Bone marrow biopsy.

The bone marrow in polycythemia vera is hypercellular as a result of an

increase in myeloid, erythroid, and megakaryocytic elements. (Hematoxylin-eosin stain, ×40.)
Bone marrow biopsy.The bone marrow in polycythemia vera is hypercellular as a result of an
increase in myeloid, erythroid, and megakaryocytic elements. (Hematoxylin-eosin stain, ×40.)

Polycythemia vera

Definition and Etiology

PV is a clonal disorder characterized by the overproduction of mature red blood cells in the bone
marrow.1 Myeloid and megakaryocytic elements are also often increased. No obvious cause
exists.4 Genetic and environmental factors have been implicated in rare cases. Familial PV has
been associated with mutation of the erythropoietin receptor.5 An increased number of cases has
been reported in survivors of the atomic bomb explosion in Hiroshima during World War II.

Epidemiology

The disorder typically occurs in the sixth or seventh decade of life. The prevalence of the disease
is approximately 5 per million population; it occurs more commonly in men and in men and
women of East European Jewish ancestry.1,4
Pathophysiology

The primary defect involves a pluripotent stem cell capable of differentiating into red blood
cells, granulocytes, and platelets.4 Clonality has been demonstrated through glucose-6-phosphate
dehydrogenase (G6PD) studies as well as restriction fragment length polymorphism of the active
X chromosome.5 Erythroid precursors in PV are exquisitely sensitive to erythropoietin, which
leads to increased red blood cell production. Precursors in PV are also more responsive to
cytokines such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor, and
steel factor. Myeloid and megakaryocytic elements are often increased in the bone marrow (Fig.
1). More than 60% of patients have endogenous megakaryocyte colony unit formation.

Figure 1: Click to Enlarge

Increased red blood cell production in PV leads to an increased red cell mass and increased blood
viscosity. This in turn can lead to arterial or venous thrombosis, bleeding, or both.1 The
hematocrit is directly proportional to the number of thrombotic events.4 Investigators have
demonstrated a reduction in cerebral blood flow in patients with hematocrits between 53% and
62%.5 An increased platelet count can also contribute to bleeding and thrombosis. Although
platelet aggregation abnormalities exist in most patients, these abnormalities do not appear to
correlate with the risk of bleeding or thrombosis. Increased production and breakdown of blood
cells can lead to hyperuricemia and hypermetabolism.

Signs and Symptoms

Patients may be asymptomatic at the time of diagnosis and have only isolated splenomegaly,
erythrocytosis, or thrombocytosis.5 However, most patients develop symptoms as the hematocrit,
platelet count, or both increase. An elevated white blood cell (WBC) count is found in 50% to
60% of patients. Symptoms of hyperviscosity associated with an elevated hematocrit include
headache, blurred vision, and plethora.1

Thrombosis in small blood vessels can lead to cyanosis, erythromelalgia (painful vessel dilation
in the extremities), ulceration, or gangrene in the fingers or toes. Thrombosis in larger vessels
can lead to myocardial infarction, deep venous thrombosis, transient ischemic attacks, and
stroke. A cerebrovascular event precedes the diagnosis in 35% of patients with PV.4 Unusual
sites of thromboses also tend to be seen more frequently in PV—splenic, hepatic, portal, and
mesenteric.

Of patients with Budd-Chiari syndrome (hepatic–inferior vena cava obstruction), 10% have
coexisting PV. Abnormalities in platelet function lead to epistaxis, bruising, and gastrointestinal
and gingival bleeding in 2% to 10% of patients. Severe bleeding episodes are unusual.
Hypermetabolism caused by increased blood cell turnover can lead to hyperuricemia, gout,
stomach ulcers, weight loss, and kidney stones. Pruritis is especially common after a warm bath
or shower. As the disease progresses, many patients develop abdominal pain secondary to
hepatomegaly, splenomegaly, or both.

Diagnosis

PV should be suspected in men with a hematocrit higher than 50% and in women with a
hematocrit higher than 45%.5 Confirmation of an elevated hematocrit involves measuring a red
blood cell mass1 using direct tagging of red blood cells with chromium 51, a test unfortunately
not widely available. These studies might not be needed in men with hematocrits higher than
60% or in women with hematocrits higher than 55%.

Secondary causes of polycythemia also need to be ruled out: hypoxia caused by heart or lung
disease or smoking and cysts or tumors in the liver, kidneys, or brain, all of which can secrete
erythropoietin. Serum erythropoietin levels should be low to normal in patients with PV but high
in patients with secondary polycythemia, although there may be some overlap. Molecular testing
for the JAK2 V617 or other functionally similar mutation plays a central role in the diagnosis of
PV as a way of separating neoplastic from reactive myeloid proliferations.

The initial diagnostic criteria defined by the PVSG (Polycythemia Vera Study Group) have
undergone changes over the last several years. The current diagnostic criteria have been
published by WHO.6 A diagnosis of PV is met if a patient has the first two A criteria together
with any other A criterion or two B criteria. New proposed revised WHO criteria for
polycythemia vera include major and minor criteria, and diagnosis will require the presence of
both major criteria and 1 minor criterion or the presence of the first major criterion together with
2 minor criteria.3

A Criteria

 Elevated red cell mass more than 25% above mean normal predicted value, or
hemoglobin higher than 18.5 g/dL in men or 16.5 g/dL in women, or higher than the 99th
percentile of method-specific reference range for age, sex, and altitude of residence
 No cause of secondary erythrocytosis, including:
o Absence of familial erythrocytosis
o No elevation of erythropoietin caused by:
1. Hypoxia (arterial Po2 <92%)
2. High oxygen affinity hemoglobin
3. Truncated erythropoietin receptor
4. Inappropriate erythropoietin production by tumor
 Splenomegaly
 Clonal genetic abnormality other than the Philadelphia chromosome or BCR/ABL1 fusion
gene in marrow cells
 Endogenous erythroid colony formation in vitro

B Criteria
  Thrombocytosis higher than 400 × 109/ L
 Leukocytosis higher than 12 × 109/ L
 Bone marrow biopsy showing panmyelosis with prominent erythroid and megakaryocyte
proliferation
 Low serum erythropoietin levels

Major Criteria

 Hemoglobin greater than 18.5 g/dL in men, 16.5 g/dL in women or other evidence of

increased red cell volume
1. Hemoglobin or hematocrit greater than the 99th percentile of method-specific
reference range for age, sex, altitude of residence or hemoglobin greater than
17 g/dL in men, 15 g/dL in women if associated with a documented and sustained
increase of at least 2 g/dL from a patient's baseline value that cannot be attributed
to correction of iron deficiency, or
2. Elevated red cell mass greater than 25% above mean normal predicted value
 Presence of JAK2 V617F or other functionally similar mutation such as JAK2 exon 12
mutation

Minor Criteria

 Bone marrow biopsy showing hypercellularity for age with trilineage growth
(panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation
 Serum erythropoietin level below the reference range for normal
 Endogenous erythroid colony formation in vitro

Treatment

Treatment of PV focuses on decreasing the hemoglobin level, thereby reducing plasma viscosity
and its attendant complications. Therapeutic options include phlebotomy, radioactive phosphorus
(32P), and myelosuppressive agents. The goal of therapy is a hematocrit of 45% on the basis of
cerebral blood flow studies.4 Several clinical trials have tried to address the optimal treatment of
PV.

Treatment for PV should be risk-adapted.6 Patients at high risk for thrombosis include patients
older than 60 years and those with a prior history of thrombosis. Low-risk patients include those
who are younger than 60 years with no history of thrombosis, a platelet count below 1500 ×
109/L, and the absence of cardiovascular risk factors (e.g., smoking, hypertension, congestive
heart failure). In the PSVG-01 study, thrombotic events were increased in the phlebotomy arm,
particularly in patients with a history of thrombosis, advanced age, or high phlebotomy
requirement.4 Therefore, high-risk patients should be treated with phlebotomy plus hydroxyurea
or interferon. Hydroxyurea is typically used as first-line therapy. However, interferon should be
used in women of childbearing age and in patients who cannot tolerate hydroxyurea. Low-risk or
intermediate-risk patients may be treated with phlebotomy alone.
In the PVSG-01 study, there was an increased risk of leukemia in the 32P and chlorambucil arms
(two or three times that seen in the phlebotomy arm).4 Because of the increased leukemogenicity
associated with chlorambucil, hydroxyurea, which inhibits ribonucleotide reductase, is now the
most widely used myelosuppressive agent. Side effects of hydroxyurea include
myelosuppression, macrocytosis, leg ulcers, increased creatinine level, and jaundice.5 A recent
large study has demonstrated no increased incidence of leukemia in PV patients treated with
hydroxyurea.6 For older high-risk patients, 32P can be used to help with issues of compliance and
convenience, especially if the patient's life expectancy is less than 10 years.

Myelosuppressive agents should also be used for symptomatic splenomegaly, pruritis intractable
to antihistamines, or patients with poor venous access.4 Interferon-alfa may also be used in the
place of hydroxyurea for myelosuppression, particularly in younger patients and n patients with
intractable pruritus. Side effects of interferon include flulike syndromes, fevers, neuritis, and
fatigue.5 Patients with PV who are undergoing surgery are at extremely high risk of developing
postoperative complications if their erythrocytosis is not controlled before surgery.

Patients with PV and no drug contraindications or evidence of acquired von Willebrand

syndrome should be treated with low-dose aspirin.6 One study has demonstrated an
antithrombotic benefit for low-dose aspirin (100 mg/day) in patients already receiving treatment
for PV.6 Patients with erythromelalgia also experience a rapid relief of their symptoms after low-
dose aspirin.4

Outcomes

The median survival is more than 10 years with treatment. The major causes of death in
untreated patients are thrombosis and hemorrhage.1 Less than 10% of patients develop acute
myelogenous leukemia.1 Fifteen percent of patients develop postpolycythemic myelofibrosis
(MF) at an average interval of 10 years from diagnosis.4 Once they develop MF, most patients
die within 3 years.4 MF often transforms to acute myelogenous leukemia.

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