eMedicine Specialties > Hematology > Stem Cells and Disorders

Polycythemia Vera

Author: Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Coauthor(s): Ulrich Woermann, MD, Consulting Staff, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland
Contributor Information and Disclosures

Updated: Jan 23, 2009

Introduction

Background

Polycythemia vera (PV) is a stem cell disorder characterized as a panhyperplastic, malignant, and neoplastic marrow disorder. The most prominent feature of this disease is an elevated absolute red blood cell mass because of uncontrolled red blood cell production. This is accompanied by increased white blood cell (myeloid) and platelet (megakaryocytic) production, which is due to an abnormal clone of the hematopoietic stem cells with increased sensitivity to the different growth factors for maturation.^1,2,3

Pathophysiology

Normal stem cells are present in the bone marrow of patients with polycythemia vera (PV). Also present are abnormal clonal stem cells that interfere with or suppress normal stem cell growth and maturation. Evidence indicates that the etiology of panmyelosis is unregulated neoplastic proliferation. The origin of the stem cell transformation remains unknown.

Progenitors of the blood cells in these patients display abnormal responses to growth factors, suggesting the presence of a defect in a signaling pathway common to different growth factors. The observation that in vitro erythroid colonies grow when no endogenous erythropoietin (Epo) is added to the culture and the presence of a truncated Epo receptor in familial erythrocytosis indicate that the defect is in the transmission of the signal. The sensitivity of polycythemia vera (PV) progenitors to multiple cytokines suggests that the defect may lie in a common pathway downstream from multiple receptors. Increased expression of BCLX suggests an additional decrease in cellular apoptosis.

Several reasons suggest that a mutation on the Janus kinase-2 gene (JAK2) is the most likely candidate gene involved in polycythemia vera (PV) pathogenesis, as JAK2 is directly involved in the intracellular signaling following exposure to cytokines to which polycythemia vera (PV) progenitor cells display hypersensitivity.⁴ A recurrent unique acquired clonal mutation in JAK2 was found in most patients with polycythemia vera (PV) and other myeloproliferative diseases (MPDs) including essential thrombocythemia and idiopathic myelofibrosis.

A unique valine to phenylalanine substitution at position 617 (V617F) in the pseudokinase JAK2 domain has been identified called JAK2V617F that leads to a permanently turned on signaling at the affected cytokine receptors.^5,6,7,8 How these mutations interact with the wild type kinase genes and how they manifest into different forms of MPDs need to be elucidated.

Thromboses and bleeding are frequent in persons with polycythemia vera (PV) and MPD, and they result from the disruption of hemostatic mechanisms because of (1) an increased level of red blood cells and (2) an elevation of the platelet count. There are findings that indicate the additional roles of tissue factor and polymorphonuclear leukocytes (PMLs) in clotting, the platelet surface as a contributor to phospholipid-dependent coagulation reactions, and the entity of microparticles. Tissue factor is also synthesized by blood leukocytes, the level of which is increased in persons with MPD, which can contribute to thrombosis.

Hyperhomocystinemia is a risk factor for thrombosis and is also widely prevalent in patients with MPD (35% in controls, 56% in persons with PV).

Acquired von Willebrand syndrome is an established cause of bleeding in persons with MPD, accounting for approximately 12-15% of all patients with this syndrome. von Willebrand syndrome is largely related to the absorption of von Willebrand factor onto the platelets; reducing the platelet count should alleviate the bleeding and the syndrome.

Frequency

United States

Polycythemia vera (PV) is relatively rare, occurring in 0.6-1.6 persons per million population.

Mortality/Morbidity

See Prognosis.

Race

Originally, Jewish individuals were thought to have a higher predilection for polycythemia vera (PV) than persons of other ethnic groups; however, many studies show that this condition occurs in persons of all ethnic groups.

Sex

Polycythemia vera (PV) has no sex predilection, although the Polycythemia Vera Study Group (PVSG) found that slightly more males are affected than females.³

Age

The peak incidence of polycythemia vera (PV) is age 50-70 years. However, this condition occurs in persons of all age groups, including those in early adulthood and childhood, albeit rarely.

Clinical

History

Symptoms of polycythemia vera (PV) are often insidious in onset, and they are often related to blood hyperviscosity secondary to a marked increase in the cellular elements of blood, which impairs microcirculation.

• Symptoms are related to hyperviscosity, sludging of blood flow, and thromboses, which lead to poor oxygen delivery and symptoms that include headache, dizziness, vertigo, tinnitus, visual disturbances, angina pectoris, or intermittent claudications.
• Bleeding complications (1%) include epistaxis, gum bleeding, ecchymoses, and gastrointestinal (GI) bleeding.
• Thrombotic complications (1%) include venous thrombosis or thromboembolism and an increased prevalence of stroke and other arterial thromboses.
• Abdominal pain due to peptic ulcer disease is present because polycythemia vera (PV) is associated with increased histamine levels and gastric acidity or possible Budd-Chiari syndrome (hepatic portal vein thrombosis) or mesenteric vein thrombosis.
• Splenomegaly, when present, can cause early satiety because of (1) gastric filling being impaired by the enlarged spleen or, rarely, (2) symptoms of splenic infarction. Weight loss may result from early satiety or from the increased myeloproliferative activity of the abnormal clone.
• Pruritus results from increased histamine levels released from increased basophils and mast cells and can be exacerbated by a warm bath or shower. This occurs in up to 40% of patients with polycythemia vera (PV).

Physical

Physical findings in those with polycythemia vera are due to manifestations of the myeloproliferative process and excess of the cellular elements of blood.

• The following symptoms are due to the manifestations of MPDs with extramedullary hematopoiesis:
  • Splenomegaly – Present in 75% of patients at the time of diagnosis
  • Hepatomegaly – Present in approximately 30% of patients with polycythemia vera (PV)
• Plethora or a ruddy complexion is characteristic of polycythemia vera (PV) and results from the marked increase in total red blood cell mass. This manifests in the face, palms, nailbeds, mucosa, and conjunctiva.
• Hypertension is common in patients with polycythemia vera (PV). The red blood cell mass should differentiate this condition from Gaisbock syndrome, which is hypertension and pseudopolycythemia (ie, high hemoglobin levels due to low plasma volume).
• Diagnostic laboratory tests have been developed to increase the ability to diagnose primary MPDs and to differentiate them from reactive conditions associated with increased blood cell levels, which can mimic MPDs.
• Polycythemia is characterized by increased cell counts in all cell lines in the myeloid series (ie, red blood cells, white blood cells [preferentially granulocytes], and platelets). Thus, if red blood cell levels are increased, several conditions must be excluded, including (1) conditions that increase red blood cells secondary to systemic hypoxic conditions or an artificial condition stimulating Epo secretion in the kidneys; (2) granulocytosis from infections or mobilization by secondary causes, as in leukemoid reactions; and (3) thrombocytosis from bleeding and iron deficiency. Then, once an MPD (Philadelphia chromosome negative [Ph –]) is documented, it must be differentiated from essential thrombocytosis (ET), chronic myelogenous leukemia (CML), and agnogenic myeloid metaplasia (AMM), which have manifestations that overlap with polycythemia vera (PV).Abdulkarim et al studied the long-term rate (15 years) of leukemic transformation (acute myelogenous leukemia [AML]) in 795 unselected patients with Ph– MPD in the regions of Gothenburg, Sweden, and the Côte d'Or, Burgundy, France.⁹ Fifty-six patients (7%) with Ph– MPD demonstrated transformation to AML, of whom 6 had never received cytoreductive agents and 2 had been exposed to interferon. The annual rate of AML transformation was 0.38% in patients with polycythemia vera (PV), 0.37% in those with ET, and 1.09% in individuals with idiopathic myelofibrosis (IMF).⁹ The average time from diagnosis to AML transformation was 88 +/- 56 months in the PV patients compared with 76 +/- 57 months in the ET patients and 42 +/- 33 months in those with IMF (significantly shorter than the PV and ET patients), and the investigators noted that it appeared to be a continuous event in all 3 MPDs.Another finding was that 17 of 18 patients with polycythemia vera (PV) whose condition transformed to AML were females despite the fact that the male-to-female ratio of the entire PV group was 146:171.⁹ However, the other conditions (ET and IMF) showed a slight male preponderance (ET, 1.33; IMF: 1.13). The average survival for the 56 patients with MPD who developed AML did not differ among the 3 diseases (4.6 +/- 5.5 months).⁹
• The Polycythemia Vera Study Group (PVSG) was the first to set rigorous criteria for the diagnosis of polycythemia vera (PV) in the 1970s. With the establishment of polymerase chain reaction (PCR)-based methods for detecting the JAK2 V617F mutation, this may become the first molecular diagnostic marker for polycythemia vera (PV) similar to BCR/ABL for CML. However, because of a paucity of centers doing red blood cell mass measurements, demonstrating an elevated red blood cell mass continues to become more difficult to obtain. Diagnostic criteria set by the PVSG are as follows:
  • Category A
    1. Total red blood cell mass - In males, greater than or equal to 36 mL/kg; in females, greater than or equal to 32 mL/kg
    2. Arterial oxygen saturation greater than or equal to 92%
    3. Splenomegaly
  • Category B
    1. Thrombocytosis with platelet count greater than 400,000/μL
       
       

       

       Blood film at 400X magnification demonstrating polyglobulia and thrombocytosis. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

       [ CLOSE WINDOW ]

       

       Blood film at 400X magnification demonstrating polyglobulia and thrombocytosis. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

    2. Leukocytosis with a white blood cell count greater than 12,000/μL
    3. Increased leukocyte alkaline phosphatase (ALP) greater than 100 U/L
    4. Serum vitamin B-12 concentration greater than 900 pg/mL or binding capacity greater than 2200 pg/mL
• The diagnosis is established with A1 plus A2 plus A3 or A1 plus A2 plus any 2 criteria from category B
• Among the PVSG criteria above, the red blood cell mass measurement (if elevated in addition to the other criteria) is confirmatory of polycythemia vera (PV) and specifically eliminates pseudoerythrocytosis (decreased plasma volume). The red blood cell mass is becoming difficult to obtain because the chromium-51 (⁵¹ Cr) isotope needed to perform the test is no longer readily available, and institutions willing to perform the test are few as a result of small demand and lack of profit in performing the test.
  • Measure actual total red blood cell mass with⁵¹ Cr-labeled red blood cells and, ideally, an iodine-131 (¹³¹ I) plasma volume dual technique to differentiate true erythrocytosis from pseudoerythrocytosis (decreased plasma volume).
• The major diagnostic issue related to polycythemia vera (PV) is distinguishing it from other forms of erythrocytosis, which are more common than PV. Several tests have been proposed and used to help diagnose polycythemia vera (PV), as follows:
  • Serum Epo assay: Epo levels in patients with polycythemia vera (PV) are often below the lower limit of normal compared with patients with secondary erythrocytosis and pseudoerythrocytosis, but the levels for PV and secondary erythrocytosis or pseudoerythrocytosis overlap and are nonspecific for differentiating these conditions.
  • Cytogenetics: Karyotyping the polycythemia vera (PV) bone marrow cells can detect less than 30% of patients with PV. Cytogenetic studies show the presence of an abnormal karyotype in the hematopoietic progenitor cells in approximately 34% of patients with polycythemia vera (PV), depending on which stage of the disease the study was performed. This test is not useful unless the result is abnormal.
• Clonal assays: The formation of endogenous erythroid colonies in vitro (colony-forming unit, erythroid; burst-forming unit, erythroid) is a feature that was believed to be unique to polycythemia vera (PV), but tests for this are not widely available and are not standardized. Additionally, results have been reportedly found to be insensitive because (1) identical results can occur with other MPDs; (2) results can be similar, but at a lower level, in healthy individuals; and (3) positive results can be absent in patients with polycythemia vera (PV). A study by Mustjoki et al assessed the diagnostic role of the JAK2V617F mutation and spontaneous megakaryocytic or erythroid colony formation in patients with ET or polycythemia vera (PV).⁸ The investigators found 91% of the patients with PV and 57% of the patients with ET had the JAK2V617F mutation, and all showed spontaneous growth of erythroid progenitors. However, endogenous erythroid colony formation was also seen in 9 JAK2V617F mutation–negative patients.⁸ In addition, endogenous megakaryocytic colony formation was found in 59% of the patients with PV and 53% of the patients with ET. Seven patients with ET also displayed sole spontaneous megakaryocytic colony growth without spontaneous erythroid colony growth; these individuals were all JAK2 mutation negative, but 1 had MPL mutation.⁸ Mustjoki et al concluded that in vitro cultures of hematopoietic progenitors were sensitive diagnostic tools in their group of MPD patients who demonstrated JAK2 mutation–negative ET and patients with polycythemia vera displaying sole spontaneous erythroid or megakaryocytic colony growth.
• Bone marrow morphology and histology: Overall hypercellularity with expansion of all cell lines with megakaryocytic proliferation and the presence of myelofibrosis can help diagnose polycythemia vera (PV) and MPD, but patients with PV may have normal bone marrow findings. Again, these results are nonspecific and may be observed in the other Ph– negative MPDs.
• Clonal assays using G6PD markers: Clonality assays using the 2 markers for the G6PD gene expressed on females' X chromosomes can definitively demonstrate hematopoietic cells derived from a clone with a single G6PD marker associated with polycythemia vera (PV). This assay is not generally available clinically and is limited to female patients.
• Computed tomography (CT) scanning or ultrasonography: CT scanning and ultrasonography can detect nonpalpable splenomegaly, but the results for diagnosis of polycythemia vera (PV) have not been standardized.
• Research markers proposed to diagnose polycythemia vera (PV) and MPD
  • Thrombopoietin receptor MPL expression: In contrast to patients with secondary erythrocytosis, patients with polycythemia vera (PV), ET, or AMM frequently have impaired expression of MPL, showing low expression in megakaryocytes and in CD34-positive bone marrow cells.
  • Expression of PRV1 mRNA in granulocytes: PRV1 transcription is increased in circulating neutrophils in patients with polycythemia vera (PV) and in some patients with ET or AMM, but it is not increased in patients with CML or secondary erythrocytosis. PRV1 transcription is not differentially increased in the bone marrow hematopoietic progenitor cells of patients with MPD. Presently, if granulocytic PRV1 overexpression is present, then an MPD is highly likely. However, if PRV1 is not overexpressed, then an MPD cannot be excluded.

Causes

The causes of polycythemia vera (PV) are unknown, but a number of approaches are now being studied to define the molecular lesion or lesions. The JAK2 V617F mutation can give rise to a turned on cytokine receptor leading to pancytosis similar to the PV phenotype. This is similar to the biologic properties of the BCR/ABL abnormality in that they both mimic cytokine signaling.

• Clonality studies using a rare polymorphism in the G6PD gene demonstrate predominant expression of a single allele in all blood cell lines. X-chromosome inactivation studies have played a pivotal role in establishing current concepts of many hematologic malignancies. Approximately 90% of patients with polycythemia vera (PV) show a skewed pattern of X inactivation in all their blood cell lines, indicating support for the concept of a transformed multipotential stem cell.
• Cytogenetic studies show the presence of an abnormal karyotype in the hematopoietic progenitor cells in approximately 34% of patients with polycythemia vera (PV), depending on which stage of the disease the study was performed at. Approximately 20% of patients have cytogenetic abnormalities at diagnosis, increasing to more than 80% for those with more than 10 years of follow-up care.
• The following abnormalities have been observed in patients with polycythemia vera (PV). These are similar to the abnormal karyotypes observed in patients with myelodysplastic syndromes and other MPDs.
  • Deletion of 20q (8.4%)
  • Deletion of 13q (3%)
  • Trisomy 8 (7%)
  • Trisomy 9 (7%)
  • Trisomy of 1q (4%)
  • Deletion of 5q or monosomy 5 (3%)
  • Deletion of 7q or monosomy 7 (1%)

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