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ERYTHOCYTE

Erythrocytes, also known as red blood cells, are the most abundant and the smallest (at least in mammals) blood cells. Their main function is transporting O2 and CO2 between the lungs and the rest of the body. In humans, the number of erythrocytes is lower in females, around 4.6 million/mm3, than in males, about 5 million/mm3. The number is higher in humans living in places with lower amount oxygen, such as at high altitude regions. As fresh blood, erythrocytes show a red-orange color, that is why the name erythrocyte. The color is consequence of the high content in hemoglobin, protein that is also responsible for the red color of the blood. Erythrocytes rarely leave the blood stream.

1. Morphology

In vertebrates, the shape of erythrocytes is variable. They are biconcave in mammals, with a depressed central region because they have no nucleus (Figures 1 and 2), about 8 µm in diameter and 2 µm thick in the thicker part. Erythrocytes have no organelles, and they lack an inner cytoskeleton (in those regions not close to the plasma membrane). They contain about 450 mg/ml of hemoglobin. Hemoglobin is a globular protein consisting of 4 polypeptide chains, each having an heme group and an iron atom in the center of the heme group. The iron is able to be combined with O2 and with CO2. The biconcave morphology of erythrocytes provides a high surface/volume ratio, increasing the efficiency of the O2 and CO2 diffusion through the plasma membrane. In non mammal vertebrates, erythrocytes have an ellipsoid shape and biconvex because they have a nucleus with condense chromatin (Figure 3).

Erythrocytes
Figura 1. Mammal erythrocytes in blood vessels.
Erythrocytes
Figure 2. Electron microscopy image of mammal blood vessels with erythrocytes. The biconcave morphology of erythrocytes can be observed in the image on the left.
Erythrocytes
Figure 3. Most mammal species have erythrocytes without nucleus (image on the left is from human blood). Other vertebrates like fish, reptiles, and birds have erythrocytes containing a nucleus. The image in the middle is from rainbow trout, and the image on the right is from lamprey, both are fish species.

The biconcave morphology of erythrocytes is stable in normal conditions, but may also be remarkably twisted when erythrocytes go through small capillaries. Capillaries may be 3 µm in diameter, a size smaller than an erythrocyte. Furthermore, erythrocytes have to withstand strong mechanical forces in large arteries. Nonetheless, erythrocytes are really stable cells because of their cell features. The plasma membrane of erythrocytes show a cholesterol proportion above 30 %, higher than in an average cell, that makes plasma membrane less fluid, more stiff and more hydrophobe (less permeable). Therefore, the plasma membrane is more resistant and well-sealed, making breakages more difficult and preventing the lost of inner content. Furthermore, the plasma membrane is anchored to a cytoskeleton scaffold of about 100 nm thick that cover the inner surface of the inner monolayer (cytosolic). This network makes the plasma membrane resistant to changes in cell morphology.

The cytoskeleton beneath the plasma membrane is made up of transmembrane glycoproteins like glycophorins (there are five types), and band 3 proteins, as well as an associated network of spectrin, ankyrin and actin (Figure 4). Spectrin consists of two subunits, alpha and beta, that intertwine between each other to form alpha helix filaments. These filaments are anchored to glycophorins and band 3 transmembrane proteins through intermediary proteins.

Cytoskeleton
Figure 4. Molecular organization of the cytoskeleton scaffold beneath the erythrocyte plasma membrane (adapted from Modificado de Lux 2016).

The extracellular domains of glycophorin A are glycosylated and determine the blood type. There are more than 35 blood types, most of them are very rare. For blood transfusions, only ABO and Rh antigens are considered. The ABO group consists of two antigens: A and B, whereas O blood type lacks both. Rh antigen can be present or not, so there are Rh+ and Rh-, respectively. Band transmembrane proteins are transporters. Ban 3 is an exchange transporter of carbonate/chloride, and Band 4 and 5 are glucose transporters.

Animal species show a variety erythrocyte diameters. In amphibians is about 50 µm, whereas in mammals is about 10 µm. In mammals, the diameter of capillaries is sometimes smaller than 10 µm so that erythrocytes have to fold to go through the narrowest vessels. This would be very difficult for a nucleated erythrocyte, and it is thought that the lost of the nucleus is an evolutionary advantage that increases the flux stream of blood through smaller blood vessels and decreases the probability of having the thrombosis (plugged up). It may be thought that lacking a nucleus leaves more space for hemoglobin, but there are other strategies to increase the intracellular amount of hemoglobin. For example, in birds, there is hemoglobin inside the nucleus.

2. Origin and distribution

In adult mammals, erythrocytes are formed in the bone marrow from precursor cells known as colony forming units-erythroid (CFU-E). In fetuses, the production of erythrocytes is done in the spleen because there is no bone yet, and therefore no bone marrow.

Erythropoiesis is the differentiation process of CFU-E cells to erythroblasts (Figure 5). CFU-E cells first differentiate into proerythroblasts , and then into erythroblasts, and finally into mature erythrocytes. During the differentiation process there are changes in the shape and cell size (Figure 4), hemoglobin content and composition, plasma membrane structure and function, nuclear variations, and other cell trasnformations. In mammals, the nucleus, Golgi apparatus, mitochondria, and centrioles are lost. Chromatin is condensed, the nucleus reduces its volume to 1/10 of the initial size and is finally expelled from the cell. Although the nucleus is condensed in all vertebrate species, it is expelled only in mammals. During the maturation, there are cell features characteristic of inter-mitotic periods. During differentiation, hemoglobin related genes are over expressed, as well as those involved in plasma membrane and cytoskeleton behavior.

Erythrocyte differentiation
Figure 5. Differentiation process of proerythroblasts into erythrocytes in mammals. (Adapated from Ji et al., 2011)

Erythropoietin is the main cytokine involved in the differentiation of erythrocytes. In mammals, it is released by the kidneys after induction by low levels of oxygen in the blood. Eyrhtropoietin is recognized by CFU-E cell receptors and has two-fold functions: preventing apoptosis and inducing proliferation and maturation toward proerythroblasts. Each CFU-E cell gives rise to about 30 to 40 mature erythrocytes.

Erythrocytes enter the blood stream as differentiated cells, and the average life is 120-140 days in humans (more than 5 million erythrocytes die every second). In turtles, the average life of erythrocytes is 10-11 months, whereas in mice is 40 days. Erythrocytes die as they consume their enzymatic set and are remove from the blood stream by macrophages, mainly by Kupffer cell in the liver and by machrophages in the spleen. These two organs are capable of recycling several waste products that result from hemoglobin degradation. The detection and phagocytosis of aged erythrocytes may depend on sialic acid lost from the erythrocyte glycocalyx and on some other carbohydrates and markers exposed in the cell surface, which are recognized by immunoglobulins and then by macrophages. Other feature of aged erythrocytes is that they alter the plasma membrane asymmetry so that some lipids of the inner monolayer are exposed at the outer monolayer. During erythrocyte aging, there is a reduction of cell size and an increase of the cytoplasm density. It may be a consequence of the cytoskeleton disorganization leading to a fragmentation of the cell in small vesicles.

3. Functions

The biconcave shape of erythrocytes provides a large surface/volume value that improves their main function: exchange of O2 and CO2 in the lungs and in the rest of the body. Hemoglobin combines with O2 in the lungs to form oxyhemoglobin. As erythrocytes go through body organs, they release the O2 by concentration gradient. The total oxyhemoglobin of an erythrocyte may transport millions of O2 molecules. Each heme group transports one O2 molecule, there are 4 heme groups in every hemoglobin molecule and it is estimated about 280 million of hemoglobin proteins in each erythrocyte. Deoxyhemoglobin is the name of hemoglobin without O2. It gives a darker red color to the blood.

Hemoglobin also transports CO2, which diffuses from the tissues to the bloodstream. Hemoglobin loaded with CO2 is known as carbaminohemoglobin, and it travels to the lungs where CO2 is released. Gases diffusion is by concentration gradient. In body tissues with low O2 concentration and high CO2 concentration, O2 is released and CO2 is loaded. O2 is fetched loaded and CO2 is released in the lungs.

Blood clotting, hemostasis and thrombosis have not been traditional related with erythrocytes, but with platelets and blood plasma. However, many evidences point to erythrocytes in these processes. A low hematocrit (low erythrocyte density) is related to a long lasting bleeding, which is independent on platelet density. High hematocrit is more prone to thrombosis. Erythrocytes contribute to blood viscosity that increases the propensity to thrombosis. When hematocrit rises, erythrocytes tend to occupy the center of the blood vessel, pushing platelets and plasma to the periphery, close to the endothelium. This disposition is good for larger blood vessels, but it is risky in small capillaries because of blood viscosity increases. In addition, nitric oxide is released in less amount by the endothelium so that vasodilation is not activated. Erythrocyte rigidity caused by some pathologies (autoimmune hemolytic anemia, thalassemia, xerocytosis, etcetera) leads to a higher risk of thrombosis because erythrocytes go through small capillaries with more difficult.

Phosphatidylserine in the surface of platelets is important for blood clotting. In the outer surface, phosphatidylserine may be associated with clotting molecules. Changing between the inner monolayer and the outer monolayer of the plasma membrane is driven by proteins like flippases and scramblases. When calcium enters platelets, phosphatidylserine is moved from the inner monolayer to the outer monolayer of the plasma membrane. The same process also happens in erythrocytes. In erythrocytes, phosphatidylserine in the outer monolayer is the beginning of apoptosis, but only 0.5 to 0.6 % of erythrocytes start apoptosis at the same time, so that their thrombotic activity is low. However, during some pathologies the proportion of apoptotic erythrocytes may be higher, therefore increasing their influence in thrombosis. As other cells, erythrocytes are able to release extracellular vesicles during apoptosis, aging and pathological processes. These vesicles are released when the membrane asymmetry changes (exchange lipids between both monolayers) and increases the thrombosis probability. When blood is stored for a long time, erythrocytes get more rigid, start apoptosis more easily and release many extracellular vesicles.

Erythrocytes influence blood clotting and thrombosis in other ways. Hemolisis, or erythrocyte breakage, is damaging because favors thrombosis by releasing microvesicles and hemoglobin into the bloodstream. Nitric oxide is a vasodilator and hemoglobin removes nitric oxide from blood plasma. During normal conditions, there is little interaction between erythrocytes and endothelium. However, in some pathologies, the adhesion of erythrocytes to endothelial cells may be higher, increasing the probability of blood vessel obstruction. Furthermore, during blood clotting, fibrinogen and platelets may gather erythrocytes so that erythrocytes contribute by increasing the consistence and decreasing the permeability of the blood clot.

4. Pathology

The most common pathology associated to erythrocytes is anemia, which includes a variety of diseases. The parameters for detection anemia are the amount of hemoglobin (hemoglobin per erythrocyte) and mean corpuscular volume (MCV; mean erythrocyte volume). MCV is calculated as follows:

MCV=(Hct/RBC)*10. Hct: hematocrit (volume of erythrocytes out of the total blood volume) y RBC: number of erythrocytes in one militer (Figure 6).

Hematocrit
Figure 6. Hematocrit. Anticoagulant effect.

The normal hematocrit is actually a range of values. The normal values depend on the age, sex, or the altitude where the people are living. Any value lower or higher than the values of the normal interval means a decrease in the O2 and CO2 transport in the organism. There are several types of anemia:

Ferropenic anemia: lack of iron. It is caused by iron intake shortage, either by low absorption by the intestine or by blood lost (hemorrhage). Blood smears from ferropenic anemia show too hypochromic (low pigmented) and microcytic (low size) erythrocytes. Erythrocytes are also variable in size.

Megaloblastic anemia: folic acid or B12 vitamin deficiency. Hypovitaminosis affects erythrocyte precursor cells by reducing their capability for synthesizing DNA, therefore inhibiting replication. The cell cycle stops before mitosis and the cell keeps growing, but it is not able to divide. That is why it is also known as macrocytic anemia. It is characterized by large, non-mature, and non-functional cells with nucleus, that results in a reduced erythrocyte production. Hypersegmented neutrophils are a feature of this disease.

Hemolytic anemia. They are classified in two groups. Acquired hemolytic anemia, that can be immune, and hereditary hemolytic anemia, which are the most frequent. Malformation, or partial or total breakage of erythrocytes occurs in hereditary hemolytic anemia. This disease may be caused by failures of cytoskeleton proteins, erythrocyte enzymes and in the hemoglobin itself (thalasemy). Hereditary spherocytosis is characterized by a decrease in the surface/volume ratio of the erythrocytes, which leads to cell fragility and hemolisis. In blood smears, erythrocytes lack the typical faint central zone.

Bibliography

Bratosin D, Mazurier J, Tissier JP, Estaquier J, Huart JJ, Ameisen JC, Aminoff D, Montreuil J. 1998. Cellular and molecular mechanisms of senescent erythrocyte phagocytosis by macrophagues. Biochemie. 80: 173-195.

Carr JH, Rodak BF. 2010. Atlas de Hematología clínica. Ed. Panamericana. 3ed. Argentina.

Doohan J. SBCC (consultada en noviembre 2014) http://www.biosbcc.net/doohan/sample/htm/Blood%20cells.htm

Ji P, Murata-Hori M, Lodish HF. 2011. Formation of mammalian erythrocytes: chromatin condensation and enucleation. Trends in cell biology. 21: 409-415.

Lux IV SE. 2016. Anatomy of the red cell membrane skeleton: unanswered questions. Blood. 127:2

Ruíz Argüelles GJ. 2009. Fundamentos hematología. Ed Panamericana 4ed. Argentina.

Weisel J W, Litvinov RI. 2018. Red blood cells: the forgotten player in hemostasis and thrombosis. Journal of thrombosis and haemostasis. 17: 1–12. Leer el artículo

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