Polycythemia

Basics

Description

Polycythemia (sometimes referred to as erythrocytosis) is defined as an absolute increase in red blood cell (RBC) mass, most commonly suspected in the context of an elevated hemoglobin, hematocrit, or RBC count. Use of age- and gender-based norms is critical, as they fluctuate throughout childhood. Polycythemia can be categorized as follows:

Primary polycythemia: Defect within erythroid progenitors, resulting in overproduction of RBCs. Serum erythropoietin (EPO) levels are usually low.
Secondary polycythemia: stimulation of erythrocyte production by an increased level of EPO, which is either elevated appropriately in response to hypoxia or elevated inappropriately due to an EPO-producing tumor or exogenous administration
Relative polycythemia: elevated hemoglobin, hematocrit, or RBC count without a true increase in RBC mass, often caused by decreased plasma volume in the setting of dehydration

Epidemiology

Primary polycythemias are very rare in children:

Myeloproliferative neoplasms, including polycythemia vera (PV): Vast majority of cases occur in older adults, but cases of childhood PV have been described.
Primary familial and congenital polycythemia (PFCP): very rare but presents during infancy or childhood
The incidence and prevalence of secondary polycythemias depend on the respective underlying conditions.

Risk Factors

Genetics

Inherited polycythemias are very rare:

PFCP: autosomal dominant
Chuvash polycythemia: autosomal recessive disorder affecting individuals from the Chuvash Republic in Russia
2,3-bisphosphoglycerate (2,3-BPG) mutase deficiency: autosomal recessive

General Prevention

There are no preventive measures for conditions of primary polycythemia. Treatment of underlying conditions, such as correction of congenital heart disease, will prevent the development of secondary polycythemia.

Pathophysiology

Primary polycythemias:
- PV: myeloproliferative neoplasm arising from a clonal population of abnormal hematopoietic progenitor cells with EPO-independent proliferation. EPO levels are usually low. The mutation JAK2 V617F is found in the vast majority of cases.
- PFCP: Erythroid progenitors are hypersensitive to EPO. Some families have a mutation in the EPO receptor (EPO-R).
Secondary polycythemias:
- High altitude: compensation for low atmospheric oxygen pressure
- Chronic pulmonary disease or hypoventilation: compensation for inadequate oxygenation
- Cyanotic heart disease and arteriovenous malformations: right-to-left cardiac or extracardiac shunting, resulting in desaturation of arterial blood
- High oxygen-affinity hemoglobinopathies: mutation in either α- or β-globin chains leading to increased oxygen affinity and decreased oxygen delivery to tissues.
- 2,3-BPG mutase deficiency: rare defect that leads to deficiency of 2,3-BPG and decreased oxygen delivery to tissues
- Methemoglobinemia: elevated levels of Fe³⁺ hemoglobin, which has an increased affinity for oxygen compared to Fe²⁺ hemoglobin
- Carboxyhemoglobinemia: Carbon monoxide binds to hemoglobin preferentially compared to oxygen.
- Hypoxia-sensing pathway defects: Mutations in the gene von Hippel Lindau (VHL) are common in certain ethnic groups (Chuvash polycythemia).
- EPO-producing tumors: renal cell carcinoma, hepatocellular carcinoma, hemangioblastoma, pheochromocytoma, and uterine fibroids

Diagnosis

History

Age of onset:
- Neonates, who are born to mothers with preeclampsia or diabetes, are small for gestational age, undergo delayed cord clamping, or have certain chromosomal abnormalities (e.g., Down syndrome), are at increased risk for polycythemia during the neonatal period.
Weight:
- Obesity is associated with obstructive sleep apnea.
Dehydration:
- Diuretic use or abuse
- Severe diarrhea
Hyperviscosity:
- Headache, dizziness, syncope, transient blindness, history of thrombosis
Symptoms concerning for congenital heart disease or chronic pulmonary disease:
- Cyanosis
- Decreased exercise tolerance
- Shortness of breath
- Dyspnea on exertion
Pruritus:
- Seen with PV
Sleep history:
- Snoring, nocturnal apnea, mouth breathing, excessive daytime sleepiness, behavioral problems concerning for obstructive sleep apnea
Living situation:
- High altitude
- Older house with fuel-burning heaters
- Cigarette exposure
Social history:
- Smoking
- Drug use including steroids, EPO, diuretics
Family history:
- High hematocrit, hyperviscosity, or need for phlebotomy
- Household members with similar symptoms may also indicate concurrent exposure to carbon monoxide.

Physical Exam

Signs and symptoms:

Pulse oximetry
Cyanosis
Plethora
Clubbing
Cardiac murmurs or bruits
Dehydration
Splenomegaly

ALERT

Fingerstick hematocrit: Squeezing the finger to collect a specimen may give a falsely elevated hematocrit.
Capillary hematocrit: often higher than venous hematocrit
Dehydration during blood draw may result in relative polycythemia due to decreased plasma volume.
Pao₂ is only interpretable with an arterial blood gas.

Differential Diagnosis

Primary polycythemia
- PV
- PFCP
Secondary polycythemia
- High altitude
- Chronic pulmonary disease
- Hypoventilation: obstructive sleep apnea, neuromuscular disorders, severe obesity (Pickwickian syndrome), or congenital central hypoventilation syndrome
- Right-to-left cardiac shunts
- Arteriovenous malformations
- High oxygen-affinity hemoglobinopathies
- 2,3-BPG mutase deficiency
- Methemoglobinemia
- Carbon monoxide poisoning
- EPO-producing tumors: renal cell carcinoma, hepatocellular carcinoma, hemangioblastoma, pheochromocytoma, uterine fibroids
- Status—postrenal transplant
- Exogenous testosterone or EPO: competitive athletes
- Cobalt poisoning: Homemade beer may contain cobalt.
Neonatal polycythemia
- Preeclampsia or gestational hypertension
- Small for gestational age
- Gestational diabetes
- Delayed cord clamping
- Placental transfusion
- Twin-to-twin transfusion
Relative polycythemia
- Cigarette smoking
- Dehydration

Diagnostic Tests and Interpretation

Initial Tests

Many patients may be asymptomatic with polycythemia noted on routine screening.
Initial workup should include the following:
- CBC with differential: Polycythemia may be associated with abnormalities in other lineages.
- Arterial blood gas with co-oximetry: Pao₂ may be low in cardiopulmonary diseases. Co-oximetry allows for evaluation of carboxyhemoglobin and methemoglobin levels. Half-life of carboxyhemoglobin is 4 hours, so testing should be timed to accurately reflect exposures.
- BUN, serum creatinine, and urinalysis to evaluate renal function
- Serum EPO may be helpful in distinguishing primary from secondary polycythemia, but there is significant overlap in EPO levels between the two categories.
Further investigation:
- Oxygen dissociation p50: the partial pressure of oxygen at which hemoglobin is 50% saturated
- Hemoglobin electrophoresis: Normal results do not rule out the presence of high oxygen-affinity hemoglobin, as many abnormal hemoglobins can comigrate with normal hemoglobins. If there is a high index of suspicion, consider molecular genetic analysis of globin genes.
- 2,3-BPG level
- Testosterone level
- Genetic testing for JAK2 V617F mutation
Chest radiograph: for clinical findings concerning for chronic pulmonary disease
Abdominal ultrasound: for clinical findings concerning for abdominal tumors

Diagnostic Procedures/Other

EKG and echocardiogram: for clinical findings concerning for congenital heart disease
Polysomnography sleep study: for clinical findings concerning for sleep apnea
If myeloproliferative neoplasm is suspected, bone marrow aspirate and biopsy with cytogenetics should be performed.

Treatment

General Measures

Most asymptomatic patients with secondary polycythemia require no additional therapy other than management of their underlying condition.
Pediatric patients with primary polycythemia are managed with phlebotomy alone. Low-dose aspirin may be considered to reduce thrombosis risk.
In neonatal polycythemia, partial exchange transfusion should be considered based on symptoms and degree of polycythemia.

Medication (Drugs)

Primary polycythemia should be managed by a hematologist. Certain medications, such as hydroxyurea and interferon-α, may be considered.

Issue for Referral

Unexplained cyanosis, symptoms concerning for hyperviscosity, or persistent elevation in hematocrit that is not related to dehydration or neonatal etiologies

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

Periodic laboratory follow-up depending on the etiology of polycythemia. Monitor for the following:

Headache, dizziness, or syncope
Blurred vision or transient vision loss
Decreased exercise tolerance, shortness of breath, or dyspnea on exertion
Stroke or thrombosis

Prognosis

Depends on underlying condition:

PV: guarded as may progress to acute leukemia
High oxygen-affinity hemoglobinopathies: excellent
Other secondary polycythemias: depends on underlying condition

Additional Reading

Cario H, McMullin MF, Pahl HL. Clinical and hematological presentation of children and adolescents with polycythemia vera. Ann Hematol. 2009;88(8):713–719. [PMID:19468728]
Messinezy M, Pearson TC. The classification and diagnostic criteria of the erythrocytoses (polycythaemias). Clin Lab Haematol. 1999;21(5):309–316. [PMID:10646073]
Ozek E, Soll R, Schimmel MS. Partial exchange transfusion to prevent neurodevelopmental disability in infants with polycythemia. Cochrane Database Syst Rev. 2010;(1):CD005089. [PMID:20091569]
Prchal JT. Polycythemia vera and other primary polycythemias. Curr Opin Hematol. 2005;12(2):112–116. [PMID:15725900]
Sarkar S, Rosenkrantz TS. Neonatal polycythemia and hyperviscosity. Semin Fetal Neonatal Med. 2008;13(4):248–255. [PMID:18424246]
Tefferi A. Polycythemia vera and essential thrombocythemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol. 2012;87(3):285–293. [PMID:22331582]

Codes

ICD-9

238.4 Polycythemia vera
289.0 Polycythemia, secondary
776.4 Polycythemia neonatorum

ICD-10

D45 Polycythemia vera
D75.1 Secondary polycythemia
P61.1 Polycythemia neonatorum

SNOMED

109992005 Polycythemia vera (disorder)
127066000 Familial polycythemia vera (disorder)
32984002 Neonatal polycythemia (disorder)

FAQ

Q: What are common causes of polycythemia in the pediatric population?
A: Secondary polycythemias. In particular, neonates and patients with cyanotic heart disease commonly present with polycythemia.
Q: What are common causes of relative polycythemia?
A: Dehydration and heavy cigarette smoking have been associated with decreased plasma volume and relative polycythemia.
Q: When should a child with polycythemia be referred to a pediatric hematologist?
A: The child should be referred to a pediatric hematologist if there are symptoms concerning for hyperviscosity or if the elevation in hematocrit is persistent and not clearly due to dehydration or neonatal etiologies.

Authors

Benjamin J. Huang, MD

Tannie Huang, MD