Polycythemia In Childhood

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The term polycythemia applies to an increase in circulating red cell mass to above the normal upper limits of 30 mL/kg body weight (excluding hemoconcentration due to dehydration). For practical purposes, this means a hemoglobin level higher than 17 g/dL or a hematocrit level of 50% or more during childhood.

Figure 8-1 depicts the pathogenesis of polycythemia, and Table 8-4 classifies various causes of polycythemia.

Primary polycythemia results from congenital ([germline] erythropoietin receptor mutation) or acquired ([somatic] polycythemia vera) mutations that make erythroid progenitor cells exquisitely sensitive to circulating cytokines, resulting in increased red cell mass. Secondary polycythemia, on the other hand, results from the action of an excessive amount of circulating cytokines on the normal responsive erythroid progenitor cells. The cytokine usually is erythropoietin. However, in some clinical con-

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Primary polycythemia due to mutation of Epo-R

E.P.C. = Erythroid progenitor cell Epo = Erythropoietin R = Receptor

IGF = Insulin-like growth factor P. vera = Polycythemia vera

Fig. 8-1. Pathogenesis of Polycythemia - A Pictorial Presentation (See Table 8-4 for the list of clinical causes of polycythemia)

Primary polycythemia due to mutation of Epo-R

Inappropriate polycythemia from an aberrant production of Epo or other non-Epo growth factors, stimulating E.P.C. proliferation

E.P.C. = Erythroid progenitor cell Epo = Erythropoietin R = Receptor

IGF = Insulin-like growth factor P. vera = Polycythemia vera

Appropriate polycythemia from a normal response of erythron to hypoxia-induced increased Epo levels, stimulating E.P.C. proliferation

Non-Epo growth factors, e.g., androgen, IGF, angiotensin II

Appropriate polycythemia from a normal response of erythron to hypoxia-induced increased Epo levels, stimulating E.P.C. proliferation

Non-Epo growth factors, e.g., androgen, IGF, angiotensin II

Fig. 8-1. Pathogenesis of Polycythemia - A Pictorial Presentation (See Table 8-4 for the list of clinical causes of polycythemia)

Table 8-4. Classification of Polycythemia I. Relative polycythemia (hemoconcentration, dehydration)

II. Primary polycythemia (results from somatic or germline mutations of erythroid progenitor cells that make them exquisitely sensitive to erythropoietin or other cytokines)

A. Polycythemia vera (results from somatic mutation)

B. Erythropoietin receptor mutation (results from germline mutation)

III. Secondary polycythemia

A. Insufficient oxygen delivery (also known as appropriate polycythemia because it results from a normal response of erythron to hypoxia)

1. Physiologic a. Fetal life b. Low environmental O2 (high altitude)

2. Pathologic a. Impaired ventilation: pulmonary disease, obesity b. Pulmonary arteriovenous fistula c. Congenital heart disease with left-to-right shunt (e.g., tetralogy of Fallot, Eisenmenger syndrome)

d. Abnormal hemoglobins (reduced P50 in whole blood)

(1) Methemoglobin (congenital and acquired)

(2) Carboxyhemoglobin

(3) Sulfhemoglobin

(4) High oxygen affinity hemoglobinopathies" (hemoglobin Chesapeake, Ranier, Yakima, Osler, Tsurumai, Kempsey, and Ypsilanti)

(5) 2,3-DPG mutase deficiency in red cells resulting in 2-3 bisphosphoglycerate (BPG) deficiency.

B. Increase in erythropoietin (also known as inappropriate polycythemia because it results from an aberrant production of erythropoietin or other growth factors)

1. Endogenous a. Renal: Wilms' tumor,6 hypernephroma, renal ischemia, e.g., renal vascular disorder, congenital polycystic kidney, benign renal lesions (cysts, hydronephrosis).

Post-transplant erythrocytosis (occurs in 10-15% of renal graft recipients). Contributing factors include persistence of erythropoietin secretion from the recipients's diseased and ischemic kidney, and secretion of angiotensin II, androgen, and insulin-like growth factor.

b. Adrenal: pheochromocytoma, Cushing syndrome, congenital adrenal hyperplasia, adrenal adenoma with primary aldosteronism c. Liver: hepatoma, focal nodular hyperplasia,c hepatocellular carcinoma, hepatic hemangioma, Budd-Chiari syndrome (some of these patients may have overt or latent myeloproliferative disorder)

d. Cerebellum: hemangioblastoma, hemangioma, meningioma e. Uterus: leiomyoma, leiomyosarcoma

2. Exogenous a. Administration of testosterone and related steroids b. Administration of growth hormone

C. Polycythemia with characteristics of both primary and secondary polycythemias a. Chuvashian polycythemia b. Non-Chuvashian polycythemias

IV. Neonatal polycythemia

"Some of these are electrophoretically silent and require hemoglobin oxygen association kinetics for diagnosis. ^Associated with male gender, low clinical stage, and usually >16 years of age. May occur with a normal serum erythropoietin.

cHistologically stains positively for erythropoietin by immunohistochemistry.

ditions, nonerythropoietin growth factors (e.g., angiotensin II, androgens, and insulin-like growth factor I in recipients of renal graft during the post-transplant period) may also play a role in inducing erythrocytosis.

Combined Characteristics of Primary and Secondary Polycythemias

Recently, various molecular polycythemic lesions have been described. These include von Hippel-Lindau mutations, erythropoietin receptor mutations, globin mutations, and bisphosphoglycerate deficiency in decreasing order of frequency.

Von Hippel-Lindau Mutations Causing Polycythemia

• Chuvashian* polycythemia (familial benign polycythemia): Autosomal recessive inheritance mutation of von Hippel-Lindau gene results in defective hypoxic sensing by kidney cells and increased production of erythropoietin. Some patients may have a normal level of erythropoietin. However, their erythroid progenitors are hypersensitive to the normal levels of erythropoietin.

Clinical manifestations include varicose veins, thrombotic and hemorrhagic complications, strokes, increased levels of vascular endothelial growth factor and plasminogen activator inhibitor-1 but they do not develop von Hippel-Lindau syndrome and its complications (hemangioblastomas, pheochromocytoma, or renal cell carcinoma) and vice versa; patients with von Hippel-Lindau syndrome do not manifest erythrocytosis.

• Non-Chuvashian polycythemias: Several patients of other than Chuvash ethnicity have been found to have polycythemia resulting from mutations at various regions of the von Hippel-Lindau gene. These mutations may be heterozygous or homozygous.

Table 8-5 compares the clinical manifestations of polycythemia vera, primary familial and congenital polycythemia and Chuvashian polycythemia. Table 8-6 lists the criteria for a diagnosis of polycythemia vera.


1. Erythrocytosis: Partial exchange transfusions (phlebotomy) to maintain hemoglobin levels of 16-17 g/dL (i.e., less than 20 g/dL) are the mainstay of treatment for erythrocytosis. The underlying cause, if known, should be treated.

2. Polycythemia secondary to high oxygen affinity hemoglobin or deficiency of bisphos-phoglycerate: Phlebotomy is usually not beneficial in the treatment of poly-cythemia secondary to high oxygen affinity hemoglobins or those conditions resulting from deficiency of bisphosphoglycerate, because they cause a decrease in exercise tolerance.

3. Post-transplant erythrocytosis in renal graft recipients: These patients respond to drugs that cause inactivation of the renin-angiotensin system (e.g., captopril, enalapril, losartan, lisinopril, and fosinopril). Patients unable to tolerate angiotensin-converting enzyme inhibitors can be treated with an angiotensin II AT1 receptor antagonist, losartan. Theophylline, a nonselective adenosine receptor antagonist in low dose, has been found effective in suppression of erythropoiesis.

4. Congenital erythropoietin-dependent erythrocytosis: Successful treatment of congenital erythropoietin-dependent erythrocytosis, clinically similar to Chuvashian polycythemia, has been reported with the use of theophylline.

*The Chuvash Republic is located on the west bank of the Volga River in the central part of European Russia. The first reports of congenital polycythemia in Chuvashia appeared in the 1970s (Blood 1997;89:2148-54).

Table 8-5. Clinical Manifestations of Polycythemia Vera (PV), Primary Familial and Congenital Polycythemia (PFCP), and Chuvashian Polycythemia (CP)

Clinical entities

Polycythemia vera (PV)

Primary familial and congenital polycythemia (PFCP)

Chuvashian polycythemia (CP)

Frequency Inheritance Underlying cause

Symptoms of polycythemia (e.g., headache, dizziness, lethargy, blurred vision) Signs





Plethora, splenomegaly

Erythropoietin level Undetectable



Thrombosis or hemorrhage (other myeloproliferative disorders)


Unknown Dominant

Erythropoietin receptor mutation is found only in 12% Usually diagnosed on routine blood count

Plethora, no splenomegaly

Normal or low

Phlebotomy, a-IFN, ASA, HU, Anagrelide


Molecular analysis for truncation of cytosolic portion of ER and in vitro hypersensitivity to EPO Phlebotomy

Unknown Recessive

Functional deficiency of VHL


Plethora, no splenomegaly, varicosities of peripheral veins Increased but high or normal in sporadic non-CP Thrombosis or hemorrhage

Molecular analysis of VHL protein gene levels of VEGF and PAI-1


VHL, von Hippel-Lindau; VEGR, vascular endothelial growth factor; PAI-1, plasminogen activator inhibitor; a-IFN, a interferon; ASA, aspirin; HU, hydroxyurea; ER, Erythropoietin receptor; EPO, Erythropoietin.

Theophylline results in the reduction of serum levels of erythropoietin and transferrin receptor, leading to decrease in hemoglobin levels. 5. Polycythemia vera: In low-risk patients, defined as:

• Asymptomatic individuals under 40 years of age

Platelet count <1.0 million/mm3

• No comorbidities

• No history of thrombosis.

If the hematocrit is effectively controlled by phlebotomy there is no need for cytoreduction. Low-dose aspirin is also beneficial.

In high-risk patients, defined as:

• Patients 60 years of age or older or

• Symptomatic patients or

Polycythemia 207 Table 8-6. Criteria for Diagnosis of Polycythemia Vera"

Category A

1. Increased red cell volume (male >36 mL/kg; female >32 mL/kg)

2. Arterial oxygen saturation >92%

3. Splenomegaly

Category B

1. Thrombocytosis (>400,000 cells/mm3)

2. Leukocytosis (>12,000 cells/mm3)

3. Increased leukocyte alkaline phosphatase

4. Increased vitamin B12 (>900 pg/mL) or unsaturated B12-binding capacity (>2200 pg/mL) For diagnosis patient must have:

"Increased expression of m-RNA of a receptor PRV-1 (polycythemia rubra vera-1) in granulocytes, but not in their progenitors, is a useful diagnostic marker that distinguishes polycythemia vera from secondary erythrocy-tosis. Polycythemia vera patients express significantly high amount of PRV-1. Quantitative RT-PCR assay for PRV-1 has high sensitivity and specificity.

(Adapted from Berlin NI (1975): Diagnosis and classification of the polycythemias. Semin Hematol 12:339, with permission.)

• Patients with platelet counts >1.0 million/mm3 or

• Patients with comorbidities or

• Patients with a history of thrombosis.

In these cases cytoreductive therapy, preferably with a-interferon rather than hydroxyurea, in young patients is utilized. Anagrelide is also useful to decrease platelet counts. An induction dose of Anagrelide in children of 0.5 mg twice daily, followed by a maintenance dose of 0.5-1.0 mg twice a day, adjusted to maintain a platelet count within the normal range, is employed. The dosage is adjusted to the lowest effective dosage required to reduce and maintain the platelet count below 600,000/mm3, and ideally to maintain it in the normal range.

In intermediate-risk patients, defined as:

• Platelet count of 600,000/mm3 to 1.0 million/mm3. These patients are treated with phlebotomy and Anagrelide.

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