvascular events. Thus, patients who have erythromelalgia, ocular migraine, or transient ischemic attacks should be given Aspirin alleviates symptoms of microvascular events. Thus, patients who have erythromelalgia, ocular migraine, or transient ischemic attacks should be givenaspirin 81 to 100 mg orally once a day unless contraindicated (eg, because of acquired von Willebrand disease); higher doses may be required but clearly increase the risk of hemorrhage. Aspirin does not reduce the incidence of macrovascular events and thus is not indicated in patients with polycythemia vera (in the absence of other indications) who do not have symptoms.
Myelosuppressive therapy
Numerous studies have shown that many previously used myelosuppressive treatments, including hydroxyurea, radioactive phosphorus, and alkylating agents such as busulfan and chlorambucil, do not reduce incidence of thrombosis and fail to improve survival over appropriate phlebotomy because the affected hematopoietic stem cell is resistant to them. Agents such as Numerous studies have shown that many previously used myelosuppressive treatments, including hydroxyurea, radioactive phosphorus, and alkylating agents such as busulfan and chlorambucil, do not reduce incidence of thrombosis and fail to improve survival over appropriate phlebotomy because the affected hematopoietic stem cell is resistant to them. Agents such aschlorambucil, busulfan, radioactive phosphorus, and hydroxyurea can increase the incidence of acute leukemia and solid tumors; these agents are not recommended except in special circumstances in which aspirin and phlebotomy are inadequate and when agents such as interferons are contraindicated. can increase the incidence of acute leukemia and solid tumors; these agents are not recommended except in special circumstances in which aspirin and phlebotomy are inadequate and when agents such as interferons are contraindicated.Hydroxyurea should be prescribed only by specialists familiar with its use and monitoring.
If intervention other than phlebotomy is necessary (eg, because of symptoms or thrombotic events), peginterferon or ruxolitinib is preferred. Anagrelide has been used to control the platelet count but has both cardiac and renal toxicity and can cause anemia. If intervention other than phlebotomy is necessary (eg, because of symptoms or thrombotic events), peginterferon or ruxolitinib is preferred. Anagrelide has been used to control the platelet count but has both cardiac and renal toxicity and can cause anemia.
In polycythemia vera, peginterferon alfa-2b, peginterferon alfa-2a, and ropeginterferon alfa-2bpeginterferon alfa-2b, peginterferon alfa-2a, and ropeginterferon alfa-2b (5) specifically target the affected hematopoietic stem cells but not normal stem cells. These medications are usually well tolerated and are effective in controlling pruritus and excessive blood production as well as in reducing spleen size. Ropeginterferon alfa-2b need only be given every 2 to 4 weeks, much less frequently than other interferon alpha products (eg, every other day). Interferons may be safely used in pregnancy. Approximately 20% of patients achieve a complete molecular remission, which can take several years to achieve.
RuxolitinibRuxolitinib, a nonspecific JAK inhibitor, is used in polycythemia vera and in post-polycythemia vera myelofibrosis. In polycythemia vera, it is usually given starting at 10 mg orally twice a day and continued as long as response is occurring without undue toxicity. In patients intolerant to or resistant to hydroxyurea, , a nonspecific JAK inhibitor, is used in polycythemia vera and in post-polycythemia vera myelofibrosis. In polycythemia vera, it is usually given starting at 10 mg orally twice a day and continued as long as response is occurring without undue toxicity. In patients intolerant to or resistant to hydroxyurea,ruxolitinib has demonstrated better molecular response as well as superior complete remission and event-free survival rates as compared with best supportive care (6).
It is not necessary to lower the white blood cell or platelet count to normal in patients without symptoms.
Treatment of complications
Hyperuricemia should be treated with allopurinol 300 mg orally once a day if it causes symptoms or if patients are receiving simultaneous myelosuppressive therapy. should be treated with allopurinol 300 mg orally once a day if it causes symptoms or if patients are receiving simultaneous myelosuppressive therapy.
Pruritus may be managed with antihistamines but is often difficult to control; ruxolitinib and interferon are effective. Cholestyramine, cyproheptadine, cimetidine, paroxetine, or PUVA light therapy may also be successful. After bathing, the skin should be dried gently. Avoidance of triggering itching is important. may be managed with antihistamines but is often difficult to control; ruxolitinib and interferon are effective. Cholestyramine, cyproheptadine, cimetidine, paroxetine, or PUVA light therapy may also be successful. After bathing, the skin should be dried gently. Avoidance of triggering itching is important.
Thrombosis: Routine antithrombotic prophylaxis is not usually indicated, and after occurrence of a thrombotic event, standard of care anti-thrombotic agents are utilized.
Treatment references
1. Spivak JL. How I treat polycythemia vera. Blood. 2019;134(4):341–352. doi:10.1182/blood.2018834044
2. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368:22–33. doi:10.1056/NEJMoa1208500
3. Kremyanskaya M, Kuykendall AT, Pemmaraju, N, et al. Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera. N Engl J Med. 2024;390(8):723-735. doi: 10.1056/NEJMoa2308809
4. Kuykendall AT, Pemmaraju N, Petit KM, et al. Results from VERIFY, a phase 3, double-blind, placebo (PBO)-controlled study of rusfertide for treatment of polycythemia vera (PV). [2025 ASCO Annual Meeting II abstract]. J Clin Onc. 2025;43(17) suppl. doi:10.1200/JCO.2025.43.17_suppl.LBA
5. Gisslinger H, Klade C, Georgiev P, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study [published correction appears in Lancet Haematol. 2020 Apr;7(4):e279. doi: 10.1016/S2352-3026(20)30069-7.]. Lancet Haematol. 2020;7(3):e196-e208. doi:10.1016/S2352-3026(19)30236-4
6. Harrison CN, Nangalia J, Boucher R, et al. Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial. J Clin Oncol. 2023; 41(19):3534–3544. doi:10.1200/JCO.22.01935
Prognosis for Polycythemia Vera
The availability of newer treatment modalities has improved the prognosis of polycythemia vera over time (1, 2).
Thrombosis is the most common cause of morbidity and death, followed by the complications of myelofibrosis and development of leukemia.
Gene mutations and cytogenetic abnormalities may aid in the identification of prognostic subgroups.
Prognosis references
1. Spivak, JL. Myeloproliferative Neoplasms: Challenging Dogma. J Clin Med. 2024;13(22):6957.doi: 10.3390/jcm13226957
2. Abu-Zeinah G, Silver RT, Abu-Zeinah K, Scandura JM. Normal life expectancy for polycythemia vera (PV) patients is possible. Leukemia. 2022;36, 569–572. doi:10.1038/s41375-021-01447-3
Key Points
Polycythemia vera is a chronic myeloproliferative neoplasm that involves increased production of red blood cells, white blood cells, and platelets.
Polycythemia vera is caused by mutations involving JAK2 or rarely LNK mutations in hematopoietic stem cells that lead to sustained activation of JAK2 kinase, which causes excess blood cell production.
Complications include thrombosis, bleeding, and hyperuricemia; some patients eventually develop myelofibrosis or rarely transformation to acute leukemia.
Polycythemia vera is often first suspected because of an elevated hematocrit level; neutrophils and platelets are usually, but not invariably, increased.
Test for JAK2 and LNK mutations.
Bone marrow aspirate and biopsy and serum erythropoietin level are usually not diagnostically useful.
Phlebotomy to target hematocrit < 45% in men and < 42 % in women patients is essential.
Ruxolitinib and peginterferons are the preferred myelosuppressants.Ruxolitinib and peginterferons are the preferred myelosuppressants.
Drugs Mentioned In This Article
