Pediatric Polycythemia

Updated: Apr 07, 2016
  • Author: Joseph K Park, MD, PhD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Overview

Background

Polycythemia is characterized by an increase in the red blood cell (RBC) compartment in the peripheral blood and is measured by an increase in the RBC count, the hemoglobin content, and the hematocrit level above reference ranges adjusted for age, sex, race, and altitude. Polycythemia is categorized as primary or secondary due to intrinsic or extrinsic changes, respectively, to erythroid progenitors and RBCs. Both primary and secondary polycythemias can be congenital or acquired in origin.

Primary polycythemia (intrinsic)

See the list below:

  • Acquired - Polycythemia vera
  • Congenital
    • Primary familial and congenital polycythemia (PFCP)
    • Chuvash polycythemia

Secondary polycythemia (extrinsic)

See the list below:

  • Acquired
    • Physiological erythropoietin (EPO) production
    • EPO-secreting tumors
  • Congenital
    • High oxygen-affinity hemoglobin variants
    • 2,3-diphosphoglycerate (2,3-DPG) deficiency

In contrast, relative polycythemia (pseudoerythrocytosis) is caused by severe reduction of plasma volume, resulting in hemoconcentration (eg, due to severe diarrhea with subsequent dehydration).

In normal hematopoiesis, myeloid stem cells give rise to erythrocytes, platelets, granulocytes, eosinophils, basophils, and monocytes. Protein growth factors, known as cytokines, stimulate proliferation of the multi-lineage 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. See the image below.

Bone marrow film at 400X magnification demonstrati 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 initially occurs in fetal hepatocytes, subsequently occurring in the bone marrow of children and adults. The principal hormone that regulates erythropoiesis 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.

EPO gene expression is known to be affected by multiple factors, including hypoxemia, transition metals (Co2+, Ni2+, Mn2+), and iron chelators. However, the major stimulus for EPO production is decreased oxygen delivery due to decreased RBC mass or decreased oxygen saturation of hemoglobin. EPO production has been observed to increase as much as 1000-fold in severe hypoxia.

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Pathophysiology

Primary polycythemias are due to factors intrinsic to red cell precursors caused by acquired or inherited mutations. It includes the diagnoses of polycythemia vera and primary familial and congenital polycythemia.

Polycythemia vera, also known as polycythemia rubra vera, is a myeloproliferative 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, 2] 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 major criteria are as follows:

  • Hemoglobin level >18.5 g/dL in men, >16.5 g/dL in women, or other evidence of increased red cell volume (hemoglobin or hematocrit greater than 99th percentile of method-specific reference range for age, sex, altitude of residence, or hemoglobin >17 g/dL in men or >15 g/dL in women if associated with a documented and sustained increase of ≥2 g/dL from an individual's baseline value that cannot be attributed to correction of iron deficiency, or elevated red cell mass >25% above mean normal predicted value)
  • Presence of JAK2V617For similar mutation (eg, JAK2 exon 12 mutation)

The minor criteria are as follows:

  • Bone marrow biopsy findings that include hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation
  • Serum erythropoietin level below the reference range
  • Endogenous erythroid colony formation in vitro

Earlier diagnostic criteria for polycythemia vera included the following (based on the Polycythemia Vera Study Group Diagnostic Criteria): [3]

  • 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 primary myelofibrosis. The clonality of polycythemia vera is well established and was first demonstrated by Adamson et al in 1976. [4] 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.

In 2004, several groups identified a gain-of-function mutation in the gene that encodes for the JAK2 tyrosine kinase that leads to constitutive phosphorylation, and therefore constitutive activity and STAT recruitment [5, 6, 7, 8, 9] JAK2V617Fis detectable in more than 95% of patients diagnosed with polycythemia vera. [10] Several other mutations of JAK2 have since been described (eg, exon 12, JAK2H538-K539delinsI). [11, 12] 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. [10]

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 JAK2V617Fand other JAK2 mutations. [12] . 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. [16]

Primary familial and congenital polycythemia, also called benign erythrocytosis, is typically inherited as an autosomal dominant disorder and is characterized by polycythemia with low serum concentrations of EPO. Several mutations, causing hypersensitivity to EPO, 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. [17, 18] 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. [19]

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. [19]

Secondary polycythemia is due to circulating extrinsic factors that stimulate erythropoiesis, most often EPO. Physiological elevation of EPO secondary may result from functional hypoxia secondary to pulmonary, cardiac, renal, or hepatic disease. Hemoglobin variants with high oxygen affinity leads to secondary polycythemia by stimulating increased EPO production. In addition, polycythemia can be seen from EPO-secreting tumors, including renal cell carcinomas, nephroblastoma, and endocrine tumors.

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. [19]

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. [19]

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. [20]

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Epidemiology

Frequency

United States

Primary polycythemia is rare; in the United States, the overall prevalence of polycythemia vera is 45-57 cases per 100,000 people. [21, 22] The combined annual incidence is 0.01-2.61 per 100,000 people. [23] The median age is 60 years, with 0.01% of those cases observed in individuals younger than 20 years. [24] Less 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).{63}

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
  • 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. [20]

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

Polycythemia vera is somewhat more common in males, with the male-to-female ratios in several studies, ranging from 1.2-2.2. In children, it appears to affect males and females equally. [19]

Age

The median age for polycythemia vera between age 60-80 years. [19, 24] Less than 1% of polycythemia cases occur in people younger than 20 years.

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