Erythrokinetics Flashcards
Dynamics of RBC production and destruction
Erythrokinetics
Collection of all stages of RBC throughout the body in the BM, PB, vascular spaces within organs
Erythron
The entirety of all erythroid cells (rbcs), whether it is
mature or immature
Erythron
refers only to the cells in circulation
RBC mass
a stimulus to RBC production
Hypoxia
main role of RBC
carry oxygen
It has the ability to sense adequacy of oxygen supply to tissues
Primary oxygen-sensing system
Location of primary oxygen-sensing system (be very specific)
Peritubular fibroblast of the kidney
Mechanism of POSS
Once inadequacy of O2 supply is detected, it triggers EPO production
Diminished or decrease of tissue oxygenation in our body
Hypoxia
Organ responsible in detecting oxygen adequacy in tissues
Kidney
Give 2 very important features of oxygen sensing system
- It has mechanism to detect inadequacy or adequacy if O2
- It has a mechanism that can influence or trigger the increase of RBC production by triggering EPO
Major stimulatory cytokine or stimulatory hematopoietic growth factor for RBCs
erythropoietin
most sensitive cell to EPO
Colony Forming Unit - E / CFU-E
erythroid progenitor cells that has the most EPOR
CFU-E
First human hematopoietic growth factor to be identified
Erythropoietin
Location of gene for EPO
Chromosome 7
it regulates the increase of EPO production as a response / physiologic adaptation to hypoxia
Hypoxia-Inducible Factors (HIFs)
EPO is found in the ff cells:
Erythroid Progenitor Cells (BFU-E and CFU-E)
Early erythroid precursor cells (Pronormoblast and Basophilic Normoblast)
Transcription factor that mediates EPO
GATA1
It serves as the primary source of EPO from newborn to adulthood / throughout life
Kidney
Specific part of the kidney where EPO in produced
peritubular insterstitial cells of kidney
It is primary source of EPO in the newborn
Liver
Complete the statement: EPO is a thermostable, nondialyzable, glycoprotein hormone that has ________ unit & _______ unit
carbohydrate ; terminal sialic acid
Nice to know: molecular weight of EPO
34 kD
3 major actions of EPO in increasing RBC Production
- It promotes early release of reticulocytes from the BM
- MAJOR ACTION: Prevents apoptotic cell death
- Reduces the time needed for cells to mature in the BM
Refers to reticulocytes released to the peripheral blood earlier than intended
Shift / stress reticulocye
In normal process, reticulocytes will stay in the BM for:
1-2 days or 2-3 days before released in circulation
In normal process, retics are in the circulation for a period of ___ before becoming RBCs
24 hrs / day
Location of developing cells in the BM
hematopoietic / extra vascular cords
developing blood cells are separated from the vascular sinuses by 2 layers of cells, namelyL
Adventitial Cells
Endothelial Cells
What does the EPO does in the cells surrounding the developing RBCS in order to release shift reticulocytes
Conformational change that causes widening of spaces between the reticular adventitial cells
It secretes extracellular fluids that anchor developing cells
stromal cells
developing cells are arranged in their proper location by:
semi extracellular matrix
Adhesive molecule in charge of anchoring developing cells in their proper location
fibronectin
EPO’s action to be able to release shift/stress retics despite of being anchored in the hematopoietic cord
down regulate or reduce the expression of receptors for adhesive molecules
Where are receptors for adhesive molecules found
membrane of reticulocytes
In cases where the body has increase RBC demand, the reticulocytes will be released in the circulation in _____, depending on the severity of the condition
less than 24 hours
these are cells with EPOR
Erythroid progenitor cells
erythroid precursor cells
cells that respond to EPO in healthy circumstances
cells that are less sensitive to EPO
In case of hypoxia, what type of cells respond to EPO
cell that are highly sensitive to EPO
portion of EPOR where EPO binds
extracellular domain
binding of EPO to EPOR activates the signal transducer _____, which is associated with the cytoplasmic domain of EPOR
Janus Kinase 2 / JAK 2
After activation of JAK2, it will further cause the activation of diff. signal transduction pathways (STPs) going to the nucleus of the cell. One of which is the:
STAT5 Pathway / Signal transducer and activator of transcription 5
It bears the receptor
target cell
amount of RBC lost everyday
approximately 1%
Under normal conditions: Loss of 1% RBC Daily will result to EPO increase but only to _____
compensate
In severe anemia, the EPO production can increase ____ regardless of pathologic mechanism causing it
1,000-fold (1,000x)
EPO production fluctuates significantly or significantly increase particularly during:
hypoxic conditions or
anemic stress
What happens to hypoxia-inducible factors in non hypoxic conditions / normal state
HIFs are being subsequently degraded because we do not need them
In hypoxic conditions, the one that senses / responds to it first is the:
Primary Oxygen Sensing System (POSS)
What happens to HIFs in hypoxic conditions?
HIFs will accumulate then will activate certain transcription genes that will promote response to adopt to hypoxic conditions
Binding of HIFs to EPO gene leads to
increased transcription of the EPO gene, leading to increase EPO protein production
Once the normal tissue oxygenation is restored back to normal, what will then happen?
The peritubular interstitial cells detects this which leads to degradation of HIFs = No HIFs to binds to EPO genes, EPO production decreases, RBC production decreases
other function of HIFs
enhance cellular iron
intestinal absorption
stimulate maturation and proliferation of erythroid progenitor cells
How to differentiate shift/stress reticulocyte from normal/typical reticulocytes?
Apply Wright stain.
Normal polychromatic erythrocyte have pink as predominant and minimal blue.
Shift retics are more baophilic
How long does it take for shift reticulocytes to mature in the circulation
24hrs (normal) + 48hrs = 72 hours / 3 days
What causes the basophilia of shift reticulocytes
Ribosomes and rRNA
Why can’t our body store RBCs?
All of RBCs must be in circulation because their primary function is to provide oxygen to tissues. We cannot store them because of their limited life spam of 120 days. In short, all of them will age and die.
Body’s compensatory mechanism in case of emergency since we cannot store RBCs
Produces excess colony forming unit E
Why our body produces excess CFU-E, and why not just BFU-E when it will also eventually mature into RBC?
CFU is more lineage restricted on what type of cell it will differentiate into
Fas is expresses on these cells
Erythroid progenitor cells such as the BFU and CFU and early erythroid precursor cells such as pronormoblast and basophilic normoblast
FAS L is expressed on these cells
More mature erythroid precursor cell such as the polychromatophilic normoblast, orthochromatophilic normoblast, and polychromatophilic erytheocytes
In normal state, how does apoptosis occur when extra RBCs are not needed?
Fas-L bearing erythroid precursor cells collide with those Fas-bearing erythroid precursor cells. Fas-L bearing (ligand) cells bind with the Fas bearing (receptor), signal will be created and received by the cells bearing the receptors, leading to its death
Give an example of anti-apoptotic molecule
BCL-XL
Where is BCL-XL produced and expressed
Mitochondrial membrane of the developing cell
Why is BCL-XL, an apoptotic molecule, expressed on the “mitochondrial membrane” of the developing cell
The mitochondria is capable of producing apoptotic substance, named “CYTOCHROME C”. We have to prevent release of this substance in exchange of apoptosis
G0 is also known as
Resting phase
G1 is also known as
Cell growth phase
How does EPO reduces the time needed for cells to mature in the BM?
cytokine (EPO) decreases the transmit time from G0 (resting phase) to G1 (cell growth phase), for faster cell division or mitosis, thus increasing the rate of normoblastic proliferation.
Erythrocyte destruction is termed as
Eryptosis
Process of cellular aging is termed as
Senescence
