Polycythemia

BASICS

DESCRIPTION

Polycythemia is an absolute increase in red blood cell (RBC) mass. This condition should be considered when there is a noted elevated hemoglobin (HGB), hematocrit (HCT), or RBC count. Using normal value ranges for the age and sex of patients is vital for accurate interpretation of the laboratory data. The term polycythemia is used interchangeably in the literature with erythrocytosis, although there are technical differences between the two terms. Polycythemia can be categorized as follows:

Primary polycythemia: a defect within erythroid progenitors, resulting in overproduction of RBCs; serum erythropoietin (EPO) levels are typically low.
Secondary polycythemia: stimulation of erythrocyte production by an increased level of EPO, either elevated appropriately in response to hypoxia or elevated inappropriately due to an EPO-producing tumor or exogenous administration
Relative polycythemia: elevated HGB, HCT, 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 exceedingly rare in children:

Myeloproliferative neoplasms, including polycythemia vera (PV): The vast majority of cases occur in adults, but cases of childhood PV have been described.
Primary familial and congenital polycythemia (PFCP): very rare but presents during infancy or childhood; other names for this condition include congenital erythrocytosis, congenital polycythemia, and inherited polycythemia.
The incidence and prevalence of secondary polycythemias depend on the underlying conditions.

RISK FACTORS

Genetics

Conditions with an inherited cause of polycythemia include the following:

PFCP: autosomal dominant inheritance pattern with a gain of function mutation in the EPO receptor (EPOR) gene
Chuvash erythrocytosis: autosomal recessive disorder affecting individuals from the Chuvash Republic in Russia; mutation is in the Von Hippel Lindau (VHL) gene.
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 hematopoietic progenitor cells with an acquired mutation; EPO levels are usually low. The mutation JAK2 V617F is found in the vast majority of cases.
- PFCP: germline mutation of EPOR gene in erythroid progenitors which are subsequently hypersensitive to EPO
Secondary polycythemias
- Chronic pulmonary disease or hypoventilation: increased RBCs due to inadequate oxygenation to tissues
- Cyanotic heart disease and arteriovenous malformations: deoxygenated blood shunted through arterial system leading to decreased oxygenation to tissues
- 2,3-BGP mutase deficiency: rare defect that leads to deficiency of 2,3-BPG and decreased oxygenation to tissues
- High oxygen-affinity hemoglobinopathies: mutation in either α- or β-globin chains leading to increased oxygen affinity and decreased oxygen to tissues
- Methemoglobinemia: elevated Fe³ ⁺ HGB, high affinity for oxygen, and decreased delivery to tissues
- Carboxyhemoglobinemia: carbon monoxide poisoning with carbon monoxide binding preferentially to HGB molecules over oxygen
- High altitude: compensation for low atmospheric oxygen pressure
- EPO-producing tumors: rare pediatric tumors including renal cell carcinoma, hepatocellular carcinoma, 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/erythromelalgia:
- Seen with PV and PFCP
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 or inappropriate use of generators/heaters
- Cigarette exposure
Social history:
- Smoking
- Drug use including steroids, EPO, diuretics
Family history:
- Elevated HGB/HCT, hyperviscosity, or need for phlebotomy
- Household members with similar symptoms may also indicate concurrent exposure to carbon monoxide.

PHYSICAL EXAM

Signs and symptoms:

Low oxygen via pulse oximetry
Cyanosis
Plethora
Clubbing
Cardiac murmurs or bruits
Dehydration
Splenomegaly

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
- History of renal transplant
- Exogenous testosterone, anabolic steroids, 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 & INTERPRETATION

ALERT

Important reminders when interpreting bloodwork:

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.
Pao ₂ is only interpretable with an arterial blood gas.

Initial Tests (screening, lab, imaging)

Incidental finding on routine bloodwork
- Older teen and adult: defined by HGB >18.5 g/dL in males and >16.5 g/dL in females
Initial workup should include the following:
- Complete blood count (CBC) with differential: evaluation of other cell lines important in formulating the differential diagnosis
- Arterial blood gas with co-oximetry: Pao ₂ 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.
- Blood urea nitrogen, serum creatinine, and urinalysis to evaluate renal function
- Serum EPO may be helpful in distinguishing primary from secondary polycythemia.
Further investigation may include the following:
- Oxygen dissociation p50: The partial pressure of oxygen at which HGB is 50% saturated.
- HGB electrophoresis: Normal results do not rule out the presence of high oxygen-affinity HGB, as many abnormal HGBs can comigrate with normal HGBs. 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

Diagnostic Procedures/Other

Chest radiograph: for clinical findings concerning for chronic pulmonary disease
Abdominal ultrasound: for clinical findings concerning for abdominal tumors
ECG 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

Primary polycythemia should be managed by a hematologist.
Certain medications, such as hydroxyurea and interferon-α, may be considered. In addition, newer targeted agents such as ruxolitinib may be considered for therapy in the future.

ISSUES 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. doi:10.1007/s00277-009-0758-y [PMID:19468728]
McMullin MF . Genetic background of congenital erythrocytosis. Genes (Basel). 2021;12(8):1151. doi:10.3390/genes12081151 [PMID:34440325]
Mcmullin MF . The classification and diagnosis of erythrocytosis. Int J Lab Hematol. 2008;30(6):447-459. doi:10.1111/j.1751-553X.2008.01102.x [PMID:18823397]
Ozek E , Soll R , Schimmel MS . Partial exchange transfusion to prevent neurodevelopmental disability in infants with polycythemia. Cochrane Database Syst Rev. 2010;(1):CD005089. doi:10.1002/14651858.CD005089.pub2 [PMID:20091569]
Prchal JT . Polycythemia vera and other primary polycythemias. Curr Opin Hematol. 2005;12(2):112-116. doi:10.1097/01.moh.0000154029.05396.d2 [PMID:15725900]
Sarkar S , Rosenkrantz TS . Neonatal polycythemia and hyperviscosity. Semin Fetal Neonatal Med. 2008;13(4):248-255. doi:10.1016/j.siny.2008.02.003 [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. doi:10.1002/ajh.23135 [PMID:22331582]

CODES

ICD 10

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

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

John Norko, BS, MD