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Test Catalog

Test ID: REVE    
Erythrocytosis Evaluation, Whole Blood

Useful For Suggests clinical disorders or settings where the test may be helpful

Definitive, comprehensive, and economical evaluation of an individual with JAK2-negative erythrocytosis associated with lifelong sustained increased hemoglobin or hematocrit

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

This is a consultative evaluation in which the case will be evaluated at Mayo Clinic Laboratories, the appropriate tests performed at an additional charge, and the results interpreted.

 

This profile evaluates for hereditary (congenital) causes of erythrocytosis. Symptoms should be long-standing or familial in nature. All cases will be tested for p50 (if shipping control is received) and hemoglobin variants (cation exchange HPLC, capillary electrophoresis and mass spectrometry) with an interpretative report. Additional testing is guided in a reflexive manner, and may include molecular testing of the HBA1/HBA2, HBB, EPOR, VHL, EGLN1(PHD2), EPAS1(HIF2a), and BPGM genes, among others, as appropriate. See Erythrocytosis Evaluation Testing Algorithm in Special Instructions. An information sheet relaying clinical history, erythropoietin (EPO) levels, and JAK2 result s, if known, allows more complete interpretation.

 

An additional consultative interpretation that summarizes all testing, will be provided after test completion to incorporate subsequent results into an overall evaluation if any of the following molecular tests are reflexed:

-ATHAL / Alpha-Globin Gene Analysis, Varies

-WASQR / Alpha Globin Gene Sequencing, Blood

-WBSQR / Beta-Globin Gene Sequencing, Blood

-WBDDR / Beta-Globin Cluster Locus Deletion/Duplication, Blood

-WGSQR / Gamma-Globin Full Gene Sequencing, Varies

-BPGMM / 2,3-Bisphosphoglycerate Mutase, Full Gene Sequencing Analysis, Varies

-HEMP / Hereditary Erythrocytosis Mutations, Whole Blood

-VHLE / VHL Gene, Erythrocytosis Mutation Analysis

 

The following algorithms are available in Special Instructions:

-Myeloproliferative Neoplasm: A Diagnostic Approach to Bone Marrow Evaluation

-Myeloproliferative Neoplasm: A Diagnostic Approach to Peripheral Blood Evaluation

 

See Benign Hematology Evaluation Comparison in Special Instructions.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Erythrocytosis (polycythemia) is identified by a sustained increase in hemoglobin or hematocrit. An isolated increase in RBC count (in the absence of chronic phlebotomy or coincident iron deficiency) is not within the definition of erythrocytosis and may occur in thalassemia or other causes. 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, 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. It is important to differentiate polycythemia vera (PV) from heritable causes of erythrocytosis, the latter of which can be passed to progeny but do not carry the risks of clonal evolution associated with PV.

 

The most common cause of hereditary erythrocytosis is the presence of a high-oxygen-affinity (HOA) hemoglobin. A subset of hemoglobins with increased oxygen (O2) affinity result in clinically evident erythrocytosis caused by decreased O2 unloading 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 HOA hemoglobin may present with an increased hemoglobin concentration, and hematocrit, but normal leukocyte and platelet counts. The p50 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-bisphosphoglyceric acid (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 variants in the converting enzyme, bisphosphoglycerate mutase (BPGM). Variants in the genes EPOR, EPAS1(HIF2A), EGLN1(PHD2), and VHL also cause hereditary erythrocytosis and a subset are associated with pheochromocytoma and paragangliomas. The prevalence of these variants is unknown, but they appear less prevalent than variants that cause high-oxygen-affinity hemoglobin variantations, 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 variant testing and serum EPO levels are important with p50 results further stratifying JAK2-negative cases. A significant subset of HOA hemoglobin variantations can be electrophoretically silent; however, most if not all of these can be isolated with addition of the mass spectrometry method. Our extensive experience with these disorders allows an economical, comprehensive evaluation with high sensitivity.

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.

Interpretation Provides information to assist in interpretation of the test results

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). Reflex testing for EPOR, EGLN1 (PHD2), EPAS1 (HIF2a), VHL, and BPGM will be performed as needed.

 

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

The shipping control specimen is required to adequately interpret these cases, as temperature extremes can impact the integrity of the specimen.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Patnaik MM, Tefferi A: The complete evaluation of erythrocytosis: congenital and acquired. Leukemia 2009 May;23(5):834-844

2. McMullin MF: The classification and diagnosis of erythrocytosis. Int J Lab Hematol 2008;30:447-459

3. Percy MJ, Lee FS: Familial erythrocytosis: molecular links to red blood cell control. Haematologica 2008 Jul;93(7):963-967

4. Huang LJ, Shen YM, Bulut GB: Advances in understanding the pathogenesis of primary familial and congenital polycythaemia. Br J Haematol 2010 Mar;148(6):844-852

5. Maran J, Prchal J: Polycythemia and oxygen sensing. Pathol Biol 2004;52:280-284

6. Lee F: Genetic causes of erythrocytosis and the oxygen-sensing pathway. Blood Rev 2008;22:321-332

7. Merchant SH, Oliveira JL, Hoyer JD, Viswanatha DS: Erythrocytosis. In Hematopathology. Second edition. Edited by ED His. Philadelphia, Elsevier Saunders, 2012, pp 722-723

8. Zhuang Z, Yang C, Lorenzo F, et al: Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med 2012 Sep 6;367(10):922-930

9. Oliveira JL, Coon LM, Frederick LA, et al: Genotype-Phenotype Correlation of Hereditary Erythrocytosis Mutations, a single center experience. Am J Hematol 2018 May 23 PMID: 29790589

Special Instructions Library of PDFs including pertinent information and forms related to the test