eMedicine Specialties > Pediatrics: General Medicine > Hematology

Polycythemia

Author: Kristin Baird, MD, Staff Clinician, Pediatric Oncology Branch
Coauthor(s): Kathleen M Sakamoto, MD, PhD, Professor and Chief, Division of Hematology-Oncology, Vice-Chair of Research, Mattel Children's Hospital at UCLA; Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA and California Nanosystems Institute and Molecular Biology, UCLA; Yu-Waye Chu MD, Consulting Staff, Stem Cell Transplantation and Hematologic Diseases Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute
Contributor Information and Disclosures

Updated: Dec 8, 2008

Introduction

Background

Polycythemia is the increase of the RBC count, hemoglobin, and total RBC volume, accompanied by an increase in total blood volume. This must be distinguished from relative erythrocytosis secondary to fluid loss or decreased intake; this distinction can be made easily on a clinical basis. Polycythemia accompanies increased total blood volume, whereas relative erythrocytosis does not. Two basic categories of polycythemia are recognized:

• Primary polycythemias are due to factors intrinsic to red cell precursors and include the diagnoses of primary familial and congenital polycythemia (PFCP) and polycythemia vera (PV).
• Secondary polycythemias are caused by factors extrinsic to red cell precursors.

In normal hematopoiesis, myeloid stem cells give rise to erythrocytes, platelets, granulocytes, eosinophils, basophils, and monocytes. The production of each lineage is a function of cell proliferation, differentiation, and apoptosis. These various stages of differentiation rely on multiple interrelated processes. Protein growth factors, known as cytokines, stimulate proliferation of the multilineage cells (eg, interleukin [IL]-3, granulocyte-macrophage colony-stimulating activity [GM-CSF]). Other factors primarily stimulate the growth of committed progenitors (eg, GM-CSF, macrophage colony-stimulating factor [M-CSF], erythropoietin [Epo]).

Erythropoiesis is a carefully ordered sequence of events. Initially occurring in fetal hepatocytes, the process is taken over by the bone marrow in the child and adult. Although multiple cytokines and growth factors are dedicated to the proliferation of the RBC, the primary regulator is Epo. Red cell development is initially regulated by stem cell factor (SCF), which commits hematopoietic stem cells to develop into erythroid progenitors. Subsequently, Epo continues to stimulate the development and terminal differentiation of these progenitors. In the fetus, Epo is produced by monocytes and macrophages found in the liver. After birth, Epo is produced in the kidneys; however, Epo messenger RNA (mRNA) and Epo protein are also found in the brain and in RBCs, suggesting that some paracrine and autocrine function is present as well.

Erythropoiesis escalates as increased expression of the EPO gene produces higher levels of circulating Epo. EPO gene expression is known to be affected by multiple factors, including hypoxemia, transition metals (Co²⁺, Ni²⁺, Mn²⁺), and iron chelators. However, the major influence is hypoxia, including factors of decreased oxygen tension, RBC loss, and increased oxygen affinity of hemoglobin. In fact, Epo production has been observed to increase as much as 1000-fold in severe hypoxia.

Polycythemia vera

Earlier diagnostic criteria for polycythemia vera included the following (based on the Polycythemia Vera Study Group Diagnostic Criteria):¹

• Red cell mass greater than 36 mL/kg for men and greater than 32 mL/kg for women
• Arterial oxygen saturation greater than 92%
• Splenomegaly or 2 of the following:
  • Thrombocytosis greater than 400 X 10⁹/L
  • Leukocytosis greater than 12 X 10⁹/L
  • Leukocyte alkaline phosphatase activity greater than 100 U/L in adults (reference range, 30-120 U/L) without fever or infection
  • Serum vitamin B-12 greater than 900 pg/mL (reference range, 130-785 pg/mL)
  • Unsaturated vitamin B-12 binding capacity greater than 2200 pg/mL

The reference range for the clinician's laboratory should be cross-correlated. The diagnostic criteria have undergone scrutiny and several revisions in recent years. In 2001, the World Health Organization (WHO) proposed a classification system for chronic myeloid neoplasms.² The diagnosis of polycythemia vera fell under the broader category of chronic myeloproliferative diseases. This set of criteria quickly lost favor because of lack of validation³ and the discovery of JAK2 mutations in adult patients.^4,5,6,7,8,9

Currently, the diagnosis of polycythemia vera is based on the 2008 WHO criteria, which has integrated molecular diagnostics into the evaluation and screening for polycythemia vera.¹⁰ A diagnosis of polycythemia vera is made when both major and one minor criterion are present or when the first major criterion is present with any two minor criteria. The current criteria include the following:

• Major criteria
  1. Hemoglobin level of more than 18.5 g/dL in men (>16.5 g/dL in women) or other evidence of increased red cell volume
     
     or
     
     Hemoglobin or hematocrit level higher than 99th percentile of method-specific reference range for age, sex, altitude, of residence
     
     or
     
     Hemoglobin level of more 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 an individual’s baseline value that can not be attributed to correction of iron deficiency
     
     or
     
     Elevated red cell mass greater than 25% above mean normal predicted value
  2. Presence of JAK2^V617F or similar mutation (eg, JAK2 exon 12 mutation)
• Minor criteria
  1. Bone marrow trilineage myeloproliferation
  2. Subnormal serum erythropoietin levels
  3. Endogenous erythroid colony growth

Pathophysiology

Primary polycythemia

The disease is considered to be a form of the myeloproliferative syndromes that include polycythemia vera, essential thrombocythemia, agnogenic myeloid metaplasia, and myelofibrosis. The clonality of polycythemia vera is well established and was first demonstrated by Adamson et al in 1976.¹¹ Subsequent studies suggest hypersensitivity of the myeloid progenitor cells to growth factors, including Epo, IL-3, SCF, GM-CSF, and insulinlike growth factor (IGF)–1, whereas other studies show defects in programmed cell death.

Until recently, the pathophysiology of polycythemia vera was unclear. In 2005, significant progress in the understanding of polycythemia vera was made with the discovery of an activating mutation in the tyrosine kinase JAK2 (JAK2^V617F ), which now appears to cause most primary cases in adults.^4,5,6,7,8 Several other mutations of JAK2 have since been described (eg, exon 12, JAK2^{H538-K539delinsI} ).^9,12 The JAK2 mutations are thought to possibly cause hypersensitivity to Epo via the Epo receptor, although the effects of this mutation remain to be fully characterized.

Familial clustering suggests a genetic predisposition. Whether these mutations are responsible for the development of polycythemia vera in pediatric patients is unclear. Some groups have reported lower rates of JAK2 mutations in children compared with adults,^13,14,15 whereas other groups have seen similar rates with complete or near complete presence of JAK2^V617F and other JAK2 mutations.¹²

PFCP is caused by a hypersensitivity of erythroid precursors to Epo. Several mutations (approximately 14) have been identified in the Epo receptor (EPOR) gene; however, EPOR mutations have not been identified in all PFCP kindreds. Most identified EPOR mutations (11) cause truncation of the c-terminal cytoplasmic receptor domain of the receptor. These truncated receptors have heightened sensitivity to circulating Epo due to a lack of negative feedback regulation.¹⁶

Secondary polycythemia

Secondary polycythemia may result from functional hypoxia induced by lung disease, heart disease, increased altitude (hemoglobin increase of 4% for each 1000-m increase in altitude), congenital methemoglobinemia, and other high–oxygen affinity hemoglobinopathies stimulating increased Epo production. Secondary polycythemia may also result from increased Epo production secondary to benign and malignant Epo-secreting lesions. Secondary polycythemia may also be a benign familial polycythemia.

Chuvash polycythemia, a congenital polycythemia first recognized in an endemic Russian population, has mutations in the von Hippel-Lindau (VHL) gene, which is associated with a perturbed oxygen dependent regulation of Epo synthesis.

Secondary polycythemia of the newborn is fairly common and is a result of either chronic or acute fetal hypoxia or delayed cord clamping and stripping of the umbilical cord.¹⁷

Frequency

United States

Primary polycythemia is rare; the overall prevalence of polycythemia vera is 2 cases per 100,000 people. The median age is 60 years. Only 0.1% of cases of polycythemia vera are observed in individuals younger than 20 years. Fewer than 50 cases of pediatric polycythemia vera have been reported in the literature. Secondary polycythemia is seen in 1-5% of all newborns in the United States.

International

Polycythemia vera has a similar incidence in Western Europe as in the United States, and occurrence rates are very low in Africa and Asia (as low as 2 cases per million per year in Japan).

Mortality/Morbidity

Death rates for children are unavailable. The complications found in polycythemia vera are related to 2 primary factors. The first includes complications related to hyperviscosity. The second involves bone marrow–related complications. Untreated, the median survival time for these patients is 18 months. However, if patients are treated, survival is greatly extended, as many as 10-15 years with phlebotomy alone. The causes of death in adults are as follows:

• Thrombosis/thromboembolism (30-40%)
• Acute myelogenous leukemia (19%)
• Other malignancies (15%)
• Hemorrhage (2-10%)
• Myelofibrosis/myeloid metaplasia (4%)
• Other (25%)

Race

In the United States, higher rates of polycythemia vera are observed in the Ashkenazi Jewish population, and lower rates are seen in blacks.

Sex

The male-to-female ratio is 1.2-2.2:1 in adults and 1:1 in children.

Age

The median age for polycythemia vera is 60 years. Only 0.1% of polycythemia cases occur in people younger than 20 years.

Clinical

History

The clinical features associated with polycythemia are a direct result of the increase in red cell mass, which causes an expansion of blood volume. Signs of hyperviscosity and increased metabolism accompany polycythemia. A thorough history must be obtained for a history of cardiac, pulmonary (including sleep apnea), hepatic or renal disease in the patient and a complete family history for evidence of familial polycythemia.

Symptoms include the following:

• Headache
• Weight loss
• Weakness or malaise
• Dizziness
• Pruritus
• Bruising
• Ruddy or red appearance of the skin
• Diaphoresis/dyspnea
• Visual disturbance
• Paresthesias
• Arthropathies
• GI - Fullness, thirst, abdominal discomfort, constipation

Physical

A thorough physical must be completed and include specific evaluation for signs and symptoms of underlying disease that may cause secondary polycythemia; it must include pulse oximetry, careful cardiac and pulmonary evaluation, and evaluation for signs of renal or hepatic disease.

Signs of polycythemia include the following:

• Rubor, especially facial rubor
• Skin plethora
• Hypertension, both systolic and diastolic
• Hepatomegaly
• Splenomegaly
• Conjunctival plethora (engorged vessels in the bulbar conjunctiva)
• Ecchymosis
• Cardiac hypertrophy (rarely observed)

Causes

• Primary polycythemia
  • In the past, the pathophysiology was unclear, and primary polycythemias were thought to be due to both inherited and acquired mutations in erythroid progenitors, leading to abnormal red cell proliferation. However, in 2005, an activating mutation found in the tyrosine kinase JAK2 was implicated as the causative factor in polycythemia vera (PV). Five separate groups identified this mutation in approximately 80% (56-97% reported) of patients with polycythemia vera.
  • This acquired V617F mutation in JAK2 leads to constitutively activated JAK2. Activated JAK2 induces erythropoietin (Epo) hypersensitivity; although not yet completely delineated, it is thought to act through an activating EPOR.
  • Additional JAK2 mutations have been identified in exon 12,⁹ JAK2^{H538-K539delinsI} ,¹⁸ and others.¹⁹
  • Primary familial and congenital polycythemia (PFCP), which is commonly found to have mutations in the Epo receptor (EPOR) gene. Approximately 14 mutations have been identified.
• Secondary polycythemia
  • Congenital causes include high affinity hemoglobin and 2,3-Bisphosphoglycerate (2,3-BPG) deficiency.
  • Chuvash polycythemia, a congenital polycythemia first recognized in an endemic Russian population, has mutations in the von Hippel-Lindau (VHL) gene, which is associated with a perturbed oxygen-dependent regulation of Epo synthesis.
  • Acquired causes included hypoxemia and Epo-secreting tumors.
  • Polycythemia of the newborn usually results from a poor intrauterine environment or hypoxic insult during labor or delivery.

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