Definitive evaluation of an individual with JAK2-negative erythrocytosis associated with lifelong sustained increased red blood cell mass, elevated red blood cell count, hemoglobin, or hematocrit
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Erythrocytosis (increased red blood cell mass or polycythemia) may be primary, due to an intrinsic defect of bone marrow stem cells (polycythemia vera: PV), 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 (due to smoking), cyanotic heart disease, high-altitude living, renal cysts and tumors, hepatoma, and other Epo-secreting tumors. When these common causes of secondary erythrocytosis are excluded, a heritable cause involving hemoglobin or erythrocyte regulatory mechanisms may be present.
A less common cause of secondary polycythemia is the presence of a high-oxygen-affinity hemoglobin. Hemoglobins with increased oxygen (O2) affinity commonly result in erythrocytosis caused by an O2 unloading problem at the tissue level. The most common symptoms are headache, dizziness, tinnitus, and memory loss. The affected individuals are plethoric, but not cyanotic. Patients with a high-oxygen-affinity hemoglobin may present with an increased erythrocyte count, hemoglobin concentration, and hematocrit, but normal leukocyte and platelet counts. The p50 and 2,3-bisphosphoglycerate (2,3-BPG, also known as 2,3-DPG) values are low. Changes to the amino acid sequence of the hemoglobin molecule may distort the molecular structure, affecting O2 transport and the binding of 2,3-BPG. 2,3-BPG is critical to O2 transport of erythrocytes because it regulates the O2 affinity of hemoglobin. A decrease in the 2,3-BPG concentration within erythrocytes results in greater O2 affinity of hemoglobin and reduction in O2 delivery to tissues. A few cases of erythrocytosis have been described as being due to a reduction in 2,3-BPG formation. This is most commonly due to mutations in the converting enzyme, bisphosphoglycerate mutase (BPGM). Mutations in the genes EPOR, EPAS1(HIF2A), EGLN1(PHD2), and VHL also cause hereditary erythrocytosis and a subset are associated with subsequent pheochromocytoma and paragangliomas. The prevalence of these mutations is unknown, but they appear less prevalent than mutations that cause high-oxygen-affinity hemoglobin variants, and much less prevalent than polycythemia vera. Because there are many causes of erythrocytosis, an algorithmic and reflexive testing strategy is useful. Initial JAK2 V617F mutation testing and serum Epo levels are important with p50 results further stratifying JAK2-negative cases.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
Definitive results and an interpretive report will be provided.
The evaluation includes testing for a hemoglobinopathy and oxygen (O2) affinity of the hemoglobin molecule. An increase in O2 affinity is demonstrated by a shift to the left in the O2 dissociation curve (decreased p50 result).
A hematopathologist expert in these disorders will evaluate the case, appropriate tests are performed, and an interpretive report is issued.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Polycythemia vera and acquired causes of erythrocytosis should be excluded before ordering this evaluation.
The shipping control specimen is required to adequately interpret these cases, as temperature extremes can impact the integrity of the specimen.
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
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