Haemoglobin Structure and Function
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Direct answer
The sigmoid shape of the haemoglobin-oxygen dissociation curve is the visible signature of cooperativity: binding of the first oxygen to a T (tense, deoxy) subunit breaks salt bridges and flips the tetramer toward the R (relaxed) state, raising the affinity of the remaining haems — steeper than myoglobin's hyperbola. Haemoglobin A (α2β2, about 97% of adult haemoglobin) carries four haems (protoporphyrin IX chelating ferrous iron), transporting up to four oxygens with P50 near 26-27 mmHg. Three ligands tune it: hydrogen ion and carbon dioxide (the Bohr effect) shift it right to unload in acidic, CO2-rich tissues; 2,3-bisphosphoglycerate binding the β chains shifts right too; foetal haemoglobin (α2γ2) binds 2,3-BPG poorly, so its curve sits left, pulling oxygen from maternal blood.
What you must remember
- Normal fractions: HbA 97%, HbA2 (α2δ2) about 2-2.5%, HbF below 1% in adults — HbA2 raised in β-thalassaemia trait, HbF raised in thalassaemia major and hereditary persistence of foetal haemoglobin.
- Biochemistry of unloading: metabolically active tissues deliver H+ and CO2 (carried as bicarbonate via the chloride shift and carbamino compounds), protonating haemoglobin and releasing oxygen — the Bohr effect couples perfusion to metabolism.
- 2,3-BPG rules: raised at altitude, in chronic hypoxia and anaemia (right shift, better unloading); reduced in stored blood (left shift, poor initial unloading after transfusion).
- Carbon monoxide: binds haem iron with about 200-250 times oxygen's affinity, produces a cherry-red patient with normal PaO2 and falsely reassuring pulse oximetry, and shifts the remaining sites' curve left.
- Methaemoglobinaemia: ferric (Fe3+) haemoglobin cannot carry oxygen and shifts the curve left — chocolate-brown blood, cyanosis unresponsive to oxygen, treated with methylene blue (which recycles NADH methaemoglobin reductase); nitrates, dapsone and local anaesthetics are triggers.
- Cooperativity quotient: Hill coefficient near 2.8 for haemoglobin (1.0 for myoglobin) — the number that quantifies sigmoidicity in viva discussions.
- Glycation: HbA1c forms at the N-terminal valine of the β chain and reports the preceding 8-12 weeks of glycaemia.
- Thalassaemia versus haemoglobinopathy: reduced chain synthesis (quantitative) versus abnormal chain structure (qualitative) — sickle and HbE versus α- and β-thalassaemia.
A worked case: a family poisoned by a generator
After a cold night, four members of a household are found confused with headaches; a pressure generator had run indoors. Blood gas shows a normal PaO2, but carboxyhaemoglobin is 28% in the most affected. The logic: carbon monoxide outcompetes oxygen for haem binding by two orders of magnitude, so oxygen content collapses while tension looks fine; the left-shifted residual curve starves tissues of the little oxygen aboard; the pulse oximeter reads near-normal because it cannot distinguish carboxyhaemoglobin from oxyhaemoglobin — a saturation gap between co-oximetry and pulse oximetry is the bedside tell. Treatment is 100% oxygen (halving the half-life from about 4-5 hours on room air to about 1 hour) and hyperbaric oxygen for coma, seizures, pregnancy or levels above about 25%. Cyanide poisoning is the companion case: there tissues cannot use oxygen, so venous oxygen is high and lactate rises — one blocks carriage, the other blocks consumption.
Where students slip
Bohr and 2,3-BPG are both "right shifts" but by different mechanisms — protons stabilise the T state by salt bridges, while 2,3-BPG is a T-state ligand bound in the central cavity between β chains; stating the shared direction without the mechanism loses the discriminating mark. Second, HbF's left shift is reasoned as "more affinity for oxygen because it is foetal" without the 2,3-BPG-poor γ chain explanation, which is what the examiner wants. Third, stored blood's left shift is forgotten in transfusion questions — a freshly transfused patient may have adequate saturation yet poor tissue delivery for hours. Fourth, cyanosis thresholds differ: methaemoglobin causes chocolate cyanosis at far lower concentrations than reduced haemoglobin (which needs about 5 g/dL). Fifth, the PaO2 in CO poisoning is normal because it measures dissolved oxygen tension, not content — anchoring on "the blood gas was fine" delays the diagnosis.
Frequently asked questions
Why is the haemoglobin oxygen curve sigmoid?
Binding of each oxygen converts the T state to the R state and increases the affinity of remaining subunits — positive cooperativity, with a Hill coefficient near 2.8.
What is the Bohr effect and its physiological purpose?
Hydrogen ions and carbon dioxide shift the curve right, letting haemoglobin unload oxygen precisely in the acidic, CO2-rich tissues that need it most.
Why does foetal haemoglobin have a higher oxygen affinity?
Its γ chains bind 2,3-bisphosphoglycerate poorly, producing a left-shifted curve that extracts oxygen from maternal blood across the placenta.
How does carbon monoxide deceive the blood gas and oximeter?
It leaves dissolved oxygen tension normal while collapsing oxygen content, and pulse oximetry cannot distinguish carboxyhaemoglobin from oxyhaemoglobin.
How is methaemoglobinaemia treated?
Methylene blue, which uses the NADH-dependent reductase pathway to reduce ferric iron back to ferrous — avoiding further oxidant drugs.