eMedicine Specialties > Pediatrics: General Medicine > Hematology

Polycythemia

Sun Choo, MD, Pediatric Resident, University of California Los Angeles
Kristin Baird, MD, Staff Clinician, Pediatric Oncology Branch; 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

Updated: Nov 2, 2009

Introduction

Background

Polycythemia is characterized by an increase in absolute quantity of red cells or total RBC volume. In contrast, relative polycythemia (pseudoerythrocytosis) is secondary to fluid loss or decreased fluid intake resulting in hemoconcentration. Two basic categories of polycythemia are recognized:

• Primary polycythemias due to factors intrinsic to red cell precursors, including primary familial and congenital polycythemia (PFCP), idiopathic erythrocytosis, and polycythemia vera (PV).
• Secondary polycythemias are caused by factors extrinsic to red cell precursors and include a physiologic-approproriate erythropoietin (epo) production in response to tissue hypoxia and physiologic-inappropriate erythropoietin production not in response to tissue hypoxia.

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.

Bone marrow film at 400X magnification demonstrating dominance of erythropoiesis. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

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.

Pathophysiology

Primary polycythemia is due to factors intrinsic to red cell precursors caused by acquired and inherited mutations. It includes the diagnoses of primary familial and congenital polycythemia, idiopathic erythrocytosis, and polycythemia vera.

Polycythemia vera, also known as polycythemia rubra vera, is a chronic clonal myleoproliferative disorder characterized by clonal proliferation of myeloid cells. Currently, the diagnosis of polycythemia vera is based on the 2008 World Health Organization (WHO) criteria, which has integrated molecular diagnostics into the evaluation and screening for polycythemia vera.¹ 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 Epo levels
  3. Endogenous erythroid colony growth

Earlier diagnostic criteria for polycythemia vera included the following (based on the Polycythemia Vera Study Group Diagnostic Criteria):²

• 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

Polycythemia vera is considered to be a form of the myeloproliferative syndromes that include polycythemia vera, essential thrombocythemia, and myelofibrosis (agnogenic myeloid metaplasia). The clonality of polycythemia vera is well established and was first demonstrated by Adamson et al in 1976.³ 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 a gain of function mutation in the tyrosine kinase JAK2 (JAK2^V617F ), which now appears to cause most primary cases in adults.^4,5,6,7,8 . JAK2^V617F is detectable in more than 95% of patients diagnosed with polycythemia vera.⁹ Several other mutations of JAK2 have since been described (eg, exon 12, JAK2^{H538-K539delinsI} ).^10,11 The JAK2 mutations cause the enzyme to be constitutively active allowing cytokine independent proliferation of cell lines that express Epo receptors causing these cells to be hypersensitive to cytokines.⁹

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,^12,13,14 whereas other groups have seen similar rates with complete or near complete presence of JAK2^V617F and other JAK2 mutations.¹¹ . The prevalence of familial cases of chronic myeloproliferative disease is thought to be at least 7.6%, and the pattern of inheritance is consistent with an autosomal dominant pattern with decreased penetrance. Evidence of disease anticipation is noted in the second generation, presenting at a significantly younger age. However, clinical and hematological features in familial cases have not been shown to differ from those of sporadic mutations.¹⁵

Primary familial and congenital polycythemia is caused by a mutation in the Epo receptor resulting in hypersensitivity 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 This autosomal dominant trait does not necessarily carry an adverse prognosis in early life but is associated with an increased risk of thrombotic and vascular mortality in later life.¹⁷

Chuvash polycythemia, a congenital polycythemia first recognized in an endemic Russian population, is a variant of primary familial and congenital polycythemia and has mutations in the von Hippel-Lindau (VHL) gene, which is associated with a mutation in the oxygen-sensing pathway that regulates Epo synthesis. Polycythemia outside of Russia found to have a similar mechanism is referred to as primary proliferative polycythemia.¹⁷

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.

High altitude erythrocytosis is evident within the first week of high-altitude exposure. A sharp increase in Epo production is noticeable, with associated mobilization of iron stores with evidence of iron-deficient erythropoiesis.¹⁷

Abnormal high-affinity hemoglobin mutations characterized by left shift in the oxygen-hemoglobin dissociation curves lead to erythrocytosis. In most cases, no treatment is indicated for these patients because the erythrocytosis is compensatory. Similarly, in familial polycythemia with defects in 2,3-DPG metabolism, a left shift in the oxygen-hemoglobin curve is noted with a physiological response of polycythemia.¹⁷

Secondary polycythemia of the newborn is fairly common and is seen in 1-5% of all newborns in the United States. It results from either chronic or acute fetal hypoxia or delayed cord clamping and stripping of the umbilical cord.¹⁸

Aberrant erythropoietin production is seen with various renal, liver, CNS disorders and leads to physiologically inappropriate secondary polycythemia. Renal disorders frequently associated with polycythemia include renal cell carcinoma, Wilms tumor, polycystic kidneys, and renal transplantation. Erythrocytosis has also been documented in patients with hepatocellular carcinoma.

Frequency

United States

Primary polycythemia is rare; the overall prevalence of polycythemia vera is 22 cases per 100,000 people.¹⁹ The annual incidence of polycythemia vera is 2 cases per 100,000 people. The median age is 70 years,²⁰ with only 0.1% of cases of polycythemia vera observed in individuals younger than 20 years. Fewer than 50 cases of pediatric polycythemia vera have been reported in the literature. Polycythemia vera is less likely in blacks than in individuals of European ancestry, with a higher incidence in Ashkenazi Jews.

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%) -Myocardial infarctions, deep vein thrombosis, pulmonary embolus, portal splenic and mesenteric vein thrombosis
• Acute myelogenous leukemia (19%)
• Other malignancies (15%)
• Hemorrhage (2-10%)
• Myelofibrosis/myeloid metaplasia (4%)
• Other (25%)

In the neonatal period, polycythemia-induced hyperviscosity can lead to altered blood flow and subsequently affect organ function. Infants with polycythemia are at increased risk for necrotizing enterocolitis, renal dysfunction, hypoglycemia, and increased pulmonary vascular resistance with resultant hypoxia and cyanosis. Although initially thought to cause neurologic dysfunction, the decrease in cerebral blood flow seen in newborns with polycythemia is a physiologic response and does not appear to cause cerebral ischemia.¹⁸

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.¹⁷

Age

The median age for polycythemia vera is 70 years.²⁰ 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, vertigo, insomnia
• Weakness or malaise
• Pruritus (especially after exposure to warm water)
• Bruising
• Ruddy or red appearance
• Erythromelalgia (burning pain, warmth, and redness of extremities)
• Diaphoresis/dyspnea
• Visual disturbance
• Ringing in the ears
• Paresthesias
• Arthropathies
• Weight loss
• GI - Fullness, thirst, abdominal discomfort, constipation

Physical

A thorough physical examination 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 and sparing of the trunk
• Skin plethora
• Hypertension, both systolic and diastolic
• Hepatomegaly
• Splenomegaly - Usually feels hard and smooth and occurs in more than two thirds of patients
• Conjunctival plethora (engorged vessels in the bulbar conjunctiva)
• Ecchymosis
• Cardiac hypertrophy (rarely observed)

Causes

• Primary polycythemia (due to factors intrinsic to the red cell precursors)
  • 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). This mutation is found in more than 95% of patients with polycythemia vera.⁹
  • The JAK2 ^V617F mutation is a point mutation that causes a substitution of phenylalanine for valine in exon 14. The mutation causes the enzyme to be constitutively active, allowing cytokine-independent proliferation of cell lines that express erythropoietin receptors, causing these cells to be hypersensitive to cytokines. This mutation is seen in polycythemia vera, essential thrombocythemia, and primary myelofibrosis.⁹
  • Additional JAK2 mutations have been identified in exon 12,¹⁰ JAK2^{H538-K539delinsI} ,²¹ and others.²² . Exon 12 JAK2 mutations appear specific for polycythemia vera and idiopathic erythrocytosis.⁹
  • Patients with primary familial and congenital polycythemia (PFCP) are commonly found to have mutations in the Epo receptor (EPOR) gene. Approximately 14 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, which is associated with a perturbed oxygen-dependent regulation of Epo synthesis.
• Secondary polycythemia (caused by factors extrinsic to red cell precursors that lead to insufficient oxygen supply to tissues)
  • High-altitude erythrocytosis
  • Pulmonary disease - Chronic obstructive pulmonary disease, diffuse pulmonary infiltrates, kyphoscoliosis, chronic cor pulmonale
  • Cyanotic heart disease
  • Hypoventilation syndromes -Obstructive sleep apnea
  • Epo-secreting tumors - Renal cell carcinoma, hepatocellular carcinoma
• Polycythemia of the newborn - Usually results from a poor intrauterine environment or hypoxic insult during labor or delivery
• Congenital causes - High-affinity hemoglobin and 2,3-Bisphosphoglycerate (2,3-BPG) deficiency

Differential Diagnoses

Methemoglobinemia
Polycythemia
Polycythemia of the Newborn
Polycythemia Vera

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, sleep apnea)
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

Laboratory Studies

The reference range values for the clinician's laboratory findings in polycythemia should be cross-correlated.

• Red cell mass: This is less than 25% of predicted values.
• CBC count: Leukocytosis and thrombocytosis are commonly observed but not universal in patients with polycythemia. 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 erythropoietin (Epo): Elevated serum Epo levels can be used to distinguish polycythemia vera (PV) from secondary polycythemia. Elevated Epo levels are observed in secondary polycythemia. Low Epo levels suggest primary familial and congenital polycythemia (PFCP) or polycythemia vera, but Epo levels may be normal.
• Hemoglobin: Hemoglobin analysis is indicated in patients with inadequately high serum Epo levels. Oxygen dissociation curves and hemoglobin electrophoresis can be used to assess for high oxygen affinity mutants and 2,3-Bisphosphoglycerate deficiency (2,3-BPG) deficiency.
• Serum B-12: Serum B-12 levels are greater than 900 pg/mL (reference range, 130-785 pg/mL), resulting from transcobalamin release from an increased granulocytic mass.
• 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
• Endogenous erythroid colony formation: In vitro, this is characteristic for polycythemia vera; however, its specificity and sensitivity limits its use for diagnosis.
• Gene testing: Screen for EPOR mutation and JAK2 mutation if primary polycythemia is suspected.
• Molecular analysis: Consider molecular analysis of the VHL gene.

Imaging Studies

• Abdominal ultrasonography is indicated to exclude underlying renal and hepatic pathology.
• CT scanning is indicated if physical examination reveals neurologic deficits.

Other Tests

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

Histologic Findings

• If a bone marrow biopsy is performed, the marrow in polycythemia vera is typically hypercellular, including all marrow elements and displaced marrow fat.
• The number of megakaryocytes is usually increased with wide variation in size.
• Stainable iron is decreased or absent, and, later in the disease course, fibrosis and marrow reticulin fibers are increased.²³

Treatment

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 less than 45% for men and less than 42% for women. The mean survival time of adult patients treated solely with phlebotomy is 13.9 years; however, a high risk of thromboembolic complications is observed.
  • In the past, the use of anticoagulants, including antiplatelet drugs such as aspirin and dipyridamole (Persantine), was associated with an 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,²⁴ 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 were noted.
  • Hydroxyurea as a myelosuppressive agent is also widely used in high-risk patients with polycythemia vera (ie, >60 y, history of thrombosis) who require cytoreductive therapy, reducing the need for phlebotomy.²⁵ However, similarly to those treated with chlorambucil, these patients also experience higher rates of malignancy.
  • Interferon alpha is effective in eliminating J AK2^V617F expression and inducing hematologic remission. Its use is limited by side effects, cost, and route of administration. The pegylated form and low dose treatment has decreased the rate of discontinuation of the drug secondary to side effects. In a French study, patients with polycythemia vera treated with interferon alpha showed a high rate of hematologic and molecular response.²⁶
  • In the past, patients have been treated with chlorambucil and busulfan. However, these patients exhibited the highest rates of secondary malignancy including acute leukemia, lymphocytic lymphomas, and skin and GI 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 (³² P) 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 with³² P treatment is 10.9 years; therefore, phosphorous is rarely used.
  • Current recommendations for treatment of young patients primarily rely 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.
• 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

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

Antineoplastic agents

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

Interferon alfa 2a and 2b (Roferon-A [alfa-2a], Intron A [alfa-2b])

A recombinant purified protein used IV for CML, hairy cell leukemia, and Kaposi sarcoma. Inhibits cellular growth and alters cell differentiation.

Dosing

Adult

CML: 9 million U/d IM/SC; initiate with 3 million U/d, increase by 3 million U every third day; not to exceed 9 million U/d

Pediatric

2.5-5 million U/d IM/SC

Interactions

Theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in brain metastases, severe hepatic or renal insufficiencies, seizure disorders, multiple sclerosis, or compromised CNS; use has been associated with depression, suicidal ideation and suicide attempts, and GI hemorrhage

Chlorambucil (Leukeran)

Antineoplastic alkylating agent of nitrogen mustard type used for CLL, giant follicular lymphoma, Hodgkin lymphoma, and lymphosarcoma.

Dosing

Adult

0.1-0.2 mg/kg/d PO; adjust dose according to blood count

Pediatric

Not established; limited data available

Interactions

Live virus vaccines (eg, MMR) may result in severe or fatal infection when used in immunosuppressed patients

Contraindications

Documented hypersensitivity; previous resistance to medication

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in history of seizure disorders or current bone marrow suppression

Hydroxyurea (Hydrea)

Inhibitor of deoxynucleotide synthesis. PO antineoplastic agent used in CML, melanoma, ovarian carcinoma, and some head and neck carcinomas.

Dosing

Adult

20-30 mg/kg/d PO

Pediatric

Administer as in adults

Interactions

Coadministration with fluorouracil can increase neurotoxicity; live virus vaccines (eg, MMR) may result in severe or fatal infection when used in immunosuppressed patients

Contraindications

Documented hypersensitivity; severe pancytopenia (WBC <2.5 X 10⁹/L, platelets <100 X 10⁹/L, severe anemia)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Closely monitor CBC counts, LFT findings, and renal function regularly throughout therapy

Busulfan (Myleran)

Potent cytotoxic drug that, at recommended dosage, causes profound myelosuppression. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Dosing

Adult

4-8 mg/d PO; may administer up to 12 mg/d; maintenance dosing range is 1-4 mg/d to 2 mg/wk; discontinue regimen when WBC reaches 10,000-20,000 cells/mL; resume therapy when WBC reaches 50,000/mL

Pediatric

0.06-0.12 mg/kg/d or 1.8-4.6 mg/m²/d PO; titrate dose to maintain WBC >40,000/mL; reduce dose by 50% if WBC is 30,000-40,000/mL; discontinue if WBC <20,000/mL

Interactions

CYP3A3/4 enzyme substrate; acetaminophen, cyclophosphamide, itraconazole, and thioguanine may increase toxicity; phenytoin may decrease levels

Contraindications

Documented hypersensitivity; severely depressed bone marrow function; breastfeeding women; failure to respond to previous treatment

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; may cause pulmonary fibrosis; if WBC count is high, hydration and allopurinol should be used to prevent hyperuricemia

Pipobroman (Vercyte, Vercite)

The mechanism of action is not fully understood; however, the drug is considered to be an alkylating agent. Pipobroman has been used with some success for treatment of polycythemia vera and chronic granulocytic leukemia. The product was discontinued by the manufacturer in the United States in 1996 but is available in Europe.

Dosing

Adult

1 mg/kg/d PO initially for at least 30 d; if refractory, may increase to 1.5-3 mg/kg/d
Maintenance: 0.1-0.2 mg/kg/d PO; typically initiated when hematocrit has decrease by 50-55%

Pediatric

<15 years: Not established
>15 years: Administer as in adults

Interactions

May decrease effect of live virus vaccines (eg, MMR) when administered within 3 mo of vaccination

Contraindications

Documented hypersensitivity; myelosuppression (severe thrombocytopenia)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor hematocrit or hemoglobin, platelet count, and differential leukocyte counts to evaluate the degree of leukopenia and thrombocytopenia; serum uric acid determinations should be monitored for possible occurrence of hyperuricemia; monitor for signs and symptoms of infection secondary to myelosuppression; hematuria, bruising, or bleeding may signal thrombocytopenia; caution with previous radiation or chemotherapy (potential additive toxicity); common adverse effects include leukopenia, thrombocytopenia, and anemia; acute leukemia risk increases with treatment duration and total cumulative dose

Follow-up

Inpatient & Outpatient Medications

• 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 for patients with polycythemia vera (PV) 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

Medicolegal Pitfalls

• Polycythemia vera is exceedingly rare in children. Ensuring that the erythroid proliferation is not secondary to elevated erythropoietin (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.

Multimedia

Media file 1: Bone marrow film at 400X magnification demonstrating dominance of erythropoiesis. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

References

1. [Guideline] Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood. Aug 15 2007;110(4):1092-7. [Medline].

2. Streiff MB, Smith B, Spivak JL. The diagnosis and management of polycythemia vera in the era since the Polycythemia Vera Study Group: a survey of American Society of Hematology members' practice patterns. Blood. Feb 15 2002;99(4):1144-9. [Medline].

3. Adamson JW, Fialkow PJ, Murphy S, et al. Polycythemia vera: stem-cell and probable clonal origin of the disease. New England Journal of Medicine. 1976;295:913-916. [Medline].

4. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. Apr 28 2005;434(7037):1144-8. [Medline].

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Keywords

polycythemia vera, PV, polycythemia rubra vera, erythrocytosis, absolute erythrocytosis, relative erythrocytosis, familial erythrocytosis, primary familial and congenital polycythemia, PFCP, primary familial polycythemia, treatment, diagnosis

Contributor Information and Disclosures

Author

Sun Choo, MD, Pediatric Resident, University of California Los Angeles
Disclosure: Nothing to disclose.

Coauthor(s)

Kristin Baird, MD, Staff Clinician, Pediatric Oncology Branch
Disclosure: Nothing to disclose.

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
Kathleen M Sakamoto, MD, PhD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, Society for Pediatric Research, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Scott MacGilvray, MD, Clinical Associate Professor of Pediatrics, East Carolina University School of Medicine
Scott MacGilvray, MD is a member of the following medical societies: American Academy of Pediatrics and American Medical Association
Disclosure: MedImmune Speakers Bureau Honoraria Speaking and teaching

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society
Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

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