eMedicine Specialties > Pediatrics: General Medicine > Hematology
Polycythemia Vera
Updated: Sep 20, 2007
Introduction
Background
Polycythemia vera is a disorder of the multipotent hematopoietic stem cell that manifests as excess production of normal erythrocytes and variable overproduction of leukocytes and platelets. It is grouped with the Philadelphia Chromosome Negative Myeloproliferative Disorders and can usually be differentiated from them by the predominance of erythrocyte production.
Pathophysiology
Key biologic features
Two key aspects of the biology of polycythemia vera can be scrutinized to identify this disorder:
- Clonality
- Erythropoietin (Epo) independence
Clonality
In polycythemia vera, a single clonal population of erythrocytes, granulocytes, B cells, and platelets arises when a hematopoietic stem cell gains a proliferative advantage over other stem cells. T lymphocytes and natural killer cells remain polyclonal in polycythemia vera; this situation is related to their longevity. Clonality can currently be tested only in female patients. The test is done by examining X-chromosomal polymorphisms and by taking advantage of inactivation of the X chromosome.
Epo independence
Epo independence is the ability of erythroid colonies formed from the hematopoietic stem cell in the setting of polycythemia vera to grow without Epo. Although the colonies do not require Epo, they remain responsive to it. In fact, the Epo receptor (EpoR) is normal, without defects in function or quantity. Experiments in which antibodies are used to neutralize Epo or block the EpoR do not abolish the formation of Epo-independent erythroid colonies.
Molecular mechanisms
Our understanding of the molecular mechanisms underlying polycythemia vera was greatly enhanced in the last 2 years. Genome-wide scanning, in which clonal polycythemia vera cells and nonclonal cells from the same individual were compared, revealed a loss of heterozygosity in chromosome 9p. Such a loss is found in approximately 30% of patients with polycythemia vera. This is not a classic chromosomal deletion, but rather a duplication of a portion of a chromosome and the loss of the corresponding parental region. The process is called uniparental disomy. The 9p arm contains a gene encoding for the JAK2 tyrosine kinase. The JAK family of kinases is critical in cytokine receptor signaling and transmits the activating signal in the Epo-EpoR signaling pathway. Inhibition of JAK2 eliminates the Epo independence of erythroid progenitors.
Following these observations was the identification of a loss-of-function somatic mutation in an autoinhibitory JAK2 domain. The mutation essentially produces a gain-of-function mutation affecting the kinase. This occurs when a point mutation leads to a valine-to-phenylalanine mutation at codon 617 of the JAK2 gene. The JAK2V617F mutation leads to constitutive phosphorylation activity and the recruitment of signal transducer and activator of transcription (STAT) molecules, which provides the necessary proliferative advantage seen in polycythemia vera. This process occurs in the absence of Epo and accounts for both the Epo independence and the Epo hypersensitivity of polycythemia vera colonies.
A murine model of this mutation produced a clinical phenotype consistent with polycythemia vera. Several groups rapidly confirmed these data, each showing that more than 90% of patients with polycythemia vera carry the JAK2V617F mutation.
Of note, compelling data strongly suggest that this mutation is not a disease-initiating alteration. Rather, an as-yet unidentified mutation or mutations may predispose an individual to acquire the JAK2V617F mutation, which plays a major role in behavior and in the clinical complications associated with polycythemia vera clones.
Diagnostic criteria
The diagnostic criteria for polycythemia vera are in flux. Clinical features were historically used to define the disease because laboratory testing was not possible or available. Now, because of advances in molecular biology and because of increased knowledge about the biology of polycythemia vera, laboratory testing can be done. Results of these tests are being incorporated into the diagnostic criteria for polycythemia vera.
Identification of the JAK2V617F mutation is another extremely important diagnostic tool. However, the mutation is not exclusive to polycythemia vera. For example, approximately 50% of patients with essential thrombocythemia and idiopathic myelofibrosis carry this mutation. In addition, small frequencies of this mutation has been identified in many other hematologic disorders. Moreover, some patients with polycythemia vera do not have this mutation.
Multiple diagnostic criteria and algorithms exist. All of the new ones incorporate the JAK2V617F allele, which has prognostic significance. The JAK2V617F mutation was present in 96 of 116 patients with polycythemia vera. Hematocrits, WBC counts, and lactate dehydrogenase levels were positively correlated with the level of the mutation. The highest levels of JAK2V617F at diagnosis was predictive of a risk of splenomegaly, presenting pruritus, or an eventual need for chemotherapy.
Also, the rate of major thromboses was positively correlated with high mutation values. In fact, a multivariate analysis including age, leukocytosis, hematocrits, platelet count, and therapies indicated that the JAK2V617F/JAK2 wild-type ratio was an independent risk factor for major vascular events (P = .027).
Frequency
United States
The prevalence of polycythemia vera is reported to be 4.9 cases per 100,000 people in Baltimore, Maryland.
International
The prevalence of polycythemia vera is reported to be 6.7 cases per 1,000,000 population in Israel.
Mortality/Morbidity
Phases of polycythemia vera
The course of polycythemia vera may or may not follow several phases.
- The plethoric phase usually occurs first and is characterized by hyperproliferation of cellular components. The principle manifestations during this phase are thrombosis and hemorrhage. As a consequence, treatment is aimed at ameliorating symptoms.
- The plethoric phase can last for a few years to as many as 20 years.
- After the plethoric phase, the spent phase is characterized by progressive anemia, fibrosis, and splenomegaly. Smears demonstrate findings of anemia, thrombocytosis, and leukocytosis. In contrast to the plethoric phase, patients in the spent phase are often transfusion dependent.
Leukemia
Patients are at risk for leukemic transformation throughout the entire course of disease, though the rate is highest during the spent phase. The Polycythemia Vera Study Group (PVSG) found that the mode of treatment affected the incidence of leukemia.1 Treatment with phlebotomy alone, P32, or chlorambucil resulted in incidence of 1.5%, 10%, and 13%, respectively.
Survival and mortality risk
Except for the potential for leukemic transformation, appropriately treated polycythemia vera is compatible with a near-normal life. Without treatment, 50% of patients die within 18 months of diagnosis. The usual cause is a thrombotic event. Survival with treatment depends on the modality of therapy. Median survival is 13.9 years for phlebotomy alone, 11.8 years for P32 treatment, and 8.9 years for chlorambucil therapy (see Treatment).
In a recent European study, Marchioli and colleagues (2005) attempted to further define the prognosis of patients with this disease.2 They prospectively followed up 1638 patients to describe the clinical history of polycythemia vera. The primary limitation of this study was the mean follow-up period of 2.7 years. The overall mortality rate was 3.7 deaths per 100 persons per year, which was primarily caused by a moderate rate of cardiovascular death (1.7 deaths per 100 persons per year) and a high rate of death from noncardiovascular causes, mainly hematologic transformations (1.8 deaths per 100 persons per year). Cardiovascular mortality accounted for 45% of all deaths. Hematologic transformation (13% of all deaths) and solid tumors (19.5%) were also notable causes of mortality.
As seen in previous studies, age older than 65 years and history of thrombosis were significantly associated with the mortality risk. The cumulative rate of cardiovascular events was 5.5 events per 100 persons per year. Rates of combined malignancy, hematologic transformation, and malignancies not related to polycythemia vera were 3.0, 1.3, and 1.7 events per 100 persons per year.
Race
The disease appears to be most common among Jews of European extraction than among most non-Jewish populations. Some familial forms of polycythemia vera exist, but their mode of inheritance is unclear.
Sex
Polycythemia vera affects more men than women. The male-to-female ratio is 1.2-2.2:1.
Age
The onset of disease is typically in the sixth decade, and the prevalence peaks at 60-80 years of age.
Clinical
History
Polycythemia vera frequently comes to the attention of clinicians because routine laboratory testing demonstrates an elevated hematocrit. Some patients will have been asymptomatic, whereas others will have had various nonspecific symptoms that are now recognized in the context of polycythemia vera. About 30% of patients have headaches, weakness, dizziness, and sweating (in order of decreasing frequency). Many of these symptoms can be attributed to an excessive hematocrit.
Patients may alternatively present with a complication of polycythemia vera. Approximately 33% present with thrombosis or hemorrhage; 75% of these patients have arterial thrombosis, and 25%, venous thrombosis. Sequelae of thrombosis due to polycythemia vera include cerebrovascular accidents, myocardial infarction, deep venous thrombosis, and pulmonary embolism (in that order).
A less frequent but more specific finding for polycythemia vera that those described above is Budd-Chiari syndrome (thrombosis of the hepatic vein). A patient who presents with Budd-Chiari syndrome should alert the physician to consider polycythemia vera, as it is the most common underlying disease. Approximately 2-10% of patients with polycythemia vera have Budd-Chiari syndrome. Many patients do not have an elevated hematocrit at the time of presentation, but they may have other laboratory abnormalities indicative of polycythemia vera. If patients survive, they eventually develop a myeloproliferative phenotype.
One study of 41 patients with idiopathic Budd-Chiari syndrome revealed that 58% had the JAK2V617F mutation.3 Another study showed that serum Epo levels can be elevated in patients with Budd-Chiari syndrome and the JAK2V617F mutation.4 The presence of an elevated Epo has traditionally been thought to make the diagnosis of polycythemia vera extremely unlikely.
Unrecognized thrombosis of the hepatic or splenic vein can result in portal hypertension and varices. Other GI symptoms include peptic ulcer disease, which occurs 4-5 times more frequently in patients with polycythemia vera than in the general population.
Hemorrhagic presentations are usually mild, with gum bleeding and easy bruising. However, serious GI hemorrhage can occur.
Approximately 40% of patients have life-altering pruritus. The pruritus typically worsens after a warm shower or bath; this reaction is known as aquagenic pruritus. Pruritus has been attributed to increased numbers of mast cells and elevated levels of histamine.
Less than 5% patients have erythromelalgia. This is erythema and warmth of the distal extremities—especially the hands and feet—in association with a painful burning sensation. Erythromelalgia can result in digital ischemia if it is prolonged. Because it is also associated with essential thrombocythemia, a role for platelet aggregation has been proposed. In fact, the syndrome frequently, but not always, responds within hours to low-dose aspirin therapy.
Patients with polycythemia vera sometimes present with cardiovascular symptoms due to myocardial infarction and congestive heart failure, neurologic symptoms due to spinal cord compression caused by extramedullary hematopoiesis, and an elevated uric acid level with subsequent gout due to increased cellular turnover.
Physical
Potential physical findings include plethora and ruddiness of the face, erythromelalgia of the distal extremities, bruising, and splenomegaly. Specific attention should be directed to sternal tenderness, which may indicate transformation to acute myeloid leukemia (AML).
More on Polycythemia Vera |
 Overview: Polycythemia Vera |
| Differential Diagnoses & Workup: Polycythemia Vera |
| Treatment & Medication: Polycythemia Vera |
| Follow-up: Polycythemia Vera |
| References |
| Next Page » |
References
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Further Reading
Keywords
PV, primary polycythemia, polycythemia rubra vera, PRV, Osler-Vaquez disease, Osler disease, Osler's disease, Vaquez disease, Vaquez' disease, erythremia, splenomegalic polycythemia, erythrocytosis megalosplenica, cryptogenic polycythemia, erythropoietin independence, Epo independence, primary familial and congenital polycythemia, PFCP, Chuvash polycythemia
