<aside> ↪️

High-yield buzzwords:

• Right shift = ↓ affinity, ↑ unloading
• Left shift = ↑ affinity, ↓ unloading
• CADET right
• P50 reflects affinity
• Cooperativity (sigmoid curve)

NBME test-taking strategy (1 line): Ask: does hemoglobin want to hold oxygen or give it up?

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<aside> ⬅️ P50 refers to the partial pressure of oxygen at which hemoglobin is 50% saturated.

• Hemoglobins with high oxygen affinity have a decreased P50 that is represented by a leftward shift of the oxygen dissociation curve.
• The reduced ability to release oxygen within the peripheral tissues leads to renal hypoxia, increased erythropoietin synthesis, and compensatory erythrocytosis.

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• The oxygen-hemoglobin dissociation curve describes the relationship between the partial pressure of oxygen (x-axis) and the hemoglobin oxygen saturation (y-axis).

• Oxygen saturation increases in a sigmoidal fashion as the pO2 increases because of the increase in oxygen-binding affinity that occurs after the first oxygen molecule binds to hemoglobin.  As more oxygen molecules bind to hemoglobin, the number of available binding sites decreases and the curve eventually flattens out.

• Oxygen-hemoglobin dissociation curve

  • sigmoidal shape is characteristic of positive cooperativity
    • binding of 1 O2 molecule to 1 subunit of deoxyhemoglobin increases affinity for O2 in adjacent subunits
  • P50 is PO2 at which hemoglobin is 50% saturated
    • ↑ P50 → ↓ hemoglobin affinity for O2
      • 50% saturation achieved at higher-than-normal P50
    • ↓ P50 → ↑ hemoglobin affinity for O2
      • 50% saturation achieved at lower-than-normal P50

• Loading and unloading of oxygen

  • in lungs
    • PaO2 ≈ 100 mm Hg
    • hemoglobin % saturation ≈ 100%
    • facilitates maximal O2 loading into arterial blood in lungs
  • in peripheral tissues
    • PvO2 ≈ 40 mm Hg
    • hemoglobin % saturation ≈ 75%
    • facilitates O2 unloading into peripheral tissues

RIGHT SHIFT — “Let go of O₂” (VERY high yield)

CADET right

• CO₂ ↑
• Acid (↓ pH)
• DPG ↑
• Exercise
• Temperature ↑

🔑 Physiologic purpose: Actively metabolizing tissues need more oxygen

• Shift to right
  • mechanism
    • ↑ P50 → ↓ hemoglobin affinity for O2 → ↑ O2 unloading
  • causes
    • ↑ PCO2, ↓ pH (Bohr Effect)
      • ↑ PCO2 → ↑ H+ → ↓ pH
        • CO2 + H2O → H2CO3 → H+ + HCO3
          • ↑ PCO2 → equilibrium reaction shifts right
            • Le Chatelier's principle
      • ↑ CO2, ↑ H+ bind hemoglobin and stabilize low O2 affinity T (taut) state
        • ↓ hemoglobin affinity for O2 → ↑ O2 unloading
          • e.g., exercise → ↑ PCO2, ↓ pH
            • ↑ O2 unloading ensures O2 delivery meets O2 demand in skeletal muscle
    • ↑ temperature
      • e.g., ↑ tissue metabolism → ↑ temperature
    • ↑ 2,3-bisphosphoglycerate (2,3-BPG)
      • high altitude → hypoxemia → ↑ synthesis of 2,3-BPG
        • Also seen in heart failure, anemia, morbid obesity, etc.
      • ↑ 2,3-BPG binds hemoglobin and stabilizes low O2 affinity T (taut) state
        • ↓ hemoglobin affinity for O2 → ↑ O2 unloading

LEFT SHIFT — “Hold onto O₂”

Causes

• ↓ CO₂
• ↑ pH (alkalosis)
• ↓ temperature
• ↓ 2,3-DPG
• Fetal hemoglobin (HbF)
• Carbon monoxide poisoning

🔑 Common theme: Oxygen is not being released

| --- | --- |

• The partial pressure of oxygen in the blood at which hemoglobin is 50% saturated is known as the P50 (dotted black line in diagram above); this value is a standard measure of hemoglobin's affinity for oxygen and is about 26 mm Hg in normal individuals.
• A leftward shift of the oxygen-hemoglobin dissociation curve occurs when hemoglobin has increased oxygen affinity (ie, a lower P50).  Because decreased temperatures help to stabilize the bonds between oxygen and hemoglobin, hypothermia increases hemoglobin's oxygen affinity and shifts the dissociation curve to the left.
• 2,3-bisphosphoglycerate (2,3-BPG) concentrations increase in erythrocytes when oxygen availability is reduced, as occurs in chronic lung disease, heart failure, and chronic exposure to high altitudes.  Elevated levels of 2,3-BPG decrease hemoglobin O2 affinity (right-shifted curve), allowing release of additional O2 in the peripheral tissues.
• Anemia severe enough to cause lactic acidosis will result in lower blood pH, shifting the hemoglobin curve to the right.  Similarly, hypoventilation causes increased CO2 retention and respiratory acidosis that shifts the curve to the right.
• Strenuous exercise will cause increased tissue oxidative phosphorylation, increased tissue CO2 levels, and decreased tissue pH.  This results in a shift of the dissociation curve to the right and decreased hemoglobin O2 affinity.

• Factors that alter the oxygen-hemoglobin dissociation curve: "CADET" for CO2, Acid, 2,3-Diphosphoglycerate, Exercise, and Temperature

<aside> ⬅️ Left latches when low

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<aside> ➡️ Right removes when raised

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• Mutations that cause production of hemoglobin with high oxygen affinity (left shift; eg, hemoglobins Chesapeake and Kempsey) reduce the ability of hemoglobin to release oxygen within the peripheral tissues.