Forty ISS male cosmonauts at the age of 36 to 61 years participated in investigations of the hematological parameters and erythrocyte indices including those used to detect a latent iron deficit (MAF, LHD%). The cosmonauts were divided into 3 groups. Group-1 consisted of 9 cosmonauts who had made 8 to 14-day missions; groups-2 consisted of 27 cosmonauts whose mission duration was 125 to 215 days; group-3 consisted of 4 cosmonauts who had accomplished 355 to 371-day long missions. The data show that post-recovery changes of the erythrocyte morfo-functional properties are compensatory and aimed to overcome the stress from re-adaptation to Earth's gravity. Missions of 8-14-d duration do not affect erythrocytes dramatically. After 125-215-d and 355-371-d missions we observed signs of a hypochromic anemic syndrome that depended on length of life in microgravity. Irrespective of mission duration, the width of erythrocyte distribution by volume decreases considerably during early recovery which implies reduction of heterogeneity in the erythrocyte population.

The review presents the results of studying the hemocoagulation system in Soviet and Russian experiments modeling effects of some spaceflight factors on the human organism. The most adequate models of microgravity are head-down bed rest (BR) and immersion. Effects of g-loads were reproduced by rotation on a centrifuge. In the course of these experiments, the procoagulant, anticoagulant and fibrinolytic activities displayed different trends and dependence on the period of locomotion reduction. In immersion, the procoagulant activity increased, fibrinolytic activity decreased and the anticoagulant potential changed in the either direction. Some data suggest that hypergravity increases the anticoagulant and fibrinolytic activities on the background of hypocoagulation; however, there are also other data suggesting the contrary, i.e. hypergravity leads to hypercoagulation and activation of fibrinolysis. According to investigators, the combination of gravitational loads and limited locomotion decreases the procoagulant activity and increases the fibrinolytic one. Discrepancy between the post-flight and ground-based data is attributed to the impossibility to reproduce in laboratory all the factors that act on the human organism in space flight.

The bed rest experiment involved 6 healthy men aged 24 to 41 years. The subjects were in the supine position for 21 days, the angle of inclination in the cranial direction was -6°. In citrated blood plasma on days 2, 5, 8 and 21 of exposure, as well as 7 days after its end, the following hemostasis parameters were determined: thrombin time, prothrombin time, activated partial thromboplastin time, fibrinogen and D-dimer concentrations, as well as activity of protein C. In comparison with background, there was slight elongation in prothrombin time on the 2nd and 5th days of the experiment, as well as on the 7th day of the recovery period, a slight shortening of the thrombin time on the 8th and 21st days of the experiment and on the 7th day of the recovery period, moderately elongated activated partial thromboplastine time on 5th and 21st day. The concentration of D-dimer was significantly reduced relative to the background in all periods of the survey, except for the 21st day, approaching the background values on the 7th day after the end of exposure. The activity of protein C did not change significantly during the entire experiment and was significantly lower than the background values only on the 7th day after the end of the experiment. The concentration of fibrinogen did not change significantly during all periods of the examination. The results of the study indicate minor changes in the parameters of the plasma component of the hemostatic system, indicating a decrease in procoagulant potential in the early stages of exposure and its increase in the later stages of hypokinesia and in the recovery period.

Aim To assess the role of clinical indicators and parameters of stress echocardiography performed according to an extended protocol as predictors for the occurrence of a composite cardiovascular endpoint (CCVEP) in IHD. Material and methods The study included 186 patients (60.2 % men, mean age 60.6 +/- 9.9 years) with an established (n=73; 39.2 %) and suspected (60.8 %) diagnosis of IHD. Stress EchoCG with adenosine triphosphate (38.2 %), transesophageal pacing (15.1 %), dobutamine (2.6 %), and bicycle ergometry on a recumbent ergometer (44.1 %) was performed. The stress EchoCG protocol included assessment of regional wall motion abnormalities (WMA), B -lines, LV contractile reserve (CTR), coronary reserve (CR), and heart rate reserve. The median follow-up period was 13 [9; 20] months. The composite CCVEP included death from cardiovascular diseases and their complications, acute coronary syndrome, and revascularization and was defined at the first of these events. Statistical analysis was performed with the Statistica 16.0 and SPSS Statistics 23.0 software packages. Differences were considered statistically significant at p<0.05. Results Invasive or noninvasive coronary angiography was performed in 90.3 % of patients; obstructive coronary disease (stenosis >= 50 %) was detected in 67.9 % of cases. During the follow-up period, 58 (31.2 %) patients had cardiovascular complications. The risk of developing CCVEP was associated with the pretest probability (PTP) of ischemic heart disease (odds ratio, OR, 1.05; 95 % confidence interval, CI, 1.02-1.08), dyslipidemia (DLP) (OR 0.40; 95 % CI 0.20-0.82), carotid atherosclerosis (OR 0.39; 95 % CI 0.18-0.86), LV ejection fraction (OR 0.96; 95 % CI 0.93-0.99), appearance at peak stress of new significant (2 LV segments or more) regional WMAs (OR 0.32; 95 % CI 0.18-6.55), decreased LV CTR (OR 0.46; 95 % CI 0.27-0.79) and CR (OR 0.33; 95 % CI 0.18-0.61); p<0.05 for all. In a multivariate analysis with Cox regression, the model with clinical indicators included PTP of IHD (OR 1.04; 95 % CI 1.01-1.07; p=0.01) and DLP (OR 0.14; 95 % CI 0.02-1.01; p=0.05) as predictors. The model with stress EchoCG parameters included the appearance of new significant WMAs (OR 0.33, 95 % CI 0.16-0.65; p=0.001) and reduced <2.0 CR (OR 0.44; 95 % CI 0.24-0.82; p=0.01). A comparative analysis of Kaplan -Meier curves confirmed statistically significant differences in the dynamics of the CCVEP occurrence depending on the absence or presence of hemodynamically significant WMAs and / or reduced CR during stress EchoCG (p<0.01). Conclusion Reduced LV CR and WMA during stress EchoCG in patients with suspected or confirmed IHD are significant independent predictors for the CCVEP occurrence. Among clinical indicators, PTP of IHD and DLP are of the greatest importance for prognosis.

The SIRIUS-21 study was designed as a 240-day isolation of healthy volunteers in controlled environment simulating a piloted mission to the Moon including operator's activities in lunar orbit and on the surface. The investigation involved an international crew of two women and 3 men at the age of 29 to 44 years. The object was metabolic reactions of healthy bodies to the simulated conditions. Crew members demonstrated a moderate stress reaction characterized by inhibition of the gastrointestinal tract secretory activity, reduction of glycolysis intensity, persistent hypercalcemia, a more intensive creatine kinase system functioning as a buffer, deficit of macroergic compounds, magnesium and essential microelements. On day 7 post isolation, the stress symptoms showed a partial leveling. Hard physical training had both the positive and negative effects on metabolism dynamics. The preventive purpose of training was to normalize the content of essential microelements in blood and suppress atherogenesis; however, training had also the negative effect of inducing hypohydration. In future isolation studies it would be appropriate to optimize training protocols and enhance the program of countermeasures to the negative effects of simulated factors.

The extreme factors associated with space flight influence pronouncedly various physiological systems of the human body. The current study focuses on the impact of factors associated with prolonged space missions lasting up to 6 months on cellular innate immunity, hormonalregulation, and hemostasis in Russian cosmonauts. Immune system adaptation to the conditions of long-term space flight was shown to be accompanied by a significant increase in the level of monocytes and granulocytes, along with a decreased number of cells expressing adhesion molecules. The coagulation cascade, main anticoagulant and fibrinolysis proteins were also evaluated. The early post-flight period was characterized by elevated D-dimer levels compared to baseline values, indicative of blood clotting and fibrinolysis activation caused by a damage of endothelium during landing. aAlterations in blood rheology during re-adaptation to Earth conditions was also observed. The blood concentrations of aldosterone, cortisol, estradiol, testosterone, osteocalcin, and erythropoietin were analyzed, and their correlation with the parameters of hemostasis was assessed. The summary findings indicate an adaptive physiological reaction in cosmonauts associated with 6 months duration of spaceflight. The observations may be related to endothelium damage, which manifested in the activation of certain components of the immune system, along with the activation of fibrin clot formation and subsequent fibrinolysis.

We studied the effects on the human system of plasma hemostasis of sequel rotations on a short-arm centrifuge with equal absolute g value and direction. Participants were 6 normal male volunteers at the age of 25 to 45 years. The volunteers were rotated 7 times in the head-to-pelvis direction (+Gz) at 2.1 g. The first rotation was performed prior to the series; the series of 5 rotations was performed with a 2-day interval between each; the final rotation was performed in 14 days after the series. Citrated plasma was used to investigate the procoagulent component of homeostasis, physiological anticoagulents, and intensity of fibrin formation and fibrinolysis. As compared to baseline data, fibrinogen concentration was increased significantly by 4 % on day 7 post rotations; thrombin time was found decreased by 5 % prior to the 6th rotation. Protein C activity was reduced significantly after rotations 3 and 5 by 8 % and 9 %, respectively. Antithrombin III was reduced by 4 % after rotation 5. Concentration of D-dimer was increased after rotations 5 and 6 by 87 % and 32 %, respectively. Rotations produced minor changes in the levels of pro- and anticoagulents, and also in the intensity of fibrin formation and fibrinolysis, that is these changes were within the physiological norm and reflected adaptive processes in organism.

Eight male volunteers aged 26 to 44 years were examined, who were in the “Arfa” hypomagnetic environment simulation facility for 4 h at a normal magnetic field level (background session), and twice within 24 h: one session during hypomagnetic environment simulation with an attenuation coefficient of 500, and one, in the conditions of the terrestrial magnetic field (placebo). Venous blood was collected at the end of each session. The values of 48 biochemical parameters reflecting the state of organs and tissues, as well as the main links of metabolism, were determined in plasma and serum. Psychological testing of the volunteers was carried out using the Assessment of Acute Physical Fatigue questionnaire by R. Kinsman and P. Weiser adapted by A.B. Leonova and Assessment of Acute Mental Fatigue by A.B. Leonova and N.N. Savicheva. The level of physical condition of the participants of the experiment was assessed according to the method of D.N. Davidenko. As a result of the first biochemical screening examination and psychological testing of volunteers who were in a simulated space-level hypomagnetic environment, it was established that the effect is stressful, accompanied by the activation of glycolysis, lipolytic processes, affects the acid–base balance of the body, the state of the vascular endothelium, and leads to changes in the hepato-biliary system. At the same time, the index of physical fatigue among the volunteers increases, and the level of physical condition significantly decreases. Subjectively, pronounced changes in the biochemical parameters of stressful orientation are not felt.

The risks of decompression sickness and its complications in professional divers and amateur divers with various methods of diving in real and simulated conditions are considered. The pathogenesis of disorders of the plasma and vascular hemostasis system under the influence of environmental factors on the body during various types of dives is discussed. Generalization of the research results showed that the mechanisms of activation of thrombosis under this influence are complex and are caused by microbubble-mediated platelet activation as well as by development of endothelial dysfunction, oxidative, and psychophysiological stress. The study of hemostasis parameters in professional and amateur divers can be one of the main methods of assessing the risk of its development. The considered means of preventing thrombosis during diving and decompression, according to the results of the studies included in the review, are quite effective.

The results of studying the correlations between biochemical and immunological parameters in volunteers under conditions of 21-day “dry” immersion are presented. It is shown that, in comparison with the baseline period, at the final stage of the experiment, the number of statistically significant correlations (p ≤ 0.05, respectively, 27 and 51) between the parameters assessing the metabolic and immunological reactions of the body increased. The increase in the number of correlations was due mainly to an increase in the number of correlations between the indices of protein, carbohydrate, and lipid metabolism and indices characterizing the state of innate immunity. At the final stage of the experiment, the influence of protein and lipid metabolism on the cellular component of adaptive immunity increased. The revealed dynamics and the nature of correlations between biochemical and immunological indices indicate the metabolic regulation of the immune response under conditions of hypodynamic support unloading.

Space flight factors are known to cause a malfunction in the human immune system and lead to damage to blood vessels. The hemostatic function of endothelium during space missions and its interaction with human immunity has not been determined so far. In this work, we investigated the markers of endothelial activation and damage (plasma concentrations of soluble thrombomodulin fraction (sTM), von Willebrand factor (vWF), highly sensitive C-reactive protein (hs-CRP)), as well as the level of D-dimer and compared them to the immunological parameters characterizing the state of human humoral and cellular immunity. The immune status of long-duration ISS crewmembers was assessed by whole-blood testing, and comprehensive postflight immune assessment included the analysis of leukocyte distribution. Flow cytometry was applied to determine the absolute counts and the percentage of lymphocyte subsets: B cells (CD19 + ), T cells (CD3 + , CD3 + CD4 + , CD3 + CD8 + ), NK cells (CD3 − CD16 + CD56 + , CD11b + CD56 + ), and activated subsets (CD3 + CD25 + and CD3 + HLA-DR + ). The in vitro basal cytokine production was investigated in whole blood cell culture. The cytokines IFN-gamma, IL-1-beta, IL-4, IL-6, IL-10, IL-18, and TNF-alpha were measured in plasma and the 24-h supernatants by a sensitive enzyme-linked immunosorbent assay. A significant increase in the plasma levels of vWF and hs-CRP and a decrease in the concentration of sTM after spaceflights were detected. Divergent changes in the parameters characterizing the state of the immune system were observed. We propose that the changes revealed may lead to an increase in the procoagulant activity of blood plasma, suppression of protein C activation and thrombin inhibition, as well as to an increase in the adhesive-aggregate potential of platelets, especially in case of changes in the rheological characteristics of blood flow during re-adaptation to ground conditions. We also speculate that the immune system might play an important role in vessel damage during long-duration missions.

In the international SIRIUS 19 experiment with a 120-day isolation in a pressurized chamber, conducted at the experimental unit of the Institute of Biomedical Problems, Russian Academy of Sciences, a crew consisting of six subjects of both sexes ranging in age from 27 to 43 years was examined. The levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoproteins A1 (ApoA1) and B (ApoB), as well as nonesterified (free) fatty acids (NEFA), were determined in the blood serum of the subjects. The concentrations of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) cholesterols, the values of the atherogenicity index, ApoB/ApoA1, and HDL ratios were calculated. A special feature of this experiment was a preventive program that included cycles of daily physical activity of various intensities, as well as regular physical load tests conducted throughout the experimental exposure. In this regard, there were no significant changes in the concentrations of cholesterol or its VLDL fraction, and the contents of lipoproteins A1 and B was at a low level. Due to the action of regular and intense physical exertion, lipolysis was activated for a long time as an additional pathway of energy production, which was characterized by a sharp increase in the content of NEFA in the blood beyond the reference range and led to changes in the synthesis of cholesterol in the liver, expressed in the redistribution of its fractions. Considering the results of this study, the preventive physical loads should be optimized in further experiments.

Citrate plasma samples gathered 31 days prior to, on days 37, 63, 120 in and on days 7 and 14 after isolation (project Sirius-19) were analyzed for blood aggregation parameters including fibrinogen (FBG), D-dimer (DD), plasminogen (PG), antithrombin III (АТ3), protein C (PC) and α2-antiplasmin (AP), thrombin time (TT), activated partial thromboplastin time (APTT), and prothrombin time (PT). DD was lowered in all samples gathered during isolation. The complex of isolation factors combined with physical exercise reduced levels of fibrin formation and fibrinolysis. However, after isolation the procoagulent activity showed an increase manifested by elevated DD and reduced APTT. Appears that in the absence of insertion and reentry effects (redistribution of body fluids in microgravity) and high psychophysiological stresses it is the appropriate use of physical countermeasures that ensures plasma efficiency within the blood aggregation control system, and good body tolerance of the spaceflight factors.

В цитратной плазме испытателей-добровольцев в эксперименте с вращением на центрифуге короткого радиуса (ЦКР) c направлением перегрузки голова-таз (+Gz) за семь суток до начала воздействий (три последовательных вращения в режимах 2,1g –30 мин., 2,4g – 30 мин., 2,9­ g, –15 мин. с интервалом 2-3 суток), а также через 5 минут после каждого вращения определяли концентрацию фибриногена (ФБГ), растворимых фибрин-мономерных комплексов (РФМК) и Д-димера (ДД); тромбиновое время (ТВ), активированное парциальное тромбопластиновое время (АПТВ), международное нормализованное отношение (МНО), а также фибринолитическую активность (ФБА). Согласно результатам исследований, не обнаружено статистически значимых изменений показателей МНО, АПТВ, ДД, ФБА относительно фона. Однако выявлено достоверное (p<0,05) укорочение ТВ и повышение уровня РФМК после третьего вращения, а также тенденция (0,05

Длительное пребывание человека в невесомости характеризуется развитием ряда неблагоприятных изменений, затрагивающих структуру и функцию основных систем организма. Создание на борту космических кораблей и станций искусственной силы тяжести с использованием центрифуги короткого радиуса может стать перспективным профилактическим методом. Основной проблемой при его разработке является подбор оптимального соотношения силы перегрузки и ее продолжительности, а также оценка возможных побочных эффектов. В эксперименте участвовали девять обследуемых мужского пола. Каждый обследованный подвергался воздействию перегрузок направлением голова-таз (+Gz) силой 2,1g (30 мин), 2,4g (30 мин) и 2,9g (15 мин). Второе вращение выполнялось через три дня после первого, а третье – через два дня после второго. Взятие венозной крови проводилось за 7 дней до первого воздействия и в течение 10 минут после завершения каждого из них. В сыворотке и плазме крови определяли значения 42 биохимических показателей, отражающих состояние внутренних органов и тканей, а также основных звеньев обмена веществ. Установлено, что действие перегрузок силой более 2,1g характеризуется развитием биохимических сдвигов, отражающих напряжение скелетной мускулатуры, признаками развития регионарной гипоксии с активацией гликолиза и липолиза, появлением острофазных реакций. Большинство изменений протекает внутри референтных диапазонов, а если и превышает их верхнюю границу, то не является клинически значимыми, отражая активацию адаптивных процессов. Не исключен эффект тренировки, вызываемый повторяемым гипергравитационным воздействием, что позволяет оценить исследованные режимы профилактических перегрузок как имеющие перспективы для применения в пилотируемой космонавтике и подлежащие дальнейшему изучению.

In the SIRIUS-18/19 project, psychological, neurohormonal and metabolic adaptation to 120-d isolation was studied with participation of 3 male and 3 female subjects at the age of 28 to 44 years. Mood assessments and biochemical investigations attested to a moderate stress. After 63 days of the life in isolation, weighing showed a significant loss of the body fat mass; blood analysis pointed to activation of lipolysis and atherogenesis. Homeostasis was relatively stable despite mobilization of deposited fats and shifts in metabolic reactions. These changes in energy metabolism and reactions to the extreme factors should be taken into consideration during planning of future isolation studies in order to minimize potential cardiac risks.

In the dynamics of the international experiment with 120-day isolation in the hermetic volume SIRIUS 19, a crew of six people of both sexes aged from 27 to 46 years was examined. The subjects were divided into two groups of three people based on gender. In addition to the impact of the pressurized volume factors, the participants were exposed to a complex of stress factors, particularly, constant intense physical exertion and exercise tests, intense operator performance in the time shortage, 24-h sleep deprivation, and imitation of extravehicular and on-planetary activities. In the blood of the volunteers, the values of 42 biochemical parameters were determined, reflecting the state of the main metabolic components, as well as internal organs and tissues. It was found that metabolic reactions of the participants in the experiment with 120-day isolation in a pressurized volume, in contrast to the previous similar experiments, were determined by the constant stress-generating effect of high-intensity preventive physical exertion and were characterized by an increase in the activity of muscle enzymes, activation of lipolysis, decrease in the level of serum iron, and deceleration of the glomerular filtration rate in kidneys due to an increase in the blood concentration of cystatin C. The gender differences between groups consisted in a greater manifestation of the detected changes in men compared with women. The detected shifts can be interpreted as adaptive.

Aim. To assess markers of chronic kidney disease (CKD) in patients with medically-controlled hypertension (HTN) (<140/90 mm Hg), as well as to analyze potential association of decreased glomerular filtration rate (GFR) <60 ml/min/1,73 m2 with clinical data and therapy; to establish significant determinants of GFR decrease in this category of patients.Material and methods. The study included 70 patients with HTN and office blood pressure (BP) <140/90 mm Hg aged 64 (57; 68) years (men, 48,6%), of whom 40 patients were examined within the Russian multicenter CHRONOGRAPH program. Office BP was 130 (120; 140)/80 (72; 82) mm Hg. GFR and albuminuria were assessed. Twenty-four-hour BP monitoring and Doppler ultrasound of renal blood flow with estimation of resistance indices (RI) were performed. The content of highsensitivity C-reactive protein (hsCRP), interleukins (IL) 1β, 6, 10 and lipid transport function parameters was determined.Results. CKD markers were detected in 31,4% of patients (in 27,1% — a decrease in GFR <60 ml/min/1,73 m2; in 12,9% — pathological albuminuria). Patients with CKD markers were older, had higher office systolic BP and nocturnal pulse pressure, higher blood hsCRP and RI levels throughout the renal flow, and lower high-density lipoprotein cholesterol levels. In the presence of CKD markers, calcium channel blockers, aldosterone receptor antagonists and statins were used more often. The results of correlation analysis were used to determine the determinants of GFR decline. In the general group, GFR values had inverse correlations with age (Rs=-0,58, p<0,0001), segmental intrarenal artery RI (Rs= -0,4232, p=0,0005), blood hsCRP (Rs=-0,3998, p=0,0007), IL-1β (Rs=-0,3139, p=0,0086), office BP and some 24-hour BP parameters. In the presence of CKD markers, a direct association of GFR and IL-10 was determined (Rs=0,4293, p=0,046). In the absence of such markers, GFR had an inverse correlation with IL-1β content (Rs=-0,3110, p=0,0333). A multiple linear regression model included following independent determinants of GFR: age, blood hsCRP and RI in the segmental intrarenal arteries.Conclusion. Among patients with medically-controlled HTN of high cardiovascular risk, a high prevalence of CKD markers was revealed (31,4%). Compared with patients with preserved renal function, in the presence of CKD markers, there were higher levels of office systolic BP, nocturnal pulse pressure, blood hsCRP, and intrarenal artery RI. Associations were established between GFR and the levels of hsCRP, IL-1β and IL-10, which confirms the pathological role of inflammatory biomarkers in developing renal dysfunction in high-risk HTN. Age, elevated blood hsCRP levels, and intrarenal artery RI are independent determinants of decreased GFR in patients with medically-controlled HTN of high and very high cardiovascular risk. The data obtained shows the need for early prescription of combination antihypertensive therapy with nephro- and vasoprotective effects in this category of patients, as well as with an ability to depress the chronic subclinical inflammation.