Oxygen - Hemoglobin Affinity


By Donald R. Elton, MD, FCCP
Lexington Pulmonary and Critical Care


Introduction
It is commonly thought that shifts in the oxyhemoglobin dissociation curve are important factors in adaptation to hypoxic conditions. In actual fact, the subject is more complex than is generally recognized and benefits (or detriments) resulting from changes in hemoglobin's affinity for oxygen can only be demonstrated under extreme conditions. Structure = Function Human hemoglobin exhibits a sigmoid relationship between PO2 and hemoglobin saturation. This shape of curve offers benefits in that almost complete saturation can be obtained over a wide range of oxygen partial pressures at the lung while large quantities of oxygen can be delivered to peripheral tissues once the oxygen partial pressure falls to lower levels than those normally encountered at the alveoli. Several factors can cause shifts of the curve but the sigmoidal shape of the curve is ordinarily preserved except in cases of carbon monoxide poisoning. The sigmoidal shaped curve results from steric interactions between adjacent heme molecules as they bind successively with oxygen.

P50
It is common to use the concept of P50 to describe the affinity of a given hemoglobin for oxygen. The P50 is the PO2 at which the hemoglobin becomes 50% saturated with oxygen. As the P50 decreases, oxygen affinity increases and visa verse. Normal adult Hemoglobin A has a P50 of 26.5 mm Hg while Fetal Hemoglobin F has a P50 of 20 mm Hg and sickle cell anemia Hemoglobin S has a P50 of 34 mm Hg.

Oxygen Pickup & Delivery
It is convenient to divide the function of hemoglobin into oxygen pickup and oxygen delivery. Oxygen is initially added to the circulation in the lungs in the form of dissolved gas and delivery to end tissue mitochondria is by the same mechanism. Movement of oxygen in the physically dissolved state is dependent upon movement across a short distance according to a partial pressure/concentration gradient. In the lungs, oxygen will move into blood if the oxygen partial pressure in the alveolus exceeds the partial pressure in the pre-alveolar capillary blood. Oxygen present in the dissolved state reversibly binds with available hemoglobin at a rate determined by the affinity of that hemoglobin for oxygen. Once the partial pressure in the capillary exceeds about 150 mm Hg, no more oxygen can be loaded onto hemoglobin and saturation is complete. In the tissues, as physically dissolved oxygen is removed from the circulation by mitochondria, the local PO2 falls. The oxygen removed in this manner is replaced by oxygen that dissociates from available hemoglobin until the hemoglobin has no more oxygen to give or until the oxygen delivery exceeds the consumption requirements of the mitochondrion. Oxygen can continue to move into functioning mitochondrion as long as there is at least a 1 mm Hg partial pressure gradient and mitochondrial function has been demonstrated at a local PO2 of 1 mm Hg.

Adaptation to Changes in Oxygen Affinity
There are several ways that tissues compensate for changes in hemoglobin's affinity for oxygen that prevent changes in oxygen delivery that might otherwise occur.

Oxygen Affinity at the Lung
If oxygen affinity is increased at the lung level, complete saturation will occur at lower ambient PIO2. This can result in the arterial content approaching nearly normal levels even at high altitude. A reduced oxygen affinity (rising P50) can result in reduced oxygen content and delivery potential at the lung level. Again, under most usual circumstances, these are negligible effects over the usual range of P50 values found with normal hemoglobins though there are animal and some abnormal human hemoglobins with P50 values ranging from as low as 10 to as high as 70 mm Hg. When these grossly abnormal human hemoglobins occur, they usually make up less than half of the total hemoglobin available. If oxygen affinity is decreased, then oxygen delivery can still be maintained either by an increased cardiac output or an increased hemoglobin concentration. Local factors such as pH and other chemical mediators can also influence the oxygen affinity back toward normal under some circumstances.

Oxygen Affinity at the Tissues
As hemoglobin's affinity for oxygen rises at the tissue level (P50 going down), oxygen extraction will fall if the PO2 and blood flow are held constant. In vivo, however, the PO2 falls and oxygen extraction and blood flow is constant. Only when the PO2 reaches very low levels will the local blood flow increase and severe anemia must frequently be present to actually demonstrate this effect when the P50 has been experimentally reduced.

Natural Models
There are several models that demonstrate effects of altered P50. Some are experimental models while others occur naturally in nature. In the human fetus, a reduced P50 aids in pickup of oxygen at the placenta owing to the increased oxygen affinity of fetal hemoglobin (which interestingly results from an alteration in fetal hemoglobin's sensitivity to levels of 2,3-DPG). So long as severe anemia or severely reduced blood flow to tissues is avoided, the effects of this reduced P50 at the tissue level is negligible. Llamas and humans who are chronically adapted to life at high altitudes have been shown to have reduced P50 levels which presumably offer benefits similar to those seen with fetal hemoglobin in the normal human fetus. The short-term effects of high altitude on two human subjects with a high oxygen affinity hemoglobin (inherited) were tested by Hebbel who found that in contrast to normal subjects, at 3,100 meters, the high affinity subjects had lesser increases in resting heart rate, minimal increases in erythropoietin, and no decrement in maximal oxygen consumption.

Experimental Models
In a study of the effects of increased oxygen affinity of hemoglobin in monkeys (caused by transfusions of blood lacking 2,3-DPG), Riggs found that mixed venous PO2's fell while cardiac output, A-V difference, and oxygen consumption remained constant. A study by Malmberg of rats exchange transfused with blood of differing oxygen affinity showed that rats with a normal P50 were more likely to survive experimental shock and anemia than those with a reduced P50. Summary Leftward shifts in the oxyhemoglobin dissociation curve (falling P50) would appear to have benefits in preserving oxygen delivery and extraction under circumstances of severe hypoxic stress such as might be found in cases of hypoperfusion, anemia, and ambient hypoxia. Under the vast majority of circumstances, however, these effects are minimal because of the human's large capacity for adaptive compensation by means of polycythemia, increased cardiac output, increased oxygen extraction, and regional changes in blood flow. It remains to be demonstrated whether there are any therapeutic benefits to be gained by attempting to artificially alter the P50 and attempts to do so would be complicated by the body's attempts to restore the P50 toward normal.

References
Hebbel RP, Eaton JW, Berger EM, Kronenberg RS, Zanjani ED, Moore LG: Hemoglobin oxygen affinity and adaptation to altitude: evidence for pre-adaptation to altitude in humans with left-shifted oxyhemoglobin dissociation curves. Trans Assoc Am Physicians, 91:212-28, 1978.
Klocke RA, Saltzman AR: Gas Transport, pp 173-94, in Textbook of Pulmonary Diseases, edited by Baum GL, Wolinsky E, Little Brown and Company, 1989.
Riggs, TE, Shafer, AW, Guenter, CA: Acute changes in oxyhemoglobin affinity: Effects on oxygen transport and utilization. J. Clin. Invest. 52:2660, 1973.
Malmberg PO, Hlastala MP, Woodson RD: Effect of increased blood-oxygen affinity on oxygen transport in hemorrhagic shock. J. Appl. Physiol. 47:889, 1979.