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. [14, 15]
Symptoms include the following:
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Headache, dizziness, vertigo
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Weakness, malaise, or myalgias
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Visual disturbances
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Tinnitus
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Diaphoresis
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Pruritus (especially after exposure to warm water)
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Erythromelalgia (burning pain, warmth, and redness of extremities)
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Dyspnea
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Arthropathies
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Epigastric discomfort, satiety, constipation, weight loss
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Chest pain
Symptoms especially suggestive of polycythemia vera include postbath pruritus, erythromelalgia (burning pain and erythema of the hands and feet), gout, thromboses, and bleeding.
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. [4]
Signs and symptoms of polycythemia are attributed to the expanded total blood volume and resultant slowing of blood flow. Clinical findings of polycythemia include the following (frequency in parentheses):
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Splenomegaly (70%)
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Skin plethora (67%)
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Conjunctival plethora (59%)
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Hepatomegaly (40%)
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Systolic blood pressure >140 mm Hg (72%)
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Diastolic blood pressure >90 mm Hg (32%)
Evaluating neonates with polycythemia, Vlug et al found thrombocytopenia in 51% (71 out of 140) of these patients and severe thrombocytopenia in 9% (13 out of 140) of them. The investigators also determined, through multiple regression analysis, that thrombocytopenia was independently associated with small size for gestational age. In addition, a negative correlation was found between platelet count and hematocrit. [16]
Causes
Primary polycythemia
Causes include the following:
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Primary familial and congenital polycythemia (PFCP)
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Chuvash polycythemia
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Rare mutations resulting in disordered hypoxia sensing (prolyl hydroxylase 2 [PHD2], HIF2α)
Polycythemia vera
Polycythemia vera is considered to be a form of the myeloproliferative syndromes that also include essential thrombocythemia and primary myelofibrosis. The clonality of polycythemia vera is well established and was first demonstrated by Adamson et al in 1976. [17] Subsequent studies suggest hypersensitivity of the myeloid progenitor cells to growth factors, including Epo, interleukin (IL)–3, stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and insulin-like 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 [18, 19, 20, 21, 22] The JAK2 V617F mutation is a point mutation that causes a substitution of phenylalanine for valine in exon 14. JAK2V617F is detectable in more than 95% of patients diagnosed with polycythemia vera. [5] Several other mutations of JAK2 have since been described (eg, exon 12, JAK2H538-K539delinsI). [6, 7, 23, 24] The JAK2 mutations result in the enzyme being constitutively active, allowing cytokine-independent proliferation of cell lines that express Epo receptors, causing these cells to be hypersensitive to cytokines. [5]
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, [25, 26, 27] whereas other groups have seen similar rates, with complete or near complete presence of JAK2V617Fand other JAK2 mutations. [7] . 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 hematologic features in familial cases have not been shown to differ from those of sporadic mutations. [28]
Currently, the diagnosis of polycythemia vera is based on the 2016 World Health Organization (WHO) criteria, which have integrated molecular diagnostics into the evaluation and screening for polycythemia vera. [29, 30, 31] A diagnosis of polycythemia vera is made when all three major criteria are present or when the first two major criteria and a minor criterion are present.
The major criteria are as follows:
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Increased Hgb (>16.5 g/dL in men or >16.0 g/dL in women) or Hct (>49% in men or >48% in women) or other evidence of increased red cell volume
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Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis), including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)
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JAK2V617F or JAK2 exon 12 mutation
The minor criterion is as follows:
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Serum erythropoietin level below the reference range for normal
The second major criterion may not be required if there is sustained absolute erythrocytosis (Hgb >18.5 g/dL or Hct >55.5%, in men; Hgb >16.5 g/dL or Hct >49.5%, in women) and the third major criterion and the minor criterion are present.
Primary familial and congenital polycythemia (PFCP)
Patients with PFCP are commonly found to have mutations in the EPOR gene, the gene that codes for the erythropoietin receptor. Approximately 14 mutations have been identified. Unlike patients with polycythemia vera, patients with PFCP lack splenomegaly, neutrophilia, basophilia, thrombocytosis, and a JAK2 mutation. PFCP is generally thought to be benign, but it carries an increased risk of cardiovascular disease.
Chuvash polycythemia
Chuvash polycythemia, a congenital polycythemia first recognized in an endemic Russian population, is caused by a mutation in the von Hippel-Lindau (VHL) gene resulting in a perturbed oxygen-dependent regulation of Epo synthesis. Clinically, these patients have increased incidence of thrombosis, elevated pulmonary pressures, and an increased mortality independent of the increase in Hct.
Several mutations in addition to Chuvash polycythemia have been discovered which result in disordered hypoxia sensing. The dominantly inherited gain-of-function HIF2α (encoded by EPAS1) gene mutation and loss-of-function PHD2 variants (encoded by the EGLN1 gene) have features of both primary and secondary polycythemia.
Secondary polycythemia
Causes include the following:
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Physiologic Epo production - Chronic pulmonary disease, right-to-left cardiac shunts (Eisenmenger complex), hypoventilation syndromes (obstructive sleep apnea), high altitude, red cell defects
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Epo-secreting tumors - Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, hemangioblastoma; uterine fibroids, polycystic kidney disease
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Hereditary - High oxygen-affinity hemoglobin variants; 2,3-diphosphoglycerate (2,3-DPG) deficiency; congenital methemoglobinemia
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Environmental factors - Blood "doping" (autologous transfusion of red blood cells), self injection of Epo, toxins (cobalt, carbon monoxide exposure), smoking
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Androgen excess - Functional endocrine tumor, anabolic steroids
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Post–renal transplant
Physiologic Epo production
Secondary polycythemias are polycythemias that develop in response to Epo, whether it be an appropriate or inappropriate response. Appropriate responses to Epo are generally a result of tissue hypoxia, as related to conditions such as pulmonary disease, Eisenmenger syndrome (right-to-left shunting), high-altitude polycythemia, and the presence of hemoglobins with increased affinity for oxygen (and therefore decreased delivery of oxygen to tissues, with the resulting tissue hypoxia leading to compensatory erythrocytosis).
Inappropriate Epo
Inappropriate polycythemia stems from aberrant production of Epo, such as via Epo-producing tumors (hepatocellular carcinoma, renal cell carcinoma, hemangioblastoma, pheochromocytoma, uterine myomata), or from self administration of Epo.
Red blood cell enzyme deficiencies
Deficiencies of 2,3-diphosphoglycerate (2,3-DPG) result from a congenital mutation in the 2,3-BPG mutase gene. This is a rare mutation that can lead to a high-affinity hemoglobin.
Methemoglobin reductase deficiency can lead to congenital methemoglobinemia. These patients exhibit mild polycythemia.
Polycythemia of the newborn
Polycythemia at birth is often a normal physiologic response to intrauterine hypoxic insults during labor and delivery. In addition, infant red blood cells have a high level of hemoglobin F, which is a high–oxygen-affinity hemoglobin. (See Polycythemia of the Newborn.)
Hyperbilirubinemia, which can result from polycythemia, often occurs in newborns of mothers who had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy. Moreover, research has linked the infection to the development of placental vascular malperfusion. A single-center Italian study by Monzani et al found that a cohort of healthy neonates born between March and November 2020, during the first phase of the coronavirus disease 2019 (COVID-19) pandemic, demonstrated a high prevalence of polycythemia and hyperbilirubinemia, which led the investigators to propose that even an asymptomatic SARS-CoV-2 infection in the mother could lead to these outcomes. Thirteen of 73 neonates (17.8%) developed hyperbilirubinemia that required phototherapy, their mean Hct value being 66.3%. The report suggested that even when asymptomatic, SARS-CoV-2 infection during pregnancy can result in placental malperfusion, with polycythemia developing in the fetus as a compensatory response. [32]
Toxins
Cobalt administration causes erythropoiesis by increasing HIFs. Smoking results in the formation of carboxyhemoglobin, a form of hemoglobin that cannot carry oxygen. The resulting tissue hypoxia stimulates Epo and red cell production. Carbon monoxide (CO) exposure, from engine exhaust or products of combustion, also results in preferential formation of carboxyhemoglobin and subsequent hypoxia.
Functional endocrine tumors
Excess androgens can be made from functional endocrine tumors, such as androgen-secreting tumors of the ovary or adrenal glands. Excess androgens can also be seen in conditions such as polycystic ovarian syndrome, congenital adrenal hyperplasia, and adrenal carcinoma. The erythropoietic effect of androgens comes from their ability to stimulate Epo production, as well as to induce differentiation of stem cells.
Dermoid cysts of the ovary and aldosterone-producing adenomas have been associated with elevated Epo and erythrocytosis. Hemoglobin levels return to normal after removal of these tumors. The pathophysiology associated with these lesions is not clear, but suggested mechanisms include Epo secretion, interaction between aldosterone and Epo, and mechanical compression of the renal artery.
Post–renal transplant erythrocytosis
Post–renal transplant erythrocytosis is found in 5-10% percent of renal allograft recipients. The erythrocytosis usually develops within 8-24 months after transplant and spontaneously resolves in 2 years. The pathophysiology is not well understood, but it is believed to be attributed to an increase in activity of and sensitivity to angiotensin II. [33]
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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.
