Red Blood Cell Overview

Erythropoietin

regulates production RBCs

Created in kidneys

works on bone marrow

EPO has ___ sugars

4

EPO utilizes Glycoprotein hormone with ____ glycosylation sites

4

for EPO, the ends of carbohydrate chains are

variably sialylated

sialic acid moieties in epo

serum half life

as O2 drops, EPO ____

increases

in a healthy person, EPO is in a _________ with _____ levels of EPO.

steady state; low

EPO in a hypoxic patient

2 hypoxia-inducible factors (HIF-1alpha and HIF-1beta) will dimerize and bind to hypoxia-responsive elements in EPO gene promoter, which causes increase EPO production.

HIF-1alpha and HIF-1beta are produced under _______ conditions.

all

healthy people always have a little EPO production but it is dramatized when in ______.

oxidative stress

Ubiquitin tag

added under normal conditions

tags proteins for cellular destruction when the protein is not necessary

EPO effect on bone marrow

promotes proliferation, differentiation and survival

EPO stimulates differentiation of

progenitors → precursors → reticulocytes → erythrocytes

EPO pushes _____ out earlier than normal

reticulocytes

increased EPO shields _________ from apoptosis.

erythroid precursors

definition of proliferation during increase EPO in bone marrow

increasing number of different precursor cells while allowing products to differentiate.

allows quicker differentiation.

hemoglobin

globular protein made of 2 different pairs of polypeptide chains and 4 heme groups.

alpha-like globin family consists of genes:

HBZ

HBA2

HBA1

alpha-like globin family is found on chromosome(s)

16

alpha-like globin family produces chains:

zeta. alpha

main developmental stage in which alpha globin is used

embryonic, fetal→ adult

beta-like globin family is found on genes:

HBE1

HBG2

HBG1

HBD

HBB

beta-like globin family is found on chromosome:

11

beta-like globin family produces these chains:

epsilon, gamma, delta, beta

epsilon chain of beta-like globin is used

embryonic stage

gamma chain of beta-like globulin is used

feta

delta chain of beta-like globulin is used

adult, minor

beta chain of beta-like globulin is used

adult, major

zeta chain of alpha like globulin is used

embryonic stage

HBE1 gene produces __ chain

epsilon

HBG1 and 2 gene produces __ chain

gamma

HBD gene produces __ chain

delta

HBB gene produces __ chain

beta

alpha-globin gene cluster

beta globulin gene cluster

1

alpha

2

alpha

4

beta

5

epsilon

6

zeta

7

gamma

8

delta

9

alpha

10

beta

during yolk sac phase ____ are produced

hemoglobin gower 1

hemoglobin gower 2

hemoglobin portland

hemoglobin gower 1

2 zeta; 2 epsilon

hemoglobin gower 2

2 alpha, 2 epsilon

hemoglobin portland

2 zeta; 2 gamma

hemoglobin f

fetal hemoglobin

2 alpha; 2 gamma

dominates during late pregnancy and declines just before birth

hemoglobin at birth

hemoglobin f

hemoglobin a

hemoglobin a

2 alpha; 2 beta

10-40% of total hemoglobin

hemoglobin f

2 alpha; 2 gamma

60-90%

adult hemoglobin

hemoglobin a

hemoglobin a2

hemoglobin f

hemoglobin a2

2 alpha; 2 delta

minor component (3.5%)

alpha chains of hemoglobin contains ~ ____ amino acids

141

Beta chains of hemoglobin contain ~_____ amino acids

146

steps to heme biosynthesis

1. mitochondria creates amino levulinic acid

2. moves to cytoplasm and is converted to porphobilinogen

3. enzymes convert porphobilinogen to coproporphyrinogen

4. transported back to mitochondria to continue converting to protoporphyrin IX

5. combines with Fe2+ to make heme

6. protoporphyrin IX/Fe moved to cytoplasm to combine with globulin

iron is one of the _______ metals in the human body

most essential

iron in the metabolic processes

plays a critical role, important for oxygen transport and cellular respiration

body cannot excrete excess iron

iron balance is maintained through controlled absorption in GI tract

we lose small amounts of iron each day through

shedding of skin, hair or sloughing of intestinal epithelial cells

adult person typically eats ____ mg iron /day

10-20

the _____ absorbs 1-2 mg iron/ day

duodenum

body iron losses _____ mg/day

1-2

Heme

ferrous (Fe2+)

comes from animal sources

ionic/non-heme

ferric (Fe3+)

comes from mostly vegetable sources and must be reduced to Fe2+ before use

Hephaestin

oxidizes Fe2+ to Fe3+ to allow transport of iron to Apotransferin

Apotransferin

transferrin without iron bound

plasma protein

holotransferrin/ transferrin

transferrin molecule with 2 iron molecules bound.

allows for safe travel through the body/ storage of iron

once transported, cells will endocytose iron to transport across the cell membrane and it can either

1. convert to Fe2+ form for immediate cellular function

2. store in Fe3_ form using Ferritin or Hemosiderin

Ferritin

cytosolic protein used to store iron to be readily-accessible for release when needed

goes to bone marrow and muscles or liver

hemosiderin

cytosolic protein used to store iron for longer term storage (less accessible)

liver (Fe3+)

iron distribution in red blood cells

~70% iron is incorporated into hemoglobin in circulating RBC and developing erythroid precursors

iron distribution in storage

~20%

stored in ferritin or hemosiderin forms

stored in hepatocytes, macrophages of spleen and bone marrow

“other components” in distribution of iron

myoglobin within muscle

cytochromes

iron-containing enzymes (everywhere in the body)

plasma (bound to transferrin molecules)

pronormoblast

12-20 micrometers

oval nucleus

N:C ratio 8:1

dark blue cytoplasm

can divide and create two daughter cells

function: gathering compounds to start hemoglobin production

Basophilic normoblast

10-15 micrometers

more condensed nucleus; N:C ration 6:1

extremely dark cytoplasm

can divide into 2 daughter cells that can mature

function: hemoglobin synthesis occurs

polychromatic normoblast/ rubricyte

10-12 micrometers

super condensed nucleus with N:C 4:1

cytoplasm start to get lighter due to increased hemoglobin concentrations

last stage that can divide into two daughter cells that can mature

function: hemoglobin synthesis is ramping up

orthochromatic normoblast

8-10 micrometers

completely condensed nucleus N:C 1:1

cytoplasm is almost fully pink due to increase Hb concentrations

function: hemoglobin synthesis fully underway; cell will eventually eject nucleus entirely

an erythrocyte cannot create new hemoglobin after

nucleus ejection

polychromatic erythrocyte

8-8.5 micrometers

no nucleus present

cytoplasm is pinker but has blue/purple tint due to remnants of RNA and ribosomes

called “reticulocyte” when stained with supravital stain

can be released into the bloodstream and visualized on a blood smear

Erythrocytes

7-8 micrometers

cytoplasm is fully pink with clear central pallor

most mature stage and most predominant cell type in peripheral blood

function: hemoglobin is working full time to transport oxygen throughout the body

full maturation sequence in order

pronormoblast → basophilic normoblast → polychromatic normoblast → orthochromatic normoblast → polychromatic erythrocyte → erythrocyte

purpose of fully mature and loaded hemoglobin cell

to transport oxygen from the lungs, and through the blood stream to other tissue cells

oxygen transport function of hemoglobin

binds oxygen in the lungs to drop it off in the tissues

can carry up to 4 O2 molecules

CO2 transport hemoglobin function

diffuses into RBC and mixes with water to create carbonic acid (H2CO3)

breaks down to release H+ and bicarbonate (HCO3)

Nitric Oxide Transport hemoglobin function

secreted by vascular endothelial cells and triggers relaxation and vasodilation of capillaries and veins

hemoglobin has an ______ binding capacity

allosteric

increased hemoglobin-O2 affinity (left shift) results in

decreased CO2

decreased temperature

decreased [H+]

decreased DPG

increased pH

decreased hemoglobin-O2 affinity (right shift) results in

increased CO2

increased temperature

increased [H+]

increased DPG

decreased pH

RBC membrane is made of

50% proteins, 40% phospholipids, 10% cholesterol

phospholipid function in RBC membrane

provides fluidity

cholesterol in rbc membrane

provides rigidity

protein complement in rbc membrane

provides functionality

composed of integral membrane proteins and peripheral membrane proteins

integral membrane proteins

pass completely through the membrane

transport molecules across the membrane

peripheral membrane proteins

internal layer of bilayer

signals inside layers

deformability

ability of RBC to squeeze through narrow capillaries and splenic slits without rupturing

phospholipid outer layer

phosphatidylcholine and sphingomyelin

inner layer of phospholipid bilayer

phosphatidylethanolamine and phosphatidylserine

flippases and floppases

maintain the composition/structure of the phospholipid asymmetry by facilitating the movement of phospholipids between the inner and outer leaflets.

flippase

moves phospholipids from the outer layer to the inner layer

requires ATP