THE ERYTHROPOIESIS PAGE

RBC's

Erythrocytes (RBC's) & several white blood cell (WBC or leukocyte) types are derived from common "hematopoietic stem cells" (hemocytoblasts) in the bone marrow.  These "pluripotential" stem cells (hemocytoblasts) in early developmental stages in the bone marrow can even form lymphocytes and platelets (this ability to replace every circulating cell type is important during recovery from severe infection - see below).

Erythropoiesis (RBC production) and granulocytic WBC production (neutrophils, eosinophils and basophils) occur in bone marrow.  Monocytes develop in bone marrow, but their final development occurs when they are converted to macrophages upon leaving the circulation and entering the mucosal tissues.  Platelets also develop in bone marrow.  Lymphocytes are produced in the bone marrow, but often leave marrow to undergo maturation elsewhere, for example, in the lymph glands, small intestine, spleen, skin & thymus.  However, the pluripotential stem cells found in bone marrow are capable of developing into lymphocyte and platelet stem cells in the bone marrow if necessary (eg. in bone marrow transfers or following severe infections that wipe out most of the lymphocytes).

lymphocytes

lymph glands

Platlets

Erythropoiesis (formation of erythrocytes = RBC's)

RBC's carry O₂ to all cells of the body. They also assist in the removal of CO₂ and H⁺ (acid) from the tissues.  Because of their large protein content (they are 33% by weight hemoglobin), they act as excellent carriers of an important part of the "protein buffering system."  Mature RBC's are anucleate and have few organelles.  RBC's have no mitochondria and must generate ATP via anaerobic glycolysis, presumably so that they don't use up the O₂ they transport.

"Spectrin" is a flexible cyto-skeletal protein which allows RBC's to bend & squeeze through capillaries.  In order to allow the cell membrane to flex, the "hinge-like" spectrin is found lining only the inside of the RBC membrane.  The RBC lifespan is approximately 120 days, at which point the spectrin proteins are breaking apart such that the RBC is "fractured" within the microcirculation of the spleen.

Just a few little facts about RBC's:

RBC's outnumber WBC's about 800 to 1

Human female RBC count is about 4-5 million/mm³

Human male RBC count is about 5-6 million/mm³

Erythropoiesis (formation of RBC's) occurs in red bone marrow (myeloid tissue) or blood sinusoids (containing immature blood cells).  As RBC's mature, they move through the thin walls of the sinusoids to enter the bloodstream.  All blood cells arise from hematocytoblasts (multipotential or pluripotential cells) in the red bone marrow.  "Committed" cells cannot change pathway.

Myeloid stem cell -> progeny cell -> pro-erythroblast (committed) -> erythrocyte (several stages)-takes 3-5 days; individual RBC matures like this:

1) the immature erythrocytes produce lots of ribosomes

2) the ribosomes produce lots of hemoglobin

3) the erythrocyte nucleus is ejected & most organelles are lost (RBC's are actually released into circulation at the reticulocyte stage - reticulocytes still contain some ribosomal RNA; reticulocytes mature into "adult" RBC's within 1 day in circulation.

RBC destruction & formation must occur in balance.  If there is an insufficiency of RBC's (anemia) we will suffer hypoxia.  If there is an excess of RBC's (polycythemia), the blood becomes overly viscous, making blood passage through capillaries more difficult.  The increased resistance to blood flow associated with polycythemia puts excess strain on the heart, and is one of the major reasons that traditional blood doping methods were not successful.

Adult RBC production is approximately 200 billion RBC's per day.  Each day, we produce approximately the volume of RBC's that would be found in 100 mL's of whole blood.  This means that RBC's are produced at the astonishing rate of 2.3 million/sec in healthy adults.

Nutrient requirements for erythropoiesis are "universal."  This means that, since we are building a large number of cells, and all nutrients are required to build cells, all nutrients are required for erythropoiesis.  More specifically, erythropoiesis depends on ferrus iron (Fe²⁺) and "Vitamin B complex" for Hb synthesis.

Erythropoietin (EPO):  Erythropoiesis is promoted by the hormone erythropoietin.  Erythropoietin is a glycoprotein hormone produced and released primarily from the kidneys but also from the liver in response to decreased partial pressure of arterial O_2.   Thus, RBC production may be compromised in kidney or liver disease. Erythropoietin stimulates maturation of committed cells. Testosterone also stimulates erythropoietin production, and, together with the higher muscle mass in males, seems to account for the higher PCV in males than in females.

RBC Breakdown, and Iron Metabolism: The RBC lifespan is about 100-120 days. Eventually RBC's are fractured in the small circulatory channels of the spleen.  For this reason, the spleen is sometimes referred to as the "RBC graveyard."  As RBC's are ruptured they release large quantities of Hb.  The iron that is contained in the Hb must be handled very carefully by the body.  There is very little free iron in the body; iron is a heavy metal and is toxic.  About 65% of the iron in the body is complexed with Hb (the rest is in the liver, spleen & bone marrow bound to "ferritin" (also known as "hemosiderin") in cells or bound to "transferrin" in blood.  Ferritin and transferrin are "iron binding proteins."  Iron released during RBC destruction is complexed and stored for later use or lost in feces, urine & even perspiration.

Dying erythrocytes are engulfed by macrophages.  Products of RBC destruction are processed in the spleen and liver to produce globin and heme.   The globin portions are simply broken down to their component amino acids and used to produce energy or new proteins.  Heme is degraded to biliverdin -> biliverdin is then degraded to iron and bilirubin (bilirubin is a bile pigment) ---> bilirubin then combines with a plasma protein and is transported to the liver.  In the liver, bilirubin is conjugated with a glucuronic acid moiety, making the bilirubin less lipid soluble so it can be removed from the body, and then the bilirubin is secreted into the bile.

Macrophages

Heme

Look through the steps above and you will see why bilirubin accumulates when liver function is compromised.  If liver function is impaired, some of the bilirubin will not be inactivated by conjugation with glucuronic acid and cannot be secreted in the bile.  If all of the bilirubin is not secreted, it will begin to accumulate in the body.  As bilirubin is a bile pigment, it will cause body tissues to become "jaundiced" (yellow color).

In the colon, bilirubin is converted to stercobilin, a brown pigment, by bacterial action.  A small amount of bilirubin may be converted to urobilin by gut bacteria, the liver and the spleen.  Urobilin, like bilirubin, is a yellow pigment, and is excreted in urine.