Blood doping

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Blood doping is a form of doping in which the number of red blood cells in the bloodstream is boosted in order to enhance athletic performance. Because such blood cells carry oxygen from the lungs to the muscles, a higher concentration in the blood can improve an athlete's aerobic capacity (VO2 max) and endurance. [1] Blood doping can be achieved by making the body produce more red blood cells itself using drugs, giving blood transfusions either from another person or back to the same individual, or by using blood substitutes.

Contents

Many methods of blood doping are illegal, particularly in professional sports where it is considered to give an artificial advantage to the competitor. Anti-doping agencies use tests to try to identify individuals who have been blood doping using a number of methods, typically by analyzing blood samples from the competitors.

History

Fig. 1 Achieving maximum aerobic capacity Achieving Maximum Aerobic Capacity.png
Fig. 1 Achieving maximum aerobic capacity

Blood doping is defined as the use of illicit products (e.g. erythropoietin (EPO), darbepoetin-alfa, hypoxia-inducible factor (HIF) stabilizers) and methods (e.g. increase aerobic capacity by maximizing the uptake of O2) in order to enhance the O2 transport of the body to the muscles. [2]

The body undergoes aerobic respiration in order to provide sufficient delivery of O2 to the exercising skeletal muscles and the main determining factors are shown in figure 1. The rate of maximum O2 uptake (O2max) depends on cardiac output, O2 extraction and hemoglobin mass. The cardiac output of an athlete is difficult to manipulate during competitions and the distribution of cardiac output is at the maximum rate (i.e. 80%) during competitions. In addition, the O2 extraction is approximately 90% at maximal exercise. Therefore, the only method to enhance the physical performance left is to increase the O2 content in the artery by enhancing the hemoglobin mass. In other words, hemoglobin concentration and blood volume contribute to hemoglobin mass. [2]

Methods

Drug treatments

Many forms of blood doping stem from the misuse of pharmaceuticals. These drug treatments have been created for clinical use to increase the oxygen delivery when the human body is not able to do so naturally.

Erythropoietin

Erythropoietin (EPO) is a glycoprotein hormone produced by the interstitial fibroblasts in the kidney that signal for erythropoiesis in bone marrow. The increased activity of a hemocytoblast (RBC stem cell) allows the blood to have a greater carrying capacity for oxygen. EPO was first developed to counteract the effects of chemotherapy and radiation therapy for cancer patients. [3] EPO also stimulates increased wound healing. [4] Because of its physiological side effects, particularly increased hematocrit, EPO has become a drug with abuse potential by professional and amateur cyclists.

Hypoxia-inducible factor (HIF) stabilizer

Hypoxia-inducible factor stabilizer (HIF stabilizer) is a pharmaceutical used to treat chronic kidney disease. Like most transcription factors, the HIF transcription factor is responsible for the expression of a protein. The HIF stabilizer activates the activity of EPO due to anemia-induced hypoxia, metabolic stress, and vasculogenesis (the creation of new blood vessels). [5] HIF stabilizers as used by cyclists in combination with cobalt chloride/desferrioxamine stimulate and de-regulate the natural production of erythropoietin hormone. [6] At physiologically low PaO2 around 40 mmHg, EPO is released from the kidneys to increase hemoglobin transportation. [7] The combination of drugs consistently releases EPO due to increased transcription at the cellular level. The effect wears off when the HIF stabilizers, cobalt chloride/desferrioxamine is excreted and/or decayed by the body.

Myo-inositol trispyrophosphate (ITPP)

Myo-inositol trispyrophosphate (ITPP), also known as compound number OXY111A, is an allosteric effector of hemoglobin which causes a rightward shift in the oxygen–hemoglobin dissociation curve, increasing the amount of oxygen released from red blood cells into surrounding tissue during each passage through the cardiovascular system. [8] ITPP has been a subject of anti-doping research in both humans [9] and racehorses. [10]

Blood transfusion

Blood transfusions can be traditionally classified as autologous, where the blood donor and transfusion recipient are the same, or as allogeneic/homologous, where the blood is transfused into someone other than the donor. Blood transfusion begins by the withdrawal of 1 to 4 units of blood (1 unit = 450 mL of blood) several weeks before competition. The blood is centrifuged, the plasma components are immediately reinfused, and the corpuscular elements, principally red blood cells (RBCs), are stored refrigerated at 4 °C or frozen at −80 °C. [11] As blood stored by refrigeration displays a steady decline in the number of RBCs, a substantial percentage, up to 40%, of the stored RBCs may not be viable. [12] The freezing process, conversely, limits the aging of the cells, allowing the storage of the blood for up to 10 years with a 10% to 15% loss of RBCs. [13] Stored RBCs are then reinfused, usually 1 to 7 days before a high-endurance event. As a significant amount of iron is removed by each autologous transfusion, an adequate time for recovery of not less than 3 days from the last donation, and appropriate iron supplements, are usually required for patients undergoing autologous donations. Nearly 50% of autologous donations are not used by the donor and are discarded, as current standards do not allow transfusion of these units to another patient for safety reasons.[ citation needed ]

Blood substitutes

Biochemical and biotechnological development has allowed novel approaches to this issue, in the form of engineered O2 carriers, widely known as "blood substitutes". The blood substitutes currently available are chiefly polymerized haemoglobin solutions or haemoglobin-based oxygen carriers (HBOCs) and perfluorocarbons (PFCs). [14] [15]

Hemoglobin-based oxygen carriers (HBOCs)

Hemoglobin-based oxygen carriers are intra/ inter-molecularly engineered human or animal hemoglobins, only optimized for oxygen delivery and longer intravascular circulation. The presence of 2,3-diphosphoglycerate within erythrocytes maintains the normal affinity of hemoglobin for oxygen. HBOCs do not contain erythrocytes and lose this interaction, thus, unmodified human HBOC solutions have a very high oxygen affinity which compromises their function. Chemical methods developed to overcome this problem have resulted in carriers that effectively release oxygen at the physiological pO2 of peripheral tissues. [16]

A common feature of all HBOCs is their resistance to dissociate when dissolved in media, which contrasts hemoglobin of natural dissociation under non-physiological conditions. HBOCs may hypothetically supply greater benefits to athletes than those provided by the equivalent hemoglobin in traditional RBC infusion. Recent developments have shown that HBOCs are not only simple RBC substitutes, but highly effective O2 donors in terms of tissue oxygenation. Additional effects include increases in blood serum iron, ferritin, and Epo; [17] up to 20% increased diffusion of oxygen and improved exercise capacity; [18] increased CO2 production; and lower lactic acid generation in anaerobic activity. [19] HBOCs have been shown in trials to be extremely dangerous in humans. Because HBOCs increase both the risk of death and risk of myocardial infarction clinical trials were ended. They are not commercially available in the US or Europe and there is no approved use for them. [20]

Perfluorocarbons (PFCs)

PFCs, also known as fluorocarbons, are inert, water-insoluble, synthetic compounds, consisting primarily of carbon and fluorine atoms bonded together in strong C–F bonds. PFCs are substantially clear and colorless liquid emulsions that are heterogeneous in molecular weight, surface area, electronic charge, and viscosity; their high content of electron-dense fluorine atoms results in little intramolecular interaction and low surface tension, making such substances excellent solvents for gases, especially oxygen and carbon dioxide. [14] Some of these molecules can dissolve 100 times more oxygen than plasma. PFCs are naturally hydrophobic and need to be emulsified to be injected intravenously. Since PFCs dissolve rather than bind oxygen, their capacity to serve as a blood substitute is determined principally by the pO2 gradients in the lung and at the target tissue. Therefore, their oxygen transport properties differ substantially from those of whole blood and, especially, from those of RBCs. [21] At a conventional ambient pO2 of 135 mmHg, the oxygen content of 900 mL/L perfluorocarbon is less than 50 mL/L, whereas an optimal oxygen content of 160 mL/L, which is still lower than that of whole blood in normal conditions, can be achieved only by a pO2 greater than 500 mmHg. In practice, at a conventional alveolar pO2 of 135 mmHg, PFCs will not be able to provide sufficient oxygenation to peripheral tissues. [21] [22]

Due to their small size, PFCs are able to permeate circulation where erythrocytes may not flow. In tiny capillaries, PFCs produce the greatest benefit, as they increase local oxygen delivery much more efficiently than would be expected from the increase in oxygen content in larger arteries. [23] In addition, as gases are in the dissolved state within PFCs, it pO2 promotes efficient oxygen delivery to peripheral tissues. Since the mid-1980s, improvements in both oxygen capacity and emulsion properties of PFCs have led to the development of second-generation PFC-based oxygen carriers; two PFC products are currently being tested in phase III clinical trials. [24]

Cobalt chloride administration

Transition metal complexes are widely known to play important roles in erythropoiesis; as such, inorganic supplementation is proving to be an emerging technique in blood doping. Particularly of note is the cobalt complex, cobalamin (Vitamin B12) commonly used as a dietary supplement. Cobalamin is an important complex used in the manufacture of red blood cells and thus was of interest for potential use in blood doping. Experimental evidence, however, has shown that cobalamin has no effect on erythropoiesis in the absence of a red blood cell/oxygen deficiency. [25] These results seem to confirm much of what is already known about the functioning of cobalamin. [25] The signaling pathway that induces erythropoietin secretion and subsequently red blood cell manufacture using cobalamin is O2 dependent. Erythropoietin is only secreted in the kidneys when there is an O2 deficiency, as such, RBC manufacture is independent of the amount of cobalamin administered when there is no O2 deficiency. Accordingly, cobalamin is of little to no value in blood doping.

More potent for use in blood doping is Co2+ (administered as Cobalt(II) chloride, CoCl2). Cobalt chloride has been known to be useful in treating anemic patients. [26] [27] Recent experimental evidence has proved the efficacy of cobalt chloride in blood doping. [26] Studies into the action of this species have shown that Co2+ induces hypoxia like responses, the most relevant response being erythropoiesis. Co2+ induces this response by binding to the N-terminus (loop helix loop domain) of the Hypoxia inducing transcription factors HIF-1α and HIF-2α, and thus stabilizes these protein complexes. [27] [28] Under normal O2 conditions, HIFs are destabilized as proline and asparagine residues are hydroxylated by HIF-α hydroxylases, these unstable HIFs are subsequently degraded following a ubiquitin-proteosome pathway, as such, they cannot then bind and activate transcription of genes encoding Erythropoietin (EPO). [27] [28] With Co2+ stabilization, degradation is prevented and genes encoding EPO can then be activated. The mechanism for this Co2+ N terminus stabilization is not yet fully understood. In addition to N-terminus binding, it has also been hypothesized that replacement of Fe2+ by Co2+ in the hydroxylase active site could be a contributing factor to the stabilizing action of Co2+. [27] It is understood however, is that Co2+ binding permits Ubiquitin binding but prevents proteosomal degradation. [28]

Detection of blood doping

Detection for homologous blood doping

In 2004, a test for detection allogeneic/homologous blood transfusion doping was implemented. Flow cytometry is the method of choice. By examining markers on the surface of blood cells, the method can determine whether blood from more than one person is present in an athlete's circulation. The test utilizes 12 antisera directed against the blood group antigens, obtained from donor plasma. The antigens are labeled with secondary antibodies, which are conjugated with phycoerythrin to label IgG or IgM-coated RBCs and enhance the detection by flow cytometry [2] [29] The flow cytometry is able to detect minor variance in blood group antigens. The assessment was able to distinguish the blood of subjects who had earlier received at least one unit of allogeneic blood. [29] This technique is able to detect small (<5%) populations of cells that are antigenically distinct from an individual's own RBCs. [29]

Detection for autologous blood doping

Autologous blood doping detection is done indirectly via CO rebreathing technique to measure the nonphysiologic increases in Hb mass. The principle of CO rebreathing method used currently requires an O2-CO gas mixture inhalation for about 10-15mins. [30] By measuring the difference in carboxyhemoglobin concentration (HbCO) before and after rebreathing, the volume of CO and the binding capacity of Hb for CO ( 1.39ml g-1), total Hb mass can be calculated. [30] This detection method is problematic for an athlete as it is not desirable to breathe in CO shortly before a competition, which may potentially affect their performances.

Detection of blood hemoglobin-based oxygen carrier

Detection method for hemoglobin-based oxygen carriers (i.e. Oxyglobulin) is done in four separate steps. Step one involves the elimination of abundance proteins in the blood samples by immunodepletion (i.e. Proteo Prep 20 plasma immunodepletion kit). [31] This process ensures that other proteins (i.e. albumin and immunoglobulin) do not interfere with capillary electrophoresis (CE) separation by changing the ionization. Second step, CE separation is done under certain condition, in this case background electrolyte consisting of ammonium formate (75mM at pH 9.5) in order to provide sufficient resolution between HBOC and Hb. [31] Third step, UV/Vis detection was performed at 415 nm to selectively detect HBOC and HB. Fourth step, time-of-flight or mass spectrometer allowed increased accuracy in selectivity between hemoproteins and other proteins and definite determination of HBOC uptake. [32] The detection limits for CE-UV/Vis at 415 nm and CE-ESI-TOF/MS results to be 0.20 and 0.45g/dL for plasma respectively. [31]

Detection of cobalt concentration by utilizing the biokinetic model

Cobalt can be detected by laboratory blood analysis if the intake amount is greater than 400 μg per day. As the whole blood concentration is greater than 1 μg/L and the urinary concentration is greater than 10 μg/L after at least 10 days of administration. The dose, which increases the red blood cell production to approximately 16%-21%, is about 68 mg Co per day for at least 10 days of oral administration. The predicted whole blood concentration of cobalt exceeds 200 μg/L two hours after the last intake and the average urine concentrations of cobalt exceed 3000 μg/L within 24 hours of intake. A study was carried out where 23 subjects were to take 900 μg per day in the form of CoCl2 for 10 days. The model predictions were then compared to the study. The result shows that the model prediction for blood and urine are between the median concentration of the male and female groups, which indicate the model predictions sufficiently represent the test population as a whole. [33]

Military use

As early as 1947, military research scientists were studying ways to increase fighter pilots' tolerance for hypoxia at high altitude. In one such study, red blood cells were transfused into ten males at the US Naval Research facility, resulting in increased oxygen capacity. [34]

In 1993, U.S. Special Forces commanders at Fort Bragg started experimenting with blood doping, also known as blood loading. Special Forces operators would provide two units of whole blood, from which red blood cells would be extracted, concentrated, and stored under cold temperatures. 24 hours before a mission or battle, a small amount of red blood cells would be infused back into the soldier. Military scientists believe that the procedure increases the soldiers' endurance and alertness because of the increase in the blood's capability to carry oxygen.[ citation needed ]

In 1998, the Australian Defence Forces approved this technique for the Special Air Service Regiment. Senior nutritionist at the Australian Defence Science and Technology Organisation Chris Forbes-Ewan is quoted as saying that, unlike in sport, "all's fair in love and war". "What we are trying to gain is an advantage over any potential adversary", Forbes-Ewan said. [35] In this study, over 50 performance-enhancing drugs and techniques were rejected. The six that were approved are caffeine, ephedrine, energy drinks, modafinil, creatine, and blood-loading. [36]

Notable blood doping cases

Kaarlo Maaninka (208), the subject of the first known blood doping case, in the 1980 Summer Olympics 5,000 m race. Olympic Games 1980 - 5000 m race.jpg
Kaarlo Maaninka (208), the subject of the first known blood doping case, in the 1980 Summer Olympics 5,000 m race.

Blood doping started in the late 1960s [37] but was not outlawed until 1986. While it was still legal, it was commonly used by middle and long-distance runners. The first known case of blood doping occurred at the 1980 Summer Olympics in Moscow as Kaarlo Maaninka was transfused with two pints of blood before winning medals in the 5 and 10 kilometer track races, though this was not against the rules at the time. [38] Cyclist Joop Zoetemelk admitted to receiving blood transfusions during the 1976 Tour de France, where he finished second, although he claimed that these were intended to treat his anaemia rather than enhance his performance. [39] [40] In the same year cyclist Francesco Moser used blood transfusions to prepare for his successful attempt to break the hour record. [39] "Blood doping" was banned by the International Olympic Committee (IOC) in 1985, though no test existed for it at the time. [40]

Cyclist Niklas Axelsson tested positive for EPO in 2000.

Cyclist Tyler Hamilton failed a fluorescent-activated cell sorting test for detecting homologous blood transfusions during the 2004 Olympics. He was allowed to keep his gold medal because the processing of his sample precluded conducting a second, confirmatory test. He appealed a second positive test for homologous transfusion from the 2004 Vuelta a España to the International Court of Arbitration for Sport but his appeal was denied. Hamilton's lawyers proposed Hamilton may be a genetic chimera or have had a 'vanishing twin' to explain the presence of red blood cells from more than one person. While theoretically possible, these explanations were ruled to be of "negligible probability". [41]

Tour de France rider Alexander Vinokourov, of the Astana Team, tested positive for two different blood cell populations and thus for homologous transfusion, according to various news reports on July 24, 2007. Vinokourov was tested after his victory in the 13th stage time trial of the Tour on July 21, 2007. A doping test is not considered to be positive until a second sample is tested to confirm the first. Vinokourov's B sample has now tested positive, and he faces a possible suspension of two years and a fine equal to one year's salary. [42] He also tested positive after stage 15. [43] [44]

Vinokourov's teammate Andrej Kashechkin also tested positive for homologous blood doping [45] on August 1, 2007, just a few days after the conclusion of the 2007 Tour de France (a race that had been dominated by doping scandals). His team withdrew after the revelation that Vinokourov had doped.

According to Russian investigators, 19-year-old New York Rangers prospect and Russian hockey player Alexei Cherepanov was engaged in blood doping for several months before he died on October 13, 2008, after collapsing on the bench during a game in Russia. He also had myocarditis. [46]

The German speed skater and five-fold Olympic gold medalist Claudia Pechstein was banned for two years in 2009 for alleged blood doping, based on irregular levels of reticulocytes in her blood and the assumption that these levels were always highest during competitions. Her mean reticulocyte count over the ten years from 2000 to 2009 was 2.1% during top events like Olympic Games and during world championships. At world cup races the mean reticulocyte was 1.9% and during training phases 2.0%. [47] The Court of Arbitration for Sport confirmed the ban in November 2009 after her haematologist excluded the possibility of a blood disease. [48]

In September 2010, the Swiss Federal Supreme Court rejected the athlete's appeal, stating that Pechstein's inherited blood anomaly had been known before. [49]

On May 20, 2011, Tyler Hamilton turned in his 2004 Olympic Gold Medal to the U.S. Anti-Doping Agency [50] after admitting to doping in a 60 Minutes interview.

On August 23, 2012, Lance Armstrong was stripped of his seven Tour de France titles and banned for life by cycling's governing body following a report from the U.S. Anti-Doping Agency that accused him of leading a doping program during his cycling career. He later admitted to using banned substances including blood doping with transfusions and EPO in an interview with Oprah Winfrey on January 17, 2013. [51]

In June 2014, UFC fighter Chael Sonnen tested positive for EPO. [52] One month later, another UFC fighter, Ali Bagautinov also tested positive for EPO. [53]

In February 2018, Bahraini steeplechase and 3000 m steeplechase world record holder Ruth Jebet tested positive for EPO and on 4 March, she was suspended for four years. [54] [ failed verification ]

Adverse effects

The simple act of increasing the number of red blood cells in blood may be associated with hyperviscosity syndrome which is characterized by increased blood viscosity and decreased cardiac output and blood flow velocity which results in the reduction of peripheral oxygen delivery. [55] For instance, an overdose of EPO can thicken blood into a highly viscous and artery-clogging sludge. This increases the chances of heart attack, stroke, phlebitis, and pulmonary embolism, which has been seen in cases where there is too much blood reintroduced into the blood stream. Because blood doping increases the volume of red blood cells, it effectively introduces a condition called polycythemia, a blood disorder that has known adverse outcomes such as heart attacks or strokes.

Blood contamination during preparation or storage is another issue. Contamination was seen in 1 in every 500,000 transfusions of red blood cells in 2002. [56] Blood contamination can lead to sepsis or an infection that affects the whole body.

Certain medications used to increase red blood cells can reduce liver function and lead to liver failure, pituitary problems, and increases in cholesterol levels. [57]

See also

Related Research Articles

<span class="mw-page-title-main">Hypoxia (medicine)</span> Medical condition of lack of oxygen in the tissues

Hypoxia is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Hypoxia may be classified as either generalized, affecting the whole body, or local, affecting a region of the body. Although hypoxia is often a pathological condition, variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise.

<span class="mw-page-title-main">Hemoglobin</span> Metalloprotein that binds with oxygen

Hemoglobin is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin in the blood carries oxygen from the respiratory organs to the other tissues of the body, where it releases the oxygen to enable aerobic respiration which powers an animal's metabolism. A healthy human has 12 to 20 grams of hemoglobin in every 100 mL of blood. Hemoglobin is a metalloprotein, a chromoprotein, and globulin.

<span class="mw-page-title-main">Red blood cell</span> Oxygen-delivering blood cell and the most common type of blood cell

Red blood cells (RBCs), referred to as erythrocytes in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cell and the vertebrate's principal means of delivering oxygen to the body tissues—via blood flow through the circulatory system. Erythrocytes take up oxygen in the lungs, or in fish the gills, and release it into tissues while squeezing through the body's capillaries.

<span class="mw-page-title-main">Anemia</span> Reduced ability of blood to carry oxygen

Anemia is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin available for oxygen transport, or abnormalities in hemoglobin that impair its function. The name is derived from Ancient Greek ἀν- (an-) 'not' and αἷμα (haima) 'blood'.

<span class="mw-page-title-main">Erythropoietin</span> Protein that stimulates red blood cell production

Erythropoietin, also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bone marrow. Low levels of EPO are constantly secreted in sufficient quantities to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO include any anemia, and hypoxemia due to chronic lung disease and mouth disease.

<span class="mw-page-title-main">Methemoglobinemia</span> Condition of elevated methemoglobin in the blood

Methemoglobinemia, or methaemoglobinaemia, is a condition of elevated methemoglobin in the blood. Symptoms may include headache, dizziness, shortness of breath, nausea, poor muscle coordination, and blue-colored skin (cyanosis). Complications may include seizures and heart arrhythmias.

A blood substitute is a substance used to mimic and fulfill some functions of biological blood. It aims to provide an alternative to blood transfusion, which is transferring blood or blood-based products from one person into another. Thus far, there are no well-accepted oxygen-carrying blood substitutes, which is the typical objective of a red blood cell transfusion; however, there are widely available non-blood volume expanders for cases where only volume restoration is required. These are helping doctors and surgeons avoid the risks of disease transmission and immune suppression, address the chronic blood donor shortage, and address the concerns of Jehovah's Witnesses and others who have religious objections to receiving transfused blood.

<span class="mw-page-title-main">Hematocrit</span> Volume percentage of red blood cells in blood

The hematocrit, also known by several other names, is the volume percentage (vol%) of red blood cells (RBCs) in blood, measured as part of a blood test. The measurement depends on the number and size of red blood cells. It is normally 40.7–50.3% for males and 36.1–44.3% for females. It is a part of a person's complete blood count results, along with hemoglobin concentration, white blood cell count and platelet count.

<span class="mw-page-title-main">Polycythemia</span> Laboratory diagnosis of high hemoglobin content in blood

Polycythemia is a laboratory finding in which the hematocrit and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called erythrocytosis, and there is significant overlap in the two findings, but the terms are not the same: polycythemia describes any increase in hematocrit and/or hemoglobin, while erythrocytosis describes an increase specifically in the number of red blood cells in the blood.

<span class="mw-page-title-main">Erythropoiesis</span> Process which produces red blood cells

Erythropoiesis is the process which produces red blood cells (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell.

<span class="mw-page-title-main">Altitude training</span> Athletic training at high elevations

Altitude training is the practice by some endurance athletes of training for several weeks at high altitude, preferably over 2,400 metres (8,000 ft) above sea level, though more commonly at intermediate altitudes due to the shortage of suitable high-altitude locations. At intermediate altitudes, the air still contains approximately 20.9% oxygen, but the barometric pressure and thus the partial pressure of oxygen is reduced.

Alpha-thalassemia is a form of thalassemia involving the genes HBA1 and HBA2. Thalassemias are a group of inherited blood conditions which result in the impaired production of hemoglobin, the molecule that carries oxygen in the blood. Normal hemoglobin consists of two alpha chains and two beta chains; in alpha-thalassemia, there is a quantitative decrease in the amount of alpha chains, resulting in fewer normal hemoglobin molecules. Furthermore, alpha-thalassemia leads to the production of unstable beta globin molecules which cause increased red blood cell destruction. The degree of impairment is based on which clinical phenotype is present.

<span class="mw-page-title-main">2,3-Bisphosphoglyceric acid</span> Chemical compound

2,3-Bisphosphoglyceric acid (2,3-BPG), also known as 2,3-diphosphoglyceric acid (2,3-DPG), is a three-carbon isomer of the glycolytic intermediate 1,3-bisphosphoglyceric acid (1,3-BPG).

Anemia of prematurity (AOP) refers to a form of anemia affecting preterm infants with decreased hematocrit. AOP is a normochromic, normocytic hypoproliferative anemia. The primary mechanism of AOP is a decrease in erythropoietin (EPO), a red blood cell growth factor.

<span class="mw-page-title-main">Erythropoiesis-stimulating agent</span> Medicine that stimulates red blood cell production

Erythropoiesis-stimulating agents (ESA) are medications which stimulate the bone marrow to make red blood cells. They are used to treat anemia due to end stage kidney disease, chemotherapy, major surgery, or certain treatments in HIV/AIDS. In these situations they decrease the need for blood transfusions. The different agents are more or less equivalent. They are given by injection.

<span class="mw-page-title-main">Oxygen saturation (medicine)</span> Medical measurement

Oxygen saturation is the fraction of oxygen-saturated haemoglobin relative to total haemoglobin in the blood. The human body requires and regulates a very precise and specific balance of oxygen in the blood. Normal arterial blood oxygen saturation levels in humans are 96–100 percent. If the level is below 90 percent, it is considered low and called hypoxemia. Arterial blood oxygen levels below 80 percent may compromise organ function, such as the brain and heart, and should be promptly addressed. Continued low oxygen levels may lead to respiratory or cardiac arrest. Oxygen therapy may be used to assist in raising blood oxygen levels. Oxygenation occurs when oxygen molecules enter the tissues of the body. For example, blood is oxygenated in the lungs, where oxygen molecules travel from the air and into the blood. Oxygenation is commonly used to refer to medical oxygen saturation.

Fish are exposed to large oxygen fluctuations in their aquatic environment since the inherent properties of water can result in marked spatial and temporal differences in the concentration of oxygen. Fish respond to hypoxia with varied behavioral, physiological, and cellular responses to maintain homeostasis and organism function in an oxygen-depleted environment. The biggest challenge fish face when exposed to low oxygen conditions is maintaining metabolic energy balance, as 95% of the oxygen consumed by fish is used for ATP production releasing the chemical energy of nutrients through the mitochondrial electron transport chain. Therefore, hypoxia survival requires a coordinated response to secure more oxygen from the depleted environment and counteract the metabolic consequences of decreased ATP production at the mitochondria.

<span class="mw-page-title-main">Peter J. Ratcliffe</span> British nephrologist (born 1954)

Sir Peter John Ratcliffe, FRS, FMedSci is a British physician-scientist who is trained as a nephrologist. He was a practising clinician at the John Radcliffe Hospital, Oxford and Nuffield Professor of Clinical Medicine and head of the Nuffield Department of Clinical Medicine at the University of Oxford from 2004 to 2016. He has been a Fellow of Magdalen College, Oxford since 2004. In 2016 he became Clinical Research Director at the Francis Crick Institute, retaining a position at Oxford as a member of the Ludwig Institute of Cancer Research and director of the Target Discovery Institute, University of Oxford.

<span class="mw-page-title-main">Gregg L. Semenza</span> American physician (born 1956)

Gregg Leonard Semenza is an American pediatrician and Professor of Genetic Medicine at the Johns Hopkins School of Medicine. He serves as the director of the vascular program at the Institute for Cell Engineering. He is a 2016 recipient of the Albert Lasker Award for Basic Medical Research. He is known for his discovery of HIF-1, which allows cancer cells to adapt to oxygen-poor environments. He shared the 2019 Nobel Prize in Physiology or Medicine for "discoveries of how cells sense and adapt to oxygen availability" with William Kaelin Jr. and Peter J. Ratcliffe. Semenza has had thirteen research papers retracted due to falsified data.

<span class="mw-page-title-main">Molidustat</span> Chemical compound

Molidustat is a drug which acts as an HIF prolyl-hydroxylase inhibitor and thereby increases endogenous production of erythropoietin, which stimulates production of hemoglobin and red blood cells. It is in Phase III clinical trials for the treatment of anemia caused by chronic kidney disease. Due to its potential applications in athletic doping, it has also been incorporated into screens for performance-enhancing drugs.

References

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