Effects of long-term high-altitude exposure on fibrinolytic system.

OBJECTIVE: High altitude (HA), with the main feature of hypobaric hypoxia, is an independent risk factor for thrombosis. However, little is known on the alterations of fibrinolytic system in adaptation to HA. In this study, we investigated changes of fibrinolytic system parameters between individuals permanently living at HA and low altitude (LA) regions, and provided data for further studies on HA-induced thrombotic disease. MATERIAL AND METHODS: A total of 226 eligible participants, including 103 LA participants, 100 healthy HA subjects and 23 high altitude polycythemia (HAPC) patients, were recruited in this study. Six fibrinolytic parameters, i.e. fibrinogen (Fbg), D-dimer (DDi), antithrombin III (AT-III), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and plasminogen (PLG) were analyzed respectively. PAI-1 and tPA were performed by using bio-immuno-assays and an automated coagulation analyzer was used to conduct Fbg, DDi, AT-III and PLG tests. RESULTS: Plasma levels of Fbg, DDi, PAI-1 and PLG were significantly higher in healthy HA group than in LA group (all p < 0.05), whereas tPA was significantly lower in healthy HA group. No significant difference in AT-III was observed between healthy HA and LA groups (p > 0.05). All these fibrinolytic parameters showed no significant distinctions between healthy HA subjects and HAPC patients (all p > 0.05). HGB showed no relationship with fibrinolytic parameters in HA cohort. CONCLUSION: This study demonstrates that HA environment has a significant effect on fibrinolytic system and provides a foundation for further studies on HA hypobaric hypoxia-induced thrombotic disease.

Alterations of Human Plasma Proteome Profile on Adaptation to High-Altitude Hypobaric Hypoxia.

For individuals migrating to or residing permanently in high-altitude regions, environmental hypobaric hypoxia is a primary challenge that induces several physiological or pathological responses. It is well documented that human beings adapt to hypobaric hypoxia via some protective mechanisms, such as erythropoiesis and overproduction of hemoglobin; however, little is known on the alterations of plasma proteome profiles in accommodation to high-altitude hypobaric hypoxia. In the present study, we investigated differential plasma proteomes of high altitude natives and lowland normal controls by a TMT-based proteomic approach. A total of 818 proteins were identified, of which 137 were differentially altered. Bioinformatics (including GO, KEGG, protein-protein interactions, etc.) analysis showed that the differentially altered proteins were basically involved in complement and coagulation cascades, antioxidative stress, and glycolysis. Validation results demonstrated that CCL18, C9, PF4, MPO, and S100A9 were notably up-regulated, and HRG and F11 were down-regulated in high altitude natives, which were consistent with TMT-based proteomic results. Our findings highlight the contributions of complement and coagulation cascades, antioxidative stress, and glycolysis in acclimatization to hypobaric hypoxia and provide a foundation for developing potential diagnostic or/and therapeutic biomarkers for high altitude hypobaric hypoxia-induced diseases.

Plasma proteome profiling of high-altitude polycythemia using TMT-based quantitative proteomics approach.

High-altitude polycythemia (HAPC) is one of the classic chronic mountain sicknesses and has been a serious public health problem in high-altitude regions. Despite numerous studies on HAPC via genomics or transcriptomics approaches, the pathogenesis of HAPC is still unclear. Here, we performed a TMT- based comparative quantitative proteomics analysis to reveal the changes of plasma proteomics profiles between HAPC subjects and healthy controls. Of identified 818 proteins, 7 and 12 proteins were up-regulated and down-accumulated, respectively, compared HAPC patients with healthy controls. GO and KEGG pathway analyses revealed the dysregulated proteins were primarily involved in complement and coagulation cascades, inflammation and immune response. ELISA validation demonstrated that C4A, C6 and CALR were down-regulated, and MASP1 and CNDP1 were up-regulated in HAPC patients. By ROC analysis, combinations of these five proteins (i.e., C4A, C6, CALR, MASP1 and CNDP1) resulted in a high AUC value (0.919; 95% CI, 0.817-961; p < .0001) to diagnose HAPC patients. Moreover, CNDP1 seems to be a robust biomarker for HAPC. This study not only provided a comprehensive dataset on overall proteomics changes in HAPC patients compared with healthy controls, but also indicated that CNDP1 can serve as a strong plasma biomarker of HAPC for the diagnostic and therapeutic potential. SIGNIFICANCE: HAPC, one of the classic chronic mountain sicknesses, has been a serious public health problem in high-altitude regions. Despite numerous studies on HAPC via genomics or transcriptomics approaches, the pathogenesis of HAPC is still largely unknown to date. In this study, we addressed this issue by performing TMT-based quantitative analyses of the plasma proteome profiles of HAPC patients and healthy controls. We identified 818 proteins, of which 19 were differentially expressed. Bioinformatics analysis revealed the differentially expressed proteins were mainly involved in complement and coagulation cascades, inflammation and immune response. By ROC analysis, combinations of C4A, C6, CALR, MASP1 and CNDP1 resulted in a high AUC value (0.919, p < .0001) to distinguish HAPC patients from healthy controls. Collectively, the current study provided a comprehensive dataset on overall proteomic changes in HAPC patients for the first time, and it also revealed C4A, C6, CALR, MASP1 and CNDP1 can be served as candidate plasma biomarkers of HAPC for their diagnostic and therapeutic potential.

Correlation between RBC changes and coagulation parameters in high altitude population.

OBJECTIVE: To explore the correlations between RBCs indexes and the basic coagulation parameters, and provide data for further studies on high altitude-induced thrombotic disease. METHODS: A total of eligible 433 volunteers were divided into different groups according to HGB concentration and HCT, respectively. PT, APTT, TT and Fbg were measured by clotting assays. HGB content, HCT and PLT count were assessed by automated hematology analyzer. RESULTS: APTT and PT were significantly higher in group 4 (high HGB or HCT groups) (p < 0.05 for all comparison) and PLT count was significantly lower in group 4 than in other groups (p < 0.01 for all comparison). APTT and PT showed negative correlations with HGB concentration (r = -0.168 and -0.165 resp.; both p < 0.01), whereas positive correlations were found between APTT and HCT, PT and HCT (r = 0.225 and 0.258, resp.; both p < 0.01). PLT, TT and Fbg showed no correlation with HGB and HCT. CONCLUSIONS: HGB and HCT may not correlate with basic coagulation parameters in high altitude population, their predictive value for high altitude-induced thrombotic disease may relatively independent and this remain to be determined in further studies.