High-Altitude Erythrocytosis: Mechanisms of Adaptive and Maladaptive Responses

Villafuerte, Francisco C.; Simonson, Tatum S.; Bermudez, Daniela; León‐Velarde, Fabiola

doi:10.1152/physiol.00029.2021

Cited by 25 publications

(29 citation statements)

References 120 publications

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“…Hematocrit (Hct), the percent volume of red blood cells in whole blood is, on average, higher in Andeans than Tibetans ( 1 ) and proportional to [Hb] (Hct ≈ 3*[Hb], [Hb] in grams per deciliter). EE, an overproduction of red blood cells and hallmark of chronic mountain sickness (CMS), is more prevalent in Andean than Tibetan men and associated with pulmonary hypertension, myocardial infarction, and cor pulmonale ( 33 ).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, variants within EPAS1 have been associated with relatively lower [Hb] in Tibetan groups, which are linked, indirectly or directly, to an adaptive phenotype [e.g., protection from excessive erythrocytosis (EE)] ( 3 , 5 ). Although Tibetans demonstrate lower average [Hb] than Andeans, Andean highlanders exhibit substantial intrapopulation variation in this phenotype ( 1 ), with values ranging from sea level to excessively high levels ( 33 ). While many of the same candidate gene regions studied in Tibetans have been identified as potential targets of selection in Andeans ( 12 ), including EPAS1 ( 10 , 25 ), adaptations upon the same genes and associated phenotypes have not been found.…”

Section: Introductionmentioning

confidence: 99%

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Functional EPAS1 / HIF2A missense variant is associated with hematocrit in Andean highlanders

Lawrence,

Gu,

Bohlender

et al. 2024

Sci. Adv.

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Hypoxia-inducible factor pathway genes are linked to adaptation in both human and nonhuman highland species. EPAS1 , a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans. We provide evidence for an association between an adaptive EPAS1 variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth. CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations and validation in a lowland population. Although this genocopy of relatively lower hematocrit in Andean highlanders parallels well-replicated findings in Tibetans, it likely involves distinct pathway responses based on a protein-coding versus noncoding variants, respectively. These findings illuminate how unique variants at EPAS1 contribute to the same phenotype in Tibetans and a subset of Andean highlanders despite distinct evolutionary trajectories.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional EPAS1 / HIF2A missense variant is associated with hematocrit in Andean highlanders

Lawrence,

Gu,

Bohlender

et al. 2024

Sci. Adv.

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“…Other changes are observed in the cardiovascular or respiratory systems, as well as in the utero-placental circulation [ 3 ]. Erythrocytosis, or increased production of red blood cells, is one of the most well-documented physiological traits that varies within and among HA populations [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

A Critical Analysis of the Automated Hematology Assessment in Pregnant Women at Low and at High Altitude: Association between Red Blood Cells, Platelet Parameters, and Iron Status

Figueroa-Mujica

Ccahuantico

Ccorahua-Ríos

et al. 2022

Life

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The objectives of the study were to determine differences in the parameters of red blood cells (RBC), white blood cells (WBC), and platelets at low altitude (LA) and at high altitude (HA) and with the gestation being advanced, and to determine correlations between parameters of RBC and platelets. We also studied the association of RBC and platelets with markers of iron status. In addition, markers of iron status and inflammation were measured and compared at each trimester of gestation in pregnant women at LA and HA. A cross-sectional comparative study was conducted at Lima (150 m above sea level) and Cusco at 3400 m above sea level from May to December 2019. Hematological parameters in pregnant women (233 at LA and 211 at HA) were analyzed using an automated hematology analyzer. Serum ferritin levels, soluble transferrin receptor (sTfR), hepcidin, erythropoietin, testosterone, estradiol, and interleukin-6 (IL6) levels were measured by ELISA. One-way ANOVA supplemented with post hoc test, chi-square test, and Pearson correlation test statistical analyses were performed. p < 0.05 was considered significant. Pregnant woman at HA compared to LA had significantly lower WBC (p < 0.01), associated with higher parameters of the RBC, except for the mean corpuscular volume (MCV) that was no different (p > 0.05). Platelets and mean platelet volume (MPV) were higher (p < 0.01), and platelet distribution width (PDW) was lower at HA than at LA (p < 0.01). A higher value of serum ferritin (p < 0.01), testosterone (p < 0.05), and hepcidin (p < 0.01) was observed at HA, while the concentration of sTfR was lower at HA than at LA (p < 0.01). At LA, neutrophils increased in the third trimester (p < 0.05). RBC parameters decreased with the progress of the gestation, except RDW-CV, which increased. The platelet count decreased and the MPV and PDW were significantly higher in the third trimester. Serum ferritin, hepcidin, and serum testosterone decreased, while sTfR and serum estradiol increased during gestation. At HA, the WBC and red blood cell distribution width- coefficient of variation (RDW-CV), PCT, and serum IL-6 did not change with gestational trimesters. RBC, hemoglobin (Hb), hematocrit (Hct), mean corpuscular hemoglobin concentration (MCHC), and platelet count were lower as gestation advanced. MCV, MPV, and PDW increased in the third trimester. Serum ferritin, testosterone, and hepcidin were lower in the third trimester. Serum estradiol, erythropoietin, and sTfR increased as gestation progressed. Direct or inverse correlations were observed between RBC and platelet parameters and LA and HA. A better number of significant correlations were observed at HA. Hb, Hct, and RDW-CV showed a significant correlation with serum ferritin at LA and HA. Of these parameters, RDW-CV and PDW showed an inversely significant association with ferritin (p < 0.05). In conclusion, a different pattern was observed in hematological markers as well as in iron status markers between pregnant women at LA and HA. In pregnant women a significant correlation between several RBC parameters with platelet marker parameters was also observed. Data suggest that pregnant women at HA have adequate iron status during pregnancy as reflected by higher serum ferritin levels, lower sTfR levels, and higher hepcidin values than pregnant women at LA.

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“…An elusive disease caused by sustained insufficiency of O 2 , its major pathogenic etiology is the excessive erythropoietic response, or polycythemia, which originates outcomes collectively known as CMS [ 20 ]. Thus, tracking hematological changes enables monitoring of hypoxia adaptation [ 21 , 22 ]. Alternate valid markers of maladaptation include the development of pulmonary hypertension (PH), a frequent condition at altitude, which may be accompanied by right ventricle hypertrophy and failure.…”

Section: Oxygen and Hypoxiamentioning

confidence: 99%

The Oxygen Cascade from Atmosphere to Mitochondria as a Tool to Understand the (Mal)adaptation to Hypoxia

Samaja¹,

Ottolenghi

2023

IJMS

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Hypoxia is a life-threatening challenge for about 1% of the world population, as well as a contributor to high morbidity and mortality scores in patients affected by various cardiopulmonary, hematological, and circulatory diseases. However, the adaptation to hypoxia represents a failure for a relevant portion of the cases as the pathways of potential adaptation often conflict with well-being and generate diseases that in certain areas of the world still afflict up to one-third of the populations living at altitude. To help understand the mechanisms of adaptation and maladaptation, this review examines the various steps of the oxygen cascade from the atmosphere to the mitochondria distinguishing the patterns related to physiological (i.e., due to altitude) and pathological (i.e., due to a pre-existing disease) hypoxia. The aim is to assess the ability of humans to adapt to hypoxia in a multidisciplinary approach that correlates the function of genes, molecules, and cells with the physiologic and pathological outcomes. We conclude that, in most cases, it is not hypoxia by itself that generates diseases, but rather the attempts to adapt to the hypoxia condition. This underlies the paradigm shift that when adaptation to hypoxia becomes excessive, it translates into maladaptation.

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High-Altitude Erythrocytosis: Mechanisms of Adaptive and Maladaptive Responses

Cited by 25 publications

References 120 publications

Functional EPAS1 / HIF2A missense variant is associated with hematocrit in Andean highlanders

Functional EPAS1 / HIF2A missense variant is associated with hematocrit in Andean highlanders

A Critical Analysis of the Automated Hematology Assessment in Pregnant Women at Low and at High Altitude: Association between Red Blood Cells, Platelet Parameters, and Iron Status

The Oxygen Cascade from Atmosphere to Mitochondria as a Tool to Understand the (Mal)adaptation to Hypoxia

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