Red Blood Cells
- Hemocytoblasts (special stem cells) produce pronormoblasts, which produce three stages of normoblasts (basophilic, polychromatophilic, and orthochromic).
- Normoblasts go on into the blood stream and develop into reticulocytes and erythrocytes.
- It is erythrocytes with which we are most concerned when it comes to anemias.
RBCs are among the smallest cells in the body (the smallest is sperm) and the most numerous type of cell present in the blood. They account for about half of all the cells in the body. A typical RBC has a diameter of 7.7 µm (micrometer) and a maximum thickness of roughly 2.6 µm, but the center narrows to about 0.8 µm. In one cubic mm (millimetre equals one microliter) of blood, there are about 5 million RBCs, which are normally disc-shaped, soft and flexible, and red in color. Since there is approximately 5 liters of blood in the body, this means there are about 25 trillion RBCs present at any given time in the body -- normally.
The unusual shape of the RBC gives it a relatively large surface area and allows rapid diffusion between the cytoplasm and surrounding plasma. The total surface area of the RBC in the blood of a typical adult is roughly 3800 square meters -- 2000 times the total surface area of the body. The flattened area also enables them to form stacks (like dinner plates) called rouleaux ("little rolls"). An entire rouleaux can pass along a blood vessel little larger than the diameter of a single erythrocyte, whereas individual cells would bump the walls, bang together, and form log jams that could block the circulatory passageways.
In addition, the slender profile of an erythrocyte gives the cell considerable flexibility. By changing shape, individual RBCs can squeeze through capillaries as narrow as 4 µm. After traveling about 700 miles in its 120-day lifespan, the RBC either breaks down or is destroyed by phagocytic cells. Destruction takes place in the liver and spleen (the liver is the largest gland in the body and the spleen is the largest ductless endocrine gland in the body). About 1% of the circulating erythrocytes are replaced each day and in the process, approximately 3 million new erythrocytes enter the circulation each second. However, despite the ageing and death of these cells, the iron in the hemoglobin does not die with them and is not wasted. The iron is saved and used over and over again to produce new RBCs.
The characteristic features of RBCs are important because of their function in carrying oxygen to body tissues. The disc-shape ensures that each cell has a large surface area which enables them to take up oxygen efficiently when the blood reaches the lungs. The softness and flexibility of the red cells allows them to squeeze through the tiny blood vessels called capillaries so that oxygen can reach all parts of the body.
A red blood cell (an erythrocyte) is described in any of the following ways:
- normocytic - normal in size and shape
- normochromic - normal in color and, thus, in hemoglobin content
- microcytic - smaller than normal
- macrocytic - larger than normal
- hypochromic - paler in color than normal (indicating insufficient hemoglobin)
- hyperchromic - deeper in color than normal
- anisocytosis – abnormal variations in size
- poiklocyte – abnormally shaped
- MCV (mean corpuscular volume index);
- MCH (mean corpuscular hemoglobin);
- MCHC (mean corpuscular hemoglobin concentration).
Hemoglobin
The basic formula for hemoglobin was established by Zinofsky in 1885. He found that for each iron atom, the hemoglobin molecule contains 712 carbon, 1,130 hydrogen, 214 nitrogen, 243 oxygen, and 2 sulfur atoms. However, he did not know how many iron atoms were in each molecule of hemoglobin. Later, it was found to have four irons in each molecule with a molecular weight of about 67,000. Ninety percent of the weight of a red blood cell is hemoglobin.
The red color of blood is the result of a pigment called hemoglobin, which consists of iron and protein (heme refers to the iron-holding part and globin to the protein-holding part). The two parts were named in the 1860s by a German scientist named Felix Hoppe-Seyler. Heme is the part that combines with oxygen, picking it up in the lungs and releasing it into tissues where there is less oxygen. One heme unit attaches to four protein chains (two alpha and two beta chains) in a hemoglobin molecule. Therefore, one hemoglobin molecule carries four oxygen molecules.
Hemoglobin is the most important protein in the body. Each molecule is comprised of twenty different amino acids from which the red cell must assemble alpha and beta chains. It is but one of the 30,000 or so different proteins that the body is able to manufacture. Molecules of hemoglobin account for over 95% of the protein in an erythrocyte and give the cell its color. Heme was found to belong to a class of compounds called iron porphyrins which include two of the most important molecules in nature: hemoglobin and chlorophyll. The first is responsible for respiration in animals and the second for photosynthesis in plants. This explains why the heme form of iron is found in meat while the non-heme form is found in plants.
There are approximately 300 million molecules of hemoglobin in each RBC; and, because one hemoglobin molecule contains four heme units, each erythrocyte can potentially carry more than a billion molecules of oxygen. Even though we speak of hemoglobin as a single substance, there are actually over 700 variants of the hemoglobin molecule. Some are normal components of the human body while others are genetic abnormalities. Transporting hemoglobin is almost the only thing that the red blood cell does.
Humans need oxygen to process their food, as well as to breathe. A person who consumes 2,000 calories a day, for example, needs about 400 liters (95 gallons) of oxygen or about one cup per minute in order to process those calories. One cup of oxygen contains roughly this many oxygen molecules -- 6,500,000,000,000,000,000,000 (65 x 1020).
In sickle cell disease, when hemoglobin S (HbS) molecules come into contact with one another, they polymerize to form rigid rods that cause the cells to sickle. One of the reasons that people with sickle cell disease are encouraged to drink large amounts of fluids is that fluids cause the red blood cell to absorb more water, and water dilutes the hemoglobin. In concentrated solutions, molecules that are closer together are more likely to come in contact with each other.
Sickling is greatly influenced by the presence of other hemoglobins. The kind and the amount matters. In sickle cell trait, where some of the hemoglobin in the cell is HbS and the rest is HbA, HbS does not usually polymerize. The reasons for this are twofold: First, the more HbA there are, the fewer HbS there are, so fewer Hb S are available for polymer formation. Secondly, HbA does not readily enter into polymers.
The following are all the hemoglobin variants known to have been the result of amino acid substitions in the beta chain.
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HbC: Soon after HbS was discovered and identified, another type of hemoglobin was found. This one had an amino acid substitution in the 6th position of the beta chain. It was called HbC. In this case, the glutamic acid normally found at beta 6 was replaced by lysine. HbC is found in about 3% of American Blacks; and, for some reason, it is more common in women than in men, at a ratio of 3:1. In some regions of Africa, the frequency of the HbC trait is 20%. However, it can also be found in Italians, Greeks, Turks, and Arabs. About one in 6,000 have the disease, but with the HbC trait (AC) people generally experience no clinical symptoms as this heterozygous condition is completely benign. However, a few do experience a slight degree of anemia or mild forms of sickle cell anemia.
HbD: Hemoglobin D is often called HbD-Los Angeles (because that is where it was first discovered) and HbD-Punjab (because that is where it is most common). In the Punjab region of India and Pakistan, approximately 3% of the people are carriers of the trait. It is also found in the British Isles – partly as a result of the intermarriage between British and Indians during the British occupation of the area and as a result of immigration to the United Kingdom. In North America, the trait occurs in fewer than 1 out of 5,000 people; but this number could also rise as immigration increases.
HbE: Hemoglobin E is the third most frequently seen hemoglobin variant in the United States, but world-wide it may be more common than HbS. Approximately 30 million people are thought to have HbE disease (EE) or carry the trait (AE). HbE occurs with the greatest frequency in Southeast Asia and appears to be limited to people whose ancestors came from that region. The trait produces few, if any, symptoms. Those with the disease may show some symptoms of slight anemia because the E beta chains are not synthesized as fast as the A beta chains.
The following variants are the result of a mutation in the sequence of bases on the DNA molecules. The mutation either alters the amino acid for which the DNA molecule codes or eliminates a stop codon, resulting in extended chains. However, the mutation of Hb Lapore is different.
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HbG-Philadelphia: It is the most common variant involving the alpha chains and is the only alpha chain variant seen with any real frequency in the US. HbG-Philadelphia appears to be limited to American and African Blacks (1 in 5,000) and has not been seen in any other ethnic group. Both the trait and the homozygous form are benign and show no adverse clinical symptoms. This form seems to be frequently associated with alpha-thalessemia because of a gene with a coding error and a missing alpha gene on the chromosome. Since this has no influence on health, it is of interest only to scientists and those who carry the HbG-Philadelphia trait.
Hb-Köln: In northern Europe, one of the most common hemoglobin variants is HbKöln. It appears to be associated with people of German, Dutch, or English ancestry and has not been found in any other ethnic groups. This form can produce mild anemia, but generally does not cause any real disability.
HbM: Although not particulary common, HbM disorders are interesting because of their effect on the individual. There are over twenty known HbM variants, and all involve the amino acid substitution that permits the iron to hold on more tightly to oxygen. Thus, two of the heme-globin units will not give up oxygen at all or will give it up reluctantly.
This phenomenon was first reported in 1948 when it was noticed that a family had several members who had a bluish tint to their skin and especially noticeable around the lips and fingers. Normally, these symptoms are seen in someone poisoned by cyanide or had a reduced delivery of oxygen to the tissues (cyanosis). Investigators at the time (Hölein and Weber) found that the hemoglobin in the blood of the affected individuals had some unusual properties, including a dark, or brownish, color. This report preceded the work of Linus Pauling by a year. It was later discovered that the family had HbM-Saskatoon.
A similar inherited condition with cyanosis had been observed in Japan since the 19th century. The condition was known as “Kochikuro” (black mouth) and “Chikuro” (black blood). In the 1950s, it was found to be caused by an HbM with an amino acid substitution at alpha87. It was named M-Iwate after the region in which the carriers lived.
Some HbM variants involve amino acid substitution on the alpha chain, while others are on the beta chain and only heterozygous HbM individuals have been found. So far, it is assumed that the homozygous form is not compatible with life. The only clinical manifestation appears to be reduced oxygen delivery.
Hb-Constant Springs: resulted because of a mutation at the termination codon for alpha gene 2, resulting in the protein chain containing 31 extra amino acids. The hemoglobin molecule produced is stable and the carriers of this form usually have only 1-2% of the variant in their blood. Hb-Constant Springs is found in relatively high frequency in Southeast Asia. By itself, it presents no problem; but, since it is often seen in conjunction with alpha-thalaseemia, its presence is essentially the same as if a gene were missing. Thus, someone with Hb-Constant Spring trait and alpha-thalassemia-1 trait, has only one fully functioning alpha gene and will have the same symptoms as someone with HbH disease.
Hb Lepore: is a variant with a globin chain that starts as a delta and finishes as a beta, with the two codes being fused together. This is the result of a mutation that occurs during the production of the reproductive cells, that is, the sperm and the egg. There have actually been three Hb Lapores discovered and differ from each other as to the actual place on the chain where the fusion occurs. Someone with Hb Lapore will produce 10-15% of the variant and the trait condition is similar to that of beta-thalassemia. It has little effect on the health of the carrier.
Other variants: There are literally hundreds of them; but, because most are rare and the symptoms are relatively mild, they are not considered here.
