Clinical Information

Erythrocytosis (polycythemia) is identified by a sustained increase in hemoglobin or hematocrit. An isolated increase in red blood cell count (in the absence of chronic phlebotomy or coincident iron deficiency) may occur in thalassemia or other causes and does not indicate erythrocytosis. Erythrocytosis may occur as a primary disorder, due to an intrinsic defect of bone marrow stem cells, or secondary, in response to increased serum erythropoietin (EPO) levels. Secondary erythrocytosis is associated with a number of disorders, including chronic lung disease, chronic increase in carbon monoxide, cyanotic heart disease, high-altitude living, kidney cysts and tumors, hepatoma, and other EPO-secreting tumors. Rare plasma cell dyscrasia-associated syndromes such as POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) and TEMPI (telangiectasias, elevated EPO and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting) can be associated with increased hemoglobin levels. When these causes of secondary erythrocytosis are excluded, a heritable cause involving hemoglobin or erythrocyte regulatory mechanisms may be present. It is important to differentiate polycythemia vera (PV) from heritable causes of erythrocytosis, the latter of which can be passed to progeny but does not carry the risks of clonal evolution or marrow fibrosis associated with PV.

The most common cause of hereditary erythrocytosis is the presence of a high-oxygen-affinity (HOA) hemoglobin variant. A subset of hemoglobins with increased oxygen (O2) affinity result in clinically evident erythrocytosis caused by decreased O2 unloading at the tissue level. Many are asymptomatic; however, some patients have recurrent headaches, dizziness, fatigue, and restless legs. A subset of patients experience thrombotic episodes. Affected individuals can be plethoric, and many are misclassified as polycythemia vera, particularly prior to more recent genetic testing availability. The O2-dissociation curve is left-shifted (p50 values are decreased) in HOA variants. Changes to the amino acid sequence of the hemoglobin molecule may distort the protein structure, affecting O2 transport or unloading and the binding of 2,3-bisphosphoglyceric acid (2,3-BPG). 2,3-BPG stabilizes the deoxygenated state of hemoglobin. Therefore, a decrease in the 2,3-BPG concentration results in greater O2 affinity of the normal hemoglobin molecule. Rare cases of erythrocytosis have been associated with a reduction in 2,3-BPG formation. This is due to variants in the converting enzyme, bisphosphoglycerate mutase (BPGM). Truncating variants in the erythropoietin receptor gene, EPOR, have been shown to be a cause of the autosomal dominant primary familial and congenital polycythemia (OMIM 133100).

In addition, O2-sensing pathway variants, EPAS1(HIF2A) (OMIM 611783); EGLN1(PHD2) (OMIM 609820), and VHL (OMIM 263400) cause hereditary erythrocytosis, and a subset are associated with pheochromocytoma and paragangliomas. All have shown an autosomal dominant pattern of inheritance, except VHL-associated erythrocytosis, which is an autosomal recessive disorder. Homozygous VHL R200W alterations have been shown to be causative of Chuvash polycythemia, an endemic heritable erythrocytic disorder first described in Russia but subsequently found in other ethnic groups. The prevalence of causative variants in EPOR and the O2-sensing pathway genes is unknown; however, in our experience, they are less prevalent than genetic variants that cause HOA hemoglobin variants and are much less prevalent than polycythemia vera. Because there are many causes of erythrocytosis, an algorithmic and reflexive testing strategy is useful for evaluating these disorders. Initial JAK2 V617F alteration testing and serum EPO levels are useful. Importantly, a significant subset of HOA hemoglobin variants can be electrophoretically silent on multiple routine screening platforms; however, most, and possibly all, HOA hemoglobin variants can be identified with addition of the intact mass spectrometry method. Our extensive experience with these disorders allows an economical, comprehensive evaluation with high sensitivity.