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Polycythemia vera (PV) is an idiopathic chronic myeloproliferative disorder characterized by an increase in RBC mass, which often manifests as an increased Hct. There is an increased risk of thrombosis and, rarely, acute leukemia and myelofibrotic transformation. Hepatosplenomegaly may also occur. Diagnosis is made by CBC, testing for JAK2 mutations, and clinical criteria. Treatment involves low-dose aspirin for all patients and myelosuppressive drugs for high-risk patients; phlebotomy, once standard, is now controversial.
PV is the most common of the myeloproliferative disorders; incidence in the US is estimated to be 1.9/100,000, with incidence increasing with age. PV may be slightly more common in men. The mean age at diagnosis is around 60 yr. PV is very rare in children.
Pathophysiology
PV involves increased production of all cell lines, including RBCs, WBCs, and platelets. Thus, PV is sometimes called a panmyelosis because of elevations of all 3 peripheral blood components. Increased production confined to the RBC line is termed erythrocytosis; erythrocytosis may occur with PV but is more commonly due to other causes (secondary erythrocytosis—see Myeloproliferative Disorders: Secondary Erythrocytosis). In PV, RBC production proceeds independently of erythropoietin levels.
Extramedullary hematopoiesis may occur in the spleen, liver, and other sites that have the potential for blood cell formation. Peripheral blood cell turnover increases. Eventually, progression to a spent-phase may occur, with a phenotype indistinguishable from primary myelofibrosis. Transformation to acute leukemia is rare, although the risk is increased with exposure to alkylating agents and radioactive phosphorus, which should only be used rarely, if ever.
Complications
In PV, blood volume expands and hyperviscosity develops. Patients are prone to develop thrombosis. Thrombosis can occur in most blood vessels, resulting in stroke, transient ischemic attacks, deep venous thrombosis, MI, retinal artery or vein occlusion, splenic infarction (often with a friction rub), or Budd-Chiari syndrome (see Vascular Disorders of the Liver: Budd-Chiari Syndrome). Previously, most experts believed hyperviscosity was the predisposing factor for thrombosis. Newer studies suggest that risk of thrombosis may be primarily related to the degree of leukocytosis. However, this hypothesis has yet to be confirmed in dedicated, prospective trials.
Platelets may function abnormally, predisposing to increased bleeding. Increased cell turnover may cause hyperuricemia, increasing the risk of gout and urate kidney stones.
Genetic basis
Clonal hematopoiesis is a hallmark of PV, suggesting that a mutation of hematopoietic stem cells is the cause of proliferation. The JAK2 V617F mutation (or one of several other rarer JAK2 mutations) is present in virtually all patients with PV. However, one or more other disease-initiating mutations almost certainly exist. These mutations lead to sustained activation of the JAK2 protein, which causes excess cell production, independent of erythropoietin levels.
Symptoms and Signs
PV itself is often asymptomatic. Occasionally, increased red cell volume and viscosity produce weakness, headache, light-headedness, visual disturbances, fatigue, and dyspnea. Pruritus often occurs, particularly after a hot bath. 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). Hepatomegaly is common, and > 75% 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 GI) occurs in about 10% of patients.
Hypermetabolism can cause low-grade fevers and weight loss and suggests progression to spent-phase polycythemia, which is clinically indistinguishable from primary myelofibrosis.
Diagnosis
PV is often first suspected because of an abnormal CBC (eg, Hb > 18.5 g/dL in men or > 16.5 g/dL in women), but it must be considered in patients with suggestive symptoms, particularly Budd-Chiari syndrome (however, some patients develop Budd-Chiari syndrome before the Hct increases). Neutrophils and platelets are often, but not invariably, increased; in patients with only elevated Hb, PV may be present, but secondary erythrocytosis, a more common cause of elevated Hb, must first be considered (see Myeloproliferative Disorders: Secondary Erythrocytosis). PV should also be considered in the rare patient with a normal Hb level but microcytosis and evidence of iron deficiency; this combination of findings can occur with iron-limited hematopoiesis, which is a hallmark of some cases of PV.
New WHO criteria for diagnosis have been established (see Table 3: Myeloproliferative Disorders: WHO Criteria for Diagnosis of Polycythemia Vera* ). Thus, patients suspected of having PV typically should have testing for JAK2 mutations; bone marrow examination is not always necessary.
When done, bone marrow typically shows panmyelosis, large and clumped megakaryocytes, and sometimes reticulin fibers. However, no bone marrow findings absolutely differentiate between PV and other disorders of excessive erythrocytosis, such as congenital familial polycythemia.
Patients with PV typically have low or low-normal serum erythropoietin levels. Elevated levels suggest secondary erythrocytosis.
Sometimes in vitro testing for endogenous erythroid colony formation is done (erythroid progenitors from peripheral blood or bone marrow from patients with PV, unlike those from healthy people, can form erythroid cells in culture without the addition of erythropoietin).
RBC mass determination with chromium-labeled RBCs can help differentiate between true and relative polycythemia and can also help to differentiate between PV and other myeloproliferative disorders. However, this test is technically difficult and is usually not done due to its limited availability and the fact it has been standardized only at sea level.
Nonspecific laboratory abnormalities that may occur in PV include elevated vitamin B12 and B12-binding capacity, hyperuricemia and hyperuricosuria (present in ≥ 30% of patients), increased expression of PRV-1 gene in leukocytes, and decreased expression of C-mpl (the receptor for thrombopoietin) in megakaryocytes and platelets. These tests are not needed for diagnosis.
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Table 3
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| WHO Criteria for Diagnosis of Polycythemia Vera*
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Level
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Specifics
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Major criteria
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Evidence of increased RBC volume, including ≥ 1 of the following:
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Hb > 18.5 g/dL in men or > 16.5 g/dL in women
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Hb or Hct > 99th percentile of method-specific reference range for age, sex, and altitude of residence
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Hb > 17 g/dL in men or 15 g/dL in women if associated with a documented and sustained increase of at least 2 g/dL from the patient's baseline value not accounted for by correction of iron deficiency
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Elevated RBC mass > 25% above mean normal predicted value
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Presence of JAK2 617VF or other functionally similar mutation (eg, JAK2 exon 12 mutation)
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Minor criteria
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Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) and prominent erythroid, granulocytic, and megakaryocytic proliferation
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Serum erythropoietin level below the reference range for normal
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Endogenous erythroid colony formation in vitro
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*Diagnosis requires presence of the 2 major criteria and one minor criterion or the presence of the first major criterion plus 2 minor criteria.
1This research was originally published in Blood. Adapted from Tefferi A, Thiele J, Orazi A, et al: Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: Recommendations from an ad hoc international expert panel. Blood 110:1092, 2007 © the American Society of Hematology.
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Prognosis
Generally, PV is associated with a shortened life span. Median survival for all patients is around 8 to 15 yr, although many patients live much longer. Thrombosis is the most common cause of death, followed by complications of myelofibrosis and development of leukemia.
Treatment
Because PV is the only form of erythrocytosis for which myelosuppressive therapy may be indicated, accurate diagnosis is critical. Therapy must be individualized according to age, sex, medical status, clinical manifestations, and hematologic findings. Patients are classified as high-risk or low-risk. High-risk patients are > 60 yr and have a history of thrombosis or transient ischemic attacks or both.
Aspirin
Aspirin (81 to 100 mg po once/day) reduces the incidence of thrombotic complications. Thus, patients undergoing phlebotomy alone or phlebotomy and myelosuppression should be given aspirin unless contraindicated. Higher doses of aspirin are associated with an unacceptably increased risk of bleeding.
Phlebotomy
Phlebotomy has been the mainstay of therapy for high- and low-risk patients because experts believed it decreased the risk of thrombosis. However, use of phlebotomy is now controversial because recent studies suggest that the Hct level may not correlate with risk of thrombosis, and some clinicians no longer adhere to the strict phlebotomy guidelines. However, this issue requires further study, and phlebotomy may still be considered for any patient. In a minority of patients with symptomatic rubor and hyperviscosity symptoms, phlebotomy can be therapeutic. Common thresholds for phlebotomy are Hct > 45% in men and > 42% in women. Initially, 300 to 500 mL of blood are removed every other day. Less blood is removed (ie, 200 to 300 mL twice/wk) from elderly patients and from patients with cardiac or cerebrovascular disorders. Once the Hct is below the threshold 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.
Myelosuppressive therapy
Myelosuppressive therapy is indicated for high-risk patients.
Radioactive phosphorus (32P) has long been used as a treatment for PV. It has a success rate of 80 to 90%. Remission may last 6 mo to several years. Radioactive phosphorus is well tolerated and requires fewer follow-up visits once the disorder is controlled. However, radioactive phosphorus is associated with an increased incidence of acute leukemic transformation, and the leukemia that develops after this therapy is often resistant to induction chemotherapy and is never curable. Thus, use of radioactive phosphorus requires careful patient selection (eg, used only for patients who are expected to die of other disorders within 5 yr). It should be used rarely; many clinicians do not use it at all.
Hydroxyurea, which inhibits the enzyme ribonucleoside diphosphate reductase, is also used to achieve myelosuppression. It has not been clearly shown to be leukemogenic; however, the possibility of leukemic conversion, although small, does exist. Hydroxyurea is started at a dose of 500 to 1000 mg po once/day. Patients are monitored with a weekly CBC. When a steady state is achieved, the interval between CBCs is lengthened to 2 wk and then to 4 wk. If the WBC count falls to < 4000/μL or the platelet count to < 100,000/μL, hydroxyurea is withheld and reinstituted at 50% of the dose when those values normalize. It is reasonable to titrate the hydroxyurea dose to achieve a near-normal Hct, although there is no evidence that titration is beneficial. It is likely that normalization of the WBC count is more important, but this theory has not been demonstrated prospectively. There is no evidence that normalization of the platelet count is necessary, and some clinicians do not increase the hydroxyurea dose as long as the platelet count is < 1.5 million/μL. Acute toxicity is infrequent; occasionally patients develop a rash, GI symptoms, fever, nail changes, and skin ulcers, which may require stopping hydroxyurea.
Interferon alfa-2b has been used if hydroxyurea does not control blood counts or is not tolerated. However, pegylated interferon alfa-2b is usually well tolerated. This drug affects the disease at the molecular level with relatively low toxicity.
Alkylating agents are leukemogenic and should be avoided.
Several inhibitors of the JAK2 pathway are currently in clinical trials, primarily in patients with advanced myelofibrosis.
Treatment of complications
Hyperuricemia should be treated with allopurinol 300 mg po once/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; myelosuppression often is most effective. Cholestyramine 4 g po tid, cyproheptadine 4 mg po tid to qid, cimetidine 300 mg po qid, or paroxetine 20 to 40 mg po once/day may be successful. After bathing, the skin should be dried gently. Aspirin relieves symptoms of erythromelalgia; higher doses may be required but clearly increase the risk of hemorrhage.
Secondary Erythrocytosis
(Secondary Polycythemia)
Secondary erythrocytosis is erythrocytosis that develops secondary to circulating erythropoiesis-stimulating substances.
In secondary erythrocytosis, only the RBC line is increased.
Common causes of secondary erythrocytosis include
Less common causes include certain congenital disorders such as
Spurious erythrocytosis may occur with hemoconcentration (eg, from burns, diarrhea, diuretics).
In patients who smoke, reversible erythrocytosis results mainly from tissue hypoxia due to elevation of blood carboxyhemoglobin concentration; levels often normalize with smoking cessation.
Patients with chronic hypoxemia (arterial Hb O2 concentration < 92%), typically due to lung disease, right-to-left intracardiac shunts, renal transplantation, prolonged exposure to high altitudes (see Altitude Diseases), or hypoventilation syndromes, often develop erythrocytosis. The primary treatment is to alleviate the underlying condition, but O2 therapy may help, and some degree of phlebotomy may decrease viscosity and alleviate symptoms. Because in some cases the elevated Hct is physiologic, phlebotomy may cause harm because it decreases tissue oxygenation.
Tumor-associated erythrocytosis can occur when renal tumors, cysts, hepatomas, cerebellar hemangioblastomas, or uterine leiomyomas secrete erythropoietin. Removal of the lesion may be curative.
High O2–affinity hemoglobinopathies are very rare. This diagnosis is suggested by a family history of erythrocytosis; it is established by measuring the P50 (the partial pressure of O2 at which Hb becomes 50% saturated) and, if possible, determining the complete oxyhemoglobin dissociation curve. Standard Hb electrophoresis may be normal and cannot reliably exclude this cause of erythrocytosis.
Evaluation
Tests done when erythrocytosis is present include
A low or low-normal serum erythropoietin level suggests PV. Patients with hypoxia-induced erythrocytosis have an elevated level or inappropriately normal level for their elevated Hct. Patients with tumor-associated erythrocytosis typically have elevated erythropoietin levels. Patients with elevated erythropoietin levels or microscopic hematuria should undergo abdominal imaging, CNS imaging, or both to seek a renal lesion or other tumor sources of erythropoietin.
P50 measures the affinity of Hb for O2; a normal result excludes a high-affinity Hb (a familial abnormality) as the cause of erythrocytosis.
Last full review/revision September 2009 by Josef T. Prchal, MD; Scott Samuelson, MD
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