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.

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.

This review contains the results of the studies of the hemostasis system in airline passengers and crew members, as well as ground-based model experiments simulating the effect of specific flight factors. According to most researchers, flight factors shift the coagulation balance towards increasing the procoagulant potential. However, the occurrence of thrombotic conditions in passengers is associated with the individual presence of certain endogenous risk factors, such as age, constitution, diseases of the cardiovascular system and hereditary pathology of the hemostasis system, and some types of hormone therapy. Aircraft pilots whose flight time significantly exceeds that of passengers have described cases of thrombosis. No mention of cases of hemorrhagic conditions in civil aviation flight personnel has been found in the available literature.

The aviation flight is characterized by significant psychophysiological stress in combination with noise, overloads, low barometric pressure, low partial pressure of oxygen, ionizing and non-ionizing radiation. All of above mentioned factors increases the likelihood of stress in body adaptive systems, system of blood coagulation including. The analysis of the literature data of blood coagulation system state in professional pilots showed that the aviation flight factors have multidirectional impact. However, according to most studies data, flight factors total effect leads to coagulation balance shift towards hypercoagulation. A case of thrombophilic condition in pilot during a long-haul flight was noted. No mentions of hemorrhagic condition cases in the literature have been found. The results of analysis indicate the theme relevance and the need for further coagulation status in aviation medicine comprehensive studies since hypercoagulation is closely associated with cardiovascular diseases, which is the most common reason for aircraft pilots disqualification.

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.

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

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.

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 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.

У космонавтов, участников длительных экспедиций, в ходе полетов наблюдаются прогрессивные сдвиги липидного, в том числе холестеринового, обмена, что повышает риск развития сердечно-сосудистых заболеваний в отдаленные сроки после завершения миссий. Перспективным средством профилактики может стать создание на борту космических кораблей и станций искусственной силы тяжести, генерируемой с помощью центрифуги короткого радиуса (ЦКР). В связи с этим, большой интерес представляет исследование липидного обмена при воздействии на человека перегрузок малой силы, создаваемых с помощью ЦКР. В эксперименте участвовали девять мужчин от 24 до 41 года, прошедших отбор и подписавших Информированное согласие. Использовали 3 режима вращения на ЦКР, с направлением перегрузки голова-таз (+Gz):1-й – 2,1g, 30 мин, 2-й ‒ 2,4 g, 30 мин, 3-й ‒ 2,9 g, 15 мин. Каждый обследуемый участвовал во всех режимах вращения. Интервал между первым и вторым вращением был 2 суток, между вторым и третьим – 3 суток. Венозную кровь отбирали за 7 суток до первого воздействия и в течение 10 минут после каждого вращения. В сыворотке крови определяли концентрацию холестерина (ХС), ХС липопротеидов высокой плотности, аполипопротеинов А1 и В (АпоА1 и АпоВ), триглицеридов. Рассчитывали содержание ХС липопротеидов низкой и очень низкой плотности, индекс атерогенности и величину индекса АпоВ/АпоА1. При перегрузке в 2,1g не наблюдалось значимых изменений определяемых параметров. С увеличением силы перегрузок выше 2,1g показатели липидного обмена отражали сначала развитие стресс-реакции, сопровождающейся активацией липолитических процессов (2,4g), а затем формирование начальных сдвигов холестеринового обмена атерогенной направленности на фоне липолиза (2,9g). Все обнаруженные изменения происходили внутри диапазона физиологической нормы и характеризовали протекание адаптивных процессов.

Blood samples from six 25–40 y.o. male subjects in a 5-d dry immersion (DI) experiment were analyzed for cholesterol, cholesterol of high- (HDLP), low- (LDLP) and very low density lipoproteins, triglycerides, apolipoproteins А1 (аpoА1) and apolipoproteins В (аpоВ), non-esterified (free) fatty acids (NEFA), β-hydroxibutyrate and phospholipids. Atherogenic indices were calculated, as well as the ratios of cholesterol, аpоВ/аpоА1 and cholesterol/phospholipids. No significant changes in cholesterol or lipoprotein fractions were determined. Increases in the triglyceride level and apoB/apoA1 ratio as harbingers of incipient atherogenesis showed up on the final day in DI and disappeared two days later. The process of readaptation to normal conditions is accompanied by the development of a stress reaction characterized by increased use of lipid substrates (phospholipids, β-hydroxybutyrate, NEFA) for energy synthesis.

The aim of this study was to determine the general patterns of pathogenetic changes in the blood coagulation system and in non-specific proteinases and their inhibitors during the development of experimental ischemiareperfusion injury. Materials and methods. The study was conducted on 48 male Wistar rats (180–200 g). We used a model of ischemia-reperfusion injury achieved by applying rubber tourniquets to both hind limbs at the inguinal fold level for 6 hours. Revascularization was performed for 6, 12, or 24 hours following the application of tourniquets, after which we examined the state of the internal and external blood coagulation pathways and the activity of nonspecific proteinases and their inhibitors. Results. Indicators of blood coagulation system change show the development of blood hypocoagulation changes as the reperfusion time increases. By the 6th hour of reperfusion, the prothrombin time (PT) was lengthened by 112.0% ( p = 0.0142) and the activated partial thromboplastin time (APTT) by 170.0% ( p = 0.0147) compared with values in the control group. By the 12th reperfusion hour, the PT was lengthened by 174.2% ( p = 0.0389), and the APTT increased 4.9-fold ( p = 0.0002). When the reperfusion period was increased to 24 hours, it was characterized by lengthened PT and APTT, accompanied by an increase in antithrombin III by 11.5% ( p = 0.0371) and a decrease in protein C by 71.4% ( p = 0.0071). Changes in the non-specific proteinases and their inhibitors were characterized by a 2.8-fold increase in the trypsin-like proteinase activity ( p < 0.001) relative to the control, as well as a 2.2-fold decrease in antitrypsin activity and acid-stable inhibitors ( p < 0.001), which reached a maximum after 24 hours of reperfusion. A direct correlation was found between indicators characterizing the deficiency of coagulation system factors and a decrease in antiproteinase potential. Conclusion. Hemostatic system disorders are characterized by the development of hypocoagulation during ischemia-reperfusion injury as the result of an increase in the trypsin-like proteinase activity and a decrease in the levels of inhibitors. The established changes may be associated with the deficiency of coagulation factors and proteinase inhibitors and share common pathogenic mechanisms.