Red Blood Cells

Red Blood Cells (RBCs) are the most numerous cells in the blood and give blood its characteristic color. They are responsible for normal oxygen transport from the lungs to the rest of the body. Since they lack the machinery for cell division (in particular, they lack a nucleus), they are incapable of dividing or repairing themselves and must be continually produced and removed. Almost all vertebrates have evolved elaborate systems for controlling the production and removal of RBCs, and most of hematology is devoted to the study of RBCs in health and disease.

Normal blood cells including erythrocytes (E), a lymphocyte (L), a platelet (P) and a reticulocyte (R). The cell to the left of the reticulocyte is probably a more mature reticulocyte. Source: NASA.

Other Names

• Erythrocyte
• Red blood corpuscle (a term used infrequently to emphasize that, because RBCs don't have nuclei, they fail an important test of whether they can properly be called a "cell").
• Red cell
• Haematid
• Erythron (refers to red blood cells and the specialized bone marrow cells that give rise to them, the erythroid precursor cells).

Types

Depending on their shape, hematologists may refer to erythrocytes with more specific names. Occasionally the appearance of abnormally-shaped RBCs helps in diagnostic workups.

• Discocytes are normally-shaped red cells. They show a shallow but visible round depression in the central portion of the cell.
• Spherocytes are rounded, spherical red cells that have lost their normal central area of depression
• Dacryocytes are teardrop-shaped red cells
• Echinocytes and acanthocytes have spike-like projections
• Codocytes are target-shaped red cells
• Schistocytes are tiny fragments of red cells with pointed contours
• Sickle cells are elongated cells with pointed ends. They are diagnostic for sickle cell anemia.

Description

RBCs are smaller than most other human cells and are binconcave discoid in shape. Several membrane and intracellular proteins contribute to the overall shape, including glycophorin A, band 3, spectrin, and ezrin. Red cells have a unique metabolism, since they lack nuclei and mitochondria. In particular, RBCs rely almost entirely on glucose for their energy needs.

The most important and prevalent molecule in RBCs, by far, is hemoglobin (Hb), a globular protein composed of four subunits and weighing about 68,000 daltons. The protein part of the Hb molecule surrounds a heme ring with an iron atom at its core. The iron atom is responsible for loading oxygen gas as the RBC flows through lung capillaries, and for unloading oxygen in the rest of the body.

Role of Red Blood Cells in the Body

Hematopoietic stem cells give rise to RBCs, white blood cells, and platelets. Source: NIH.

In the adult, the bone marrow provides a special environment for RBC production and maturation. The process starts with the hematopoietic stem cell which can divide without differentiation (forming more stem cells) or can divide and differentiate into erythroid precursor cells committed to becoming red blood cells. The rate of production is tightly regulated and depends on appropriate amounts of signaling molecules, notably erythropoietin, a hormone from the kidney that increases the rate of RBC production.

During the process of RBC maturation, cells begin making Hb at the expense of almost every other protein. The Hb remains dissolved at a very high concentration in a flexible matrix, which is important to maintain RBC flexibility. Over 250 million Hb molecules eventually crowd into each RBC as the nucleus is extruded and other remnants of normal cell functioning (mitochondria, mRNA, etc.) are lost. Immature RBCs eventually change their surface characteristics enough to become detached from adjacent cells and leave the bone marrow as reticulocytes, so called because a small amount of mRNA remains visible in the matrix of Hb. After a few days, the mRNA is lost and the fully mature RBC circulates for 120 days (with an average range of 100 to 140 days).

During its tour, the average RBC will travel through the heart over 500,000 times and through about 1000 miles of arteries, veins, and capillaries. The cumulative effects of age result in RBCs that are smaller and less flexible than before—signals detected by the spleen, which filters out and destroys senescent or damaged RBCs and packages the iron for recycling.

How It Works

Concentration in peripheral blood

Normal values vary slightly between laboratories and institutions, and with the age of the patient. All three measurements are usually reported together, with Hb concentration usually accorded the most importance.

• Hb concentration refers to the amount of hemoglobin protein present per unit volume of peripheral blood. Normal men have 136-175 g/L and normal women have 120-155 g/L.
• Hematocrit refers to the volume taken up by RBCs compared to the volume taken up by everything else in blood (i.e., plasma, white blood cells, and platelets). Values for normal men are 39-49% and normal women, 35-45%.
• RBC count is simply the number of red cells per unit volume. The normal range is 4.7-6.1 million RBCs per microliter.

RBC characteristics

• Size and variability in size: MCV and RDW refer to mean corpuscular (or cell) volume and red cell distribution width. Normal RBC volume is 80-100 femtoliters. Smaller cells are called microcytes and are helpful in diagnosing a class of anemias (the microcytic anemias). Larger cells are called macrocytes; these are present in macrocytic anemias. The RDW is a measurement of how much the red cells vary in size. An increased RDW indicates that the red cells have a large variation in size (some are very small and some are very large). A decreased RDW indicates that there is little variability (all the red cells are essentially the same size). The RDW is helpful in distinguishing certain types of anemias, particularly iron-deficiency anemia (which is characterized by an increased RDW) and thalassemia (which may have a decreased RDW).
• Hemoglobin content and concentration: MCH and MCHC refer to mean cell hemoglobin and mean cell hemoglobin concentration. Each RBC normally contains 26-34 picograms of Hb at a concentration of 310-360 g/L.
• Surface antigens: ABO Blood Group System (ABO) and Rhesus Blood Group System (Rh) blood groups are the most important antigens on the surface of red cells and were the first to be described.^[1] They are critically important in determining whether RBCs may be safely given to a candidate transfusion recipient.

Volume of RBCs in the body

• Red cell volume refers to the volume taken up by all of the body's RBCs and is rarely reported, since it requires an invasive and time-consuming estimation procedure. The normal range is 25-35 mL/kg. ^[2] Extremely fit individuals may have higher values—significantly more red cells in their bodies and significantly more oxygen-carrying capacity—but still maintain normal hematocrit values.

Diseases of Red Blood Cells

A wide range of diseases affect RBCs. They are usually categorized as deficiencies in Hb (anemia), overabundance of Hb (polycythemia), or problems with the Hb molecule itself (hemoglobinopathy).

Anemia

Anemia is a feature of many other diseases and brings with it a constellation of signs and symptoms attributable to inadequate oxygen delivery. Mild cases may be asymptomatic or only associated with a slight increase in dyspnea (shortness of breath) upon exercise. More severe cases bring symptoms of exercise intolerance, marked dyspnea, generalized weakness and dizziness that may lead to fainting, and mental status changes such as disorientation and confusion. Severe or sudden blood loss can, of course, be rapidly fatal.

Anemias are usually subdivided according to whether they result from inadequate RBC production, deranged RBC maturation, or increased RBC loss.

• The hypoproliferative anemias result from inadequate RBC production; there are several subtypes.
  • Iron deficiency anemia
  • Acute and chronic inflammation
  • Decreased erythropoietin response
  • Bone marrow damage
• The maturation disorders include a wide range of diagnostic categories.
  • Cytoplasmic maturation defects can result from diseases such as the thalassemias or sickle cell anemia in which Hb synthesis is abnormal or disrupted.
  • Nuclear maturation defects can sometimes be attributed to deficiencies in nutrients such as vitamin B12 or folic acid.
• The hemorrhagic and hemolytic anemias result from blood loss and RBC destruction, respectively.
  • Blood loss anemia can be rapidly fatal if it is acute. The most dramatic cases are when blood leaves the body entirely, but bleeding can also occur into the peritoneal cavity or hollow organs such as the stomach or lungs. Chronic blood loss (e.g., into the intestine) can also cause anemia.
  • Hemolytic anemia results from the destruction of RBCs and can be acute or chronic.

Polycythemia

Polycythemia is a condition in which there are too many RBCs in the blood. Polycythemia is not as common as anemia.

Hemoglobinopathies

Many variant forms of the hemoglobin molecule exist in human populations, some of which confer a survival advantage, and some of which lead to increased destruction of red cells.

Management of Red Blood Cell Disorders

Successful management depends on an accurate diagnosis and access to appropriate resources. The wide range of RBC disorders corresponds to a wide range of treatment options including transfusion, nutrient or vitamin replacement, growth factor administration, and bone marrow transplantation.

Related Professions

Hematology is the medical specialty dedicated to the diagnosis, treatment, prevention, and investigation of the disorders of the hematopoietic, hemostatic, and lymphatic systems, and disorders of the interaction between blood and blood vessel wall. A hematologist is a physician with specialized training in hematology. ^[3]

Interesting Facts

• The ice fish is one of the few (and perhaps the only) vertebrate that doesn't have RBCs. ^[4]

• Vertebrate RBCs vary considerably in their size and shape. The largest RBCs belong to the salamander Amphiuma; these average 65 x 30 x 13.5 µm (volume ~10,000 fL), compared to the typical human RBC diameter of 7 µm (volume ~90 fL). Avian RBCs are elliptical and have nuclei (in contrast to the round, non-nucleated human RBCs). Mice and deer have smaller, spherical RBCs.^[5]

History

The first scientist to describe the red blood cell after viewing it under a microscope in 1658 was Dutch biologist Jan Swammerdam (1637-1680).

The red cell was also described in 1674 by Dutch biologist Antony van Leeuwenhoek] (1632-1723).

In 1909, Karl Landsteiner, a Professor and biochemical researcher from Vienna, classified the blood into the A, B, AB, and O groups and showed that transfusions between individuals of groups A or B do not result in the destruction of new blood cells; that this destruction occurs only when a person is transfused with the blood of a person belonging to a different group. He received the Nobel Prize in Medicine in 1930.

Research

Recent discoveries

Researchers at the Whitehead Institute in Cambridge, MA, recently modeled the process by which red blood cells lose their nucleii. ^[6] The researchers plan to further investigate the entire process of red blood cell formation, which may lead to insights about genetic alterations that underlie certain red blood cell disorders.

MIT researchers, in 2007, studied how red blood cells change shape to pass through blood vessels that are narrower than the cell. ^[7]

Future Research

The Puget Sound Blood Center is studying a family of proteins (the adducin proteins) that appear to determine the shape of the red blood cell and the genes that control the production of these proteins. If the regulation of these proteins is understood, the genes may be able to be manipulated to increase production of normal red blood cells and avoid diseases related to abnormalities in red blood cell structure. ^[8]

Other Resources

Tierney LM, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis and Treatment, 2004. Lange Medical Books, New York, pp. 1706-1710

References

1. ↑ Daniels G. A century of human blood groups. Wien Klin Wochenschr. 2001 Oct 30;113(20-21):781-6. Abstract
2. ↑ Lucia A, Earnest C, Arribas C. The Tour de France: a physiological review. Scand J Med Sci Sports. 2003 Oct;13(5):275-83. Abstract
3. ↑ American Society of Hematology web site. Defining the American Hematologist.
4. ↑ Ruud, JT. Vertebrates without erythrocytes and blood pigment. Nature 1954 173:848-850. Abstract
5. ↑ Withers, PC. Comparative Animal Physiology, Ch. 15. ISBN 0030128471
6. ↑ Ji P, Jayapal SR, Lodish SH. Enucleation of cultured mouse fetal erythroblasts requires Rac GTPases and mDia2. Nat Cell Biol. 2008 Mar;10(3):314-21. Epub 2008 Feb 10. Abstract | PDF
7. ↑ Massachusetts Institute of Technology news office. MIT shows how blood cells change shape.
8. ↑ Puget Sound Blood Center web site. Research: Gilligan Lab.