D.2.2. Erythrocytes Production


A. Where are the RBC’s produced?
1.
The production of the blood cells is called: hemopoiesis (hemo = blood, poiesis = to make).
Production of red blood cells in the bone marrow
2.
The erythrocytes are produced by the bone marrow (= tissue inside the bones). In adults, this occurs mostly in the sternum, the ribs and the vertebra.
3.
In babies and children, who need a lot of blood for growing up, it is also produced in the marrow of long bones such as the femur and the humerus.
4.
Inside the bone marrow, there are stem cells that can produce all types of blood cells (erythrocytes, leukocytes etc).

Production of red blood cells in the bone marrow
5.
Of course, the stem cells must first replicate themselves or else everything will stop!




6.
Depending on the needs of the body, biochemical signals are sent to a stem cell to differentiate into either a red blood cell, a white blood cell or a platelet. In this diagram, signals were sent to “commit” a cell to a proerythroblast.
7.
From the proerythroblast, the cells mature; they gradually lose their nucleus, synthesize haemoglobin and acquire iron. Once all their organelles have been ejected, they become reticulocytes.
8.
These reticulocytes, leave the bone marrow and enter the blood stream. In 2-3 days, the reticulocytes have finished maturing and have become erythrocytes.

9.
Note that in the first two steps (proerythroblast and erythroblast), these cells replicate themselves a lot.
10.
In other words, at that stage, they need a lot of DNA. This is important if there is a diet deficiency, as you will see later.

B. What regulates RBC production? top?
1.
The signal to differentiate stem cells into erythrocytes is a hormone called erythropoietin. It is mainly the kidney that secretes this hormone.



2.
This is a negative feedback system (link); if there is not enough oxygen in the tissues (=hypoxia), then more erythropoietin will be released. This will increase the production of erythrocytes which, in turn, will transport more oxygen. If there is too much oxygen, the reverse will happen.
3.
There are many situations where there is a lack of oxygen and therefore an increase in erythropoietin production. This reaction by the body is useful because more erythrocytes will transport more oxygen.
4.
Here are four examples or situations that induce an increase in erythropoietin and an increase in RBC production:
a. high altitude
b. blood loss
c. diseases
d. doping

The Hematocrit
4.a.
High altitude (= high in the atmosphere, there is less air and therefore less oxygen). This is for example famous in the people who live in the Andes Mountains (in South America). These people look very healthy with red cheeks. In reality, their cheeks are red because the blood vessels in the skin are filled with erythrocytes.
4.b.
Blood loss: After bleeding, when one has lost 1-2 litres of blood; in an accident for example. This is actually an anaemia (= lack of enough erythrocytes).




4.c.
Diseases: there are many types of heart and lung diseases that reduce the transportation of oxygen. This will increase, as compensation, by more erythropoietin, the number of erythrocytes.


4.d.
Doping: unfortunately, an increase in erythrocytes is also useful in sport activities. Some people will try to enhance their performance unfairly. One way to do this is by auto-transfusion but a more popular method nowadays is by taking artificial erythropoietin called EPO (=ErythroPOetin).

C. RBC production requires three crucial compounds: top?
1.
For the production of red blood cells, next to the usual mixture of amino acids etc, there are three vital components required.

2.
These can only be obtained from the food that is ingested.


3.
If the diet is not balanced (typically not enough vegetables, such as in junk food), a shortage of any of these compounds may occur which can lead to a shortage of erythrocytes (=anaemia).




4.
The three compounds are:
a. Folic Acid: this is required for the duplication of DNA during the replication of stem cells and their differentiation into erythrocytes.
b. Vitamin B12: also required for DNA formation
c. Iron (Fe2+): We need about 1-2 grams per day (fertile women a bit more than men because of their regular menstruations).

D. Folic Acid: top?
1.
Folic acid is obtained from food (green vegetables etc) in the small intestine. It is absorbed in the small intestine and stored in the liver.

2.
There can be a shortage of folic acid when there is a chronic intestinal disease or a higher demand of folic acid, especially during pregnancies. Folic acid is then often given to the expectant mother as a supplement.

E. Vitamin B12: top?
1.
The story about vitamin B12 is a bit more complex. Vitamin B12 is also absorbed from ‘healthy” food in the small intestine.

2.
To protect the vitamin B12 from the acid juices in the stomach, it is bound, in the stomach, to a carrier. This carrier is called the “intrinsic factor”.
3.
This duo (vitamin B12 and the intrinsic factor) flows with the food from the stomach into the small intestine.
4.
In the distal small intestine (= ileum), the duo is absorbed into the blood stream, then the bound is broken, and the vitamin B12 is stored in the liver to be used by the bone marrow when needed.

The Hematocrit

F. Problems with the Intrinsic Factor: top?
1.
If there is no or not enough intrinsic factor (=IF), then not enough vitamin B12 is absorbed. This will lead to an anemia.



2.
Because the intrinsic factor is made in the mucosa of the stomach, all diseases in which the stomach mucosa is destroyed or not functioning will cause lack of intrinsic factor. No vitamin B12 will then be absorbed into the blood.
3.
Such stomach diseases can be caused by a removal of the stomach by surgery (for example to remove a stomach cancer) or a destruction of the mucosa by a toxic fluid (too much alcohol) but also sometimes by an infection that affects the gastric (=stomach) mucosa.
4.
Normally, most of the intrinsic factors is stored in the liver. In fact, there is so much IF stored that it takes 3-6 months after removing the stomach before symptoms of anaemia starts to occur!

5.
An old fashioned test to determine whether the patient suffers from a lack of intrinsic factor is the Schilling test.


6.
The point of this test is to determine whether vitamin B12 is absorbed in the ileum, a step that requires an intrinsic factor (this test was developed in those days when intrinsic factor could not be measured in the blood).
Production of red blood cells in the bone marrow
7.
The test consists of giving orally a small amount of radioactive vitamin B12. If the vitamin B12 is NOT absorbed, then the vitamin B12 will be lost with the stool. But if the vitamin B12 is absorbed, then the kidney will secrete it in the urine where it can be detected.

In other words, if the radioactive vitamin B12 appears in the urine, then the patient has intrinsic factor.
8.
But there is a small complication; the small amount of absorbed vitamin B12 could also “disappear” into the liver and then not enough will be secreted in the urine to be detected.

To avoid this, one also injects a large amount of non-radioactive vitamin B12 in the blood to saturate the liver stores. Then, the small amount of radioactive vitamin B12 is injected and, if absorbed, will appear in the urine.


G. Iron (this is also a bit complex): top?
1.
Fe (=iron) is also obtained from healthy food (and meat).

2.
It is absorbed, in the small intestine, with the help of a transporter called apotransferrin (apo = precursor; trans = transport; ferrin = iron).
3.
When it is coupled to apotransferrin, the complex (Fe + apotransferrin) is called: transferrin.
4.
This transferrin circulates, in the blood, to all tissues in the body but mostly to the liver.

5.
Once it arrives to a cell (usually the liver cell), the Fe is decoupled from apotransferrin, passes through the cell membrane, and couples with a special carrier inside the cell. This second, intracellular, carrier is called apoferritin. The reaction is similar: apoferritin + Fe = ferritin.
6.
Both ferritin (which is intracellular) and transferrin (which is extracellular) are reversible. This means, when there is a need for iron, that iron is removed from ferritin, goes out of the cell, and is transported as transferrin to the bone marrow, where it is used for the production of erythrocytes.
Production of red blood cells in the bone marrow
7.
When there is a shortage of ferritin (which means a shortage of iron stored in the body), then less erythrocytes will be made (=anaemia). This can occur with poor diet or when there is an increased need for iron and erythrocytes, such as during pregnancies.


8.
Some people will take iron supplement, even if they don’t need it. In that case, there could be too much iron inside the body. This can be dangerous. As you saw in (5), iron is stored inside cells as ferritin. If there is not enough apoferritin to store additional iron, then the iron will arrive into the cell but is not coupled to apoferritin. Then the iron will crystallize.
9.
These iron crystals are very toxic for the cells, may damage easily the cell membranes and are irreversible. They can no longer be made solvent and used again. These iron crystals are called hemosiderin.


10.
If you have to much hemosiderin, the function of your tissues will decline. For example, if this occurs in the eye, you may become blind! It all depends where the hemosidirin is stored.

So, please, don’t take iron supplements if you don’t need it!

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D.2.2. Erythrocytes Production

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