(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 1.9/100,000, 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.
Polycythemia vera involves increased production of red blood cells (RBCs), white blood cells (WBCs), and platelets. Thus, polycythemia vera is a panmyelosis because of elevations 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 erythropoietin level.
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 the secondary erythrocytoses, 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.
Iron deficiency may eventually occur because of the increased need for iron to produce RBCs. In the presence of iron deficiency of any kind, RBCs become increasingly smaller (microcytic erythrocytosis) 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 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 compatible with primary myelofibrosis but with a better survival.
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 radioactive phosphorus (mostly of historic significance). Some series also suggest that risk is increased with hydroxyurea. Acute leukemia is more common in men, particularly after age 60.
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 tyrosine kinase family of enzymes and is involved in signal transduction for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor (G-CSF) among other entities. Specifically, the JAK2V617F mutation or the JAK2 exon12 mutation is present in most patients with polycythemia vera. However, recently calreticulin (CALR) mutations have been found 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 of polycythemia vera include
In polycythemia vera, 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 > 1,500,000/mcL (> 1,500,000 × 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.
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 red 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 (which may be massive).
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.
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. Along with erythrocytosis, the neutrophil and platelet counts are usually, but not invariably, increased. In patients with only an elevated hematocrit, polycythemia vera may be present, but secondary erythrocytosis, a 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. Thus, multiple findings must be integrated.
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 clear erythrocytosis is strongly suggestive of polycythemia vera. If erythrocytosis is not clearly present, direct measurement of red cell mass and plasma volume (eg, with chromium-labeled RBCs, although this test is usually available only at specialized centers) is done 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 examination is not diagnostic of polycythemia vera. When done, bone marrow examination 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 ≥ 80% of patients), and decreased expression of MPL (the receptor for thrombopoietin) in megakaryocytes and platelets. These tests are not needed for diagnosis.
The World Health Organization diagnostic guidelines are based on hemoglobin and hematocrit levels and red cell mass determination, but are limited because they ignore leukocytosis, thrombocytosis, and splenomegaly.
Recent studies cite a median survival of 24 years, but many patients live much longer, even when myelofibrosis develops, and survival is anticipated to improve further as new therapies become more widely used.
Thrombosis is the most common cause of morbidity and death, followed by the complications of myelofibrosis and development of leukemia. In the future, gene expression profiling or other characteristics may aid in the identification of prognostic subgroups.
Therapy must be individualized according to age, sex, medical status, clinical manifestations, and hematologic findings. However, previous criteria used to stratify treatment by high- or low-risk classification such as age and extreme thrombocytosis (1,000,000/mcL [1,000,000 × 109/L]) have not been prospectively validated and are not recommended to guide therapy. Although very high leukocyte counts (> 30,000/mL [> 30,000 × 109/L]) have been correlated with disease acceleration, there is no evidence that lowering the leukocyte count with chemotherapy prolongs survival.
Phlebotomy is the mainstay of therapy. The targets for phlebotomy are a hematocrit < 45% in men and women. A randomized controlled trial published in 2013 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% (1). 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 asymptomatic patients.
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.
Aspirin alleviates symptoms of microvascular events. Thus, patients who have or have had symptoms of erythromelalgia, ocular migraine, or transient ischemic attacks should be given 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 asymptomatic patients with polycythemia vera (in the absence of other indications), particularly in patients > 70 years of age.
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 stem cell is resistant to them. Alkylating agents such as chlorambucil and hydroxyurea also increase the incidence of acute leukemia and solid tumors; these drugs are no longer recommended except in special circumstances.
If intervention other than phlebotomy is necessary (eg, because of symptoms or thrombotic events), interferon or ruxolitinib is preferred. Anagrelide has been used to control the platelet count but has both cardiac and renal toxicity and can cause anemia.
Pegylated interferon alfa-2b or interferon alfa-2a specifically targets the affected cell and not normal stem cells in polycythemia vera. These drugs are usually well tolerated and are effective in controlling pruritus and excessive blood production as well as reducing spleen size. About 20 % of patients achieve a complete molecular remission.
Ruxolitinib, 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. If JAK inhibitor drugs are not available and cytoreduction is needed, pegylated interferon is the drug of choice.
Hydroxyurea is in widespread use in polycythemia vera. However, although it has some antiplatelet activity, it does not prevent either arterial or venous thrombosis and is inferior to JAK inhibitors such as ruxolitinib. Hydroxyurea should be prescribed only by specialists familiar with its use and monitoring. .
It is not necessary to lower the white blood cell or platelet count to normal.
Hyperuricemia 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.
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 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 hemoglobin level; neutrophils and platelets are usually, but not invariably, increased.
Test for JAK2, CALR, or LNK mutations and sometimes obtain bone marrow specimen for examination and serum erythropoietin level.
Phlebotomy to target hematocrit < 45% is essential.
Ruxolitinib and interferon are the preferred myelosuppressants.
For more information about treatment of polycythemia vera, see
1. Spivak, JL: How I treat polycythemia vera. Blood 134: 341–352, 2019.
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