Individual Assignment

Hematology-Oncology Module/2017/1nd Term/3st Grade

By Nabilla Merdika Putri Kusuma, 1406642385

PBL-GD1: Blood Cells Turnover

I. Red Blood Cells Turnover

Red blood cells are manufactured from the hemopoietic stem cells in the bone marrow. These cells
are are known as erythtropietic bone marrow cells and are partially differentiated. When red blood
cells have to be manufactured, these cells go through various phases of development until the
mature red blood cell can be released into the bloodstream. This process of developing from
erythropoietic bone marrow cells to mature red blood cells takes about 7 days.1

The stimulus for producing red blood cells is hypoxia (low oxygen state). However, hypoxia alone
will not be sufficient to trigger the production of new red blood cells unless the
hormone erythropoietin is circulating in the bloodstream. This hormone is primarily produced by
the kidneys. The process of manufacturing red blood cells in known as eryrthropoiesis.1,2

I.I Normal red cell destruction

Red cell destruction usually occurs after a mean lifespan of 120 days when the cells are removed
extravascularly by the macrophages of the reticuloendothelial (RE) system, especially in the
marrow but also in the liver and spleen. As the cells have no nucleus, red cell metabolism gradually
deteriorates as enzymes are degraded and the cells become non‐viable. The RBCs destruction
process might happen at two sites, within the blood vessels or at tissues outside of it, where
macrophages reside.1

• Intravascular Destruction

If the red cell membrane is breached in the circulation the red cell is destroyed. This mode of
demise of the erythrocyte occurs at a low frequency normally, but may be the predominant mode of
destruction in pathologic conditions such as hemolytic disorders.2
• Extravascular Destruction
Most commonly the life of the red cell comes to an end when it is ingested by a macrophage.
Clearly, signals that allow the macrophage to distinguish the viable normal red cell from a damaged
or senescent cell must exist. Such signals may consist of decreased deformability and/or altered
surface properties:2
1. Decreased Deformability
The red cell does not circulate as the biconcave disc customarily observed under the microscope.
Instead, it is normally greatly distorted by the shear stresses in the circulation and such distortion is
an absolute requirement for the red cell to be able to negotiate the narrow slits that separate the
splenic pulp from the sinuses. The red cell membrane, a lipid bilayer, bends readily but has very
little capacity to stretch. Thus, deformability is largely a function of the excess red cell membrane
intrinsic to the biconcave disc shape of the cell, membrane composition, and to some extent, of the
viscosity of the hemoglobin solution within the cell. As the red cell loses membrane it may become
spherical in shape and loses its ability to deform.3
2. Altered Surface Properties
Most commonly happen in hemolytic anemia. The surface of the red cell membrane can be altered
by binding of antibodies to surface antigens, by binding of complement components, and by
chemical alterations, particularly oxidation of membrane components. Immunoglobulin (Ig) G-
coated red cells and red cells coated by the third component of complement (C3) are bound by Fc
receptors on macrophages and undergo partial phagocytosis. This results in the formation of a
spherocyte. The exact physiologic mechanism still needs further investigations.2

II. Fate of Destroyed Red Cells

1. Intravascular Destruction
• Hemoglobin
When red cells are destroyed in the vascular compartment, the hemoglobin escaping into the plasma
is bound to haptoglobin. A dimeric glycoprotein, each molecule of haptoglobin can bind two
hemoglobin dimers. The haptoglobin-hemoglobin complex is cleared from the plasma with a half-
life of 10 to 30 minutes. After the complex is carried to the liver parenchyma, the heme of the
hemoglobin is converted to iron and biliverdin by heme oxygenase and the biliverdin is further
catabolized to bilirubin. Free haptoglobin, in contrast to the hemoglobin-haptoglobin complex, has
a half-life of 5 days, and when large amounts of the rapidly turned over haptoglobin-hemoglobin
complex are formed, the haptoglobin
content of the plasma is depleted.2
• Heme
Free heme that is released into the
circulation is bound with plasma
glycoprotein hemopexin, which is
cleared from the plasma with a half-life
of 7 to 8 hours. The heme-hemopexin
complex is taken up by a low-density
lipoprotein-related receptor, CD91,
which are abundant in hepatocytes.
When the capacity of hemopexin to bind
heme is saturated, excess heme may
bind to albumin to form
3
methemalbumin.
Figure 1. Intravascular Destruction of RBCs (2)
2. Extravascular Destruction
Red cells that are engulfed by phagocytic cells are degraded within lysosomes into lipids, protein,
and heme. The proteins and lipids are reprocessed in their respective catabolic pathways. The
breakdown of haem from haemoglobin by microsomal heme oxygenase liberates iron for
recirculation via plasma transferrin mainly to marrow erythroblasts, and protoporphyrin, which is
broken down to bilirubin.2
3. Bilirubin Excretion
Bilirubin circulates to the liver where it is conjugated to glucuronides, which are excreted into the
gut via bile and converted to stercobilinogen and stercobilin (excreted in faeces). Stercobilinogen
and stercobilin are partly reabsorbed and excreted in urine as urobilinogen and urobilin. Globin
chains are broken down to amino acids which are reutilized for general protein synthesis in the
body.2
 Figure 2. Extravascular and Intravascular Destruction of RBCs (1)

II. White Blood Cells Turnover

The white cells are made up of four types of phagocyte, neutrophils, eosinophils, basophils and
monocytes, which protect against bacterial and fungal infections, and of lymphocytes, which
include B cells, involved in antibody production, and T cells (CD4 helper and CD8 suppressor),
concerned with the immune response and in protection against viruses and other foreign cells.
White cells have a wide range of lifespan.3

Figure 3. The Lifespan of WBCs (1)

Neutrophils are the most numerous peripheral blood leucocytes. They have a short lifespan of
approximately 10 hours in the circulation. About 50% of neutrophils in peripheral blood are
attached to the walls of blood vessels (marginating pool). After emigrating into tissue, the life span
of neutrophils can be significantly prolonged (24-48 hours). Programmed cell death (apoptosis)
accounts for significant removal of tissue neutrophils through phagocytosis by macrophages.
Apoptotic neutrophils lose the ability to release granular enzymes in response to external stimuli,
and marked changes in cell surface proteins occur, thus leading to phagocytosis.The constitutive
rate of apoptosis of neutrophils is altered by inflammatory cytokines and chemokines.3,4

Eosinophils have similar kinetics of production, differentiation and circulation to neutrophils; the
growth factor IL-5 is important in regulating their production. Release of their granule contents onto
larger pathogens aids their destruction and subsequent phagocytosis. Furthermore, apoptosis is the
universal mechanism by which cells undergo cell senescence in a manner that allows them to be
efficiently removed by macrophages without inducing an inflammatory response. Morphologic
observations have shown that eosinophil apoptosis is an unusual event in tissue and that most
eosinophils either die by cytolysis or migrate into the lumen where they do become apoptotic.3,4

Basophils are closely related to mast cells, both are derived from granulocyte precursors in the bone
marrow. The granule contents include histamine and heparin and are released following binding of
IgE to surface receptors. Monocytes circulate for 20–40 hours and then enter tissues, become
macrophages, mature and carry out their principal functions. Within tissues, they survive for a long
period of time, possibly months or years, and termed as reticuloendothelial system (RE). Tissue
macrophages are relatively resistant to apoptosis, compared with neutrophils, but this changes
during infection. Their active membrane turnover and endocytosis make them susceptible to toxic
agents, making them targets for clearance by surviving macrophages. Sublethal injury and infection
can also induce autophagy, increasingly recognized as an important component of inflammatory
and infectious diseases. Lymphocytes live for about 100 to 300 days. During this period, most
continually recycle among the lym- phoid tissues, lymph, and blood, spending only a few hours at a
time in the blood. erefore, only a small part of the total lym- phocytes are in transit in the blood at
any given moment.2,4

Conclusion
After erythropoiesis have completed and mature red blood cells are released into bloodstream, red
blood cells have a lifespan for about 120 days before they are being broken down into various
substances, which are further eliminated or reused by the body to produce new RBCs. This
destruction process could happen both intra- or extravascular, mostly at liver or spleen. White blood
cells’ lifespan and turnover vary broadly, ranging from hours to years, and highly depend on
various events which elicit immune response and the recruitments of leukocytes.1,2

References

1. Hoffbrand A, Moss P. Hoffbrand's essential haematology. 1st ed.

2. Lichtman M, Williams W. Williams hematology. 1st ed. New York: McGraw-Hill Medical;
2011.
3. Mehta A, Hoffbrand A, Gschmeissner S. Haematology at a glance. 1st ed. Chichester, England:
Wiley; 2014.
4. Sherwood L, Ward C. Human physiology. 1st ed. 2012.