Polycythemia vera is a chronic myeloproliferative neoplasm characterized by an increase in morphologically normal red cells (its hallmark), but also white cells and platelets. Ten to 15% of patients eventually develop myelofibrosis and bone marrow failure; acute leukemia occurs spontaneously in 1.0 to 2.5%. 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 or rarely
(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 about 60 years, but it occurs much earlier in women, who may present in their second and third decades, sometimes with the Budd-Chiari syndrome.
General reference
1. Anía BJ, Suman VJ, Sobell JL, Codd MB, Silverstein MN, Melton LJ 3rd: Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935-1989. Am J Hematol 47(2):89–93, 1994. doi:10.1002/ajh.2830470205
Pathophysiology of Polycythemia Vera
Polycythemia vera involves increased production of red blood cells (RBCs), white blood cells (WBCs), and platelets. Thus, polycythemia vera is a panmyelosis because of increases of all 3 peripheral blood components. 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 have the potential for 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, RBCs become increasingly smaller (microcytosis) because the red cell hemoglobin concentration (MCHC) is defended at the expense of red cell volume (mean corpuscular volume [MCV]). Although patients with iron deficiency from other causes become anemic, patients with polycythemia vera have increased RBC production and thus, even when iron-deficient initially patients with polycythemia vera can have a normal hematocrit level but an elevated red cell count and microcytic RBC indices; this combination of findings is a hallmark of polycythemia vera.
Eventually, about 10 to 15% of patients progress to a syndrome similar to primary myelofibrosis but with a better survival.
Transformation to acute leukemia
Genetic basis
Polycythemia vera is caused by a mutation in an hematopoietic stem cell.
Mutations of 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 mutation or the JAK2 exon12 mutation is present in 95% 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 the 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/mcL (> 1,000,000 × 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 about 10% of patients.
Hypermetabolism can cause low-grade fevers and weight loss and suggests progression to secondary myelofibrosis, which is clinically indistinguishable from primary myelofibrosis but has a better prognosis.
Diagnosis of Polycythemia Vera
Complete blood count (CBC)
Testing for JAK2 mutations, CALR mutations, or LNK mutations (done sequentially)
Sometimes 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
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 and evidence of iron deficiency; 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 typically should have testing for JAK2V617F(exon 14) and JAK2 exon12 mutations. If these results are negative, testing for CALR and LNK mutations is done. 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 done (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 is not diagnostic of polycythemia vera. When done, 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 test.
Nonspecific laboratory abnormalities that may occur in polycythemia vera 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
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/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 controlled 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 solutions.
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.
A new class of agents, hepcidin mimetics such as rusfertide, is 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.
Aspirin
aspirin 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, particularly in patients > 65 years of age.
Myelosuppressive therapy
chlorambucil, busulfan, radioactive phosphorus, and hydroxyurea can increase the incidence of acute leukemia and solid tumors; these agents are not recommended except in special circumstances. Hydroxyurea should be prescribed only by specialists familiar with its use and monitoring.
In polycythemia vera, (4) 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. About 20% of patients achieve a complete molecular remission, which can take several years to achieve.
ruxolitinib demonstrated better molecular response as well as superior complete remission and event-free survival rates as compared with best supportive care (5).
It is not necessary to lower the white blood cell or platelet count to normal in patients without symptoms.
Treatment of complications
Hyperuricemia
Pruritus
Treatment references
1. Spivak JL: How I treat polycythemia vera. Blood 134(4):341–352, 2019. 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 368:22–33, 2013.
3. Handa S, Ginzburg Y, Hoffman R, Kremyanskaya M: Hepcidin mimetics in polycythemia vera: resolving the irony of iron deficiency and erythrocytosis. Curr Opin Hematol 30(2):45–52, 2023. doi:10.1097/MOH.0000000000000747
4. 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 Feb 25;:]. Lancet Haematol 7(3):e196–e208, 2020. doi:10.1016/S2352-3026(19)30236-4
5. 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 41(19):3534–3544, 2023. doi:10.1200/JCO.22.01935
Prognosis for Polycythemia Vera
A large study of patients with polycythemia vera reported a median survival of 14.1 years, and this was significantly worse than that of an age- and sex-matched control population (1).
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 reference
1. Tefferi A, Rumi E, Finazzi G, et al: Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia 27(9):1874–1881, 2013. doi:10.1038/leu.2013.163
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 due to mutations involving JAK2, or rarely the CALR or 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, CALR, or LNK mutations.
Bone marrow aspirate and biopsy and a serum erythropoietin level are usually not useful diagnostically.
Phlebotomy to target hematocrit < 45% in men and < 42 % in women patients is essential.
