eMedicine Specialties > Pediatrics: General Medicine > Hematology

Polycythemia Vera

Author: Josef T Prchal, MD, FRCP, Professor of Medicine (Hematology), Adjunct Professor of Pathology and Genetics, University of Utah School of Medicine
Coauthor(s): Scott J Samuelson, MD, Fellow in Hematology and Oncology, Huntsman Cancer Institute, University of Utah School of Medicine
Contributor Information and Disclosures

Updated: Sep 3, 2009

Introduction

Background

Polycythemia vera (PV) 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

Two key aspects of polycythemia vera biology can identify it: clonality and erythropoietin (Epo) independence. In polycythemia vera, a single clonal population of erythrocytes, granulocytes, platelets, and variable clonal B cells arises when a hematopoietic stem cell gains a proliferative advantage over other stem cells. The T lymphocytes and natural killer cells remain polyclonal in polycythemia vera; this is related to their longevity. Clonality can currently only be tested in females using X-chromosome polymorphisms that take advantage of X-chromosome inactivation.

Erythropoietin independence is the ability of erythroid colonies formed from the polycythemia vera hematopoietic stem cell to grow without erythropoietin. Although the colonies do not require erythropoietin, they remain responsive to it, and the erythropoietin receptor (EpoR) is normal without defects in function or quantity. Experiments using antibodies to neutralize Epo or block the EpoR do not abolish erythropoietin–independent erythroid colony formation.

The understanding of the molecular mechanisms underlying polycythemia vera has been greatly enhanced over last 2 years. Genome-wide scanning that compared clonal polycythemia vera and nonclonal cells from the same individuals revealed a loss of heterozygosity (LOH) in chromosome 9p. This is found in approximately 30% of patients with polycythemia vera. This is not a classical chromosomal deletion but rather a duplication of a portion of a chromosome and the loss of the corresponding parental region. This process is called uniparental disomy.

The 9p region contains a gene that encodes 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 has been shown to eliminate Epo independence of erythroid progenitors. Subsequently, these observations were followed by the identification of a loss-of-function somatic mutation in an auto-inhibitory JAK2 domain, which essentially produces a gain-of-function mutation that affects the kinase. This occurs when a point mutation in exon 14 leads to a valine-to-phenylalanine mutation at codon 617 of the JAK2 gene.

The JAK2V617F mutation leads to constitutive phosphorylation, thus constitutive activity and STAT recruitment, which provides the proliferative advantage seen in polycythemia vera. This process occurs in the absence of Epo and explains both the Epo independence and Epo hypersensitivity of polycythemia vera colonies. A mouse model of this mutation produced a clinical phenotype consistent with polycythemia vera. These data were rapidly confirmed by several groups; each reported that more than 90% of patients with polycythemia vera carry the JAK2V617F mutation.¹ However, compelling data strongly argue that this mutation is not a disease-initiating mutation.² Rather, an as-of-yet unidentified mutation or mutations predispose to the acquisition of polycythemia vera. Patients with the JAK2V617F mutation tend to have the clinical phenotype of essential thrombocytopenia.

The quantitative allele burden (ratio of mutant to wild type expression) of JAK2V617F also has a clinical impact. Data from Vannucchi et al reveal that higher quantitative levels of the JAK2V617F allele correlated with higher values for hematocrit.³ WBC and lactate dehydrogenase levels were positively correlated with the level of the mutation. The highest JAK2V617F levels at diagnoses predicted patients more likely to have splenomegaly, develop presenting pruritus, or eventually require chemotherapy.

Also, the rate of presenting major thromboses was positively correlated with higher mutation values. In fact, a multivariate analysis that included age, leukocytosis, hematocrit, platelet count, and therapies indicated that JAK2V617F/JAK2 wild type ratio is an independent risk factor for major vascular events. This was also validated by Silver et al, suggesting greater JAK2V617F allele burden correlates with higher white cell count, splenomegaly, and thromboembolic disease.^4,5 They also suggested a higher frequency of myelofibrosis.

Carobbio et al demonstrated that the JAK2V617F allelic burden in JAK2V617F- positive essential thrombocytopenia and polycythemia vera is the only risk factor that correlated with increased vascular events 5 years after diagnosis.⁶

Frequency

United States

The incidence of polycythemia vera is reported to be 4.9 cases per 100,000 population in Baltimore. A more recent review of polycythemia vera in Connecticut reported an incidence of 22 cases per 100,000 population.

International

The incidence of polycythemia vera is reported to be 6.7 cases per 1,000,000 population in Israel. In recent Swedish and Italian reviews they estimate 30 cases per 100,000 population in their respective countries.

Mortality/Morbidity

The course of polycythemia vera may or may not follow 2 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. Consequently, treatment is aimed at ameliorating symptoms. The plethoric phase can last for a few years to as many as 20. Following the plethoric phase, the spent phase is characterized by progressive anemia, fibrosis, and splenomegaly. The smear demonstrates anemia, thrombocytosis, and leukocytosis. In contrast to the plethoric phase, patients in the spent phase are often transfusion dependent.

Patients are at risk for leukemic transformation throughout the entire course of disease although the rate is higher during the spent phase. The incidence of leukemia was found by the Polycythemia Vera Study Group (PVSG) to be affected by the mode of treatment.⁷ Treatment with phlebotomy only, Phosphorus-32 (P32), and chlorambucil resulted in a leukemic incidence of 1.5%, 10%, and 13% respectively.

Except for potential leukemic transformation, appropriately treated polycythemia vera is compatible with near normal life. Without treatment, 50% of patients die within 18 months of diagnosis, usually from a thrombotic event. Survival with treatment depends on modality. Median survival is 13.9 years for phlebotomy alone, 11.8 years for P32, and 8.9 years for chlorambucil.

A European study by Marchioli and colleagues attempted to further define the prognosis of this disease;⁸ 1,638 patients were prospectively followed in an attempt to describe the clinical history of polycythemia vera. The primary limitation of this study is a mean follow-up of 2.7 years. The overall mortality rate was 3.7 death per 100 persons per year. This 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 noncardivascular causes (1.8 deaths per 100 persons per year), primarily hematologic transformations. Cardiovascular mortality accounted for 45% of all deaths. Hematologic transformation (13% of all deaths) and solid tumors (19.5%) were also significant causes of mortality.

As previously seen in other studies, age older than 65 years and history of previous thrombosis were also significantly associated with mortality risk. Cumulative rate of cardiovascular events was 5.5 per 100 persons per year. Rates of combined malignancy, hematologic transformation, and non–polycythemia vera related malignancies were 3, 1.3, and 1.7 per 100 persons per year, respectively.

Race

The disease appears more common in Jews of European extraction than in most non-Jewish populations. Some familial forms of polycythemia vera are noted, but the mode of inheritance is not clear.

Sex

Men are preferentially affected over women. The male-to-female ratio is 1.2-2.2:1.

Age

Onset is typically in the sixth decade, and the peak incidence is at age 60-80 years.

Clinical

History

Polycythemia vera (PV) frequently comes to the attention of clinicians because of an elevated hematocrit level found on routine laboratory testing. Some patients are asymptomatic, whereas others have various nonspecific symptoms that are recognized in the context of polycythemia vera. Thirty percent of patients report headache, weakness, dizziness, and sweating (in order of decreasing frequency). Many of these symptoms can be attributed to excess hematocrit.

Alternatively, the patient may present with a complication of polycythemia vera. Approximately 33% of patients present with thrombosis or hemorrhage; 75% of these have arterial thrombosis, and 25% have venous thrombosis. Cerebrovascular accidents, myocardial infarction, deep venous thrombosis, and pulmonary embolism (in order of decreasing frequency) can result from thrombosis due to polycythemia vera.

Budd-Chiari syndrome (hepatic vein thrombosis) is less common in polycythemia vera but is more specific to it. A patient who presents with Budd-Chiari syndrome should alert the physician to consider polycythemia vera because it is the most common underlying disease. Approximately 2-10% of patients with polycythemia vera have Budd-Chiari syndrome. Many presenting patients do not have an elevated hematocrit at the time of presentation but have other polycythemia vera laboratory abnormalities; if they survive, they eventually develop a myeloproliferative phenotype. One study of 41 patients with idiopathic Budd-Chiari syndrome found that 58% of these patients had the JAK2V617F mutation.⁹ Another group reported that patients with Budd-Chiari syndrome and the JAK2V617F mutation can have an elevatedserum erythropoietin(Epo) level.¹⁰ Classically, the presence of anelevated Epo level was believed to make the diagnosis of polycythemia veraextremely unlikely.

Less than 5% of patients have erythromelalgia (ie, erythema and warmth of the distal extremities, especially of the hands and feet, with a painful burning sensation that can result in digital ischemia if prolonged). A role for platelet aggregation has been proposed; in fact, the syndrome responds frequently (but not always) within hours to low-dose aspirin therapy.

Less commonly, polycythemia vera presents with cardiovascular symptoms due to myocardial infarction and congestive heart failure, pulmonary hypertension from chronic thromboembolic disease, neurological symptoms due to spinal cord compression by extramedullary hematopoiesis, and elevated uric acid with subsequent gout due to increased cell turnover.

Unrecognized hepatic or splenic vein thrombosis can result in portal hypertension and varices. Other GI symptoms include peptic ulcer disease, which occurs 4-5 times more frequently than in the general population. Hemorrhagic presentations are usually mild, with gum bleeding and easy bruising; however, serious GI hemorrhage can occur. Forty percent of patients experience life-altering pruritus. Typically, the pruritus is worse after a warm shower or bath; this is known as aquagenic pruritus. It has been attributed to increased numbers of mast cells and elevated histamine levels.

Physical

Potential physical findings include plethora and ruddiness of the face, erythromelalgia of the distal extremities, bruising, and splenomegaly. Specific attention should be directed towards sternal tenderness, which may indicate transformation to acute myeloid leukemia.

Causes

See Pathophysiology.

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