Week 2 Flashcards
(44 cards)
what is hemoglobin production dependent on and when is it made
-iron supply and delivery
-protoporphyrin synthesis (heme is composed of Protoporphyrin IX and 1 central Ferrous iron)
-globin and heme synthesis
-heme allows for reversible oxygen binding by hemoglobin and Globin surrounds and protects the heme molecule
-65% of hemoglobin is synthesized in the nucleated stages and the rest occurs in Retics
-mature RBCs cannot make hemoglobin because they do not have nuclear parts or organelles like ribosome to allow them to make proteins
1 heme to 4 O2
what is hemoglobin
-protein composed of long amino acid chains with different AA sequences which combine to house the heme molecule
how are globin chain synthesized
-there are different types of globin chains with different AA sequences
-occur in combinations of two - 2 alpha and 2 others
-globin chain production occurs in RBC precursors via gene transcription and translation into polypeptide chains on ribosomes in RBC cytoplasm where molecule assembly takes place
how is Heme made
-ingest iron is absorbed in the GI tract as Ferrous iron (Fe2+)
-iron is then transported to BM as transferrin and reoxidized to Ferric ion (Fe3+)
-RBC precursors have receptors to Transferrin which when bound are taken into the erythroblast by endocytosis and Ferric ions are released into the cytoplasm
-Iron will then go into the mitochondria and be reduced to ferrous state and taken into Protoporphyrin IX to make heme
-Heme then leaves the mitochondria to join the globin chains
Dimers of 1 alpha heme + 1 non alpha heme = tetramer
what are the energetics involved with hemoglobin
- energy is NOT required to exchange O2/CO2 its passive
-Energy IS REQUIRED for RBC metabolic processes - RBCs cant produce enzymes - anucleate
-ATP production in RBC relies on glucose from plasma and enzyme pathways but once the enzymes run out, the cell will lose membrane function
what are the 4 metabolic pathways important for hemoglobin energetics
Embden-Meyerhof Pathway
-anaerobic glycolysis
-ATP production
Hexose Monophosphate Shunt /pentose shunt
-oxidative glycolysis - producing NADPH and GSH protecting RBC from oxidative injury
Methemoglobin Reductase Pathway
-maintains iron in reduced functional state
Leubering - Rapoport Shunt
-maintains 2,3 BPG production as per O2 demands from tissues
What is the function of hemoglobin
-protein in mature RBCs
-helps with gas exchange ; carries O2 from lungs to tissues and return CO2 from tissue to lungs
-helps with acid base balance; acts as pH buffer by binding and releasing hydrogen ions
-transports nitric oxide which is a vascular patency regulator
-dont undergo simultaneous oxygenation and de oxygenation
-deoxygenated hgb has little affinity for oxygen
-the more O2 binds the higher the HGB avidity
in the lungs HGB binds to O2- high pH
-needs high O2 affinity meaning Hgb will not give up the O2
Hgb transports and releases O2 to tissues - low pH
-needs low O2 affinity
what is HGB affinity
- relationship seen on oxygen dissociation curve where partial pressure of O2 is on the x axis and Oxygen saturation is on the y axis
-27mm Hg results in 50% O2 saturation
what condition cause a left vs right shift on the O2 dissociation curve
Left shift - occurs as PP less than 27 mm Hg causing increased O2 affinity of Hgb meaning less O2 for tissues
-Lowered body temp
-Decreased 2,3-BPG
-Multiple transfusions
-Increased blood pH (Alkalosis)
-Presence of other Hgb variants with high affinity for oxygen
RIGHT SHIFT- occurs at pp greater than 27mm Hg meaning decreased O2 affinity of Hgb so more O2 is available to the tissues
-Increased body temp
-Increased 2,3-BPG
-Decreased blood pH (Acidosis)
-Presence of other Hgb variants with low affinity for oxygen
how does the Concentration of 2,3 - bisphosphoglycerate (2,3-BPG) affect oxygen affinity:
TENSE or deoxygenated Hgb with 1 2,3 BPG molecule
-lower affinity of O2- does not transport it
-tight binding structure with 2,3 BPG in the middle
-O2 released from Hgb to tissues
RELAXED or oxygenated Hgb -2,3-BPG is released:
-Hgb binds O2 by pulling chains tight ; the 2,3 BPG is released
-high affinity for O2- can transport it -oxyhaemoglobin
-relaxed structure
what are the Physiological Adaptations in Anemia
-decreased Hgb therefore lower O2 delivery to tissues
-increase EPO production and secretion by kidneys
-RBC precursor stimulation in BM
-increase RBC in circulation
-tissue hypoxia triggers 2,3 BPG increase shifting curve to right decrease O2 affinity of Hgb allowing increased O2 delivery to tissues
what role does 2,3 - BPG play in IDA
-IDA is low iron
-2,3 BPG needs iron for synthesis
-therefore when 2,3 BPG concentration is reduced Hgb binds O2 and its release into tissues is decreased manifesting as hypoxia
what are dyshemoglobins - two types
- dysfunctional hemoglobin’s that dont transport O2
1-Variant hemoglobin - genetic changes in globin genes - structurally abnormal Hgb
Hgb S in sickle cell
Decrease in globin chains that cause thalassemia
2-Dyshemoglobins - hgb changed by drugs or chemical
Methemoglobin
Sulfhemoglobin
Carboxyhemoglobin
What is Methemoglobin -Dyshemoglobins
-contains Ferric Fe 3+
-O2 cant bind to Fe3, however when the fe3 is bound to heme it increases O2 affinity by changing its tetramer shape causing left shift resulting in a decrease of O2 delivery to tissues
-Methemoglobin levels are <1% of Hgb and are measured via CO oximetry
can be acquired - after drug/chemical exposure
can be congenital - globin chain mutation
what are the symptoms of Methmoglobinemia
brown blood
Tissue hypoxia
Shortness of breath
Cyanosis (decreased O2 in tissue) - BLUE SKIN
Mental status changes
Headache
Fatigue
Exercise intolerance
Dizziness
Loss of hairlines
Seizures
Coma
Death
What is sulfhemoglobin -Dyshemoglobin
- hemoglobin with a sulfur atom on porphyrin ring
-cant bind to O2
-stay for the entirety of RBC life
-drug induced
-resolves itself with RBC turnover; transfusion may be needed
symptoms include:
-cyanosis : blue skin or mucous membrane
-green pigment to blood sample
-cell count may not show abnormality
What is Carboxyhemoglobin (COHb) Dyshemoglobin
-Carbon monoxide and heme iron complex
-shift O2 dissociation curve to left - CO binds Hgb on same sites as O2 but tighter and releases 10000x slower. There fore less O2 for the whole body
-cause hypoxia quickly - silent killer
symptoms - cherry red skin , unconsciousness
what is Normal RBC Destruction
-RBC live for 120 days
-mature RBC have no nucleus, ribosomes or mito therefore they lose ATP over time
-as RBC get older the membrane get rigid and fragile - membrane loses deformability . Selective permeability decreases and the cells become more permeable to water resulting in a spheroid shape
-hemolysis is mostly Extravascular or Macrophage Mediated Hemolysis with destruction primarily in spleen and liver
-there is also Intravascular, Mechanical or Fragmentation Hemolysis which occurs less frequently but in the blood vessels
what is Extravascular Hemolysis
-RBCs are phagocytosed and lysed by macrophages in spleen
-macrophage phagosome enzymes salvage or metabolize RBC contents
-Globin chains are broken down into individual AA that are used to make new proteins
-Iron is released from HEME and returned to plasma via ferroportin, oxidized to Fe3, it is binds to transferrin in plasma to be stored in tissues or used in cells in BM, RBC or to make new Hgb
-Protoporphyrin degraded into Bilirubin, Bile or Urobillinogen
what is Intravascular Hemolysis
-when there is internal trauma causing Hgb release directly into plasma
-trauma like
Turbulence in vessels- mechanical or traumatic stress
Damage to blood vessels - small fibrin clots that trap RBCs
-free plasma Hgb attaches to transport proteins that are taken to liver or removed through the kidney
how can we prevent oxidation of Hgb iron
-Hgb binds Haptoglobin (liver produced plasma protein)
-Haptoglobin-Hemoglobin complex is ingested by macrophages where iron is separated from the protoporphyrin ring and delivered back to the BM
-Oxidized iron- forms Metheme binds Hemopexin
which is then Transported to liver- Heme broken down into components- bilirubin with reuse of iron
Metheme-Albumin system
Hemoglobin Portland I
hemoglobin at embryonic and fetal life
two zeta chains and two gamma chains.
What are the sources of iron and their forms
-Ingested and absorbed in GI tract as FE2 or ferrous iron
Stored in liver as:
Ferritin: Iron-Apoferritin complex
Apoferritin (cage like protein)- fe3 or Ferric iron
Hemosiderin:
Form of intracellular storage found in liver, spleen, and BM - a breakdown product of ferritin
Transported via:
Transferrin: plasma iron transport protein that moves iron between absorption and storage site in hematopoietic tissue to become normoblasts
what is iron used for
- critical for energy production and oxygen transport
-no excretion mechanism
-excess can be harmful
-distributed into 3 compartments :Functional, Storage, and Transport
