Are coagulation profiles in Andean highlanders with excessive erythrocytosis favouring hypercoagulability?

Chronic mountain sickness is a maladaptive syndrome that affects individuals living permanently at high altitude and is characterized primarily by excessive erythrocytosis (EE). Recent results concerning the impact of EE in Andean highlanders on clotting and the possible promotion of hypercoagulability, which can lead to thrombosis, were contradictory. We assessed the coagulation profiles of Andeans highlanders with and without excessive erythrocytosis (EE+ and EE-). Blood samples were collected from 30 EE+ and 15 EE- in La Rinconada (Peru, 5100-5300 m a.s.l.), with special attention given to the sampling pre-analytical variables. Rotational thromboelastometry tests were performed at both native and normalized (40%) haematocrit using autologous platelet-poor plasma. Thrombin generation, dosages of clotting factors and inhibitors were measured in plasma samples. Data were compared between groups and with measurements performed at native haematocrit in 10 lowlanders (LL) at sea level. At native haematocrit, in all rotational thromboelastometry assays, EE+ exhibited hypocoagulable profiles (prolonged clotting time and weaker clot strength) compared with EE- and LL (all P < 0.01). At normalized haematocrit, clotting times were normalized in most individuals. Conversely, maximal clot firmness was normalized only in FIBTEM and not in EXTEM/INTEM assays, suggesting abnormal platelet activity. Thrombin generation, levels of plasma clotting factors and inhibitors, and standard coagulation assays were mostly normal in all groups. No highlanders reported a history of venous thromboembolism based on the dedicated survey. Collectively, these results indicate that EE+ do not present a hypercoagulable profile potentially favouring thrombosis.

Making a virtue out of an evil: Are red blood cells from chronic mountain sickness patients eligible for transfusions?

We investigated highlanders, permanently living at an altitude of 5100 m and compared Chronic Mountain Sickness (CMS) patients with control volunteers. While we found differences in systemic parameters such as blood oxygen content, hematocrit, hemoglobin concentration, and blood viscosity, the mechanical and rheological properties of single red blood cells did not differ between the two investigated groups.

Expedition 5300: limits of human adaptations in the highest city in the world.

Exposure to chronic hypobaric hypoxia imposes a significant physiological burden to more than 80 million humans living above 2500 m throughout the world. Among them, 50 000 live in the world's highest city, La Rinconada, located at 5000-5300 m in southern Peru. Expedition 5300 is the first scientific and medical programme led in La Rinconada to investigate the physiological adaptations and altitude-related health issues in this unique population. Dwellers from La Rinconada have very high haemoglobin concentration (20.3 ± 2.4 g/dL; n = 57) and those with chronic mountain sickness (CMS) exhibit even higher concentrations (23.1 ± 1.7 g/dL; n = 150). These values are associated with large total haemoglobin mass and blood volume, without an associated iron deficit. These changes in intravascular volumes lead to a substantial increase in blood viscosity, which is even larger in CMS patients. Despite these large haematological changes, 24 h blood pressure monitoring is essentially normal in La Rinconada, but some results suggest impaired vascular reactivity. Echocardiography revealed large right heart dilatation and high pulmonary arterial pressure as well as left ventricle concentric remodelling and grade I diastolic dysfunction. These changes in heart dimension and function tend to be more severe in highlanders with CMS. Polygraphy evaluations revealed a large reduction in nocturnal pulse oxygen saturation (median SpO2  = 79%), which is even more severe in CMS patients who also tended to show a higher oxygen desaturation index. The population of La Rinconada offers a unique opportunity to investigate the human responses to chronic severe hypoxia, at an altitude that is probably close to the maximum altitude human beings can permanently tolerate without presenting major health issues.

Blood viscosity and its determinants in the highest city in the world.

KEY POINTS: Highlanders develop unique adaptative mechanisms to chronic hypoxic exposure, including substantial haemoglobin and haematocrit increases. However, a significant proportion of populations living permanently at high altitude develop maladaptive features known as chronic mountain sickness (CMS). This study aimed to assess the effects of permanent life at high altitude on clinical and haemorheological parameters (blood viscosity and red blood cell aggregation) and to compare clinical and haemorheological parameters of dwellers from the highest city in the world according to CMS severity. Blood viscosity increased with altitude, together with haemoglobin concentration and haematocrit. At 5100 m, highlanders with moderate-to-severe CMS had higher blood viscosity mainly at high shear rate and even at corrected haematocrit (40%), with a lower red blood cell aggregation. Blood viscosity may contribute to CMS symptomatology but the increased blood viscosity in CMS patients cannot solely be explained by the rise in haematocrit. ABSTRACT: Chronic mountain sickness (CMS) is a condition characterised by excessive erythrocytosis (EE). While EE is thought to increase blood viscosity and subsequently to trigger CMS symptoms, the exact relationship between blood viscosity and CMS symptoms remains incompletely understood. We assessed the effect of living at high altitude on haemoglobin, haematocrit and haemorheological parameters (blood viscosity and red blood cell aggregation), and investigated their relationship with CMS in highlanders living in the highest city in the world (La Rinconada, Peru, 5100 m). Ninety-three men participated in this study: 10 Caucasian lowlanders, 13 Andean highlanders living at 3800 m and 70 Andean highlanders living at 5100 m (35 asymptomatic, CMS score ≤5; 15 with mild CMS, CMS score between 6 and 10; 20 with moderate-to-severe CMS, CMS score >10). Blood viscosity was measured at native and corrected haematocrit (40%). Haemoglobin concentration and haematocrit increased with the altitude of residency. Blood viscosity also increased with altitude (at 45 s-1 : 6.7 ± 0.9 mPa s at sea level, 14.0 ± 2.0 mPa s at 3800 m and 27.1 ± 8.8 mPa s at 5100 m; P < 0.001). At 5100 m, blood viscosity at corrected haematocrit was higher in highlanders with moderate-to-severe CMS (at 45 s-1 : 18.9 ± 10.7 mPa s) than in highlanders without CMS (10.2 ± 5.9 mPa s) or with mild CMS (12.1 ± 6.1 mPa s) (P < 0.05). In conclusion, blood viscosity may contribute to CMS symptomatology but the increased blood viscosity in CMS patients cannot solely be explained by the rise in haematocrit.

Micro- and macrovascular function in the highest city in the world: a cross sectional study.

Background: Since vascular responses to hypoxia in both healthy high-altitude natives and chronic mountain sickness (a maladaptive high-altitude pathology characterised by excessive erythrocytosis and the presence of symptoms-CMS) remain unclear, the role of inflammation and oxidative/nitrosative stress on the endothelium-dependent and -independent responses in both the micro- and macrocirculation, in healthy Andeans at different altitudes and in CMS patients, was examined. Methods: 94 men were included: 18 lowlanders (LL), 38 healthy highlanders permanently living at 3800 m (n = 21-HL-3800) or in La Rinconada, the highest city in the world (5100-5300 m) (n = 17-HL-5100/No CMS). Moreover, 14 participants with mild (Mild CMS) and 24 with moderate to severe CMS (Mod/Sev CMS) were recruited. All undertook two reactivity tests: i) local thermal hyperaemia (microcirculation) and ii) flow-mediated dilation (macrocirculation). Endothelium-independent function (glyceryl trinitrate) was also assessed only in La Rinconada. Findings: Conductance and skin blood flow velocity during the microcirculation test, as well as macrocirculation progressively decreased with altitude (LL > HL-3800 > HL-5100/No CMS). CMS also induced a decrease in macrocirculation (HL-5100/No CMS > Mild CMS = Mod/Sev CMS), while glyceryl trinitrate restored vascular function. Both oxidative stress and nitric oxide metabolites increased with altitude only. Principal component analysis revealed that increasing inflammation with altitude was associated with a progressive decline in both micro- and macrovascular function in healthy highlanders. Interpretation: Both micro and macrovascular function are affected by chronic exposure to hypoxia, the latter being further compounded by CMS. Funding: The "Fonds de dotation AGIR pour les maladies chroniques", the "Air Liquide Foundation", and the "French National Research Agency".

Cardiac remodelling in the highest city in the world: effects of altitude and chronic mountain sickness.

AIMS: A unique Andean population lives in the highest city of the world (La Rinconada, 5100 m, Peru) and frequently develops a maladaptive syndrome, termed chronic mountain sickness (CMS). Both extreme altitude and CMS are a challenge for the cardiovascular system. This study aims to evaluate cardiac remodelling and pulmonary circulation at rest and during exercise in healthy and CMS highlanders. METHODS AND RESULTS: Highlanders living permanently at 3800 m (n = 23) and 5100 m (n = 55) with (n = 38) or without CMS (n = 17) were compared with 18 healthy lowlanders. Rest and exercise echocardiography were performed to describe cardiac remodelling, pulmonary artery pressure (PAP), and pulmonary vascular resistance (PVR). Total blood volume (BV) and haemoglobin mass were determined in all people. With the increase in the altitude of residency, the right heart dilated with an impairment in right ventricle systolic function, while the left heart exhibited a progressive concentric remodelling with Grade I diastolic dysfunction but without systolic dysfunction. Those modifications were greater in moderate-severe CMS patients. The mean PAP was higher both at rest and during exercise in healthy highlanders at 5100 m. The moderate-severe CMS subjects had a higher PVR at rest and a larger increase in PAP during exercise. The right heart remodelling was correlated with PAP, total BV, and SpO2. CONCLUSION: Healthy dwellers at 5100 m exhibit both right heart dilatation and left ventricle concentric remodelling with diastolic dysfunction. Those modifications are even more pronounced in moderate-severe CMS subjects and could represent the limit of the heart's adaptability before progression to heart failure.

High-Altitude Environment and COVID-19: SARS-CoV-2 Seropositivity in the Highest City in the World.

Champigneulle, Benoit, Ivan Hancco, Richard Renan, Stéphane Doutreleau, Emeric Stauffer, Aurélien Pichon, Julien V. Brugniaux, Hélène Péré, Pierre Bouzat, David Veyer, and Samuel Verges. High-altitude environment and COVID-19: SARS-CoV-2 seropositivity in the highest city in the world. High Alt Med Biol. 22: 000-000, 2021. Background: A reduced coronavirus disease 2019 (COVID-19) diffusion has been suggested in high-altitude areas but remained questionable. Aims of this study were to estimate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seropositivity as well as the risk factors associated in La Rinconada, the highest city in the world (5,100-5,300 m), a gold-mining town located in southeastern Peru where >50,000 dwellers live in precarious sanitary conditions. Materials and Methods: We performed a cross-sectional study during a 1-week period in October 2020, using point-of-care lateral flow serological assays allowing detection of antibodies directed against SARS-CoV-2 among voluntary dwellers in La Rinconada. Participants were also questioned about potential occupational and environmental risk factors of COVID-19 occurrence. Results: In a sample of 159 dwellers tested in La Rinconada, 48.4% [95% confidence interval, CI: 40.5-56.4] were seropositive for the SARS-CoV-2. Occurrence of at least one symptom compatible with the COVID-19 over the past 6 months remained the only significant factor associated with SARS-CoV-2 seropositivity (adjusted odds ratio: 3.27; [95% CI: 1.70-6.44]; p < 0.001). Conclusions: The high rate of SARS-CoV-2 seropositivity observed in this small sample of highlanders does not support a protective effect of high-altitude against the COVID-19 spread and demonstrates its large dissemination in vulnerable populations. Clinical Trial Registration number: NCT04604249.

Excessive Erythrocytosis and Chronic Mountain Sickness in Dwellers of the Highest City in the World.

BACKGROUND: While millions of people are living permanently at high altitude (>2,500 m) worldwide, the mechanisms underlying their tolerance to chronic hypoxia and those responsible for the occurrence of chronic mountain sickness (CMS) remain to be elucidated. Excessive erythrocytosis (EE) is thought to be the main mechanism responsible for CMS symptoms and is included in the definition of CMS, but the precise interplay between EE and symptoms of CMS requires further investigations. METHODS: The present study benefits from an exceptional dataset coming from 1,594 dwellers of La Rinconada, the highest city in the world (5,100-5,300 m). Based on individual clinical characteristics, subjects were categorized according to the presence of EE and CMS diagnosis, based on current guidelines. RESULTS: In this population of relatively young [32 (23; 39) years] highlanders residing in La Rinconada for only a few years [3 (2; 5) years], the internal prevalence of EE (44%) was high, whereas the internal prevalence of CMS (14%) was similar compared to previous reports in highlander populations living at lower altitude (∼4,000 m) in the Andes. Individuals with EE reported less symptoms compared to individuals with lower hematocrit values. Multivariable analysis revealed that age and sex are the main factors associated with EE, whereas age, hematocrit and number of years living at La Rinconada are factors associated with CMS symptoms. CONCLUSION: In this specific population of La Rinconada, high hematocrit values were observed but were associated with limited symptoms. These results raise important questions regarding the definition of EE and CMS and their underlying mechanisms in high-altitude populations.

Hemostasis in highlanders with excessive erythrocytosis at 5100 m: Preliminary data from the highest city of the world.

Little is known about hemostasis modifications induced by chronic hypoxic exposure in high-altitude residents, especially in those who develop excessive erythrocytosis (EE, i.e. hemoglobin concentration ≥ 21 g·dL-1 in male and ≥ 19 g·dL-1 in female). The aim of this preliminary study was to assess coagulation alterations in highlanders with or without EE using simple hemostatic tests such as bleeding (BT) and clotting (CT) times. Eighty-one male (43 ± 7 years), permanent residents from La Rinconada (Peru), the highest city in the world (5,100-5,300 m), were evaluated. Thirty-six subjects (44 %) presented with EE. EE subjects compared to non-EE subjects had lower BT (3.6 ± 1.2 vs. 7.0 ± 1.9 min, p < 0.001) and CT (11.7 ± 1.7 vs. 15.1 ± 2.3 min, p < 0.001). These results support the notion that highlanders with EE are in a state of hypercoagulability and call for further hemostasis investigations in this population using more detailed hemostatic methods.

Importancia de la medición de la Viscosidad sanguínea: retos y limitaciones

La sangre es una mezcla de componentes que tiene su propia identidad. Una de las propiedades físicas que adquiere es su viscosidad, la cual es la resistencia que ofrece para desplazarse. A diferencia de sus componentes (como glucosa, hemoglobina, colesterol, etc.), la sangre no posee un nivel único de viscosidad, sino que esta es variable debido a diversos factores. Exponemos algunos principios físicos que nos permitirán entender mejor esta dinámica de la viscosidad sanguínea, y su posible aplicación en algunos fenómenos hemodinámicos, así como la complejidad de su medición en la práctica clínica habitual.

Blood is a mixture of components that has its own identity. One of the physical properties that it acquires is its viscosity, which is the resistance it offers to move. Unlike its components (such as glucose, hemoglobin, cholesterol, etc.), blood does not have a single level of viscosity, but it is variable due to various factors. We present some physical principles that will allow us to better understand these dynamics of blood viscosity, and its possible application in some hemodynamic phenomena, as well as the complexity of its measurement in routine clinical practice.