Decreased plasma soluble erythropoietin receptor in high-altitude excessive erythrocytosis and Chronic Mountain Sickness

Abstract

Excessive erythrocytosis (EE) is the hallmark of chronic mountain sickness (CMS), a prevalent syndrome in high-altitude Andean populations. Although hypoxemia represents its underlying stimulus, why some individuals develop EE despite having altitude-normal blood erythropoietin (Epo) concentration is still unclear. A soluble form of the Epo receptor (sEpoR) has been identified in human blood and competes directly for Epo with its membrane counterpart (mEpoR). Thus, reduced levels of circulating sEpoR could lead to higher Epo availability and ultimately to EE. We characterized the relationship between Epo and sEpoR, with hematocrit and hemoglobin concentration in healthy highlanders and CMS patients at 4,340 m in Cerro de Pasco, Peru. Our results show that EE patients show decreased plasma sEpoR levels and can be subdivided into two subgroups of normal and high plasma Epo concentration for the altitude of residence, with hemoglobin concentration rising exponentially with an increasing Epo-to-sEpoR ratio (Epo/sEpoR). Also, we showed that the latter varies as an inverse exponential function of arterial pulse O2 saturation. Our findings suggests that EE is strongly associated with higher Epo/sEpoR values, leading to elevated plasma Epo availability to bind mEpoR, and thereby a stronger stimulus for augmented erythropoiesis. Differences in the altitude normal and high Epo CMS patients with a progressively higher Epo/sEpoR supports the hypothesis of the existence of two genetically different subgroups suffering from EE and possibly different degrees of adaptation to chronic high-altitude hypoxia.

Keywords: Chronic Mountain Sickness; erythropoietin; excessive erythrocytosis; high-altitude; soluble erythropoietin receptor.

Fig. 1.

Erythropoiesis-related parameters in healthy highlanders and Chronic Mountain Sickness (CMS) patients. The figure shows the scatter graphs with individual values in each group for Hb concentration ([Hb]; A), plasma erythropoietin (Epo) concentration (B), plasma soluble Epo receptor (sEpoR) concentration (C), and the Epo-to-sEpoR ratio (Epo/sEpoR; D) between healthy highlanders and CMS individuals with normal and high plasma Epo concentration (Normal-Epo CMS and High-Epo CMS, respectively) at high-altitude. Horizontal lines represent means ± SE. *P < 0.05, **P < 0.01, ***P < 0.001.

Fig. 2.

Relationship between the Epo/sEpoR, [Hb], and arterial pulse O₂ saturation (Sp_O2). The figure shows nonlinear best fit for mean Hb values as a function of mean Epo/sEpoR (A), and for mean Epo/sEpoR values as a function of Sp_O2 (B), including sea level residents, healthy highlanders, and Normal-Epo CMS and High-Epo CMS patients. Values are means ± SE.