Physiology
Hemoglobin and Oxygen
The S-shaped binding curve that delivers oxygen where it's needed
Hemoglobin is the oxygen-carrying protein in red blood cells — a tetramer of two alpha and two beta chains, each with a heme containing iron. Each hemoglobin binds four oxygen molecules cooperatively, producing the sigmoidal oxygen dissociation curve. P50 is the partial pressure at 50% saturation, normally 26.5 mmHg. Right shift (lower affinity, more O2 release) — increased temperature, CO2, H+ (acidosis), 2,3-BPG; favors tissue delivery during exercise. Left shift (higher affinity, less release) — alkalosis, hypothermia, low 2,3-BPG, fetal hemoglobin; favors uptake. Carbon monoxide binds hemoglobin 240× more avidly than O2 and shifts the curve left, blocking both binding and release. Adult hemoglobin levels — 14 g/dL men, 12 g/dL women; each gram carries 1.34 mL O2.
- StructureTetramer; 2α + 2β chains; 4 hemes
- O2 capacity1.34 mL O2 per gram Hb
- P5026.5 mmHg normal adult
- CooperativityHill coefficient ~2.8
- CO affinity240× greater than O2
- Normal Hb14 g/dL men, 12 g/dL women
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Why hemoglobin physiology matters
- Anemia evaluation. Microcytic, normocytic, macrocytic indices direct workup.
- Oxygen delivery. DO2 = CO × CaO2; manage hypoxia in critical care.
- Altitude medicine. 2,3-BPG and erythropoiesis adapt to hypoxia.
- Sickle cell crises. Hydration, pain control, oxygen, transfusion as needed.
- CO poisoning. Recognize and treat with 100% or hyperbaric O2.
- Pulse oximetry pitfalls. Methemoglobinemia, COHb, severe anemia mislead.
- Transfusion thresholds. Restrictive (Hb <7) reduces complications in stable patients.
Common errors
- Trusting SpO2 in CO poisoning. Use co-oximetry on ABG.
- Hyperventilating intubated patient routinely. Alkalosis left-shifts curve, impairing tissue delivery.
- Calling cyanosis at low Hb significant. Cyanosis requires ~5 g/dL deoxyhemoglobin; severe anemia masks it.
- Forgetting iron status in microcytic anemia. Ferritin first; thalassemia trait if normal iron.
- Methylene blue in G6PD deficiency. Triggers hemolysis; use ascorbic acid.
- Aggressive transfusion in stable patient. Hb >7-8 threshold improves outcomes for most adults.
Frequently asked questions
Why is the curve sigmoidal?
Cooperative binding. The first O2 binding to hemoglobin alters quaternary structure (T to R state), increasing affinity for subsequent O2 molecules. This makes hemoglobin both efficient at uptake (high affinity in lungs at PaO2 ~100 mmHg, ~98% saturated) and efficient at release (low affinity in tissue at PaO2 ~40 mmHg, ~75% saturated). A linear oxygen carrier (myoglobin, single subunit, hyperbolic curve) cannot do both. The Hill equation models this with Hill coefficient n ~2.8 for hemoglobin.
What is the Bohr effect?
Increased CO2 and H+ shift the dissociation curve right, lowering O2 affinity. In tissues — high CO2 from metabolism, low pH — promotes oxygen release. In lungs — low CO2 (exhaled), high pH — promotes oxygen binding. Mechanism — H+ stabilizes T state. Christian Bohr discovered this in 1904. Also explains hyperventilation alkalosis worsening hypoxia symptoms — left shift impairs tissue delivery despite higher saturation.
What is 2,3-BPG?
2,3-bisphosphoglycerate, a glycolytic byproduct in red blood cells. Binds beta chains in T state, lowering O2 affinity, shifting curve right. Increases at altitude, anemia, chronic lung disease — adaptation to improve tissue delivery. Stored blood loses 2,3-BPG; massive transfusion risks left-shifted hemoglobin and impaired delivery. Fetal hemoglobin (alpha2-gamma2) doesn't bind 2,3-BPG well — left-shifted curve helps fetus extract O2 from maternal blood across placenta.
How does carbon monoxide kill?
CO binds hemoglobin with 240× the affinity of O2, forming carboxyhemoglobin. Each bound CO also shifts remaining sites' curve left — released O2 falls dramatically. SpO2 reads falsely normal (CO-Hb absorbs similar wavelength to O2-Hb). Symptoms — headache, dizziness, confusion at 10-30%; coma and death >50%. Treat with 100% oxygen (reduces half-life from 5 hours to 90 min); hyperbaric oxygen for severe poisoning, pregnancy, persistent symptoms. Sources — fires, faulty heaters, generators, methylene chloride.
What's a pulse oximeter measuring?
Absorbance of two wavelengths (660 nm red, 940 nm IR) through pulsatile arterial blood. Distinguishes oxy- from deoxy-hemoglobin. Pitfalls — methemoglobinemia reads ~85% regardless of true saturation; carboxyhemoglobin reads falsely normal; severe anemia, low perfusion, nail polish, dark skin (slight overestimation in low-saturation states), motion all degrade accuracy. Co-oximetry on arterial blood gas measures all hemoglobin species directly.
How do hemoglobinopathies cause disease?
Sickle cell (HbS) — Glu6Val on beta chain; deoxygenated HbS polymerizes; rigid sickle cells occlude microvasculature. Pain crises, acute chest, stroke, splenic sequestration. Hydroxyurea induces HbF, reducing crises. Voxelotor stabilizes oxy form. Crizanlizumab P-selectin inhibitor. Stem cell transplant or gene therapy curative. Beta-thalassemia — reduced beta-chain synthesis; ineffective erythropoiesis, hemolysis, iron overload. Transfusion-dependent forms need iron chelation. Alpha-thalassemia — alpha gene deletions on chromosome 16.
What is methemoglobinemia?
Iron oxidized from Fe2+ to Fe3+ — cannot bind O2. Causes — congenital (cytochrome b5 reductase deficiency, hemoglobin M), acquired (dapsone, benzocaine, nitrites, nitric oxide, aniline dyes). Cyanosis at >10%; symptoms at >20%; lethal >70%. SpO2 ~85% regardless of true saturation. Chocolate-brown blood. Treat with methylene blue 1-2 mg/kg IV (reduces Fe3+); avoid in G6PD deficiency. Ascorbic acid as alternative.