Hemoglobin & O₂ Dissociation

Hemoglobin: The first quaternary protein discovered (it's not an enzyme—it's a transport protein).

The 4 Subunits

Each subunit has:

• Heme molecule: Iron atom at the center of a carbon ring honeycomb (porphyrin)
• Globin: A protein chain that wraps around the heme like a blanket

Types of Hemoglobin

Type	Subunits	Prevalence	Notes
Hb A	2α + 2β	98% of adult Hb	The workhorse
Hb A₂	2α + 2δ	2% of adult Hb	Minor variant
Hb F	2α + 2γ	Fetal only	Decreases after birth, adult level by 6 months

Acidosis: The 4 Bad Things

When acidosis hits (low pH):

1. GABA increases → brain depresses, confusion
2. Proteins denature → enzymes stop working
3. Hyperkalemia → K+ spills out → cardiac arrhythmias
4. Kussmaul breathing → deep rapid breathing (body trying to blow off CO₂)

Hb F: The Fetal Oxygen Bandit

Hb F is produced in the fetus, peaks around birth, then decreases after birth to reach adult levels (0-1%) within 6 months.

Key quirk: Hb F has LOW affinity for 2,3-DPG → it holds oxygen VERY TIGHTLY → HIGH O₂ affinity (except in severe fetal hypoxia).

Why This Matters for the Fetus

Baby's blood crosses mom's blood at the placenta. Baby's Hb F must forcibly rip O₂ off mom's Hb A across the placental membrane. It's like a stronger magnet pulling iron filings away from a weaker magnet.

Why Hb F Doesn't Work for Adults

If an adult had Hb F instead of Hb A, the hemoglobin would refuse to release O₂ to tissues. Tissues starve = bad news.

Hydroxyurea: The Sickle Cell Game-Changer

Hydroxyurea induces Hb F in sickle cell patients. Why does this work?

• Hb F won't release O₂ to tissues
• RBCs stay round (not crescent-shaped)
• Cells don't clog vessels
• Catch: wipes out entire bone marrow (first gene expressed = Hb F)

Normal ABG Values to Know

Parameter	Normal Value	Range
PO₂	80-100	60-100 adequate
PCO₂	40	35-45
HCO₃	24	22-26
pH	7.40	7.35-7.45

Two Different Things

O₂ CONTENT = bound oxygen (Hb) + dissolved oxygen (pO₂)

Most O₂ is bound to hemoglobin. The dissolved portion is tiny but measurable.

What Blood Tests Measure

• pO₂ measurement = dissolved portion only
• Hemoglobin measurement = bound portion only

The Board Trap: Anemia ≠ Hypoxia

Anemia: Hb goes down but pO₂ stays the same. Not hypoxia.

Patient is anemic, not hypoxic. O₂ content is low because Hb is low, not because lungs are failing.

Late / Extreme Exercise: The "Second Wind" Phenomenon

During intense exercise:

1. Hb desaturates almost completely
2. Body generates ↑CO₂, ↑2,3-DPG, ↑H+
3. All three factors force remaining O₂ off hemoglobin → RIGHT SHIFT
4. Muscles suddenly get O₂ flood after pain plateau → second wind

Endurance training increases pain threshold before second wind kicks in. You stay in aerobic metabolism longer.

What is Myoglobin?

Myoglobin: A quaternary protein (wait, no—it's actually NOT quaternary, it's monomeric like no other oxygen carrier).

• Reserve energy source for muscle
• Found ONLY in muscle (cardiac and skeletal)
• Weak acid → damages kidneys first when it leaks out

When Myoglobin Leaks: Myositis

CPK leaks out → Inflammation of muscle.

Myositis: One muscle inflamed

Polymyositis: Multiple muscles inflamed

Causes of Myositis (#1 → #4)

1. #1 Most Common: Hypothyroidism (↓ metabolism → weak muscles)
2. Cushing's syndrome (cortisol → muscle wasting)
3. Drugs: statins, INH, rifampin, steroids
4. Infection: Trichinella spiralis from raw/undercooked bear or pork

Rhabdomyolysis: Severe Myositis

When myoglobin floods the bloodstream (severe muscle breakdown).

MCC: Trauma/crush injury (car accidents)

#2 MCC: Drugs (especially statins)

What Happens at High Altitude

Hypoxia → Hb desaturates → RIGHT SHIFT

Also: ↑Temperature, ↑BMR (body working harder)

3 Adaptations the Body Makes

1. Polycythemia: EPO released → more RBCs → more O₂-carrying capacity
2. Increased mitochondrial density: More ATP factories, stay in aerobic (first-order) metabolism longer
3. Increased angiogenin: More blood vessels → more O₂ delivery to muscles

Return to Sea Level: Blood Doping Advantage

High-altitude athlete returns with:

• ↑Hematocrit (extra RBCs)
• ↑ Mitochondrial density
• ↑ Angiogenesis
• Normal/low EPO (body's feedback = "enough oxygen available")

At sea level = huge advantage. Hematocrit up, EPO down = blood doping equivalent.

Chronic Hypoxia: Clubbing

Chronic low O₂ → angiogenesis in fingertips → leaky new vessels → swelling of fingernails and tissue.