Erythrokinetics Flashcards
Collection of all stages of
RBC throughout the body in the
bone marrow, peripheral blood,
vascular spaces within organs
Erythron
All RBCs regardless of their stage
throughout the body
Erythron
refers only to the cells in circulation
RBC Mass
STIMULUS TO RED BLOOD CELL PRODUCTION
Hypoxia
Location of the Primary oxygen-sensing system
Peritubular fibroblast of the kidney
Peritubular fibroblast is also known as
___________________ because they are primarily located in the interstitium of the kidney.
Peritubular interstitial cells
Actions of Primary oxygen-sensing System
Ability to sense whether
there is adequate O2 supply to the
tissues (particularly in kidney); once
inadequacy of O2 supply is
detected, they influence/trigger
EPO production
Two important functions of the primary
oxygen-sensing system
To sense inadequacy in oxygen
Subsequently influence or stimulate EPO Production
First human hematopoietic
growth factor to be identified
Erythropoietin
Gene for EPO is located at
chromosome 7
EPO is regulated by
Hypoxia-inducing Factors (HIFs)
How does hypoxia influence EPO
production?
- Once there is hypoxia, HIFs bind with the EPO gene.
- Binding of HIFs and EPO gene results in the transcription of EPO gene to EPO encoding and
production. - After EPO production, EPO is secreted by peritubular fibroblasts
- Secreted EPO binds with EPOR through the extracellular domains. Once it binds, there occurs conformational change in the receptor.
- Once conformational change in the receptor happens, it activates Janus Activated Kinase 2 (JAK-2) signal transducer
- Once JAK-2 is activated, it activates the signal transduction pathway and STAT5 pathway which results to transcription of specific genes in nucleus, enabling erythroid progenitor to differentiate or younger erythroid precursor cells to mature.
How does EPO influence RBC
production?
- For every ligand (substance that
binds to the receptor), there is a
corresponding receptor. Hence,
for every EPO receptor (EPOR),
there is a corresponding EPO ligand
Two domains of EPOR
Extracellular and Cytoplasmic domain
EPO activates this signal transducer located in the cytoplasmic domain of EPOR
Janus Activated Kinase 2 (JAK-2)
It is activated by JAK-2
Signal transduction and STAT5 pathway
Mediates the EPO (an intrinsic factor)
GATA1
EPO is produced primarily by
primarily in the kidneys (peritubular interstitial cells) in adult
Produced also EPO but in minimum amount
Liver
Structure of EPO
Thermostable, nondialyzable
Liver is a primary source of EPO in the glycoprotein hormone that has
carbohydrate unit and terminal sialic acid
Actions of EPO
■ Promotes early release of reticulocytes from the BM (SHIFT/ STRESS RETICS)
■ Preventing apoptosis cell death (major), thereby increasing the number of cells that will be able to mature into circulating RBCs
■ Reducing the time needed for cells to mature in the BM (↑ rate of cellular processes, ↓ cell cycle times)
How many days does Reticulocyte stay in the BM prior to their release?
1-2 days
Once Reticulocyte is in the Circulation, how many hours will it take to mature?
24 hours
shift in the release of the reticulocyte is termed as
Shift Reticulocyte
Called as _____________ because
in the event of physiological stress, such
as anemic stress, the body requires
increased production of RBCs.
Stress Reticulocytes
How does EPO force the release of
reticulocytes from the hematopoietic
cords?
- Reticular adventitial cells and endothelial cells - layer of cells that serves as barrier that separates the developing cells in the hematopoietic cords from that of the vascular sinuses.
- The developing cells must go through the layers of cells before going to the circulation from the bone marrow
Two Mechanisms of EPO in Promoting Early Release of Reticulocytes
- Creates conformational change in the adventitial cell layer
- Down regulates the receptor for adhesive molecules located in the membrane of developing cells
an adhesive molecule, is a composition of ECM secreted by stromal cells which anchors developing cells. This holds EPO in place.
Fibronectin
Mechanism to prevent apoptosis by EPO:
- Indirect Avoidance of Apoptosis
- Direct Avoidance of Apoptosis
- Induces production of anti-apoptotic molecule
two proteins needed to facilitate cell death:
- fasL (ligand)
- fas (receptor)
located or expressed by more mature erythroid precursor cells (polychromatophilic
normoblast, orthochromic normoblast, and polychromatophilic erythrocyte)
fasL
located or expressed by younger erythroid
precursor cells (pronormoblast and basophilic normoblast)
fas
How does Indirect Avoidance of Apoptosis of EPO happens?
● depletes the number of mature erythroid
precursor cells from bone marrow by promoting early release of these cells expressing fasL
lack of ____ inhibits apoptosis of fas-bearing
receptors among younger cells.
fasL
● reduced production of fasL in more mature
erythroid precursor cells to inhibit apoptosis thus the younger cells avoid the apoptotic signal from the older cells
Direct Avoidance of Apoptosis
Expressed anti-apoptotic molecules prevent the release of ______________
cytochrome C
initiator of apoptosis in the cell
cytochrome C
Activation of ______ activates the _______________ which produces anti-apoptotic molecules in cells bearing EPOR.
JAK-2 ; STAT5 pathway
Does hastened process of maturation affect the quality of the cells?
No, there are no general consequences to the quality of the cells since they still follow the process only that it is sped up.
have more basophilic cytoplasm because their stay in the bone marrow is not enough to dismantle organelles, amount of rRNA, as well as the basophilia of cytoplasm.
Premature reticulocytes
Erythrocyte Destruction
Eryptosis
process of cellular aging
Senescence
Changes that occur as the RBC ages:
● Alteration in the membrane – loss of sialic acid and lipids
● ↓ ATP levels – due to loss of glycolytic enzymes**
● ↑ calcium
● Appearance of senescent antigen – which makes RBCs more susceptible to destruction
● ↓ pH – promotes iron oxidation
Because RBCs lack mitochondria, they rely on
___________ which are needed for glycolysis (anaerobic pathway) for. production of adenosine triphosphate (ATP).
glycolytic enzymes
As the RBC mature/ages, the glycolytic
enzymes become exhausted, hence ____
is also depleted
ATP
uncontrolled movement of calcium inside the cell
calcium influx
Example of enzyme that regulate the concentration and movement of cations in and out of the cell
Calcium ATPase
Once there is a calcium influx, the cell will lose its
deformability or flexibility
The acidic pH will now promotes oxidation of iron (ferrous to ferric), hence _________ is formed which is incapable of transporting oxygen
methemeglobin
2 Ways in which RBC is Damaged
(RBC being destroyed in the process is
NORMAL, aged RBC must be removed
from the circulation)
Macrophage-Mediated Hemolysis (Extravascular Hemolysis)
Mechanical Hemolysis (Fragmentation or
Intravascular Hemolysis)
RBC destruction outside blood vessel by splenic macrophage
90% aged red cell destruction
Macrophage-Mediated Hemolysis
↑ Unconjugated bilirubin, Urine/fecal
urobilinogen
Spherocytosis, RH incompatibility
Macrophage-Mediated Hemolysis
RBC rupture within the blood vessel
10% aged red cell destruction
Mechanical Hemolysis
↓ Haptoglobin, Hemopexin
Schistocytes
ABO incompatibility
Mechanical Hemolysis
An increased in hemolysis extravascularly, will result to increased release of the protoporphyrin ring will be metabolized into
Bilirubin
spherocytes are present in this hemolysis
Extravascular Hemolysis
Major site of RBC destruction is the
red pulp of the spleen
serve as the major site of production after your RBC is being damaged due to normal aging
Spleen
serve as active site of RBC
destruction specifically for those RBC
that are severely damaged
Liver
Volume of blood that circulates in the
spleen is approximately
350ml
Movement through the red pulp is
usually
sluggish
In extravascular hemolysis, the available glucose in the surrounding blood is
depleted quickly as cell flow stagnates causing
slow down of glycolysis
RBC utilizes ______________ in order to generate ATP.
plasma glucose
e responsible for maintaining the high level of intracellular potassium while pumping sodium out of the cells
Sodium Potassium pump
IN Extravascular Hemolysis, The discoid shape is lost and the cell becomes a
Spheroid (Spherocytes)
the ability of cells to pass through narrow capillaries or small splenic spores that are even smaller than the size of RBC
Deformability
When an RBC lyses within a macrophage, _____ is removed from the heme. It can be stored in the macrophage as ______
Iron ; ferritin
The ___________ component of heme is degraded through several intermediaries to bilirubin, which is released into the blood and ultimately excreted by the liver in bile.
protoporphyrin
Fragmented cells are called
Schistocytes
❖ In intravascular hemolysis, the rupture
of RBCs results in the release of RBC
contents (particularly hemoglobin) which
leads to the presence of
free plasma hemoglobin
❖ Three ways to salvage free plasma
hemoglobin:
- binding of haptoglobin to free plasma hemoglobin
- binding of hemopexin to metheme
- metheme binds to albumin
binding of haptoglobin to free plasma hemoglobin will form
haptoglobin-Hb complex
Heme portion of methemoglobin is
called
metheme/hemin
When hemopexin is not yet available, metheme binds to
albumin
