Chapter 5 ERYTHROKINETICS Flashcards
dynamics of RBC production and destruction
Erythrokinetics
name given to the collection of all stages of erythrocytes throughout the body
Erythron
the developing precursors in the bone marrow and the circulating erythrocytes in the peripheral blood and vascular spaces within organs, such as the
spleen
When the term erythron is used, it conveys the concept of a
The erythron is the entirety of erythroid cells in the body
unified functional tissue
The erythron is distinguished and refers only to the cells in circulation
RBC mass
If tissue oxygen is inadequate, RBC production and the functional efficiency of existing cells must be
enhanced
primary oxygen-sensing system of the body is located in
peritubular fibroblasts of the kidney
too little tissue oxygen, is detected by the peritubular fibroblasts, which then produce erythropoietin (EPO)
Hypoxia
major stimulatory cytokine for RBCs
erythropoietin (EPO)
increased RBC destruction, or other factors that diminish the oxygen-carrying capacity of the blood, the production of EPO is increased
hemorrhage
Increased EPO production, caused by hypoxia, is regulated by a family of transcription factor proteins, called
hypoxiainducible factors (HIFs)
Erythropoietin: Structure
EPO is a thermostable, nondialyzable, glycoprotein hormone with a molecular weight of
34 kD
Erythropoietin: Structure
both of which play a role in the biologic activity of the hormone
carbohydrate unit and a terminal sialic acid unit
Erythropoietin: Action
EPO is a true hormone, being produced at one location and acting at a distant location
one location (kidney) and acting at a distant location (bone marrow)
Erythropoietin: Action
It is a growth factor (or cytokine) that initiates an intracellular message to the developing erythroid cells; this process is called
signal transduction
The interaction of EPO with its receptor initiates a cascade of intracellular events that ultimately leads to increased cell division and maturation
increased intestinal iron absorption and hemoglobin synthesis, and more RBCs entering the circulation
signal transducers that are associated with the cytoplasmic domains of the EPO receptor
Janusactivated tyrosine kinase 2 (JAK2)
EPO has three major effects:
(1) allowing early release of reticulocytes from the bone marrow,
(2) preventing apoptotic cell death, and
(3) reducing the time needed for cells to mature in the bone marrow.
EPO induces changes in the adventitial cell layer of the bone marrow/sinus barrier that increase the width of the spaces for RBC egress into the sinus.
Early release of reticulocytes
reticulocytes that are still very basophilic because they have not spent as much time degrading their ribosomes and RNA or making hemoglobin as they normally would before entering the bloodstream. These are called
because they have been shifted from the bone marrow early
shift reticulocytes
can be released early in cases of extreme anemia when the demand for RBCs in the peripheral circulation is great
nucleated RBCs (i.e., erythroblasts or normoblasts)
decreasing apoptosis, the programmed death of RBC progenitors
Inhibition of apoptosis
18 to 21 days to produce an RBC from stimulation of the earliest erythroid progenitor (BFU-E) to release from the bone marrow
Apoptosis: programmed cell death
instead of storing mature cells for emergencies
body produces more CFU-Es than needed at all times
the erythroid progenitors have about an 8- to 10-day head start in the production process
increased demand for RBCs
sequential process characterized by, among other things, the degradation of chromatin into fragments of varying size that are multiples of 180 to 185 base pairs long
not associated with inflammation
Apoptosis
During the sequential process of apoptosis, the following morphologic changes can be seen:
condensation of the nucleus,
causing increased basophilic staining of the chromatin;
nucleolar disintegration; and
shrinkage of cell volume with concomitant increase in cell density and compaction of cytoplasmic organelles
produces nuclear DNA fragments consisting of multimers of 180 to 185 base pair segments
last stage of degradation
many erythroid progenitors will undergo apoptosis
One effect of EPO is an indirect avoidance of apoptosis by removing an apoptosis induction signal
Evasion of apoptosis by erythroid progenitors and precursors
cell production should be at a low rate because hypoxia is not present. The excess early erythroid
precursors should undergo apoptosis
EPO levels are low
A second mechanism for escaping apoptosis exists for erythroid progenitors:
direct EPO rescue from apoptosis
able to stimulate production of various antiapoptotic molecules, which allows the cell to survive and mature
EPO
EPO’s effect is mediated by the transcription
factor, _____ which is essential to red cell survival
GATA1