Blood – Erythrocytes Flashcards
What is the shape of erythrocytes (RBC)?
biconcave disc
Why is it important that erythrocytes have high SA:V ratio?
blood needs easy access to oxygen to be able to carry as much oxygen as possible
Do erythrocytes have nuclei?
no
Why are erythrocytes deformable?
need to deform when moving through capillary beds – some capillaries have smaller diameter than RBC
What does the rouleaux formation of erythrocytes do?
prevents deformation (can block blood flow to a region)
How is rouleaux formation of erythrocytes formed?
higher protein content in blood promotes sedimentation of RBC, causing them to stick together and stack in rouleaux formation
What is the carbonic anhydrase concentration of erythrocytes?
high – important for carbonate buffering system
What are erythrocyte membranes highly permeable to?
anions (Cl- and HCO3-)
What do erythrocytes bind?
gas (particularly O2)
also takes CO2 from tissue back to lungs
What is hemolysis?
hypotonic ECF – low [solute] in plasma
movement of fluid from plasma (low osmolality) to cells (high osmolality)
swelling of cells → burst
What is crenation?
hypertonic ECF – high [solute] in plasma
movement of fluid from cell (low osmolality) to plasma (high osmolality)
shrinking of cell
Where does erythropoiesis occur?
primarily in bone marrow
How long does it take for reticulocytes to become erythrocytes?
once reticulocytes are released from bone marrow, they mature in 1-2 days
What are factors involved in erythropoiesis? (6)
- tissue oxygen
- erythropoietin (Epo)
- cytokines (IL-3)
- metals
- folic acid and vitamin B12
- sex steroids
Factors Involved in Erythropoiesis
Tissue Oxygen
- decreased O2 due to hemorrhage
- decreased O2 due to high altitude
Factors Involved in Erythropoiesis
Metals
- iron: for biosynthesis of heme
- copper: component of ceruloplasmin (oxidizes Fe2+ to Fe3+)
Factors Involved in Erythropoiesis
Folic Acid and Vitamin B12
coenzymes in reaction that affects DNA synthesis
Factors Involved in Erythropoiesis
Sex Steroids
- testosterone: increases erythropoiesis
- estrogen: decreases erythropoiesis
What is erythropoietin (Epo)?
hormone that regulates generation of new erythrocytes
What is hypoxia?
low oxygen delivery, sensed in kidney
What promotes synthesis of Epo?
hypoxia-inducible factors (HIF-1α and β)
What can hypoxia result from?
- ↓ blood volume
- ↓ pulmonary function
- ↓ cardiac function
- ↓ erythrocyte oxygen carrying capacity
Epo Regulation of Erythropoiesis
- burst forming unit erythroid (BFU-E) and colony forming unit erythroid (CFU-E) are both responsive to Epo stimulation – increased survival
- when plasma Epo increases, increased progenitor survival enhances proliferation
- Epo inhibits apoptosis
Iron Metabolism Process
- Absorption: Fe2+ (ferrous) is absorbed through intestinal mucosa
- Oxidation: ceruloplasmin oxidized Fe2+ to Fe3+ (ferric)
- Transport: in circulation (plasma), Fe3+ binds to and is transported by transferrin
- Uptake: iron is delivered to tissues with transferrin receptors (ie. bone marrow, liver, spleen) by transferrin
- Incorporation: in erythroblasts, Fe3+ is reduced to Fe2+ and incorporated into heme, which is then incorporated into hemoglobin
- Storage: ferritin will bind and store excess iron (primarily in bone marrow and liver)
Hemoglobin Synthesis Process
- Fe3+ uptake into erythroblasts occurs through transferrin receptor-mediated endocytosis
- Once released into cytosol, Fe3+ can be:
- reduced to Fe2+ by ferrireductase for entry into mitochondrion
- stored by ferritin (Fe3+ form) in cytosol
- Ferrochelatase catalyzes insertion of Fe2+ into protoporphyrin (mitochondrion) to form heme
- Heme joins with a polypeptide to form a hemoglobin chain (α or β)
What is the first step in hemoglobin synthesis?
bottleneck in hemoglobin synthesis
need vitamin B6 to initiate process
What is the last step in hemoglobin synthesis?
protoporphyrin incorporates iron into middle of porphyrin ring
protoporphyrin + iron = hemo molecule
need iron in heme because it coordinates binding of oxygen
Why do we need iron in heme?
coordinates binding of oxygen
What is the structure of adult hemoglobin (HbA)?
tetramer composed of four hemoglobin chains
- two α chains and two β chains (α2β2) – each has heme group
- each hemoglobin molecule can bind four O2 molecules – one O2 molecule to ferrous iron in each heme group
What does it mean by oxygen binding is cooperative?
if one oxygen binds, it becomes easier for other chains to bind oxygen
What does 2,3-DPG do?
lowers affinity for hemoglobin or oxygen
What are 2 other forms of hemoglobin (other than HbA) found in adult blood?
- HbF (α2γ2): fetal hemoglobin – < 1% in adults
- HbA2 (α2δ2)
How does HbF differ from HbA?
curve is shifted left of HbA curve – helps with oxygen transfer from maternal blood to fetal blood (higher ability to bind oxygen than maternal Hb)
What is hemoglobin switching?
changes in global chain production during development
Which chromosomes are involved in production of alpha chain of hemoglobin?
chromosome 16
Which chromosomes are involved in production of beta chain of hemoglobin?
chromosome 11
Which chromosomes are involved in production of gamma chain of hemoglobin?
chromosome 11
What type of chains does HbF have?
2 alpha and 2 gamma chains
How does HbF turn into HbA?
transition from HbF to HbA happens rapidly
- gamma chains decrease
- beta chains increase
Which chains are always needed for Hb?
alpha chains are always needed in Hb to form best tetramer possible
other chains change – as adults, you have a combination
What are 3 disorders of hemoglobin synthesis?
- porphyrias
- thalassemias
- sickle cell disease
What is porphyrias?
results in abnormal build-up of porphyrin precursors or porphyrins in bone marrow (erythropoietic) and/or liver (hepatic)
What causes porphyrias?
heme biosynthesis pathway has eight enzymes – absence of any one of these enzymes can result in porphyria
What are symptoms of porphyrias?
similar to things associated with vampirism
What is thalassemias?
results in reduced/absent synthesis of one or more globin polypeptide chains
inherited
What are the 2 types of thalassemias?
α-thalassemia
β-thalassemia
What is α-thalassemia?
disordered α chain synthesis
lethal in utero – not able to form functional hemoglobin
What is β-thalassemia?
disordered β chain synthesis
- slight upregulation of gamma chains, and delta chains
issues in early childhood – not relying on beta chains in utero
What do both subtypes of thalassemia do?
- alter α:β chain ratio, which reduces O2 binding to hemoglobin
- excess iron content – body increases iron absorption because it thinks you’re not getting oxygen due to iron issues
What is sickle cell disease?
results from sickle β-globin gene
- deoxygenated sickle hemoglobin can aggregate and lead to blockage of microcirculation
- mutation causes sickle shape
What are senescent erythrocytes?
display progressive weakening of their cell membrane – eventually leads to rupture of membrane and release of hemoglobin (self-destruction)
Where does erythrocyte breakdown occur?
in spleen, where erythrocytes pass through especially tight spaces (3μm wide)
weakened membrane bursts when passing through tight spaces
What phagocytoses hemoglobin?
hemoglobin rapidly undergoes phagocytosis by tissue macrophages (aka reticuloendothelial system)
- monocytes enter tissue from circulation and become fixed macrophages
- once stimulated, fixed macrophages break away to become mobile macrophages
- Kupffer cells (liver) and macrophages (spleen and bone marrow) play key role in hemoglobin degradation into globin and heme
What happens after the breakdown of hemoglobin?
globin is further broken down into amino acids, which then rejoin the amino acid pool for protein synthesis
Hemoglobin Metabolism Process
- Heme:
- releases Fe2+, which is subsequently oxidized to Fe3+ and transported in plasma by transferrin
- produces straight chain of four pyrrole nuclei, which is ultimately converted to bilirubin for excretion
- Bilirubin rapidly binds to albumin for transport in plasma
- Albumin transports plasma bilirubin to liver, where it is taken up and conjugated with glucuronic acid to form bilirubin glucuronide
- transported to bile duct - Bilirubin glucuronide is secreted from bile duct into small intestine for excretion
- Approximately 50% of conjugated bilirubin is converted into urobilinogen in intestine
- Urobilinogen can then be:
- recycled to liver, where it is then re-excreted into intestine – keeps occurring until it goes down pathway (b) or (c)
- reabsorbed into portal circulation, and subsequently transported to kidneys for filtering and excretion in urine (as urobilin – gives urine yellow colour)
- converted to stercobilin by bacteria in GI tract for excretion in feces – gives feces brown colour
