Cardiovascular Physiology Lecture Notes 01-03-2023 PDF

1st Lesson File name: (01)_Physiology _ DeVito_ 01-03-2023 Sbobinatore: Mehdi Najafipour Professor: Giuseppe De Vito Revisore: Isabella Conti...

1st Lesson File name: (01)_Physiology _ DeVito_ 01-03-2023 Sbobinatore: Mehdi Najafipour Professor: Giuseppe De Vito Revisore: Isabella Conti Date: 01/03/23 Introduction of the course: This course will be held by professor De Vito and professor Blaauw that will cover the endocrine physiology. The professors recommend attending the course in person, as there may be topics not covered in the course material. To be eligible to take the physiology exam, you must have passed the "The Human Body" and "The Building Blocks" exams. Lecture slides will be available on Moodle one day prior to each lecture. The course will cover heart physiology, kidney physiology, digestive tract physiology and endocrine physiology Professor’s contact for any questions: E-mail: [email protected] [email protected] Tel.: 0498275223 Ufficio: Istituto di Fisiologia Umana, via Marzolo 3, first-floor room 19a. Textbooks suggestions: Vander’s Human Physiology; Guyton and Hall Textbook of Medical Physiology; Ganong’s Review of Medical Physiology; West‘s respiratory physiology. The essentials. The professor highly recommends "West's Respiratory Physiology," a small book that he personally like. For those who prefer video lessons, there are also some of professor West’s lessons available on YouTube. https://youtube.com/playlist?list=PLE69608EC343F5691 CARDIOVASCULAR PHYSIOLOGY Introduction, the general organization of the cardiovascular system and the blood The first lesson will cover the introduction and blood, while the second lesson will focus on homeostasis and coagulation. Coagulation is not only an important physiological process but also has significant implications for therapy. In the medical field, you will encounter situations that require the use of anticoagulant or procoagulant treatments, so it is important to become familiar with them. Introduction The cardiovascular system is a crucial system that starts developing early in life, even during the embryonic stage. The heart of the embryo begins to beat only a few weeks after conception. The heart’s early activation is vital for distributing nutrients throughout the growing fetus. The development of the cardiovascular system begins during the embryonic stage, with the heart being the first organ to become functional. The heart’s early activation is necessary to provide organic substances and nutrients that support the fetus’s growth and development. As the cardiovascular system develops, blood vessels and capillaries form to distribute oxygen and nutrients to various parts of the body. If we consider the activity of the heart, it is similar to that of the diaphragm muscles. The heart and the diaphragm muscles play vital roles in the human body, and they are constantly active throughout life. The diaphragm muscle is responsible for separating the abdominal cavity from the thoracic cavity, which is crucial for respiration. It is an important muscle for studying the effects of activity on muscle degeneration as it never stops working, even during sedentary activities such as watching television. Patients may undergo biopsies or electromyographic sessions to assess diaphragm muscle activity in research studies. Similarly, the heart is a vital muscle that beats approximately 3 billion times during an individual’s lifespan. However, only 1% of heart cells are replaced per year, indicating a limited capacity for renewing heart muscles. This limited capacity for replacement makes heart damage such as infarction, necrosis, and the death of human muscle cells particularly severe, as the damage, cannot be fully repaired. The heart is therefore a critical organ that requires proper care and attention to maintain its function throughout an individual’s lifetime. Fundamental cardiovascular system functions: The cardiovascular system is essential for various bodily functions, and it performs three main functions: Transport of nutrients and removal of metabolic products: The first and most essential function is the transportation of nutrients, specifically oxygen, glucose, liquids, and proteins, to every cell in the body. The cardiovascular system accomplishes this task by circulating blood throughout the body via the heart, arteries, veins, and capillaries. In addition to delivering necessary nutrients, the cardiovascular system also facilitates the removal of metabolic waste, toxins, and accumulated products from damaged or deceased cells, transporting them to be eliminated or repurposed for future use. Regulation of the total extracellular fluid: Another vital function of the cardiovascular system is the regulation of the total extracellular fluid. French physiologist Claude Bernard defined the concept of an internal environment, or “milieu intérieur,”1 as essential for the evolution of the human body. This internal environment refers to the extracellular fluid, where most of the metabolic and catabolic interactions in the body occur. Therefore, regulating the total extracellular fluid is crucial for maintaining a stable internal environment. The cardiovascular system achieves this through various mechanisms and it’s one of its main tasks. Regulation of a wide variety of physiological functions, (transporting hormones, regulating body temperature, etc.) In addition to nutrient transportation and extracellular fluid regulation, the cardiovascular system also plays a critical role in hormone transportation, which is essential for maintaining homeostasis. One significant function of hormone transportation is thermoregulation, which regulates blood flow between the periphery and core of the body. The regulation of blood flow is achieved through vasodilation and vasoconstriction in response to environmental temperature changes. During vasodilation, blood vessels in the periphery of the body dilate, allowing for the dissipation of heat and exchange of heat or energy between the body and the environment. Conversely, during vasoconstriction, blood vessels in the periphery of the body constrict, restricting blood flow and conserving heat when exposed to cold. These processes are crucial for maintaining thermoregulation control in the body. As homeothermic animals, humans operate within a large optimum range of temperature, typically between 34-38, 39, or 40 degrees Celsius. This range is necessary for the maximum catalytic activity of numerous enzymes that operate in the human body. If the temperature falls outside of this range, the speed of chemical reactions in the body will be reduced. In contrast, if the temperature is too high, it can lead to the denaturation of proteins, resulting in severe health consequences. 1 NoS: check sbobina 1 of the 1st year’s physiology NoP: During my academic career, I conducted extensive research on thermoregulation in Scotland, where we focused on conducting experiments to understand this process. The components of the cardiovascular system Now we are going to say about the protagonists of these activities. The Blood: The first is blood, which can be subdivided into two main components: plasma cellular component You can easily observe this separation by spinning the blood in a centrifuge. The Heart: Then we have the driving force of this system, a biological double pack: the heart. Double pack because it is pushing the blood into two parallel circuits: the systemic circulation the pulmonary circulation These two circuits share the same characteristic of maintaining a constant amount of blood per unit of time, which is referred to as cardiac output. The cardiac output is the amount of blood ejected or pumped into the system per minute and is approximately five liters per minute. The right ventricle pumps blood into the pulmonary circulation, while the left ventricle pumps blood into systemic circulation. However, the amount of blood pumped in both of them is 5Lit/min, the difference between these two circuits lies in their pressure levels. The systemic circulation is a high-pressure circuit, while the pulmonary circulation is a low-pressure circuit. This is an essential point that will be emphasized throughout this module. Moreover, The heart is also divided into four chambers, including two superior atria and two inferior ventricles separated by unidirectional valves. These valves ensure that the blood flows in one direction, preventing any backward flow or regurgitation. The Blood Vessels: The other third protagonist of the cardiovascular system is the system of vessels, which can be divided into two different categories: Arteries: Arteries are normally low resistant large diameter tubes, while arterioles are smaller and play an important role in regulating total peripheral resistances. Arterioles: Arterioles are small in size yet play a vital role in regulating total peripheral resistances. By adjusting the caliber or diameter of arterioles, the resistance to flow and volume of blood flow to different organs can be altered. This alteration permits the modification of blood pressure and blood distribution to tissues according to their needs. When the body is at rest, the muscles receive a constantly reduced amount of blood as they are not active. However, when physical activity, such as walking, running, or other exercises, is initiated, the muscles become activated, resulting in vasodilation of the arterioles. This vasodilation allows more blood to flow to the muscles. Conversely, organs such as the kidneys or the gastrointestinal system, which do not require as much blood during physical activity, receive less blood due to vasoconstriction. Therefore, arterioles play a crucial role in manipulating the amount of blood going to specific organs according to their needs. Furthermore, arterioles are essential in regulating blood pressure because they are the main site of resistance to flow. In the upcoming lecture, we will delve into the physics of blood circulation and explore the role of arterioles in regulating blood pressure and blood flow distribution in detail. Capillaries The capillaries, located between the arterioles and veins, are characterized by their short length, thin walls made up of a single layer of cells, and slow blood flow. These structures are responsible for the exchange of oxygen and carbon dioxide between the blood and tissues. Carbon dioxide produced by the tissues is absorbed by the blood, while oxygen is transported from the blood to the tissues. However, it is important to note that this exchange of gases is not uniform throughout the capillary system, and varies from the beginning to the end of the capillary network. The short length and slow flow rate of the capillaries facilitate diffusion, which is a concentration-based transport mechanism. Venules Veins And then the venous and veins system is characterized by transport and reabsorption of blood towards the heart. Normally, there is low resistance to flow and no pressure. But despite the absence of pressure, they can accommodate the largest amount of blood. In each instant, most of the 5 liters of blood in our body is linked to the venous system, which is very distensible. This concept is known as compliance: the relationship between volume and pressure. The venous system can accommodate large volumes without raising the internal pressure. It is a compliance system where a lot of fluid can be introduced without a great increase in pressure. Low compliance means that a small amount of fluid inside will increase rigidity, sensitivity, and elasticity. NoS: compliance is defined as a change in venous volume (ΔV) related to a change in distending pressure (ΔP, compliance = ΔV/ΔP) The decreased compliance of the vessels in aging, particularly the aorta, which becomes more sclerotic, is why blood pressure measurement is an essential test for many elderly individuals during their visits to a general physician (GP). Hypertension is a common issue among individuals over the age of 60, and blood pressure checks are a critical indicator of the problem. NoP: I'm almost 65. And so for the first time in two, three months ago I started taking some anti-hypertensive drug, in a low condition. Because my systolic pressure is always 140, 145, 150. I'm an active person, but this is in respect of aging, the vessels become sclerotic. So they are less disabled to accommodate the same amount of blood. The Blood: The blood is a vital liquid that is responsible for fulfilling many needs of the body and is capable of reaching even the smallest parts of our organs. It is composed of two main components, plasma and cellular components. The yellowish part in this tube represents the plasma, while the gray and red parts mostly comprise cells. Additionally, there is a thin layer known as the buffy coat, which primarily consists of a small portion of cells such as leukocytes (white cells) and platelets. Despite the bone marrow being predominantly responsible for producing white cells, the cellular component of blood is mostly composed of red cells. In fact, approximately 99% of blood cells are erythrocytes, commonly known as red cells. This is a crucial fact to remember, as the main bulk of cells in the blood are red cells. To separate the plasma and cellular parts of the blood, we can centrifuge it, as shown in the image on the right. This process is routinely carried out in laboratories, as we may need to store only the plasma after conducting experiments or analyzing specific reactions. By centrifuging the blood, we can determine the proportion of these two components, which is known as the hematocrit. Hematocrit is a measure of the percentage of red blood cells in the blood. In general, the hematocrit of an average adult ranges from 40 to 46%. Females tend to have an average hematocrit of 40-41%, while males have a slightly higher hematocrit of 43-45%. Some individuals possess a genetically higher hematocrit of 50, 49, or 48%, which can confer greater endurance sports proficiency. Having a higher amount of red cells translates to having a higher concentration of hemoglobin, which is responsible for transporting oxygen throughout the body. This can provide an advantage in endurance sports such as cycling, marathons, and other similar activities. Individuals with a genetic predisposition towards a higher hematocrit level have a greater ability to transport oxygen, which results in higher energy levels during these activities. However, some individuals resort to doping to artificially increase their hematocrit levels to compensate for their lack of natural ability. This will be further discussed during the lecture. It is important to note that blood represents approximately 8% of the body mass in a 70kg man and typically ranges from 5 to 5.5 liters in volume in all individuals. In contrast, a newborn baby weighing 3.2 kg would have a blood volume of approximately 250 milliliters. NoP: The average 70 kilos for men is something that comes across a lot. Men’s weight should be updated. This 70 kilos for men was probably established 50 years ago. Maybe now the average man is a bit bigger, and it would be fair to include an average woman now, especially with gender equality Plasma: This table illustrates the components of the plasma: Plasma, the yellowish liquid component of blood, is primarily composed of water, with 90% of its composition being water. This makes up approximately 4% of the body mass, with the plasma volume in a typical man being around 3 liters and in a typical woman being around 2.4 liters. Aside from its role in regulating temperature and heat dissipation, plasma also contains a variety of organic and inorganic substances. In addition to water, it containsions such as: Calcium: important to regulate many functions. Sodium: plays an important role as the main solute in the body. Potassium: regulates plasma membrane, action potential, and gradient potential activities that occur within the plasma NoP: Remember that it was seen in the previous course the regulation of plasma membrane depolarization, action potential. (check sbobina 2 of 1st year’s physiology) Additionally, cholesterol, complex glycol, and other important parts of plasma include plasma proteins. The liver is responsible for producing most of the plasma proteins, with albumin being the most important among them, followed by immunoglobulins, which are also part of the plasma protein family. Plasma proteins are also involved in coagulation and in transportation of iron, with fibrinogen and prothrombin playing a role in these processes. Additionally, transferrin, a protein responsible for mediating the transport of iron, is also present in plasma. Iron is an important mineral and it is twice as important as other ions. It is an essential component of hemoglobin, and without it the production of hemoglobin is affected. Iron is a dynamic component that is continuously absorbed and eliminated in the feces, hence a continuous supply of iron is necessary. Most of the iron present in the body is not found in the blood; it is attached to transferrin and stored as ferritin. Therefore, when checking iron levels, it is important to measure transferrin and ferritin levels in addition to blood iron levels. Iron deficiency anemia is quite common, especially among young women who have a vegetarian diet that is not properly balanced. It is possible to have a complete set of essential nutrients with a vegetarian diet, but it is important to pay attention to iron intake. Iron is mostly contained in meat and fish, so vegetarians need to find alternative sources. Transferrin, along with other proteins present in plasma, plays a crucial role in the transportation of iron throughout the body, making it an essential component in maintaining iron levels. Blood cells: Now, at the main blood cells represented, we can distinguish between the erythrocytes on the left side and the leukocytes or white cells in different subcategories, and then finally the platelets. Only the leukocytes are true eukaryotes because they contain nuclei, while both the erythrocytes and platelets do not contain nuclei. A eukaryotic cell is defined by containing a nucleus. This table gives you an idea of the quantification of the total blood count, and if you do a blood analysis, you will see the hematocrit and different counts of white cells, red cells and the volume of these cells. Sometimes you have a total number but the volume is impaired or reduced, it can be an indication of a problem in blood manufacturing. The upper image depicts the quantification of erythrocytes (NoS: eritrociti) and provides a range of normal values on the right. Although the concept of a fixed internal environment proposed by Claude Bernard’s “milieu intérieur” suggests stability, we know that there is always a range. Hemoglobin (NoS: emoglobina) is typically expressed in g/l, and in this case, the hematocrit (NoS: ematocrito) is 48%, while MCV, MCH, MCHC, and RDW indicate the volume and concentration of erythrocytes. The white cells are divided into different categories, and there are ranges for each. For example, in the analysis presented, all white cell counts are within normal range. However, during a seasonal allergy, it is common for eosinophil counts to increase due to their involvement in allergic reactions. Similarly, infections may alter the white cell counts, with bacterial infections often increasing neutrophil counts. Blood analysis serves as a benchmark for immediate diagnosis, and while more sophisticated techniques have emerged, blood tests remain a fundamental tool in medicine. Hematopoietic stem cells (HSCs): Blood cells are produced normally in adult life from the bone marrow, starting from the so-called hematopoietic stem cells (HSCs). The stem cells have the ability to differentiate into various cell lines, giving rise to most of the cell lines. In this image, you can observe that all of these cell lines originate from the hematopoietic stem cell. As said, this activity is done in the bone marrow, which changes with age. Initially, during the first years of life, the tibia, ribs, and vertebrae contain a lot of activity in the red bone marrow, which is very active in producing cells. However, as age progresses, these activities gradually decrease. In the development of a fetus, blood cells are produced by the liver and the spleen. While this hematopoietic activity is lost in many cases throughout life, it can be reactivated under certain circumstances. Damage, fibrosis, tumors, inflammation, and exposure to radiation can all cause the bone marrow to lose its ability to produce blood cells on its own, even in adults. However, the spleen and liver can restart the production of blood cells in these cases. It is worth noting that 75% of cells in the bone marrow belong to the line of white blood cells, while only 25% belong to red blood cells. Despite this, red blood cells are the most abundant in the blood. Bone Marrow Transplant: Bone marrow plays a crucial role in the treatment of certain blood disorders, such as tumors or leukemia, where a transplant may be necessary. The bone marrow can be harvested from a donor through a puncture of a large bone and injected into a patient in small amounts, which can stimulate the production of a large number of blood cells. Hematopoietic stem cells are important cells that are derived from uncommitted totipotent stem cells that can develop into different cell lines. However, these cells are scarce in number, even though they are abundant in the blastocysts of embryos. This has led to a significant amount of research interest in the potential use of blastocysts taken from embryos. However, ethical concerns have been raised regarding the use of embryos for this purpose. Physiological versus Pathological Hematopoiesis: Hematopoiesis in adults normally originates from the bone marrow, although in cases of damage, fibrosis, or tumors, the spleen and liver can be reactivated, leading to a situation called pathological hematopoiesis. This is an alternative to the traditional hematopoiesis starting from the bone marrow. Red Blood Cells: Red blood cells have a small biconcave shape with thicker edges and a flattening towards the center, making them very flexible and ideal for diffusion of gases like oxygen and carbon dioxide. This shape is much more efficient in gas exchange than a spherical shape. Being flexible also allows the cell to squeeze through tiny vesicles, so instead of remaining circular, they become more elongated. In this way, they can enter into very tiny capillaries of tiny tubes, accommodate in the narrowest part of the vascular tree. The lifespan of the red cell is in avarage 120 days, four months, approximately. In this period, a red cell can travel thousands of kilometers, more than 1,000 kilometers. The spleen operates an important role in this because it’s able to accumulate the red cells, but also, acting as a filter for removing the damaged cells, and in the spleen, there are macrophages, kupffer cells, that can attack these damaged cells, destroying and eliminating the damaged red cell. Hemoglobin: The red cells contain hemoglobin, that are going to be more detailed in the respiratory physiology. Normally typical adult hemoglobin in humans are structured by four subunits, two alpha and two beta subunits (alpha2beta2). In the fetus hemoglobin, it’s different because we have two alpha and two gamma subunits (alpha2gamma2). In this image on the right you can see the four subunits, two beta and two alpha. Not only hemoglobin in adult is adult hemoglobin, there is a small amount of fetal hemoglobin, alpha2gamma2, two gamma groups that remain, in some individuals. Another important point about hemoglobin is that 2-3% of hemoglobin is so-called glycated hemoglobin. It’s a molecule with an accumulation of glucose. But the importance of glycated hemoglobin is that its level is used as a marker in the assessment of diabetes, especially in comparison to type 1, and type 2 diabetes. Normally, we have 2-3% of the total amount of glycated hemoglobin, but in a normal case, it’s okay. However, when it becomes 6, 7, 8%, it’s an indication of the gravity of the situation. The proportion of glycated hemoglobin decreases over time. So, an elevation in the glycated hemoglobin in diabetes is an indication of the progression of the disease or poor control. Type 2 diabetes is very prevalent in our modern societies, in Italy, it’s about 6% of prevalence. In China, type 2 diabetes, in people over 60, it’s over 25% of the population. You have to consider that China is a country that is evolving for 20 or 30 years, from a mostly rural, residing country to a machinic. Hemoglobins are essential components of red blood cells that help in the transportation of oxygen throughout the body. The capacity of hemoglobin to link with oxygen gives us an idea of its functionality. On average, men have about 16 g/dL of hemoglobin, while women have 14 g/dL. When glycosylated hemoglobin is detected in a 70-kilogram man, it implies that approximately 900 grams of hemoglobin are present, with 0.3 grams being destroyed while an equal amount is synthesized and released. This continuous balance is maintained through activity and nutrition. Mechanical Injuries: The lifespan of a red blood cell is approximately 120 days. However, this can be altered by physical activity. If you engage in activities such as walking or running for 10-15 kilometers a day, the lifespan of your red blood cells may be affected. The red blood cells are very flexible and can move around the body through tiny tubes. In moderate activities and rest 60-70 beats per minute are normal and do not cause alteration in red blood cells' lifespan. However, high-intensity activities such as those resulting in heart rates of 130, 160, 190, or 200 bits per minute can cause more damage to the red blood cells, resulting in a faster turnover. The red blood cells can be also damaged by heavyweight. For example, soldiers who carry heavy weights often experience damage to their RBCs. Hematuria, the presence of blood in urine, is a common symptom seen in soldiers after a long march or marathon, indicating damage to RBCs and overflow of vessels that results in blood appearing in the urine. Normal urine does not contain blood, and the presence of blood indicates an overload of flow due to damaged RBCs. Metabolic injuries: Therefore, it is crucial to pay attention to nutritional requirements to support the production of RBCs. Catabolism of Hemoglobin: Hemoglobin is a critical component of RBCs, responsible for transporting oxygen throughout the body. Hemoglobin is damaged as well as re-synthesized, and its function is represented by the function of each subunit containing heme group. A heme group is a typical group containing a porphyrin ring containing iron, which is the point where oxygen links. Each hemoglobin contains four of these heme groups, and when it is fully saturated with oxygen, it can carry four oxygen molecules. Once the lifespan of hemoglobin is over, it is destroyed and undergoes a series of reactions, releasing iron. The iron is partially reabsorbed, partially attached to transferrin, partially stored as ferritin, and partially eliminated. Hemoglobin is continuously manufactured in the human body; This fact has been established for over a century. The primary driver for the production of erythrocytes and hemoglobin is a reduction in the amount of oxygen. Our body possesses oxygen sensors that trigger the production of hemoglobin in response to low levels of oxygen in the bloodstream. Erythrocytes have the crucial task of transporting oxygen to various parts of the body. To accomplish this, they require a specialized program, which is stimulated by these oxygen sensors. When red blood cells break down, the heme group, which is the remaining part of hemoglobin, is transformed into bilirubin. Bilirubin enters the liver and forms a part of the bile, which plays a crucial role in the digestion of fat. This highlights the significance of bilirubin in gastrointestinal digestion. Once bilirubin enters the intestine, it is transformed into stercobilin, which is excreted in the feces. Additionally, a part of it is transformed into urobilin in the kidneys and excreted in the urine. It’s important to note that exposure to sunlight plays a key role in the transformation of bilirubin into lumirubin, which is a luminescent form of bilirubin. This is particularly relevant in premature infants who may have developed moderate yellowish coloration In Vitro. Exposure to UV light helps to reduce the amount of total bilirubin in their system. Determining the level of bilirubin through skin contamination and facilitating the transformation of bilirubin to stercobilin can also aid in reducing the amount of bilirubin. NoS: It's important to note that exposure to UV light can convert bilirubin into a water-soluble molecule called lumirubin, which can be excreted by the kidneys. This process is called photoisomerization and can be used as a treatment for hyperbilirubinemia, including jaundice in premature infants. Relationship between low oxygen pressure and the number of RBCs: Paul Bert and Denis Jourdanet, two prominent French medical physiologists, were pioneers in establishing the relationship between low oxygen pressure in the atmosphere and the number of red blood cells in animals and humans. In their experiments, they exposed animals to high altitudes, where the atmospheric pressure and oxygen levels are low. After a few weeks, they observed a significant increase in the number of erythrocytes in response to this exposure. Adaptation to hypoxia: Athletes have long recognized the benefits of altitude training in preparing for competitive events. By living and training at high altitudes, where oxygen levels are low, they stimulate erythropoiesis, leading to an increase in red blood cell production and ultimately improving their oxygen-carrying capacity. This, in turn, can enhance endurance and performance. One example of a popular training destination for athletes is Sardinia, where elevations of 3,000 meters offer an ideal setting for altitude training. The low oxygen levels at high altitudes limit the intensity of training, making it more challenging for athletes to maintain their usual training regimen. However, by living at high altitudes and then descending to lower altitudes to train, athletes can still challenge themselves and reap the benefits of altitude training while minimizing the risk of overexertion. The concept of “living high, training low” has been a popular strategy in exercise physiology for many years. It is based on the principle that living at high altitudes stimulates erythropoiesis, while training at lower altitudes allows athletes to maintain their usual intensity and training regimen. This approach has been found to be effective in improving athletic performance and has been used by many elite athletes in preparation for major competitions. In the United States and England, a significant study was conducted on the physiological response to adaptation to low barometric pressure. The study was done on Spanish individuals in Colorado, which is a high-altitude place. The results showed that there was a progressive increase in hemoglobin and red blood cells in response to living at high altitudes for one month. This increase was due to the hormone erythropoietin (EPO), which is produced by the kidney. The key factor that stimulates the production of erythrocytes is the presence of EPO, which is regulated by the hypoxia-inducible factors (HIF). HIFs are a group of transcription regulators that stimulate genes to produce other products in response to hypoxia, discovered in recent decades by scientists which led them to win a Nobel prize. However, EPO is not entirely independent and is also under the influence of other factors from which HIFs are amongst the most important ones. While the kidneys are responsible for the production of EPO in adult life, the liver produces it in embryonic development and can reactivate its production in response to hypoxia or stimulation by drugs. It is essential to regulate the production of erythrocytes since an excess amount of hemoglobin and red blood cells can cause other problems. The two lines in the image, are the hematocrit on the red line and the hemoglobin on the blue line. When the body is exposed to hypoxia or a lack of oxygen, it is able to activate the production of erythropoietin (EPO), which in turn facilitates the absorption of iron. Together, these processes aid in the production of hemoglobin and red blood cells. One of the key regulators of this process is the hypoxia-inducible factor (HIF). The HIF1 protein, for instance, is able to stimulate thousands of target genes, among which are erythropoietin and vascular endothelial growth factor (VEGF). This relationship between hypoxia and the production of EPO and VEGF is not only important for understanding the body’s response to low oxygen levels but also has significant implications in the study of cancer and its treatment. These markers are now being investigated as potential targets for cancer therapies. Aside from their involvement in cancer treatment, these markers also play a role in the maintenance of muscle mass. There are a lot of ongoing researches into how to block the growth of tumors by inhibiting vascular and endothelial growth factors, which can reduce vascularization and therefore potentially slow the growth of tumors. Conversely, these factors can also be used to stimulate muscle growth. However, there is a need to distinguish between the potentially harmful effects of growth in cancerous tissue and the beneficial effects in healthy tissue. Increasing vascularization and EPO levels also result in increased oxygen transportation in the body. Other factors involved in this process include IGF-2, insulin, growth factors, inhibition of apoptosis, and metabolic adaptation towards glycolytic enzymes. All of these factors are related to HIF-1 and contribute to the body’s ability to adapt to hypoxia. In addition to the importance of the sensors that regulate the production of EPO and other factors involved in the body’s adaptation to hypoxia, it is also crucial to have sufficient levels of other constituents, such as iron and sub-vitamins, to support the manufacture of red blood cells. Without these necessary components, anemia can occur, which is a condition characterized by a reduction in hemoglobin content. Polycythemia: Conversely, an excess of red blood cells is known as polycythemia. There are two types of polycythemia: primary and secondary. Primary polycythemia (Polycythemia vera) is a tumor or tumor-like condition that stimulates excessive production from the bone marrow. In this case, the red cell count in the blood can exceed 11 million per cubic millimeter of blood, which is significantly higher than the normal range of 5-7 million. Secondary polycythemia:, on the other hand, occurs as a result of an external factor such as hypoxia, chronic obstructive pulmonary disease, or smoking. The increase in the number of red blood cells as a response to chronic hypoxia is not a pathological condition, but rather a natural adaptation to the environmental stressor of low oxygen. This adaptation is seen in populations that live at high altitudes, such as those living in Nepal or South America. In these populations, the average erythrocyte count can be as high as 49% to 50% hematocrit, indicating a significant increase in the number of red blood cells. Note that 4000 meters is the limit of normal living condition, which leads to chronic polycythemia, above 5000 meters life is not easy to sustain. This increase in red blood cells is beneficial for individuals living in high-altitude environments because it allows for increased oxygen-carrying capacity. This adaptation is also sought after by athletes who train or live at high altitudes to improve their performance. False polycythemia:, also known as relative polycythemia, is not caused by a true increase in the number of red blood cells. Instead, it is caused by a reduction in the fluid plasma, such as dehydration, massive diarrhea, cholera, or general infection. This condition results in thick and viscous blood, which reduces blood flow speed. In the case of false polycythemia, In this panel, the red polycythemia and proportional red cells have the same red bars, and what is changing is the limit of proportion. The polycythemia linked to adaptation is the one that is beneficial, whereas the secondary one is caused by an increase, not in the red cells, but in the fluid component, and it is more or less the same. Polycythemia caused by a tumor is another condition to consider. Blood Doping Blood doping is the practice used to enhance the capacity of transforming oxygen. You can do this schematically in three ways: By doing blood transfusion, which involves taking half a liter of blood and injecting it into the circulation of the person. In this case, you expand both the plasma and the cell. By giving erythropoietin or other hormones similar to erythropoietin, which has the same effect. By doing the hemotransfusion, which involves taking your blood, centrifuging it, storing it, and then injecting it in the peripheral vein mostly red cells before the competition. In this way, you can expand in the space of one day your hematocrit. The use of performance-enhancing drugs in sports, commonly known as doping, is considered illegal. However, during the 7th and 8th centuries, many athletes extensively used these drugs to boost their performance. Despite the potential benefits, doping can pose serious health risks to athletes. One of the major dangers of doping is the risk of infection. Athletes who use performance-enhancing drugs may become more susceptible to infections due to the effects of the drugs on their immune systems. Additionally, the use of needles for administering drugs increases the risk of bacterial and viral infections, such as hepatitis, if the injection and blood manipulation is not performed in a sterile environment. In normal circumstances, the proportion of cells in the blood is well-balanced, resulting in a low viscosity that allows for easy flow. However, artificially expanding the number of red blood cells upsets this balance, increasing the cellular component and viscosity of the blood. This can lead to slowed blood flow, which makes it harder for the heart to pump and increases the risk of thrombosis. If the hematocrit, is above 47-50%, the risk of thrombosis is significant. Recent news reports have revealed that some athletes are competing with hematocrit levels as high as 57-60%. Such levels can be dangerous, as they upset the balance of blood components, resulting in increased viscosity and a higher risk of health complications. Having a hematocrit level of ~60% is comparable to having lentil soup instead of blood. This increased viscosity can lead to a range of issues. In some cases, athletes have been known to sleep with a heart rate monitor set to 45 or even 40 beats per minute, risking the development of bradycardia, as the viscosity of the blood is high it can lead to other serious complications. NoS: Bradycardia is a condition where the heart rate slows down to an abnormal level. When the heart rate drops below a certain point, it can increase the risk of serious health problems such as thrombosis, infarction, or heart attack. If an athlete’s blood is already viscous and slow-moving due to artificially elevated red blood cell levels, the risk is even higher. To prevent such health complications, athletes may cycle to reach a heart rate of around 67 before going back to sleep. They may also use a tool on their arm that beeps when their heart rate drops below a certain level. This helps them to monitor their heart rate and prevent it from dropping too low. An increased hematocrit level can significantly increase the risk of ischemic events, such as abdominal infarctions. While it is uncommon for athletes to experience such events, cases have been reported that raise suspicion of doping.When an athlete who competes at a top level, such as a cross-country cyclist, is found to have an abdominal infarction, the probability of doping is high, with estimates suggesting that it may be as high as 99%. NoS: Abdominal infarctions occur when blood flow to the abdominal organs is blocked, leading to tissue damage and potential organ failure. In addition to the risks associated with doping, there are other factors that can impact blood circulation, including viscosity. Viscosity is not just important for athletes but also for people at risk of developing an embolism or thrombosis. Individuals who have problems with their lower limb valves, which are not working correctly, may experience blood stagnation, increasing their risk of developing vessel inflammation and embolism. This risk is especially high during long flights, where prolonged periods of sitting can lead to reduced muscle contraction, limiting blood flow. To combat this, individuals at risk are advised to stand up, move around, and contract their lower limb muscles to pump blood and avoid stagnation. This advice is particularly important during long-haul flights lasting ten hours or more. Anemia: We have factors controlling erythrocyte production, such as hypoxic-induced factors and erythropoietin. Anemia is a common medical condition that can be caused by various factors. Some anemias are very common, such as low-level anemia. Anemia can be due to various reasons: Deficiency of iron (iron-deficiency anemia): The most frequent one, vitamin B12, or folic acid. Vitamin B12 is often associated with gastrointestinal problems. Some factors in the gastrointestinal system facilitate absorption that might reflect as anemia. Aplastic anemia: caused by damage to the bone marrow, the organ that manufactures the red cells, can cause anemia. This can happen due to a tumor or toxic drugs. Acute anemia is caused by massive loss of blood due to an injury (hemorrhage) or inadequate production of erythrocytes due to damage to the kidney (renal anemia). Hemolytic anemia: Another situation is when there is a genetic predisposition by which the erythrocytes are more fragile, such as sickle cell disease, a well-known condition. Abnormalities of Hemoglobin Production: Anemia is associated with abnormalities in hemoglobin production. While there are hundreds of these conditions, they can be divided into two main categories based on the type of abnormality: Thalassemia: Was discovered in areas located near the Mediterranean coasts. The problem with thalassemia is that the structure of hemoglobin is normal, but there is not enough production. The second category is characterized by alterations in the structure of hemoglobin, as seen in sickle cell anemia or sickle cell disorders. In this type of situation, the hemoglobin S (Hb-S) is altered while the alpha chain remains normal. The beta chains have a minor alteration, a single substitution of the amino acid valine for glutamic acid, which results in the production of hemoglobin S responsible for sickle cell anemia. Sickle cell anemia is mostly inherited as a heterozygous trait, where people tend to have only one gene for the disease, and the normal electrophoretic response is that there is a person with a contaminated sickle cell trait. These individuals normally do not have significant issues, but they can experience fatigue when undergoing stress or high-intensity exercise. When the disease is fully  expressed, all the hemoglobin is altered, and the individual is homozygous for the disease. Interestingly, in some populations in Africa, up to 40% of the people carry a genetic trait that provides resistance to a common form of malaria. This has allowed the trait to be perpetuated over generations, as the resistance to malaria provided by the genes is beneficial. Normally, genes of this kind tend to disappear over time, but the maintenance of these genes in populations where malaria is prevalent has led to protection from the disease. Furthermore, the red blood cells in sickle cell anemia have a C-shaped, sickle-like appearance, which is a deviation from the typical biconcave shape. Although this shape makes the cell more resistant to pressure, it is more fragile and less efficient, which leads to a tendency to break down (hemolysis). Blood Types: As a doctor, it is crucial to understand the different blood types and their associated antigens to avoid any risks during transfusions. While there are several antigens present on the surface of red blood cells, the two main groups that are typically considered are the AB0 and RH groups. AB0 : The AB0 blood group system produces antigens that can also be found in the gastrointestinal system and can be induced by food, for instance, the baby receives by breastfeeding. Type A individuals have A antigens on their red blood cells and antibodies against B antigens in their plasma. This means that they can receive blood from either A or O types, but not from B or AB types. If they were to receive incompatible blood, it could trigger a dangerous reaction with symptoms such as fever, pain, headache, cardiovascular symptoms, and even death. Conversely, type B individuals have B antigens on their red blood cells and antibodies against A antigens in their plasma, making them unable to receive blood from A or AB types. Type AB individuals have both A and B antigens on their red blood cells and no antibodies in their plasma, so they can receive any blood type. Type O individuals have neither A nor B antigens on their red blood cells and have both anti-A and anti-B antibodies in their plasma, making them able to receive only O-type blood. To ensure safe transfusions, it is crucial to conduct a rapid test to determine a patient’s blood type and expose their blood to different antigens to check for agglutination. Without this step, patients could be at risk for dangerous reactions and potentially life-threatening situations. The lymphocytes will be agglutinated together, they will be broken down, and there will be a very dramatic, potentially dangerous situation with fever, pain, headache, cardiovascular symptoms, and even death. RH group: The Rh blood group system is a critical factor to consider in blood transfusions and pregnancies. The system was named after the Rhesus macaque monkey in which this particular blood type was first discovered by scientists. There are several antigens present in this system, including A, B, and D. However, the most significant is the D antigen. In situations where an Rh-negative person is exposed to Rh-positive blood, they produce anti-Rh antibodies. This situation becomes particularly important in the case of erythroblastosis fetalis, which occurs during pregnancy. In this condition, a mother who is Rh-negative carries a fetus that is Rh-positive. As a result, the mother’s body will develop antibodies against the RH factor, but the first baby will not be affected. The problem arises in the second pregnancy if the baby is Rh-positive because the baby will be exposed to the antibodies against the Rh factor from the previous pregnancy, which can lead to agglutination problems. Hence, it is crucial to pay attention to the Rh factor when providing transfusions and during pregnancy. Even mixing up blood in a small region of the placenta infusion can lead to this type of response, which can be potentially harmful. Therefore, understanding and monitoring the Rh group is crucial in managing blood transfusions and ensuring the safety of the fetus during pregnancy. The detection of Rh factor incompatibilities is possible through various diagnostic methods, including the use of blood tests that check for Rh antibodies.