AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Polycythemia is the increase of the red blood cell count, hemoglobin, and total red blood cell 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 exist:

• 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.

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

• 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 current diagnostic criteria for polycythemia vera is now based on the World Health Organization (WHO) criteria for polycythemia vera, which includes the following:

• A criteria
• • A1 - Elevated red blood cell mass (>25% more than the mean normal predicted value) or hemoglobin >18.5 g/dL in men or >16.5 g/dL in women (or greater than the 99th percentile of method-specific reference range for age, sex, and altitude of residence)
  • A2 - No cause of secondary erythrocytosis, including absence of familial erythrocytosis, and no elevation of erythropoietin (Epo) due to hypoxia (arterial pO₂£92%), high oxygen affinity hemoglobin, truncated Epo receptor, or inappropriate Epo production by tumor
  • A3 - Splenomegaly
  • A4 - Clonal genetic abnormality other than Ph-chromosome or BCR/ABL fusion gene in marrow cells
  • A5 - Endogenous erythroid colony formation in vitro
• B criteria
• • B1 - Thrombocytosis greater than 400 X 10⁹/lb² and WBC greater than 12 X 10⁹/L
  • B3 - Bone marrow biopsy showing panmyelosis with prominent erythroid and megakaryocytic proliferation
  • B4 - Low serum erythropoietin levels

*A diagnosis of PV is made when both A1 and A2 criteria are present with any other category A criterion or both A1 and A2 criteria are present with any two category B criteria.

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], 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 red blood cell, 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 red blood cells, suggesting that some paracrine and autocrine function exists 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, red blood cell loss, and increased oxygen affinity of hemoglobin. In fact, Epo production has been observed to increase up to 1000-fold in severe hypoxia.

Pathophysiology

Primary polycythemia

The disease is considered to be a form of the myeloproliferative syndromes that include PV, essential thrombocythemia, agnogenic myeloid metaplasia, and myelofibrosis. The clonality of PV is well established and was first demonstrated by Adamson et al in 1976. 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, while other studies show defects in programmed cell death.

Until recently, the pathophysiology of PV was unclear. In 2005, significant progress in the understanding of PV was made by the discovery of an activating mutation in the tyrosine kinase JAK2, which now appears to cause most primary PV cases. The mutation in JAK2 is thought to possibly cause a hypersensitivity to Epo via the Epo receptor, although the effects of this mutation remain to be fully characterized. Familial clustering suggests a genetic predisposition.

PFCP is caused by a hypersensitivity of erythroid precursors to Epo. Several mutations have been identified in the Epo receptor (EPOR) gene; however, EPOR mutations have not been identified in all PFCP kindreds.

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.

Frequency

United States

Primary polycythemia is rare, with an overall prevalence of PV of 2 cases per 100,000 people. The median age is 60 years. Only 0.1% of cases of PV are observed in people younger than 20 years. Fewer than 20 cases of pediatric PV are 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 are related to 2 primary factors. The first includes complications related to hyperviscosity. The second relates to bone marrow–related complications. Untreated, the median survival time for these patients is 18 months. However, if patients are treated, survival is greatly extended, up to 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 PV are observed in the Ashkenazi Jewish population, and lower rates are seen in African Americans.

Sex

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

Age

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

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

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

Physical

• Signs
• • 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
  • For a long time, the pathophysiology was unclear, and primary polycythemias were thought to be due to 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 PV.
  • An acquired V617F mutation in JAK2 leads to constitutively activated JAK2. Activated JAK2 induces Epo hypersensitivity and, although not completely delineated as of yet, it is thought to be through an activating EPOR.
• • PFCP, which is commonly found to have mutations in the Epo receptor (EPOR) gene. Approximately 10 mutations have been identified.
  • Chuvash polycythemia, a congenital polycythemia first recognized in an endemic Russian population, has mutations in the von Hippel-Lindau (VHL) gene.
• Secondary polycythemia
• • Congenital causes include high affinity hemoglobin and 2,3-DPG deficiency.
  • 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Neonatal considerations (hematocrit >65%)

Normal intrauterine environment
Delayed cord clamping
Twin-twin transfusion
Maternal-fetal transfusion
Infant of a diabetic mother
Maternal smoking
Maternal heart disease
Maternal preeclampsia/eclampsia
Placental insufficiency
Maternal propranolol use
Intrauterine growth retardation
Neonatal thyroid toxicosis
Adrenal hyperplasia
Trisomy 21, trisomy 13, trisomy 18
Beckwith-Wiedemann syndrome

Hypoxia

Altitude
Cardiac disease (right to left shunt)
Lung disease (chronic obstructive lung disease)
Central hypoventilation

Hemoglobinopathy

High–oxygen affinity variety
Methemoglobin reductase deficiency
Chronic carbon monoxide exposure

Hormones

Malignant tumor (eg, renal carcinoma, Wilms tumor, hepatomas, adrenal tumors, cerebellar hemangioblastomas)
Renal disease (eg, cysts, hydronephrosis, benign renal tumors)
Adrenal disease (eg, virilizing hyperplasia, Cushing syndrome)
Anabolic steroid use

Familial/congenital polycythemia

2,3-Bisphosphoglycerate deficiency
Chuvash polycythemia

Relative erythrocytosis

Secondary to decreased plasma volume as with severe dehydration

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Primary polycythemia (The reference range values for the clinician's laboratory should be cross-correlated.)
• • CBC: Leukocytosis and thrombocytosis are commonly observed but not universal. Leukocytes are greater than 12 X 10⁹/L; platelets are greater than 400 X 10⁹/L. Large platelets are often observed. Platelets can be morphologically and qualitatively abnormal. Red cell mass is greater than 36 mL/kg in men and greater than 32 mL/kg in women. RBCs often have anisocytosis, basophilic stippling, and polychromatophilia.
  • Serum Epo: Epo levels may be within the reference range or decreased (reference range, 4-24 mU/mL).
  • Serum B-12: Serum B-12 levels are greater than 900 pg/mL (reference range, 130-785 pg/mL).
  • Leukocyte alkaline phosphatase: Activity is greater than 100 U/L (reference range adult levels, 30-120 U/L) because levels vary for age; check pediatric age-specific controls.
  • Uric acid: Uric acid levels are increased (reference range adult levels, 2-8 mg/dL). Because levels vary for age, check pediatric age-specific controls. The uric acid level can be within the reference range.
  • Elevated sedimentation rate
  • Spurious hyperkalemia
  • Increased blood viscosity
  • Artifactual prolongation of coagulation studies
  • Increased total blood volume
  • Endogenous erythroid colony formation in vitro is characteristic for PV; however, its specificity and sensitivity limits its use for diagnosis.
• Elevated serum Epo levels can be used to distinguish polycythemia vera (PV) from secondary polycythemia; elevated Epo levels are observed in the latter.

Imaging Studies

• CT scanning is indicated if physical examination reveals neurologic deficits.

Other Tests

• The need for bone marrow biopsy is still controversial. It may be helpful when trying to differentiate PV from other myeloproliferative disorders. Biopsy is not a part of the diagnostic criteria.
• Cytogenetics are not routinely performed but should be used if a question exists regarding the diagnosis and the differential includes malignancy, myelodysplastic syndrome, or other myeloproliferative disorders.

Histologic Findings

If a bone marrow biopsy is performed, the marrow is typically hypercellular, including all marrow elements and displaced marrow fat. The number and size of megakaryocytes are usually increased, stainable iron is decreased or absent, and, later in the disease course, fibrosis and marrow reticulin fibers are increased.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Primary polycythemia: The goals of therapy are to maximize survival while minimizing the complications of therapy as well as of the disease itself.
• • Phlebotomy and myelosuppressive chemotherapy are the cornerstones of therapy and have produced a median survival time of 9-14 years after the beginning of treatment. The goal of phlebotomy is to maintain normal red cell mass and blood volume, with a target hematocrit of 45%. The mean survival time of adult patients treated solely with phlebotomy is 13.9 years; however, a high risk of thromboembolic complications exists.
  • In the past, patients have been treated with chlorambucil and other alkylating agents such as pipobroman and busulfan. However, these patients exhibited the highest rates of secondary malignancy including acute leukemia, lymphocytic lymphomas, and skin and gastrointestinal carcinomas. The rates of malignancy appear lower with busulfan than with the other alkylating agents. Currently, these agents are rarely used.
  • Patients treated with phosphorus-32 (³²P) tolerate treatment well and have prolonged periods of remission. However, these patients also exhibit increased rates of acute leukemias (10-15%). The mean survival time with ³²P treatment is 10.9 years.
  • Studies suggest that the use of interferon alfa decreases the need for phlebotomy and decreases the risk of thrombotic events. Its use is limited by side effects, cost, and route of administration.
  • Recent studies using hydroxyurea as a myelosuppressive agent also show promise, reducing the need for phlebotomy. However, similarly to those treated with chlorambucil, these patients also experience higher rates of malignancy. Early clinical studies using imatinib are currently underway and are thus far inconclusive.
  • Current recommendations for treatment of young patients rely primarily on phlebotomy because the thrombosis is far less likely to occur in children and the long-term risks of leukemia over a longer life span are increased.
  • In the past, the use of anticoagulants, including antiplatelet drugs such as aspirin and dipyridamole (Persantine) had demonstrated increased risk of bleeding without an associated decrease in thrombotic events; therefore, anticoagulants have not previously been recommended. However, a large European study, results of which were published in the New England Journal of Medicine by Landolfi et al (2004), showed a decrease in thrombotic events in those patients receiving low-dose aspirin therapy and recommended aspirin therapy for those patients for whom no contraindications existed. This issue continues to remain under debate in the field of polycythemia treatment.
• Secondary polycythemia: Phlebotomy is used for symptomatic hyperviscosity. The goal is to treat the underlying cause of polycythemia.

Surgical Care

Surgery is not typically indicated. Occasionally, splenectomy is performed late in the course of the disease if massive splenomegaly causes adverse effects such as early satiety, anemia, or thrombocytopenia from sequestration.

Please note that these patients have a high risk of complications during surgical procedures.

Consultations

Consult a neurologist and neurosurgeon if evidence of a stroke is present.

Diet

Diet is unrestricted.

Activity

Contact sports and other activities should be limited for individuals in hypercoagulable and hypocoagulable states.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Current recommendations for treatment of young patients rely primarily on phlebotomy.

Drug Category: Antineoplastic agents

The following medications are not approved for pediatric polycythemia but are extrapolated from other pediatric treatment regimens, including leukemia and myelodysplastic syndrome.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

In/Out Patient Meds

• Allopurinol for hyperuricemia or gout
• Iron supplementation to manage the increased red cell production that may produce a functional iron deficiency that can cause red cell rigidity and increase the risk of stroke
• Folate
• Cimetidine for pruritus and upper GI distress

Complications

• Vascular occlusive events - Splenic infarcts, thrombosis (cerebral, portal vein, pulmonary embolus)
• Hemorrhage
• Marrow fibrosis resulting in pancytopenia
• Malignancy - Acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), lymphoma
• Hyperuricemia - Renal stones, nephropathy, gout
• Budd-Chiari syndrome

Prognosis

• The median survival time is 18 months for untreated patients and 9-14 years for treated patients.

Patient Education

• Inform patients that they are prone to surgical complications and are at high risk in trauma situations secondary to coagulopathies.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Polycythemia vera is exceedingly rare in children. Ensuring that the erythroid proliferation is not secondary to elevated Epo levels and another underlying disease is imperative.
• Alert patients and parents to the complications associated with the state of hyperviscosity. Inform them of the long-term effects with and without current treatment options.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: May 19, 2006