The study, led by researchers including Edgar Cristancho-Mejía and Walter Schmidt, recruited healthy, non-smoking adults who had lived at their respective altitudes for at least two years. Participants came from six locations spanning 970 to 2600 meters, including regions around Bogotá in the Central Eastern Andes and the lower Western Andes near Tuluá and Cali. Crucially, none of the participants were endurance athletes, eliminating a major confounding factor that has plagued earlier comparisons between highland populations and sea-level dwellers. The cohort included 133 men and 148 women, with ancestry distributions reflecting the regional population mix of African, European, and Native American heritage.

Measuring hemoglobin mass directly is technically demanding, and the team used the optimized carbon monoxide rebreathing method, widely regarded as the gold standard. Participants inhaled a precisely calculated dose of carbon monoxide over two minutes, and the researchers tracked how much of it bound to hemoglobin in the blood, allowing an accurate calculation of total hemoglobin mass. From this, together with venous hemoglobin concentration and hematocrit, the team derived red cell volume, plasma volume, and total blood volume. Blood samples drawn from a cubital vein provided hemoglobin concentration, hematocrit, and oxygen saturation values for each participant.

The results revealed a clear and unexpected divergence in thresholds. Hemoglobin mass rose significantly only in residents living at 2180 meters or higher, with the effect becoming firmly established at 2600 meters. Plasma volume, by contrast, was already significantly reduced at 1730 meters—roughly 450 meters lower than the erythropoietic threshold. Between the lowest and highest study locations, hemoglobin concentration increased by about 1.0 grams per deciliter in men and 1.3 grams per deciliter in women, while hematocrit rose by roughly 3.2 to 3.7 percentage points. Relative to lean body mass, hemoglobin mass was 5.8 percent higher in men and 8.9 percent higher in women at 2600 meters compared with 970 meters, while plasma volume per kilogram of lean mass fell by about 6 percent in both sexes.

The physiological logic behind these two thresholds traces back to the shape of the oxygen dissociation curve. This sigmoid curve allows arterial blood to remain nearly fully saturated with oxygen up to altitudes of roughly 2000 meters, meaning the kidneys—the primary sensors of oxygen availability—detect little reason to stimulate red cell production. Below that ceiling, the flat upper portion of the curve buffers the modest drop in ambient oxygen pressure. Once saturation begins to fall more steeply, however, the kidney responds by releasing erythropoietin, triggering the bone marrow to expand hemoglobin mass. Plasma volume regulation operates on a different logic entirely: it responds to the overall oxygen-carrying deficit rather than to a specific saturation threshold, and it does so within days rather than weeks.

When the researchers combined their data with earlier measurements taken at 420 and 3800 meters in Bolivia using the same methodology, a striking pattern emerged. Hemoglobin mass increased slowly and modestly up to about 2600 meters, then climbed sharply at higher elevations, reaching values 27 percent above near-sea-level levels at 3800 meters. Notably, within the moderate-altitude range of the current study, there was no significant relationship between hemoglobin mass and oxygen saturation—suggesting that up to roughly 2600 meters, altitude exerts only a gentle influence on erythropoiesis. Above that point, the diminishing oxygen supply becomes the dominant driver, most likely registered by oxygen-sensing mechanisms in the kidneys.

To quantify how much each component contributed to the observed rise in hemoglobin concentration, the team performed multiple regression analyses. The calculations showed that every 100-gram increase in hemoglobin mass raised concentration by 1.59 grams per deciliter, while every liter of plasma volume loss raised it by 3.07 grams per deciliter. Applying these coefficients to the altitude-related changes, the researchers found that of the 1.2 grams per deciliter elevation in hemoglobin concentration at 2600 meters, approximately 0.56 grams per deciliter was attributable to increased hemoglobin mass and 0.61 grams per deciliter to reduced plasma volume—a near-perfect split. When the team applied an alternative correction for the Fåhraeus effect, which accounts for differences between central and peripheral hematocrit, the plasma volume contribution grew even larger.

The findings carry immediate clinical weight. Hemoglobin concentration is one of the most commonly ordered diagnostic measurements in medicine, and anemia thresholds are already adjusted for altitude. Yet the hemoconcentration caused by plasma volume contraction at moderate elevations has never been factored into those thresholds. If a substantial fraction of the altitude-related rise in hemoglobin reflects a shrunken liquid blood volume rather than genuinely enhanced oxygen-carrying capacity, then current anemia criteria may misclassify residents of towns like Bogotá at 2600 meters. The study also resonates with recent work on high-altitude populations worldwide: data from Sherpa communities in the Himalayas suggest their lower hemoglobin concentrations compared with Andean highlanders stem largely from larger plasma volumes rather than smaller hemoglobin masses, underscoring that the ratio of red cells to plasma, not red cell count alone, defines the blood’s oxygen transport profile.

The authors acknowledge limitations. Sample sizes at individual altitudes were modest, and the high interindividual variability in hemoglobin mass—driven largely by differences in lean body mass—means the altitude effect, though statistically robust, is just one of several factors shaping any person’s blood profile. Ambient temperature may also play a role, since the lowland study sites were considerably warmer, and heat acclimatization is known to expand plasma volume. Plasma volume itself was calculated indirectly rather than measured directly, and the Fåhraeus correction introduces some uncertainty, though the researchers showed that an altitude-adjusted correction strengthened rather than weakened their conclusions. Nevertheless, the study provides the first systematic evidence that the blood’s response to moderate altitude unfolds in two distinct stages: plasma contracts first, at around 1730 meters, and the erythropoietic machinery follows at roughly 2180 meters. For the roughly 5 percent of humanity living above 1500 meters, that distinction may soon matter at the doctor’s office as much as on the mountain.

Subject of Research: Altitude thresholds for hemoglobin mass and plasma volume regulation and their effects on hemoglobin concentration in Andean residents

Article Title: Altitude thresholds for hemoglobin and plasma volume regulation in adult residents of different altitudes and their impact on hemoglobin concentration

Article References: Cristancho‐Mejía, E., Trompetero‐Gonzalez, A. C., Benavides‐Pinzón, W. F., & Schmidt, W. F.-J. (2026). Altitude thresholds for hemoglobin and plasma volume regulation in adult residents of different altitudes and their impact on hemoglobin concentration. Physiological Reports, 14(19), Article e71108. https://doi.org/10.14814/phy2.71108

Image Credits: AI Generated

DOI: 10.14814/phy2.71108

Keywords: hemoglobin mass, plasma volume, altitude, hypoxia, erythropoiesis, Andes, Colombia, anemia thresholds, oxygen saturation, blood volume, CO rebreathing, physiology