O2 Transport Flashcards
How is O₂ transported in the blood?
In one of 2 forms:
Bound to Hb:
◆ Accounts for 98% of the O₂ carried in blood.
◆ Each gram of fully satured Hb can bind 1.34 ml of O₂ (Hufner's constant).
Dissolved in plasma:
◆ Accounts for 2% of the O₂ carried in blood.
◆ The volume of O₂ dissolved in blood, is proportional to the PO₂ (Henry's law).
Describe what is Hufner's constant.
Each gram of fully satured Hb, can bind to 1.34 ml of O₂.
Describe what is Henry's law.
The volume of dissolved O₂ in blood, is proportional to the partial pressure of O₂ (PO₂).
How to calculate the total volume of O₂ carried by the blood?
◉ It is the sum of Hufners constant with Henry’s law.
➜ O₂ content equation.
Describe the O₂ content equation.
O₂ content per 100 ml of blood = [(1,34 x Hb x ❨SPO₂/100%❩) + (0.023 x PO₂)]
◆ 0.023 solubility coefficient for O₂.
Define Fick’s law of diffusion.
Diffusion occurs following a pressure gradient.
Explain Fick's law and the importance of the O₂ dissolved in plasma.
◆ The partial pressure of O₂ in the blood (PO₂) is measured from the dissolved amount in plasma.
➔ Relation to Fick’s law:
◆ O₂ diffuses to the tissues from the dissolved amount in the plasma (not from Hb).
◆ Plasma O₂ [.] ⬇︎
◆ O₂ dissociates from Hb to replenish the plasma.
Hb is a much more efficient means of O₂ carriage than O₂ dissolved in plasma though.
How is O₂ stored in the blood?
➜ Very little O₂ is stored in the blood (which means apnoea is quickly followed by hypoxia).
➔ Storage:
◆ In the lungs as FRC.
◆ In the blood (bound and dissolved).
◆ In the muscles bound to myoglobin.
What is the consumption of O₂ at rest in an adult?
250 ml/min.
Describe the structure of RBC’s.
◆ Small
◆ Biconcave discs
◆ Able to change form to fit through small capillaries.
◆ No nucleus
◆ Cytopalsm without mitochondria (aerobic metabolism not possible).
What is Haemoglobin?
◆ It is a large protein that contains iron (Fe).
◆ It is contained within the RBC’s.
Describe the adult HbA.
➜ HbA:
◆ Accounts for 98% of adult Hb.
➜ It has a quaternary structure compromising of 4 (polypeptide) globin subunits:
◆ 2 𝝰 chains
◆ 2 β chains
Describe the globin subunits chains
Adult HbA: 2 𝝰 chains & 2 β chains.
◆ The 4 globin chains are held together by weak electrostatic forces.
◆ Each globin chain cointains iron in the ferrous state (Fe²⁺).
How is O₂ bound to the haem group?
◆ O₂ is reversibly bound to the Fe²⁺ ion in the haem group.
◆ 4 O₂ molecules can bind to Hb (one for each haem group).
Describe cooperative binding of Hb.
It’s the increase in O₂ affinity to Hb, with each successive binding.
First step
The first O₂ molecules bind with relative difficulty.
◆ Hb is on a tense conformation due to the β-chains being far apart.
◆ Strong electrostatic charges must be overcome to achieve the required conformational change.
2nd step
◆ After the 1st Hb is bound, the conformation of the β-chains and Hb come close together.
◆ This allow a 2nd O₂ molecule to have a higher binding affinity to Hb.
3rd step
◆ After the 2nd O₂ molecule has bound the 3rd is easier to bind, and subsequently the 4th.
4th step
◆ Once the 4th O₂ binds, the Hb protein achieves its relaxed conformation.
Define what is oxyhaemoglobin and deoxhymoglobin.
Oxyhaemoglobin
• Fully saturated Hb.
Deoxhymoglobin
• Fully desaturated Hb.
Define what is the Oxyhaemoglobin dissociation curve.
- Describes the relationship between SaO₂ (arterial O₂ saturation by arterial blood gas) and PaO₂.
- The sigmoid shape of the graph is due to cooperative binding of the 4 O₂ molecules and Hb.
Draw and explain the Oxyhaemoglobin dissociation curve
X axis
◆ PaO₂
Y axis
◆ Percentage of oxyHb (measured by SaO₂)
There 3 main points in the graph:
◆ Arterial point
◆ Venous point
◆ P50
Arterial point
◆ 97 to 100% of Hb is saturated at PO₂ of 13.3 kPa (99.7 mmHg).
Venous point
◆ Hb is 75% at 5.3 kPa (39.7 mmHg)
P50
◆ The partial pressure of O₂ (PO₂) at which Hb is 50% saturated (bound to O₂).
◆ Usually at PO₂ of 3.5 kPa (26 mmHg).
◆ It is the reference point to determine left or right shift.
What is myoglobin?
► It is a large protein molecule, containing iron and capable of binding to O₂ (like Hg).
► It stores O₂ in the skeletal muscles (O₂ demand is high).
Unlike Hb, it contain only:
◆ 1 haem group
◆ 1 globin chain
◆ There is no cooperative binding
Describe the oxyMYoglobin dissociation curve.
- It’s a hyperbolic graph positioned to the left of the oxyhemoglobin curve.
- The P50 of myoglobin is much lower than Hb.
Describe the right shift of the oxyhaemoglobin curve.
➔ It causes Hb to have a lower affinity to O₂ ⟶ easier offload of O₂.
Causes:
◆ ⬆︎ PCO₂
◆ Acidosis
◆ Hyperthermia (↑Tº)
◆ ⬆︎ 2,3-diphosphoglycerate (2,3-DPG)
◆ Exercise
◆ Pregnancy
◆ Altitude
◆ Sickled cell haemoglobin (HbS)
Give examples of the physiological importance of the right shift of the OxyHb curve?
HDue to the following physiological mechanisms:
Bohr effect:
◆ When blood arrives at the capillaries, the oxyHb dissociation curve is shifted to the right, offloading O₂ where it is most needed.
Anaerobic metabolism:
◆ When cellular PO₂ ↓ below a threshold value, anaerobic metabolism predominates.
◆ Energy is produced through the breakdown of glucose to pyruvate (in a process called glycolysis);
◆ Which is then converted to lactate.
◆ 2,3-DPG is also produced.
◆ ↑ anaerobic metabolism ➝⬆︎ 2,3-DPG concentration.
◆ 2,3-DPG binds specifically to the β-chains of deoxyHb, stabilising
this configuration ➝ thus reducing the O₂-binding affinity of Hb.
◆ This mechanism means that additional O₂ is offloaded to cells undergoing anaerobic metabolism.
O₂ loading in the lungs:
◆ When blood reaches the lungs, CO₂ is exhaled and the pH normalises.
◆ The P50 of the oxyHb dissociation curve then returns to its central position.
◆ The binding affinity of O₂ therefore increases;
◆ Dissolved O₂ binds to Hb, which in turn lowers the blood O₂ tension, facilitating O₂ diffusion across the alveolar–capillary barrier.
Explain what is the Bohr effect.
Right shift of OxyHb curve
◉ Bohr effect
◆ Tissues that are metabolically active produce: CO₂, H⁺ and heat.
◆ When blood arrives to these capillaries, the oxyhaemoglobin curve shifts to the right ⟶ unloading O₂ where is needed the most.
◆ CO₂ binding to Hb reduces its affinity for O₂ and causes a right shift of the O₂-Hb dissociation curve.
Explain the Anaerobic metabolism.
Right shift of OxyHb curve
◉ Anaerobic metabolism
◆ When PO₂ falls below a certain value anaerobic metabolism ensues.
◆ Glucose breaksdown into pyruvate and produces in the process 2ATP (glycolysis).
◆ The pyruvate further breaksdown producing lactate.
◆ One of the intermediates of the glycolytic pathway is converted to 2,3-DPG in a side pathway.
◆ Hence ⬆︎ anaerobic metabolism ⟶ ⬆︎ 2,3-DPG.
◆ 2,3-DPG binds specifically to β-chains of deoxyhaemoglobin ⬇︎ the Hb affinity to O₂.
◆ This means that additional O₂ is offloaded to cells undergoing anaerobic metabolism.
Describe the left shift of the OxyHb curve.
➔ Hb has a higher affinity to O₂ ⟶ easier binding of O₂.
Causes:
◆ ⬇︎ PCO₂
◆ Alkalosis
◆ Hypothermia (⬇︎ Tº)
◆ ⬇︎ 2,3-diphosphoglycerate (2,3-DPG)
◆ Foetal Hb (P50 is 2.5) (HbF)
◆ Carbon monoxide (carboxyhaemoglobin COHb)
◆ Methaemoglobin (iron in haem group is in Fe³⁺ ferric state and cannot bind to O₂).
Explain the clininal relevance of the left shift of the OxyHb curve in foetal life.
◆ HbF has to be able to extract O₂ from maternal OxyHb.
◆ HbF must then have a higher affinity to O₂ than maternal Hb.
This is caused by:
➔ HbF causes a left shift in the OxyHb curve ⟶ ⬆︎ affinity to O₂.
➔ HbF is contains 2𝝰 and 2ɣ globin subunits.
➔ 2,3-DPG although present in foetal RBC’s It cannot bind to HbF due to lack of β-chains ⟶ This further ↑ the binding affinity of HbF for O₂.
What is the clinical relevance of 2,3-DPG in blood transfusion?
◆ In stored blood, the erytrocytes 2,3-DPG [.] rapidly ⬇︎ to zero after 1-2 weeks.
◆ OxyHb curve will shift to the left ⬆︎ the affinity to O₂.
◆ When stored blood is transfused, it takes up to 24h for erytrocyte 2,3-DPG [.] to ⬆︎.
◆ Transfused blood is not as effective at offloading O₂ to the tissues as native blood cells are.
◆ Cell-salvaged blood maintains most of its 2,3-DPG which makes it a better option.
Describe the classification of different types of Hb.
◉ Physiological
◆ HbA
◆ HbA₂
◆ HbF
◉ Pathological
◆ Thalassemia
◆ HbS
◆ MetHb
◆ COHb
Describe the HbA₂.
◆ It accounts for 2% of the adult Hb.
◆ It has 2𝝰 and 2δ globin subunits.
Normal variant
Describe the HbF.
◆ Normal variant during foetal life.
◆ It has 2𝝰 and 2ɣ globin subunits.
◆ It has a higher affinity to O₂ than HbA.
◆ HbF is produced up to 3mths.
◆ By 6 mths the all HbF is replaced by HbA.
Normal variant
Describe Thalassemia Hb.
◆ Inherited autosomal recessive blood disorder.
◆ ⬇︎ synthesis of one of the globin chains (𝝰 or β).
◆ The ensuing anaemia can be 𝝰 or β depending on which globin chain is being underproduced.
Describe the HbS (sickle cell anaemia).
◆ Inherited autosomal recessive blood disorder.
◆ There is an abnormal β globin subunit (due to a genetic mutation in the amino acid sequence where the amino acid valine is replaced
by glutamic acid)
◆ In low PaO₂, the homozygous state forms sickle cells causing the erythrocytes to obstruct the microcirculation, leading to painful crises and infarcts.
Describe the MetHb.
◆ Methaemoglobinaemia is where the ferrous iron (Fe²⁺) within the Hb molecule is oxidised to ferric iron (Fe³⁺).
◆ Fe3+ cannot bind O₂, so MetHb cannot participate in O₂ transport.
Describe the COHb.
◆ Formed when Hb binds to inhaled carbon monoxide.
Describe the Hb-binding affinity to carbon monoxide.
➔ The Hb-binding affinity to carbon monoxide is 250 times greater than that of O2.
➔ In the presence of carbon monoxide, Hb preferentially forms COHb rather than oxyhaemoglobin, resulting in a reduced O2-carrying capacity.
Describe what happens to the hemoglobin dissociation curve in the presence of COHb.
There’s a:
◆ a leftward shift of the oxyhaemoglobin dissociation curve.
That causes a:
◆ reduction in the offloading of O2 to the tissues.
Resulting in:
◆ exacerbation of tissue hypoxia.
What are the clinical features / symptoms of COHb?
- 15–20% causes mild symptoms – headache and confusion.
- At higher concentrations – weakness, dizziness, nausea and vomiting.
- At COHb >60% – convulsions, coma and death.
Describe the treatment for carbon monoxide intoxication.
◆ High FiO2
OR
◆ Hyperbaric chamber
Describe the MOA of cyanide intoxication.
► Reduced O2 carrying capacity:
◆ Cyanide binds irreversibly to the O₂ binding site of the Hb Fe₂⁺ ion.
◆ Resulting in a functioning anaemia that can’t be treated with O₂.
► Inhibition of the electron transport chain:
◆ The main toxic effect of cyanide is inhibition of cytochrome c oxidase (Complex IV) of the mitochondrial electron transport chain.
◆ The mitochondria are unable to make use of the O₂ that reaches them.
What are the clinical signs of cyanide intoxication?
◆ Bright red colour of venous blood, where the blood has passed through the tissue capillary network without offloading O₂.
In other words:
◆ Mixed venous Hb-O₂ saturation is ⬆︎, with a lactic acidosis resulting from anaerobic metabolism.
Causes of cyanide poisoning?
- Following inhalation of smoke from burning nylon materials in house fires.
- Following administration of sodium nitroprusside.
Management of cyanide intoxication?
◆ Supportive measures;
◆ Hydroxocobalamin (vitamin B12) in high doses;
◆ The cobalt cation of hydroxocobalamin binds cyanide ions;
◆ Forming cyanocobalamin (vitamin B12), which is non-toxic and renally excreted;
◆ Hydroxocobalamin can enter the mitochondria, where it irreversibly binds cyanide ions, thus restoring oxidative metabolism.
Hydroxocobalamin can enter the mitochondria, where it irreversibly binds cyanide ions forming a non-toxic and renally excreted compound, thus restoring oxidative metabolism / aerobic metabolism.
Describe the O₂-Hb dissociation curve in CO intoxication.
◆ It is shifted to the left;
◆ P50 will be reduced causing increased affinity for the few HgB left;
◆ Difficult to unload O₂ to the tissues.
