Hemorheological Alterations and Physical Activity

Abstract

Elucidating the complex processes that determine the ability of the human body to adapt to specific intense training programs is critical to improving athletic performance in elite athletes. The present work aims to describe the main hemorheological changes as a result of physical exercises of different intensity, frequency, duration and modes of loading. Sport and physical exertion induce a hemorheological response of different nature and degree, structured in the present paper as follows: erythrocyte aggregation; change in the concentration of basic plasma components; changes in blood flow; changes in blood volume; changes in the endothelial cells of the vascular walls; changes in blood pressure; changes resulting from tissue hypoxia; interacting, different in nature hemorheological consequences. The studied and described original models of hemorheological response can contribute to a more successful adaptation of the training programs—In order to improve the health status of the participants and to optimize the sports form of the elite athletes. Physical loads of different frequencies, intensities and durations induce a different hemorheological response in athletes. The effect of “regular, moderate and properly dosed physical activity” during training is also strictly individual. This fact suggests approaching the training regime of each elite athlete personally, practicing specific to his preparation, well-chosen, balanced physical exercises. This will help to achieve the so-called state of hemorheological fitness. Extensive future research is needed to elucidate the cellular, tissue and molecular mechanism of hemorheological changes in blood, blood cells, and blood plasma. It is essential to study the vascular characteristics and biomechanical properties of blood under physical loads with different regimes and variable parameters, taking into account the individual, professional, biological and mechanical profile of each athlete.

1. Introduction

The main factors determining achievements in sports are directly related to the biomechanical properties of blood and its rheological behavior. Elucidating the complex processes that determine the ability of the human body to adapt to specific intense training programs is critical to improving athletic performance in elite athletes. Physical exercise has enormous potential in combating the global “epidemic” of chronic metabolic and inflammatory diseases such as obesity, metabolic syndrome, type 2 diabetes mellitus, etc. Physiological reactions of the body under the influence of physical exercises are complex, insufficiently studied and analyzed, in view of the wide spectrum of hemorheological, metabolic, immunological and hormonal changes [1,2]. It is known that the immediate systemic physiological response to intense exercise is highly dependent on the type, intensity, cyclicity and duration of physical activity. The individual level of training (training status) of athletes also influences the body’s adaptive response to long-term changes in response to repeated physical exertion.

Extensive contemporary research has been published analyzing specific body responses in response to various training regimens and their relationship to the age, gender, training level and health status of athletes [3,4,5]. Nevertheless, there are a number of understudied problems such as the rheological properties of blood and blood cells are of particular importance for the efficient and proper functioning of the circulatory system. All hemorheological and hematological factors affecting blood flow are important: micromechanical and morphological properties of blood cells, biochemical composition, structural/ultrastructural and mechanical characteristics of the erythrocyte cell membrane, processes of erythrocyte intercellular interactions (erythrocyte aggregation and blood coagulation), biochemical composition and viscosity of blood plasma, etc. [6,7]. There are also modern scientific data on the changes of major plasma components in response to different modes of physical activity. This set of hemorheological properties of blood such as fluid, blood cells and plasma characteristics determine and regulate basic vascular functions [8].

The purpose of this review is to summarize the main hemorheological changes during and after exercises of different types, intensities, cyclicities and durations.

2. Topics and Results

Hemorheological parameters influenced by physical activity are structured in the following sequence:

The other basic biomechanical cell property, that is influenced by physical activity is erythrocyte deformability, but from the point of view of the length of the exposition and the importance of this property, we will pay attention to it in a separate work.

2.1. Erythrocyte Aggregation

The phenomenon of red blood cell aggregation is an important hemorheological factor determining the behavior of blood flow in vessels [9]. At low blood flow velocities (in postcapillary venules for example) one of the main factors determining blood viscosity is erythrocyte aggregation.

The results of numerous modern studies reflect changes in the aggregation of red blood cells in response to intense physical exercises and loads. Some conflicting results have also been reported [10,11,12,13]:

-

Lack of change in erythrocyte aggregability;

-

Increase in aggregation, associated or not with an increase in the plasma level of fibrinogen (Fb);

-

Reduction of erythrocyte aggregation.

The conflicting results listed should be considered in the context that in vitro assessment of red blood cell aggregation is usually performed on blood samples adjusted to a standardized hematocrit (usually 40%) [11]. The increased hematocrit observed during exercise likely increases red blood cell aggregation in vivo, including due to increased intercellular contacts. The reasons for the conflicting results are unclear, but may be related to differences in:

(1)

The studied population (athletes or sedentary individuals, population with accompanying diseases);

(2)

The performed exercise and type of sport (cycling, running);

(3)

The method used to measure aggregation.

The comparative study of the morphological, micromechanical and electrical properties of erythrocytes, as well as the monitoring of their intercellular interactions (formation of cell complexes—clusters and interactions with polymers such as Dextran70 and PEG), create new opportunities for elucidating the mechanisms of erythrocyte aggregation and deformability, and also for clinical application of new effective clinical diagnostic and therapeutic approaches [14].

2.2. Change in Basic Blood Plasma Components

There is extensive research analyzing specific body responses to different training regimens and their relationship with age, gender, fitness level, and health status (obesity, various chronic inflammatory diseases) [3,4,15].

From a biochemical point of view, the fact that aerobic and anaerobic training reduces the level of serum triglycerides, increases “good” cholesterol (HDL-C) and simultaneously lowers “bad” cholesterol (LDL-C) is also interesting the importance for the prevention of socially significant diseases, arterial hypertension and atherosclerosis [16]. In this aspect, individual design of training programs and plans for increased physical activity (aerobic, anaerobic, etc.) for people of different age groups is necessary, taking into account the results of their medical and laboratory tests. An accurate assessment of the number (weekly frequency) of training sessions, the intensity of physical exercise according to objective physiological (cardiovascular) indicators, the duration of exercise, its intensity and volume, etc. is also recommended [17]. The most effective and recommended for the treatment of arterial hypertension is aerobic training, including dynamic physical exercises.

There are also numerous data on the changes of blood plasma components in response to different modes of physical activity.

2.2.1. Fibrinogen

An elevated level of fibrinogen can be considered one of the main risk factors for the development of cardiovascular disease along with high blood pressure, obesity, smoking and diabetes [18]. Similarly there is a direct relation between whole blood viscosity and fibrinogen plasma concentration at different shear rates [19]. Therefore, the interest in the methods of lowering its levels in the blood plasma is also growing.

Many authors find a direct relationship between physical exertion and fibrinogen level reduction. One of the first results in this direction was reported in Russia by Dudaev et al. (1986) [20]. A group of 30 patients with cerebrovascular disease underwent regular exercise for 30 days. As a result, fibrinogen levels were significantly reduced [20].

In the Scottish Cardiovascular Disease and Health Study [21], involving 8824 people aged 40 to 59 years, significantly increased plasma fibrinogen levels were found in physically inactive subjects compared to physically active subjects [21,22].

Stratton et al. (1991) [23] formed two target groups—One consisting of 10 young men aged 24–30 years and the other of 13 older men (60–82 years). All subjects were clinically healthy as demonstrated by routine physical and laboratory tests [23]. Both groups performed physical exercises for six months, 4 or 5 times a week, with increasing load. The experimental protocol included walking, running and cycling. A statistically significant decrease in fibrinogen levels was obtained in the elderly group. No changes were observed in young men.

Wosornu et al. (1992) [24] divided 55 patients into three groups after coronary artery surgery. The first group was made up of physically inactive patients, the second of people loaded with regular aerobic exercises for 6 months, and in the third there were patients subjected to strength loads for 6 months. The intensity of the loads is from 12 to 60 min, three times a week. A decrease in plasma fibrinogen levels was found in the second group of patients subjected to aerobic exercise [24].

Ernst et al. (1991) [25] formed a group of 12 healthy subjects subjected to endurance exercise (28 h per week, for 9 weeks) and a group of 12 physically inactive subjects (control group). Again, the result is a decrease in fibrinogen levels under the influence of physical activity [22].

The described examples of lowering the levels of fibrinogen in the blood plasma after different types, duration, frequency and degree of physical exercise show that physical activity is very important for maintaining the health status of the person. It has also been shown that the inclusion of regular physical activity, especially in elderly individuals, can serve as a natural endogenous regulation of fibrinogen levels and/or as a natural complementary regimen in support of ongoing drug therapy.

2.2.2. Albumins and Globulins

Plasma albumin concentration increased statistically significantly immediately after a marathon run (42 km) reported by Weight et al. (1991) [26]. In the same study, it is proven that after the marathon, plasma globulins remain unchanged. Similar results were obtained after a 56 km marathon [27].

There are other studies that show no change in plasma albumin concentration after prolonged physical exercise [28,29], as well as a decrease in their levels with different exercise protocols [30].

The individual physiological response of the levels of plasma albumins and globulins under different modes of physical exertion indicates that a careful analysis of the causes of the cellular biochemical changes is necessary.

2.2.3. Testosterone

Testosterone is the most potent, naturally secreted steroid androgen hormone [31]. At the muscular level, testosterone is known to exert its anabolic effect through following two mechanisms: (a) stimulation of amino acid uptake and protein synthesis; (b) inhibition of protein degradation by antagonizing cortisol signaling [31,32].

Major physiological factors causing lower serum testosterone concentrations are age, high body weight, poor nutrition, stress, sleep deprivation and alcohol consumption [33,34].

Low plasma testosterone is associated with fatigue, sexual dysfunction, depressed mood, difficulty concentrating, and hot flashes. If the condition is untreated, patients may develop anemia, low bone density (osteoporosis), proatherogenic changes associated with lipoprotein metabolism [35] and muscle wasting [36]. That is why maintaining normal physiological levels of testosterone is a prerequisite for good health.

The amount of plasma testosterone during exercise can vary depending on the mode, intensity and duration of exercise [37]. Abrupt and intense physical exertion quickly increases the level of testosterone in the bloodstream. This body response is mediated by increased sympathetic activity during exercise and synthesized lactate, a metabolite produced by exercised skeletal muscle during anaerobic glycolysis [38].

Devi et al. (2014) [37] found a significant increase in plasma testosterone levels after exercise on a cycle ergometer. These authors measured serum total testosterone levels after 1 week of starting exercise and after 12 weeks of exercise. The goal is to achieve a heart rate ranging from 125–150 bpm and to do a certain amount of work per minute (670 kilopond meters per minute). The tension of the ergometer was maintained at 3 kg, other settings being equal. A statistically significant change (p ≤ 0.05) was reported after 12 weeks of exercise, with serum total testosterone level before training being 5.49 ± 1.31 and after 12 weeks of exercise being 6.41 ± 2.28. The study included 30 men, all participants led a sedentary lifestyle with almost the same fitness status and similar diet.

2.3. Blood Flow

Hemorheology is a science studying the biomechanical properties of blood and blood cells in conditions of flow in a stream. It may be added that it is a science of knowing and studying the viscosity of the blood. Due to the increased oxygen needs of the muscle cells during exercise, the blood flow from the heart to the stressed muscle groups increases. In addition to increasing the frequency of heart activity, increased blood flow is also achieved through the expansion of blood vessels, which supply the muscles with the necessary oxygen (O₂).

According to well-known Hagen-Poiseuille’s equation, blood flow Q depends on perfusion pressure ΔP, vascular geometry (length L and radius r of the blood vessel) and blood viscosity η (1).

$$Q=\frac{\Delta \mathrm{P}\mathsf{\pi }{r}^4}{8 L \eta }$$

(1)

The greatest influence on blood flow is the radius of the blood vessel r (calculated by the fourth power in the equation). This means that a small expansion of the internal diameter (d = 2r) of the corresponding blood vessel leads to a significant increase in the blood flow Q passing through its lumen (if the other factors of Equation (1) do not change). Perfusion pressure ΔP increases blood flow Q directly, while vessel length L and blood viscosity η have an inverse effect.

2.3.1. Vasodilation

The results from numerous studies prove that under normal environmental conditions (atmospheric pressure and ambient temperature), skeletal muscle blood flow increases linearly with increasing exercise intensity [8]. The increase in blood flow is a consequence of the increased tissue demand for oxygen [39,40]. This conclusion also holds for exercise performed by small muscle groups, where skeletal muscle blood flow is regulated primarily by dilation of the vessels feeding the active muscle tissue, combined with increases in cardiac output and perfusion pressure [41].

Signals of neural and/or mechanical origin are suggested to be the likely mediators of the rapid increase in blood flow (within 1 s) observed at the onset of exercise [42,43]. The processes involved in mechanically induced vasodilation are not fully understood. They can be induced and regulated by both endothelium-dependent and endothelium-independent factors [44].

Once the vasodilatation process begins, the muscle’s blood supply and oxygen demand require maintenance to ensure that the corresponding workload is met. Blood flow follows the energy and oxygen demands of working muscle tissue [45]. This means that metabolic signals produced by contracting muscles and/or blood flow may be involved in the dynamic control of vascular tone either directly or through the blood endothelium they stimulate [8,46].

At a constant intensity of a given exercise, skeletal muscle blood flow may eventually stabilize or smoothly increase in response to increasing oxygen (O₂) demand [47].

If the load involves large muscle groups (cycling or running), the relationship between blood flow and increasing load intensity is not linear. The degree of vasodilation seen, for example, during intense knee joint extensions involving the entire muscle mass would require an enormous cardiac output (about 100 L/min, far exceeding the pumping capacity of the human heart). In this way, the maintenance of adequate blood pressure is disturbed [48]. Therefore, muscle vasodilation during whole-body exercise is largely limited at high exercise loads, when skeletal muscle blood flow typically increases linearly with increasing exercise intensity up to about 80% peak power. Flow subsequently stabilizes and even decreases as muscle groups approach or exceed their maximal “aerobic threshold” [45,49].

During intense physical exercise, the change in blood flow in the skeletal muscles can be strongly influenced by environmental conditions, for example—different temperature and oxygen concentration. Decreased levels of oxygen (O₂) in inhaled air lead to a decrease in its content in arterial blood [50]. In conditions of reduced oxygen content in the arterial blood (at unloaded muscle groups or at submaximal loads through knee extension), compensatory vasodilation begins, increasing skeletal muscle blood flow, which maintains the balance between the amount of O₂ needed and delivered to the muscle tissue [51].

Aerobic exercise training is known to induce structural and functional changes in the cardiovascular system. They lead to an improvement in maximal muscle blood flow: e.g., during maximal knee extension exercise or cycling exercise [52,53]. At the same time, aerobic exercise maximizes muscle oxygen uptake [54,55]. Conversely, peak (maximal) muscle blood flow is markedly reduced in various pathological conditions [56,57], and its normalization and/or improvement can be achieved by appropriate exercises in a regular training program [58]. The improvement in muscle blood flow resulting from these exercises and training is thought to be a primary result of increased functional vessel vasodilation and/or increased vessel cross-sectional area [39,59].

At the microvascular level in the microfluid, it has been shown that regular and intense exercise leads to dilation and enlargement of the muscle capillary network [60], which contributes to:

• Increasing the effective area for exchange of oxygen (O₂) and other chemical compounds between erythrocytes and cells in the body;
• Improving tissue diffusion of oxygen (O₂) and increasing the amount of oxygen received by the muscles [61].

2.3.2. Blood Viscosity as a Regulator of Vasodilation

The shape of normal red blood cells is well known: at rest they resemble a double concave disc. Erythrocytes can undergo deformation and acquire the shape of echinocytes and stomatocytes under the influence of endogenous and exogenous factors, as well as return to their original resting shape when these factors are removed [62,63,64]. Echinocytes and stomatocytes are the most common morphological forms of red blood cells (in vitro and in vivo under the influence of various agents, as well as in various physiological and pathophysiological conditions) [65]. Eriksson’s (1990) data show that when red blood cells are suspended in buffered saline, they can be transformed into echinocytes [66]. On the other hand, the shape and arrangement of erythrocytes transversely in the vascular lumen depend on the kinematics and dynamics of blood flow, strain rate and “shear” stress [67]. Any transformation in the shape of red blood cells, including those associated with changes in the biochemistry and morphology of their cell membrane, can cause specific hemorheological changes that are of great importance in clinical practice [65].

There are data in the literature on the influence of drug-induced echinocytosis and stomatocytosis on the viscosity of blood cell suspensions. Blood viscosity has been found to be increased in echinocytosis. Reinhart et al. (2008) [65] found that under experimental conditions with erythrocyte aggregation (4 g/dL Dx 70, at a low shear rate of 0.1 s⁻¹) a low degree of echinocytosis resulted in a greatly increased suspension viscosity.

It is interesting that in all cases the viscosity of the suspension can be normalized by repeated “transformation” of echinocytes into normal red blood cells-discocytes. A lower suspension viscosity is then achieved and thus the best oxygen transport efficiency is obtained.

According to Poiseuille’s Law (1), vascular geometry is an extremely important factor determining blood flow, and blood viscosity is often ignored (except in borderline cases, such as polycythemia). With polycythemia, the hyperviscosity of the blood can contribute to the development of thrombotic complications and increase the pulse rate (tachycardia, tachyarrhythmia). The general “rheological behavior” of blood (including its rheological properties and those of its individual components-cells and blood plasma) is a key regulator of vascular functions and vascular resistance to flow.

While increased blood viscosity is generally accepted as a risk for increasing blood flow resistance, several studies have shown that moderate increases in blood viscosity can positively influence endothelial vascular function and vasomotor vascular tone [68,69]. Furthermore, on average, increased blood viscosity positively affects the physical endurance of healthy individuals during exercise [70]. An increase in blood viscosity leads to an increase in the “shear” stress (tangential stress) applied to the endothelial cells of the vessel wall. This leads to increased production of endothelial-derived nitric oxide (NO), which facilitates vasodilation, tissue perfusion, and increases the amount of O₂ delivered to cells and tissues [60,68]. It should be noted here that patients with chronic vascular disease and endothelial dysfunction may not experience the beneficial effects of a modest increase in blood viscosity as healthy individuals.

Intense exercise typically increases blood viscosity by 10–12%. This increase is mainly due to the reduced plasma volume, which leads to a higher hematocrit and an increase in viscosity. It is known that during prolonged training the hematocrit decreases (phenomenon of auto-hemodilution), and hence the viscosity of the blood also decreases [71]. It should also be emphasized that the physiological consequences for the body, and especially for the circulatory system, during a single intense physical exercise are poorly studied and are most likely influenced and depend on the individual characteristics and fitness characteristics of the exerciser.

In his studies, Connes (2010) [71] investigated the relationships between changes in blood viscosity, vascular resistance, NO synthesis and oxygen consumption induced by a single (submaximal) physical exercise in a healthy human population. From his findings, it appears that the established increase in blood viscosity during physical exercise may be a necessary condition for NO production and induction of vasodilation to achieve the highest aerobic efficiency of working muscles [71]. However, any inappropriate increase in hematocrit can also increase blood viscosity—even to very high levels, thereby affecting cardiac and aerobic performance and activity, independent of increased arterial oxygen (O₂) content.

In another study, Schuler et al. (2010) [70], demonstrated that each individual can reach an optimal level of hematocrit and/or increased blood viscosity—in order to achieve the highest aerobic efficiency when exposed to the corresponding physical load.

In an interesting analysis Karsheva et al. (2011) [72], reported that whole blood viscosity (WBV) in volleyball players increased about 15% after 15 min of exercise. At the same time, the blood viscosity of athletes is lower compared to the WBV of untrained individuals.

The short-term effect of physical (training) efforts on viscosity (hemoconcentration, hyperviscosity) is transient and does not affect the general condition of athletes whose blood and blood cells are characterized by normal rheological (hemorheological) parameters, including a lower viscosity of the overall blood (WBV), compared to untrained individuals (healthy subjects, controls).

The rheological behavior of whole blood (reported by measuring WBV) has been comparatively studied in different categories of elite athletes (nationally and internationally famous athletes in football, volleyball and karate, including in the “overtraining” syndrome) with a view to the thesis that the positive influence of fitness is associated with decreased blood viscosity. In parallel, basic biological parameters such as zinc in serum, fibrinogen in blood plasma, plasma viscosity (PV), hematocrit and other biomarkers were also investigated [73]. Positive fitness effects on hemodynamics are reported: increased blood volume and decreased whole blood viscosity. The low level of serum zinc and plasma ferritin associated with the term “zinc-deficient athletes” correlates with erythrocyte deformability and aggregability, but also requires the planning of additional future studies [73,74,75].

Hemorheological changes in blood and blood cells, such as increased blood and plasma viscosity, decreased erythrocyte and platelet deformability and increased cell (intercellular) aggregation, high levels of hematocrit and fibrinogen in the blood, are accurate and up-to-date hemorheological biomarkers. They are successfully used in modern biomedicine for the purposes of prevention, diagnosis, monitoring and prognosis of the outcome of socially significant diseases [5].

Increased blood and plasma viscosity (WBV, PV) correlate with the development of cardiovascular and neurovascular diseases, including hypertension, atherosclerosis, peripheral vascular diseases, metabolic diseases such as diabetes (type 1 and 2), various pathological metabolic processes as a result of old age (often associated with problems in cholesterol and lipoprotein levels, with smoking, alcoholism, drug addictions and other addictions, with autoimmune reactions, psychiatric disorders, malignant (neoplastic) diseases (cancer and leukemia), metabolic syndrome and others). The prevention of disease processes with social significance most often includes the detection and elimination of the main hemorheological problems, which appeared before or during the occurrence of health problems [5].

There is a growing number of modern studies that prove that regular—moderate in intensity and duration of impact, physical exercises and training improve hemorheological status and tissue perfusion in the body [76,77]. At the same time, it is striking that physical exertion changes more significantly the main hemorheological indices—WBV, PV, EI (elongation index of erythrocytes), erythrocyte deformability and aggregability, in untrained individuals (controls) compared to the stable values of the same hematometric parameters in professionally trained athletes and elite athletes. Additional hematological parameters, such as the number of erythrocytes, leukocytes and platelets, help to more comprehensively characterize the “hemorheological response” of the human organism according to the degree of physical exertion and professional training [78].

Sometimes additional problems arise related to momentary overloading of the body during overtraining [79,80].

2.4. Blood Volume

The change in blood volume in the body is an important adaptation process [81], occurring as a result of the impact of various factors: physical exercise, external stressful influences (thermal acclimatization and thermoregulation), injuries and diseases [82]. An increase in blood volume (hypervolemia) has been demonstrated after systematic training and physical endurance exercises [81].

Whole blood volume is the sum of the volume of erythrocytes (because they are the most numerous cells in the blood) and the volume of blood plasma. The volumes of the other types of blood cells are negligibly small. Both the erythrocyte and blood plasma volumes can change independently of each other and thereby change the total blood volume [82]. Sawka et al. (1999) [83] show the dependence of the three volumes (whole blood, blood plasma and erythrocytes) on body mass, specifying that the individual is not overweight. The data refer to young, non-obese men and were obtained on the basis of radioisotope examination (51Cr and 125I scan of erythrocytes and albumin). Since vascular volumes are also directly related to body weight, their reference levels are expressed per unit of body mass (L/kg). The reference values for the three vascular volumes (blood, plasma, erythrocytes) are respectively—whole blood 63–82 mL/kg; plasma volume 38–49 mL/kg and erythrocyte volume 24–33 mL/kg [83,84,85].

Normally, the increase in erythrocyte volume occurs slowly (over several weeks to months, regular physical exertion), whereas the increase in plasma volume can occur rapidly (within hours or days) [83].

An increase in plasma volume, as a component of blood volume, is reported in almost all cases of induced hypervolemia as a result of exercise training (lasting up to 2–4 weeks). After this period, the increase in blood volume can be distributed equally between plasma and red blood cell volumes. Exercise as a stimulus for hypervolemia has a thermal and non-thermal component that increases total circulating plasma levels of electrolytes and proteins [81]. Although the movement of proteins and fluids from the extravascular to the intravascular space may be considered a mechanism for rapid hypervolemia (occurring immediately after exercise), there is also evidence to support the thesis that chronic hypervolemia represents an increase in total body water and soluble substances in the body. The increase in body fluids during exercise training is associated with increased water intake and a decrease in the volume of urine output. Hypervolemia provides increased amounts of body fluids in the body to “dissipate” heat and hence for increased thermoregulatory stability. Hypervolemia contributes to greater vascular volume and cardiac filling pressure, increased systolic cardiac output, and hence improved heart rate during exercise [81].

A review article is available in the scientific literature [81] which tabulates the specific percentage increase in blood volume, plasma volume and mean erythrocyte volume with gradually increasing training duration in days, with different load regimes at different active muscle groups. Convertino’s (1991) comparative analysis [81] included 15 different author groups and their results. It is important to note that the percentage change of the three parameters—erythrocyte volume, plasma volume and whole blood volume is different in absolute value, starts at different times, but settles to a constant level after a different time interval for all three volumes. It should also be added that even doing just one workout can contribute to an increase in overall blood volume.

The observed hypervolemia in the aforementioned scientific paper shows a “plateau” in the increase in blood volume after about a week of intense exercise. The reported increase in blood volume after about 10 days of training may be mainly due to increased plasma volume, with an almost minimal increase in mean erythrocyte volume. While increasing the duration of training from 4 weeks to 4 months, the reported increased blood volume is equally distributed between changes in plasma and erythrocyte volume. The interpretation of the time course of the assessed hypervolemia requires the inclusion of other stimuli for its occurrence—the different intensity, frequency, duration and type of physical exercises used.

Changes in blood volume during endurance exercise are not affected by age and/or gender [86]. Kjellberg et al. (1949) [87] found significantly higher whole blood volumes in trained men and women compared to untrained individuals of both sexes. Another study reported increased total blood volume following a program of alpine skiing training in both men and women [88]. Furthermore, during intense physical exertion, the same reactions of the plasma protein systems were found regardless of the age of the studied participants [89].

J.E. Axsom (2016) [86] studied a group of ten people participating in the 4000 Mile Across America Program. Subjects (mean ± SD) were aged 22.4 ± 1.4 years, 175.5 ± 12.2 cm height, 75.74 ± 27.4 kg initial weight. They covered 76.5 ± 34.8 miles per week prior to the study. By the end of the study, all participants had logged an average of 560 miles per week. The results show that after a 55-day training period, the average Hct of all 10 study participants significantly (p < 0.05) increased (from 42.9% to 48.45%). Mean Hb also increased significantly (p < 0.05) (from 14.6 to 16.4 g/dL). The average weight of the participants showed a small (p > 0.05) change, from 75.74 kg before the study to 74.55 kg after it ended.

2.5. Changes in the Endothelial Cells of the Vascular Walls

Endothelial and vasodilation disorders are the first signs of cardiovascular disease. They are proven risk factors preceding cardiovascular problems [90]. Because of this, many researchers and physicians have focused their efforts on the study and evaluation of blood vessels. The main goal is to identify vulnerable groups of people susceptible to the corresponding cardiovascular disease in order to implement timely prevention.

Contraction of the smooth muscles in the vessel wall is an indication of increased vascular tone. The endothelial layer that lines the arteries and arterioles plays a significant role in regulating smooth muscle contraction and relaxation [91]. Various hormones in the body cause vasoconstriction or vasodilatation and through them regulate the intensity of the blood flow. In addition, factors affecting vessel diameter may also alter the biomechanical properties and tone of vessel walls and help regulate blood pressure.

Large arteries in the cardiovascular system, according to the structure of their vascular walls, are defined as arteries of elastic type. Examples of this group of arterial vessels are the pulmonary artery, the aorta and its immediate branches with a wide lumen, etc. Their wall consists of predominantly dense elastic elements and smooth muscle cells.

The three main layers of the vessel wall are the intima, media and adventitia. The intima consists of a well-defined endothelial layer and an internal elastic membrane (elastica interna). The media is made up of numerous concentrically arranged, interconnecting smooth muscle cells and elastic membranes that form a complexly organized elastic network. The adventitia is represented by a thin layer of connective tissue containing elastic fibers and fibroblast and pericyte cells.

Medium lumen size arteries are defined as muscular type arteries. They are characterized by their active vasomotor function, which is expressed in changing the dimensions of their lumen during vasoconstriction and vasodilatation. This function of theirs determines the regulation of the amount of blood passing through them, which is why they are also known as “distributive-type” arteries. Some arteries of the muscular type are: arterial vessels of the limbs, intercostal arteries, organ arteries in the abdominal cavity, etc. Their intima structure resembles that of the large arteries, and they are characterized by a highly pronounced internal elastic membrane. The media of these vessels is made up of circularly arranged smooth muscle fibers forming multiple layers, between which a small amount of elastic, collagen and reticular fibers are visualized. The adventitia in the arteries of the muscular type is of considerable thickness, composed of collagen and elastic fibers.

Small arterial vessels are distinguished by a simpler wall structure, with a gradual decrease in their lumen when passing to the capillaries. A change in the structure of the vascular wall is found in arteries with a diameter of 0.4 mm and is expressed in the following: a gradual disappearance of the subendothelial connective tissue, the internal elastic membrane turns into a fine network of elastic fibers, and the muscle layer located in the media decreases in volume (https://medpedia.framar.bg/anatomy/arterial-department-of-the-cardiovascular-system, accessed on 3 July 2021).

Vascular endothelial cells play an important role in regulating vascular activity by releasing vasoactive substances, such as endothelin-1 (ET-1) and nitric oxide (NO) [91].

ET-1 is a peptide vasoconstrictor that is synthesized in endothelial cells (the innermost layer of cells lining the vascular lumen and interacting directly with blood flow) [92].

The peptide vascular vasoconstrictor known as endothelin (ET) was discovered in 1985 [93]. After its discovery, Yanagisawa et al. (1988) [94] concluded that this cellular factor comprises of 21 amino acids arranged in a strictly defined sequence. Another group of authors proved that ET contains three isoforms—Endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3), which are encoded by three different genes. ET-1 is responsible for cardiovascular changes [95] and is secreted by cardiac muscle cells (cardiomyocytes), cardiac endothelial cells and cardiac fibroblasts [96]. Regarding the fact that physical activity changes blood flow to different organs (active or inactive), this physical activity is considered the most significant factor for the secretion of these isoforms (hormones).

In the study by Maeda et al. (1994) [97] monitored the plasma concentration of ET-1 in young athletic men after exercise on an ergometric bicycle (a 30-min session). Based on the results of this study, it has been shown that the plasma concentration of ET-1 increases after physical training.

The experimental evaluation in seven patients with cardiovascular syndrome by Kopeć et al. (2012) [98] also showed that after a 6-min walk, left ventricular volume and ET-1 levels increased. Author collective Boghabadi et al. (2012) [99] found that after 3 months of aerobic exercise in elderly women, blood pressure and ET-1 level normalized. The authors report a positive training effect for problems with the cardiovascular system. Moreover, Maeda et al. (2004) [100] investigated the effects of endurance training on plasma ET-1 levels in young men aged 25–27 years. Participants were enrolled in an endurance training program for 8 weeks and 3 days. The results show that despite the lack of difference between blood pressure, heart rate and maximal oxygen consumption, the plasma level of ET-1 decreases significantly.

Cosenzi et al. (1996) [101] found that plasma ET-1 levels did not change after a 15-min cycle ergometer exercise (of moderate intensity) in young athletes. Based on the results of Callaerts-Végh et al. (1998) [102] suggested that 8 weeks of aerobic exercise had no significant effect on ET-1 levels in patients with cardiovascular problems.

Due to the conflicting results of the above studies, it can be summarized that more in-depth future research is needed in this direction.

In a study by Mehrabi et al. (2015) [90] the authors compared the effect of eight weeks of moderate aerobic exercise on two groups of participants: a control group of healthy individuals and a group of patients with coronary artery disease. The same author team proved that there were no statistically significant changes in the plasma levels of ET-1 in both studied groups. The researchers concluded that it is likely that changes in plasma ET-1 level occur when exercise exceeds a certain threshold of intensity and duration of impact. These threshold levels probably also depend on many individual factors, different for each participant in the experiment.

2.6. Blood Pressure

The influence of exercise on blood pressure has been proven [103,104,105]. In this regard, a number of cellular and molecular mechanisms have been studied: neuro-hormonal, vasomotor, serum catecholamine level, coronary microcirculation and others, positively and/or negatively affecting blood pressure in normo- and hypertensive patients, as a result of physical activity and special training programs (fitness, tennis, etc.) [103].

Physical exercises modulate main cardiovascular risk factors (obesity, metabolic syndrome, dyslipidemia, inflammation, oxidative stress, diabetes mellitus type 2, arterial hypertension, etc.). In modern research, the emphasis is specifically on the type, intensity, frequency and duration of physical exercises (training) as an excellent therapeutic approach in the treatment of arterial hypertension. The effects of exercise on the CVS (cardiovascular syndrome), metabolism, gene expression, and the immune system further contribute to a positive effect on arterial hypertension [103].

From the point of view of cellular and molecular biology, the cardioprotective effects of physical exercise are associated with increased antioxidant functions of the body [105], regulated gene expression [106] and activated mitochondrial functions [107]. Improved blood flow (circulation, vascular remodeling) is achieved and the functions of endothelial cells in the vessel walls are improved [103]. In this way, the level of nitric oxide (NO) is also regulated, which is synthesized by the enzyme endothelial nitric oxide synthase (eNOS) and ensures normal vasodilation (dilation of vessels and overcoming of vascular spasm) [103]. In fact, physical activity stimulates the gene expression of NOS [104], enhancing NO-synthesis, which contributes to the expression of vasodilator factors, such as prostaglandins—with cardioprotective action and metabolic effect on vascular walls.

2.7. Sport and Hypoxia

Training and exercise “under conditions of hypoxia” favorably affect aerobic biological processes in the human organism, mainly by stimulating erythropoiesis, but also under the influence of other physiological cellular factors [108]. Such are, for example, stimulated vasodilatation by means of increased NO synthase activity in the endothelial cells of the vascular walls. As a result, their resistance is reduced and vasodilation and increased arterial blood flow are observed.

A recent study by Park et al. (2022) [108] used an experimental model of interval training under hypoxic conditions. In healthy women, training effects on arterial functions and hemorheological characteristics of blood and blood cells (erythrocyte deformability and aggregability) were monitored. Compared to interval training activity, but performed under conditions of normoxia, exercise “under hypoxia” appears to be a new, efficient model for maintaining and improving arterial (endothelial) and hemorheological functions in healthy women. Similar studies in different models of hypoxia are described by other authors [109,110,111,112].

Hemorheological responses of the human and animal organism in conditions of hypobaric hypoxia compared to the state of normoxia (normal oxidation and oxygen aerobic capacity of tissues and cells) are still insufficiently studied [108]. Hemorheological “responses” of blood and blood cells were investigated in experimental conditions of mild and moderate hypobaric hypoxia (596 mmHg-simulation at 2000 m above sea level, and 526 mmHg-simulation at 3000 m above sea level) [108]. It was established that under the above described conditions of hypobaric hypoxia, hemorheological characteristics and properties of blood and blood cells, including erythrocyte deformability and aggregability, were not affected. The opinion that physical exercises and training in conditions of hypoxia is an appropriate approach to improve metabolic processes and the sports form of the body is increasingly being asserted [113,114].

2.8. Hemorheological Changes and Their Interaction with Different Motor Activity

It is generally accepted that physical exercises and increased physical activity improve the health of the body. Their effects have been extensively studied, but they are not yet a priority research object in the field of hemorheology [115]. For example, the “paradox of hematocrit” (Hct), blood and blood plasma viscosity, hemorheology of blood cells and other basic biorheological phenomena need to be the subject of future in-depth studies so as to clarify and further illuminate the relationships between physical activity (exercise, training, “overtraining”, etc.) and the specific rheological profiles of blood and blood cells.

From previous biorheological (hemorheological) studies, it has been established that elevated values of plasma viscosity and hematocrit correlate primarily with high levels of whole blood viscosity (WBV). In the medical and sports scientific literature, the prevailing opinion is that the temporarily increased blood concentration induced as a result of training and exercise is caused by the transfer of biological fluids (blood, lymph) from the vessels to the interstitial spaces of the loose connective tissue. We must emphasize that in the described biological phenomenon, the deformability and aggregability of erythrocytes remain unchanged. In this aspect, scientific results are often contradictory, divergent and difficult to interpret. Several major stimulatory effects of physical exercise on the basic systems of blood “hemostasis” have been described: enhanced blood coagulation (blood clotting), activated platelet aggregation and increased number of platelets entering the bloodstream presumably from the bone marrow, spleen, and lung, and enhanced fibrinolysis (degradation of fibrin fibers in eventual thrombogenesis) [116].

In recent research, Freitas Leal et al. (2019) [117] proved that a walk (30–50 km) of moderate intensity, for four consecutive days, is sufficient to improve the functional activity of erythrocytes (higher deformability and reduced aggregability).

In their study, Pospieszna et al. (2021) [118] reported that changes in erythrocyte ademylate energetics are related to biological processes that depend on various factors, including the chosen type of sport as a training model.

In the literature, it is hypothesized that stress under the influence of intense physical exertion, can cause accelerated aging and functional loss of part of the erythrocytes with subsequent replacement of their cell population with “younger cells”. At the same time, the increased training activity stimulates the process of erythropoiesis in the bone marrow and the competing process erythrocyte hemolysis (degradation of vulnerable aged erythrocytes), which improves the hemorheological status of the body. The reasons for the observed positive hemorheological processes (increased amount of “young” erythrocytes, higher erythrocyte deformability, stability of erythrocyte cell membranes—lack of membrane rigidity, increased antioxidant activity) are the subject of intensive modern studies. Research groups [118,119,120] support the thesis of higher metabolic activity and improvement of hemorheological characteristics of erythrocytes in well-trained individuals.

Stimulated erythropoiesis, under the influence of increased training activity and long-term physical exercises carried out in different training models (types of sports), helps to gradually stabilize the so-called shortened erythrocyte life cycle [118].

Frequently repeated, maximally intense physical exercise probably induces increased “adenylate level” and ATP (adenosine triphosphate) concentration in erythrocytes, thus stabilizing their cellular energy efficiency.

In addition to the study of healthy individuals (athletes and non-athletes), the inclusion of patients in similar testing and monitoring schemes could lead to the discovery of new, more effective biomarkers of healthy and diseased (pathological) aging of the human organism [118,121].

In conclusion, the study by Pospieszna et al. [118] proves that active sports protect against energy depletion and maintain a good energy level of the cellular energy system of red blood cells in people of different age groups. As a result, the concentration of cellular metabolites useful for erythrocytes is higher in athletes (well-trained persons), who are distinguished from non-athletes by the prevalence of positive hemorheological indicators (blood and plasma viscosity, erythrocyte deformability and aggregability).

Modern research has shown [122,123] that the deformability of erythrocytes decreases with their aging, and their cell density increases [124].

Through clasmatoses and the release of cellular exosomes (vesicles) [124], biologically active substances (mainly proteins) enter the bloodstream, which play a certain role in intercellular communications and are influenced by internal and external stimuli (e.g., physical exercise [125]).

Physical activity is a biological factor that alters the “age distribution” of erythrocyte cell populations. For example, it has been shown that significant numbers of deformable (more flexible and lower density) “young erythrocytes” are established in the blood of elite athletes [126]. Increased deformability of erythrocytes is hypothesized to contribute significantly to athletes’ good “sports fitness” [127].

Improved erythrocyte hemorheological parameters and plasma nitric oxide (NO) levels increase vasodilation, resulting in more efficient microcirculatory blood flow and increased O₂ delivery to body tissues and cells.

The volume of erythrocytes, the elasticity of their cell membrane and their increased deformability are influenced by cellular and tissue factors, such as erythrocyte dehydration, concentration and distribution of hemoglobin (Hb) in erythrocytes, amount and distribution of their cytoskeletal proteins, etc. [11].

The results obtained by Bizjak et al. (2020) [122] support the idea that the biorheology of blood and blood cells is rapidly and effectively affected by the so-called regular exercises over time.

Future studies should include in the target monitoring program longer training periods with different intensity training: for example, a high intensity marathon, weight loss exercises, etc. In-depth and precise future research in this direction is needed to study in depth the processes of cellular adaptation and the biological reactions of the body when practicing different types of sports.

The positive effects of regular aerobic exercise are confirmed and well documented in the scientific literature. Trained athletes show an affected erythrocyte deformability, a stimulated erythrocyte cell life cycle with a prevailing proportion of “young” erythrocytes, as well as a reduced concentration of lactate in the blood.

Regular and long-term exercises (“endurance exercises”) increase the synthesis of catecholamines, cell growth factors, insulin-like factors, which (as well as hematopoietic cell growth factors) stimulate bone marrow hematopoiesis and especially erythropoiesis [119]. As a result of the stimulations, increased bone marrow cell proliferation and differentiation is observed and the number of “young” erythrocytes (including reticulocytes) in the peripheral blood and in the bloodstream increases, including and in the microcirculation.

It has also been found that the hematological indicator mean erythrocyte volume (MCV) decreases as the senile process (“aging”) of red blood cells progresses [128]. It is emphasized that an increase in MCV is beneficial for the human organism, and its decrease correlates with advancing senile processes and deterioration of hemorheological indicators (indices, parameters, biomarkers). However, new hemorheological studies in different sports and training models are needed to confirm this hypothesis.

In their paper, Nemkov et al. (2021) [129] simultaneously investigated hemorheological parameters and metabolic profiles of blood and blood cells under conditions of an intense controlled cycling test [129]. Elevated values of hematocrit (Hct), erythrocyte count (RBC) and leukocyte count (WBC) were found. The hematometric indices: platelet count (PLT), mean erythrocyte volume (MCV), mean erythrocyte hemoglobin concentration (MCHC) and the RDW index do not change. In response to this cycle test, reduced deformability and increased aggregability of red blood cells were also reported. The latter two outcomes are factors that contribute to increased whole blood viscosity (WBV) [11,130].

In the same study, the authors report a change in the metabolic profiles of blood cells under the influence of oxidative stress and conclude that only the frequently applied “omics-technologies” (proteomics, metabolomics, lipidomics) will contribute to a more accurate cellular and molecular analysis of biochemical phenomena [129,131]. In this case, from a biochemical point of view, the fact that the amount of lactate in erythrocytes during exercise correlates “significantly negatively” with the maximum degree of erythrocyte deformation, represented as “maximum index of elongation of erythrocytes along their long axis” (EI).

In the results of modern scientific research [122,132], the positive trend for increased deformability of erythrocytes in well-trained professional athletes is outlined, probably as a result of training-stimulated bone marrow erythropoiesis. Simultaneously with the creation of new populations of erythrocytes in the bone marrow, “aged” (senile) red blood cells are deposited and degraded in the spleen. Through the described cell cycle, the vital potential of the newly created erythrocyte cell populations in the bone marrow with normal hemorheological properties is stimulated and the biological balance in the body is maintained.

3. Conclusions

Hemorheological blood properties are of primary importance for the blood supply to tissues and organs in the body at rest and during sports training and physical exercises.

In the present work, we reflect the world experience of analysis of basic hemorheological changes in human blood, blood cells and plasma as a result of intense physical activity (physical exercises at different intensity, frequency, duration and load regimes).

It is a well-known fact that the influence of physical exercises on a significant number of physiological reactions of the body has not been sufficiently studied and analyzed at the level of cells, tissues and organs. The immediate physiological response to moderate physical exertion and/or intense physical activity depends on the type, duration, intensity and cycling of physical exercise, as well as on the individual levels of training status of the participants. On the basis of the results presented in this monographic work, summarized conclusions were synthesized, listed in the following separate paragraphs.

Sports and physical exertion cause changes of different nature and degree (positive or negative, strong, weak, moderate) in the biomechanical and fluid properties of blood and blood cells:

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Erythrocyte deformability and aggregation;

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Change in the concentration of basic plasma components—Fibrinogen, albumins, globulins, testosterone, etc.;

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Changes in blood flow (through vasodilatation and change in overall blood viscosity);

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Changes in blood volume;

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Changes in the endothelial cells of the vascular walls;

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Changes in blood pressure;

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Changes as a result of tissue hypoxia;

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Interacting, different in nature hemorheological changes.

In the modern scientific literature, there are data on the proven influence of regular physical exercises on basic hematological, hematometric and hemorheological indices of erythrocytes, on whole blood viscosity (WBV) and blood plasma (PV), on basic biochemical plasma components, on blood pressure, on morphological and functional changes of endothelial cells in vascular walls, etc. [31,76,77,86,90,103,108,111,114,117,118,120,122,127,129,130,133,134,135,136,137,138].

The studied and described original models of hemorheological changes can contribute to a more successful adaptation of the training programs in order to improve the health status of the participants and to optimize the sports form of the elite athletes practicing sports both in groups and individually.

Physical loads of different frequency, intensity and duration cause a different hemorheological (strictly individual) response in athletes.

The professional task of every athlete is to achieve optimal sports form. Each sports activity is characterized by specific requirements, compliance with which is reflected and manifested in the personal characteristics of athletes (genetic, physiological, morphological, cognitive, psychological and others). Motivation plays a major role in sports training, competition and productivity.

The importance of controlling hemorheological parameters as a suitable method for monitoring the efficiency of the body’s adaptation to the training process has been proven with the aim of achieving an individual optimal sports form.

The effect of “regular, moderate and properly dosed physical activity” during training is also strictly individual. This fact suggests approaching the training regimen of each elite athlete strictly individually, practicing well-chosen, balanced physical exercises specific to his preparation. Such a correct approach to the training regime of the respective athlete will help to achieve the so-called a state of hemorheological fitness [76,77]. The main, but not all, indicators for achieving this comfortable physiological state of the body are: reduced blood and plasma viscosity (WBV, PV), hematocrit (Hct) and erythrocyte aggregability, with increased deformability of red blood cells [76,77]. In this regard, we will emphasize that while whole blood viscosity (WBV) is primarily determined by the number, deformability and degree of aggregation of erythrocytes, plasma viscosity (PV) depends primarily on biochemical factors: presence of fibrinogen and other plasma proteins and macromolecules, well known in routine clinical laboratory practice.

Pathophysiological effects on the main hemorheological parameters are exerted by:

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oxidative and/or mechanical stress;

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metabolic changes in cells and tissues (reduced pH, changes in tissue oxidation, accumulation of lactate);

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changes in respiratory lung functions;

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changes in the regulation and adaptation of vascular tone (for example, in changes in the mechanoreceptors of vascular endothelial cells, as well as in the synthesis of endothelial nitric oxide synthase).

Extensive future research is needed to elucidate the cellular, tissue and molecular mechanism of hemorheological changes in blood, blood cells, blood plasma. It is essential to study the vascular characteristics and biomechanical properties of blood under physical loads with different modes and variable parameters. It is necessary to assess exactly which are the biomechanical factors causing hemorheological changes during physical exertion, taking into account the individual, professional, biological and mechanical profile of each athlete.