Erythrocyte

Erythrocyte
n., plural: erythrocytes
[əˈɹɪθɹəˌsaɪt]
Definition: A red blood cell

Erythrocyte Definition

Erythrocytes (red blood cells or RBCs) are the myeloid series of specialized cells that play an integral role in the circulatory system. They are highly specialized, biconcave-shaped, and rich in a red pigment called hemoglobin. With an optimized surface-to-volume ratio and devoid of most organelles, these selfless envoys through their remarkable flexibility and red blood cell deformability efficiently facilitate the exchange of respiratory gases like inhaled oxygen and carbon dioxide.

The erythrocytes are a unique type of blood cell that is characterized by the absence of the ability to undergo cell division and the presence of hemoglobin (a unique iron-containing molecule). Some important points to note about erythrocytes are:

• They are called by different names like:
  • Erythroid Cells
  • Red Blood Cells (RBCs)
  • Haematids
  • Red Cells
  • Red Blood Corpuscles
• They are highly differentiated.
• They don’t have cell organelles (sometimes called “anucleate” as they don’t possess a nucleus at maturity). This modality in the structure supports the maximization of space in the erythrocytes for the accommodation of hemoglobin molecules.

  

• They are devoid of the ability to divide and form new erythrocytes.
• Their physiology supports oxygen transport throughout the human body tissues.
• They are produced specifically in the red bone marrow (BM) from hematopoietic stem cells (HSCs). The process of production of erythrocytes is called “erythropoiesis” and takes place as HSCs give rise to myeloid progenitors or erythrocyte precursors. So, erythrocytes are “myeloid in origin” or belong to the myeloid series of blood cells. There are several changes (especially morphological) that cumulatively give rise to mature erythrocytes.

  

• Their average lifespan is 100-120 days (nearly 3.5-4 months).
• The production of human red blood cells in adults is estimated to be approximately 2,400,000 new cells per second.
• Their communications and interactions are wide-scoped; with endothelial cells (as in sickle cell patients), platelets (clotting cells), macrophages (a type of white blood cells), and even bacteria via membrane proteins.

  

• There are reports that RBCs can synthesize nitric oxide.
• They are biconcave in shape (for the provision of a larger “surface to volume ratio”) that eventually increases the oxygen-carrying capacity.

  

• They are filled with hemoglobin (Hb) which renders them with the ability to oxygen supply.
• The richness of Hb in the RBCs’ cytoplasm imparts a red color to blood. There is an estimate of about 270,000,000 Hb molecules in each RBC.
• The flexible nature of erythrocytes which allows their easy circulation in the circulatory system and bloodstream is due to the presence of unique lipids and proteins in the RBC membrane.
• The primary function of erythrocytes is the transportation of oxygen from the lungs to all tissues and parts of the body.
• The hematocrit value (i.e. the volume of packed erythrocytes) usually varies from men to women. For men, it ranges between 42-54% of total volume while in women, it varies from 37-47%. These values are usually lower in children. These values are higher for people living at high altitudes with low oxygen tension. Since the erythrocytes are more or less uniform in volume, we usually determine the hematocrit value by evaluating the number of erythrocytes (RBCs) per unit of blood, which are usually 4,000,000 to 6,000,000 per cubic millimeter.

  

• When understanding their representation in the total blood volume, erythrocytes represent nearly half of the total blood cells ranging between 40 to 45 percent.
• In contrast to the uptake of oxygen from the lungs by erythrocytes in mammals, oxygen is extracted from gills in fishes.
• There is a common medical terminology called “packed red blood cells/pRBC” which stands for the erythrocytes that are donated, processed, and thereby eventually stored in hospital blood banks for treatments like blood transfusion.

  

• Within the membrane of red blood cells (RBCs), a bilayer composed of lipid molecules with both hydrophilic and hydrophobic properties is connected to a framework of skeletal proteins using transmembrane proteins.

• Erythrocytes Etymology

The word erythrocyte is derived from two Greek words;

• Erythros meaning “red”
• Kytos means “hollow vessel”

The word cyte is usually translated to “cell” in modern language.

Watch this vid about erythrocytes:

Erythrocyte Structure

The erythrocyte structure is a physiological marvel. Some basic pointers to their structure are:

• Diameter: 7-8 µm
• Biconcave shape (resembling a donut)
• Thicker periphery than their central parts
• Maximum total surface areas of the cell membrane (facilitating easy oxygen transport and other gas exchange)
• Absence of a nucleus (hence the absence of DNA) and other cellular organelles
• Presence of only 2 structures namely cytoplasm and red cell membrane.

Let’s discuss the cytoplasm and cell membrane in detail.

• Cytoplasm

The cytoplasm of mature erythrocytes has the presence of no organelles. When we observe erythrocytes under a microscope after staining blood samples with hematoxylin and eosin (H&E), we see them as intensely stained red-orange cells. One point that we should note here is that hematoxylin alone doesn’t stain erythrocytes as hematoxylin specifically stains the nucleus of cells which is absent in erythrocytes.

• Cell membrane

Here are some important notes about the cell membrane of erythrocytes.

• There is a lipid bilayer membrane that covers the erythrocyte’s cytoplasm.
• Proteins: There are two types of cell membrane proteins called integral as well as peripheral proteins.
  • Peripheral proteins: Peripheral proteins found on the membrane’s inner surface help in providing an extremely elastic property to the erythrocytes.
  • Integral Proteins: these are proteins that span the entire membrane.
• Carbohydrates: the ABO blood grouping used for type for blood group characterization is based on the presence or absence of certain types of carbohydrate molecules that act as antigens on the red blood cell membrane; blood types thus are called the A, B, O, and AB blood types. Expression of blood group antigens by these integral proteins leads to exploiting ABO blood groups for medical purposes.
• Besides this ABO blood typing, the erythrocytes cell membrane can have a Rhesus (Rh) antigen (RH factor protein). The presence and absence of Rh on a person’s erythrocytes lead to the blood type being Rh positive (A+/B+/O+/AB+) or Rh negative (A-/B-/O-/AB-). Both ABO and Rh surface antigens on the erythrocyte cell membranes are integral for blood transfusions.

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• Function: The erythrocyte’s cell membrane not only supports the internal structure till the time that the cell reaches maturity by also helps in the binding of hemoglobin molecules.
• Permeability: The erythrocyte’s cell membrane is impermeable to Hb but freely permeable to:
  • Water
  • Oxygen
  • Carbon dioxide
  • Glucose
  • Urea
• Major Ions:
  • Within cell: Potassium
  • In plasma and extracellular fluids: Sodium
• Osmosis: Erythrocytes are subject to osmotic effects.
  • On suspension in hypotonic solutions: Increased volume & transition to a more spheroid shape
  • On suspension in hypertonic solutions: Loss of water leading to even more shrinkage

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• Process of Hemolysis: Upon damage to the erythrocyte’s cell membrane or alterations in the membrane skeleton, there is a leak of cell constituents like hemoglobin (Hb) and other dissolved contents. This paves the way for the ghosting of membranous structures. This is usually a result of physical damage or osmotic effects. In extreme conditions, it can also lead to hemolytic anemia (low oxygen transport capacity)

  

Life Cycle Of Erythrocytes

There are three main phases in the life cycle of erythrocytes; synthesis, lifetime, and senescence.

1. Synthesis Phase/Erythropoiesis

   • Erythrocytes are synthesized by the process called “erythropoiesis”.
   • It takes about 7 days for erythrocytes to be produced from red bone marrow cells (committed stem cells for RBC production) of the larger bones.
   • NOTE: A point to note here is that in the embryo, these erythrocytes are rather produced in the liver and not in the bone marrow cells of bones.
   • A specific hormone called erythropoietin (EPO) stimulates this synthesis process from its location in the kidney.
   • The idea of reticulocytes: While erythrocytes are being produced in the bone marrow, they are called reticulocytes just before and after they leave the bone marrow. These reticulocytes comprise only 1% of circulating erythrocytes.

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2. Lifetime Phase

   • The active lifetime of an erythrocyte is nearly 100–120 days.
   • Erythrocytes are continually on the move during their lifetimes. They move by the force of:
     • Blood flow push: in arteries (arterial blood)
     • Blood flow pull: in veins (venous blood)
     • Combination of both blood flow push and pull- in microvessels (capillaries)
   • Erythrocytes Recycling: The site of erythrocytes recycling is bone marrow.

3. Senescence Phase/Erythrocyte Destruction

   • This is the aging phase of erythrocytes where they undergo a lot of physical changes like in their plasma membranes.
   • These changes make them highly susceptible to being selectively recognized by a type of leucocytes called macrophages.
   • What follows next is the phagocytosis process by the mononuclear phagocytes and their system that’s constituted by the liver, lymph nodes, and spleen.
   • By the process of phagocytosis, old and damaged erythrocytes are continually removed from the bloodstream. This is also called “eryptosis” meaning erythrocyte’s programmed death. For example, Exposure to PS (phosphatidylserine) causes adhesion of erythrocytes to vascular endothelial cells thus interrupting their normal transport and movement.

     

   • The rate of eryptosis is usually the same as the rate of erythropoiesis. This balances the total circulating erythrocyte count (RBC count).

     

• Erythropoiesis

Erythropoiesis is the process of production of erythrocytes that takes place within the red bone marrow as a “part of hematopoiesis”. Initially, hematopoiesis generates an erythroid stem cell known as CFU-E (Colony Forming Unit – Erythroid), which initiates the process of erythropoiesis primarily under the influence of the erythropoietin hormone. These CFU-E cells are localized within erythroid islands within the bone marrow and undergo replication and differentiation to ultimately form mature erythrocytes. During the differentiation process, several generations of cells are produced, including proerythroblasts, erythroblasts, reticulocytes, and finally, erythrocytes. With each generation, the cells histologically resemble erythrocytes more closely.

• Erythrocyte destruction

The breakdown products from eryptosis are recirculated in the body.

• • Heme of the Hb: Broken down into biliverdin and Fe³⁺ ion (iron ion).
  • Biliverdin: Reduced to bilirubin (a yellow pigment)
  • Bilirubin: Release into plasma; via albumin, it is recirculated to liver
  • Iron: Released into plasma; recirculated by transferrin (a carrier protein)
  • Polypeptide globin chains: Degraded into amino acids

There are some diseases and disorders which are marked by an abnormally high rate of eryptosis like:

• • Sepsis
  • Wilson’s disease
  • Hemolytic uremic syndrome
  • Iron deficiency
  • Malaria
  • Phosphate depletion
  • Beta-thalassemia (characterized by abnormal hemoglobin/abnormal ratio of hemoglobin subunits)
  • Sickle cell disease/ sickle cell anemia (iron deficiency anemia) – Anemia can be caused due to different reasons like:
    • Due to blood loss
    • Due to defective/reduced erythrocyte production (aplastic anemia)
    • Due to excessive destruction of erythrocytes (hemolytic anemia)
    • Due to mutation in hemoglobin genes
  • Glucose-6-phosphate dehydrogenase deficiency

Note: Polycythemia (characterized by an elevated RBC count)

Functions

Erythrocytes perform many invaluable functions for the proper functioning of the body.

• Oxygen Transport

A unique protein called hemoglobin aids the process of oxygen (O₂) transport in the body. Oxygen binds to hemoglobin in the lungs. This leads to the formation of a very strong bond allowing erythrocytes to efficiently transport O₂ molecules. As erythrocytes circulate through blood vessels, they deliver O₂ to organs and tissues in need. By providing cells with the necessary O₂, erythrocytes ensure energy production and survival of the tissues and organs.

• CO₂ Transport

Erythrocytes have a crucial role in the transport of carbon dioxide produced (CO₂) in our bodies. During cellular metabolism, CO₂ is produced as a waste product. Erythrocytes aid in removing CO₂ from tissues and carrying it back to the lungs for elimination. CO₂ diffuses from cells into nearby capillaries. Within erythrocytes, CO₂ combines with water to form bicarbonate ions (HCO₃^–). This reaction is facilitated by an enzyme called “carbonic anhydrase” present in erythrocytes.

Bicarbonate ions are more soluble and can be transported easily in the blood plasma. Some of the bicarbonate ions remain within erythrocytes, while others are transported in the plasma. As erythrocytes reach the lungs, carbonic anhydrase converts bicarbonate ions into CO₂ and water. The released CO₂ is exhaled from the lungs, thus completing the process of CO₂ transport by erythrocytes.

• CO Transport

Erythrocytes can inadvertently transport carbon monoxide (CO) when it binds to hemoglobin, leading to a compromised ability to deliver oxygen to tissues.

Carbon monoxide poisoning occurs when an excessive amount of CO binds to hemoglobin. This impairs the normal oxygen-carrying function of erythrocytes.

When CO is inhaled, it readily binds to hemoglobin within erythrocytes.

Hemoglobin has a higher affinity for carbon monoxide (CO) compared to oxygen. This leads to the formation of a stable compound known as carboxyhemoglobin.

This binding of CO leads to oxygen deprivation in tissues.

The presence of carboxyhemoglobin in erythrocytes can have severe health consequences, as it interferes with normal oxygen delivery and can result in CO poisoning.

Tests

Anyone trying to understand the overall health of the body in the past 3-4 months, they can get their RBCs tested. Since the average lifespan of mature RBCs after being released in the bloodstream is 100 to 120 days, these cells can help in the appropriate description of the health state.

Glycated hemoglobin test: This HbA1c test is performed for people suffering from diabetes. It is usually recommended to get tested every 3 months to properly track the blood glucose levels. Since after every 3.5-4 months, the old erythrocytes are recycled by special cells called the macrophages in the lymph nodes, spleen, and liver, it’s important that the cycle of clinical tests in kept in sync with the natural biological renewal cycle of erythrocytes.

More of the erythrocyte-related tests and their medical significance are listed in the table below.

Data Source: Dr. Harpreet of Biology Online

Warning/Caution Note: None of these tests should be performed or interpreted at home. Recommendations and advice from physicians are mandatory.

NOTE IT!

Science underlying Hemoglobin

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Hemoglobin makes a notable presence in the erythrocyte’s cytoplasm. Hemoglobin is a tetrameric protein constituted by:

• 4 polypeptide chains: Also known as globin proteins or globin chains. Since there are 4 types of chains α, β, γ, and δ, we get 3 main classes of Hb (HbA, HbA2, and HbF). HbA is the most common in human adults.
• 4 carbon-based (C-based) heme molecules: The iron atom in each globin bound to heme plays an integral role in the binding of gases like O₂ and CO₂.

There are 2 main types of Hb:

• HbA (adult hemoglobin)
• HbF (fetal hemoglobin)

Hemoglobin binds reversibly with oxygen molecules. And this reversible binding allows to and fro transport of oxygen (O₂) and carbon dioxide (CO₂). 1 Hb holds the potential to transport 4 molecules of O₂ and CO₂.

The intricate arrangement of porphyrin and protein within the structure of hemoglobin creates an optimal setting for the iron atom, allowing it to effectively bind and release oxygen by physiological requirements. Hemoglobin exhibits such a strong affinity for oxygen that approximately 95% of its binding sites become saturated with oxygen within the lungs, where the oxygen pressure is relatively high. However, as oxygen tension decreases in the tissues, oxygen dissociates from hemoglobin, enabling its diffusion across the red blood cell membrane and plasma, ultimately reaching the sites where it is utilized. This process ensures a proportional distribution of oxygen to meet the body’s needs.

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Further Reading

• Human blood cell

References

1. Zivot, A., Lipton, J. M., Narla, A., & Blanc, L. (2018). Erythropoiesis: insights into pathophysiology and treatments in 2017. Molecular Medicine, 24, 1-15.
2. Diez-Silva, M., Dao, M., Han, J., Lim, C. T., & Suresh, S. (2010). Shape and Biomechanical Characteristics of Human Red Blood Cells in Health and Disease. MRS Bulletin, 35(5), 382–388. https://doi.org/10.1557/mrs2010.571
3. Liu, S., Grigoryan, M. M., Vasilevko, V., Sumbria, R. K., Paganini-Hill, A., Cribbs, D. H., & Fisher, M. J. (2014). Comparative analysis of H&E and Prussian blue staining in a mouse model of cerebral microbleeds. The Journal of histochemistry and Cytochemistry: official journal of the Histochemistry Society, 62(11), 767–773.
4. Dunn, J. O., Mythen, M. G., & Grocott, M. P. (2016). Physiology of oxygen transport. Bja Education, 16(10), 341-348.
5. Kinoshita, H., Türkan, H., Vucinic, S., Naqvi, S., Bedair, R., Rezaee, R., & Tsatsakis, A. (2020). Carbon monoxide poisoning. Toxicology reports, 7, 169-173.
6. Ahmed, M. H., Ghatge, M. S., & Safo, M. K. (2020). Hemoglobin: structure, function, and allostery. Vertebrate and invertebrate respiratory proteins, lipoproteins, and other body fluid proteins, 345-382.

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