Apoptosis is one cause of thrombocytopenia in patients with high-altitude polycythemia

Wang, Zhuoya; Tenzing, Noryung; Xu, Qiying; Liu, Huifang; Ye, Yi; Wen, Yi; Wuren, Tana; Cui, Sen

doi:10.1080/09537104.2022.2157381

“…The trend to higher levels of D‐dimers in the EE+ group might be explained by the older age of the EE+ participants. Regarding primary haemostasis, we observed a decrease in platelet count between EE− and EE+ similar to those previously reported in EE/CMS highlanders, for which different underlying mechanisms have been proposed (Wang et al., 2022, 2023) Among them, the inverse relationship between platelet count and mean platelet volume (Figure 1b) might suggest that an increased peripheral consumption rather than reduced platelet production might explain the lower platelet count in EE+, because newly formed platelets are known to have larger volume. This might be in agreement with a recent study suggesting an increased platelet activation and thus apoptosis in EE+, where a similar negative correlation between platelet count and mean platelet volume, in addition to lower platelet count, were shown in EE+ (Wang et al., 2023).…”

Section: Discussionsupporting

confidence: 88%

“…On the arterial side, it has been suggested that the increased haematocrit caused by altitude polycythaemia might increase the risk of cardiovascular events and strokes, although the frequent association of EE/CMS with common cardiovascular risk factors might be a confounding factor (Ortiz‐Prado et al., 2022; Villafuerte & Corante, 2016; Villafuerte et al., 2022). Furthermore, although the impact of acute altitude exposure on haemostasis in lowlanders (LL) ascending to high altitude has been studied extensively and reviewed recently (Treml et al., 2022), the impact of permanent residence at high altitude and the potential repercussions of EE on the haemostatic system remain poorly investigated (DeSouza et al., 2021; Hancco, Champigneulle, et al., 2020; Jiang et al., 2021; Wang et al., 2023; Yin et al., 2022). In particular, two recent studies on Andean highlanders reported possibly conflicting results.…”

Section: Introductionmentioning

confidence: 99%

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

Champigneulle,

Caton,

Seyve

et al. 2024

Experimental Physiology

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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.

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“…HAPC is a common chronic HA disease characterized by excessive proliferation of RBCs caused by HH conditions ( Wang et al, 2023 ). Under physiological conditions, RBC homeostasis is maintained by balancing erythropoiesis and erythrocyte clearance ( Dzierzak and Philipsen, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

Yang

¹

,

Li

²

,

Ding

³

et al. 2024

eLife

2

0

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High-altitude polycythemia (HAPC) occurs in high-altitude (HA) environments and involves an imbalance between erythropoiesis and eryptosis. Spleen/splenic macrophages are an important primary tissue/cell of eryptosis and iron recycling. However, the role of the spleen in the pathogenesis of HAPC and the effect of hypobaric hypoxia (HH) on the biology of the spleen and splenic macrophages are still unclear. We used a mouse hypobaric hypoxia (HH) exposure model to simulate an in vivo study of 6000 m HA exposure. For in vitro studies, we used a primary splenic macrophage model treated with 1% hypoxia. We found that the HH-treated mouse model promoted erythropoiesis and led to erythrocytosis. In addition, HH exposure resulted in marked splenic contraction followed by splenomegaly for up to 14 days. HH exposure impaired the red blood cell (RBC) handling capacity of the spleen, which was caused by a decrease in splenic macrophages in the red pulp. Moreover, HH treatment for 7 and 14 days promoted iron mobilization and ferroptosis in the spleen, as reflected by the expression of metabolism-related proteins and ferroptosis-related proteins. All of the protein expression levels were similar to the gene expression levels in human peripheral blood mononuclear cells. Single-cell sequencing of the spleen further demonstrated a significant decrease in macrophages in the spleen 7 days after HH exposure. In in vitro studies, we confirmed that primary splenic macrophages decreased and induced ferroptosis following hypoxic treatment, which was reversed by pre-treatment with the ferroptosis inhibitor ferrostatin-1. Taken together, HH exposure induces splenic ferroptosis, especially in red pulp macrophages, which further inhibits the clearance of RBCs from the spleen. As such, it promotes the retention of RBCs in the spleen and causes splenomegaly, which may further lead to the persistent production of RBCs and ultimately to the development of HAPC.

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“…HAPC is a common chronic HA disease characterized by excessive proliferation of RBCs caused by HH conditions [25]. Under physiological conditions, RBC homeostasis is maintained by balancing erythropoiesis and erythrocyte clearance [4].…”

Section: Discussionmentioning

confidence: 99%

High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

Yang

¹

,

Li

²

,

Ding

³

et al. 2023

Preprint

0

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High-altitude polycythemia (HAPC) occurs in high-altitude (HA) environments and involves an imbalance between erythropoiesis and eryptosis. Spleen/splenic macrophages are an important primary tissue/cell of eryptosis and iron recycling. However, the role of the spleen in the pathogenesis of HAPC and the effect of hypobaric hypoxia (HH) on the biology of the spleen and splenic macrophages are still unclear. We used a mouse hypobaric hypoxia (HH) exposure model to simulate an in vivo study of 6000 m HA exposure. For in vitro studies, we used a primary splenic macrophage model treated with 1% hypoxia. We found that the HH-treated mouse model promoted erythropoiesis and led to erythrocytosis. In addition, HH exposure resulted in marked splenic contraction followed by splenomegaly for up to 14 days. HH exposure impaired the red blood cell (RBC) handling capacity of the spleen, which was caused by a decrease in splenic macrophages in the red pulp. Moreover, HH treatment for 7 and 14 days promoted iron mobilization and ferroptosis in the spleen, as reflected by the expression of metabolism-related proteins and ferroptosis-related proteins. All of the protein expression levels were similar to the gene expression levels in human peripheral blood mononuclear cells. Single-cell sequencing of the spleen further demonstrated a significant decrease in macrophages in the spleen 7 days after HH exposure. In in vitro studies, we confirmed that primary splenic macrophages decreased and induced ferroptosis following hypoxic treatment, which was reversed by pre-treatment with the ferroptosis inhibitor ferrostatin-1. Taken together, HH exposure induces splenic ferroptosis, especially in red pulp macrophages, which further inhibits the clearance of RBCs from the spleen. As such, it promotes the retention of RBCs in the spleen and causes splenomegaly, which may further lead to the persistent production of RBCs and ultimately to the development of HAPC.

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Apoptosis is one cause of thrombocytopenia in patients with high-altitude polycythemia

Cited by 14 publications

References 68 publications

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

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

High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

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