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EDITORIAL

“A Shift to the Left” or “A Shift to the Right”

in the Regulation of Erythropoiesis

By ERNEST BEurr

The terms “shift to the left” or “shift to the right” have occupied a place in
hematologic jargon for decades. The expressions refer, of course, to the degree
of maturation of hematopoietic cells. Pulmonary physiologists, however, have
assigned a totally different meaning to these expressions; they refer to the po-
sition of the oxygen dissociation curve. A virtual explosion of new experimental
findings and interpretations now clearly indicates that the hematologist, too,
must concern himself with “a shift to the left” or “a shift to the right” of this
curve.
The fact that anemia stimulates erythropoiesis has been recognized for a
long time and has been a focal point in the search for humoral regulators of
red cell formation. Exactly how the body senses the hemoglobin concentration
of the blood so that appropriate adjustments in the rate of red cell formation
may be made is not yet known. Laboratory measurements of hemoglobin con-
centration are carried out by measuring light absorption in a diluted sample,
but animals are not endowed with spectrophotometric devices to make meas-
urements of the hemoglobin concentration in the blood. Rather, it is likely
that an oxygen-sensor serves as the hemoglobinometer of the body. Such an
assumption is strengthened by the well-known effect of hypoxia in stimulating
erythropoiesis, and of hyperoxia in depressing red cell formation. It is not diffi-
cult to visualize how such an oxygen-sensor might function. All that is required
is an area in the body in which the rate of the blood flow and the rate of re-
moval of oxygen from the blood is maintained at a constant level ( Fig. 1).
Under these circumstances the PO2 (pO2( F ), Fig. 1) would be a function of
the hemoglobin concentration of the blood, the initial oxygen saturation of
the hemoglobin when it entered the sensor, and the shape and position of the
oxygen dissociation curve. Since the oxygen content of the plasma is a linear
function of the O2, a sensor responding to the amount of oxygen in the plasma
could measure alterations in the hemoglobin concentration of the blood.
Until recently most hematologists have given little serious consideration to
the effect of the shape and position of this curve on the regulation of red cell
formation. Oxygen dissociation curves have, it seems, been of interest primarily
to the pulmonary physiologist. Now, however, there has been rapid accumula-
tion of evidence pointing to the fact that the position of the dissociation curve
can, and indeed does, influence significantly the steady-state level of the hemo-
globin concentration of the blood. Alterations of the oxygen dissociation curve
may be responsible for anemia and for polycythemia. Shifts in the position of
the oxygen dissociation curve have also become an important consideration in
blood storage.

496 BLOOD, VOL. 33, No. 3 (MARCH) 1969

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EDITORIAL 497

p02

p02(1) ci CONSTANT BLOOD FLOW PO2(F)

CONSTANT #{176}2REMOVAL

#{182}j,
Fig. 1.-The hemoglobinometer of the body, a possible scheme. This device pro-
vides a constant rate of blood flow and a constant rate of oxygen removal from the
blood. The oxygen tension at the sensor (p02(F)) is a fraction of the hemoglobin con-
centration of the blood and the arterial oxygen tension provided that the oxygen
dissociation curve is normal.

Figure 2 illustrates the position of the normal dissociation curve of red cells.
Also shown are the positions of curves which have “shifted to the right” or
“shifted to the left.” When blood is equilibrated with oxygen in the lungs the
hemoglobin becomes almost entirely saturated with oxygen. The arterial p02 is
approximately 100 mm. of Hg, nearly the same as the PO2 of the air in the
alveoli. \\Then a fixed quantity of oxygen is removed from the hemoglobin the
resulting O2 ( and consequently, oxygen content of the plasma ) depends on
the position of the dissociation curve. If, for example, 50 per cent of the bound
oxygen is removed the PO2 falls to approximately 27 mm. of Hg if the shape
and position of the dissociation curve is normal. When the curve has shifted
to the right, removing the same amount of oxygen from hemoglobin results in
a higher-than-normal partial pressure of oxygen. Consequently the tissues are
able to obtain additional oxygen more readily from the blood. The reverse situ-
ation obtains when the curve is shifted to the left. Under these circumstances,
removal of the same amount of oxygen from hemoglobin results in a lower-
than-normal partial pressure of oxygen. The oxygen-tension sensitive hemo-
globinometer of the body would interpret a sample of blood with a right-
shifted dissociation curve as containing more hemoglobin than a spectrophoto-
metric assay would disclose. A sample of blood with a left-shifted dissociation
curve flowing through the hemoglobinometer of the body would be interpreted
as containing less hemoglobin than a spectrophotometric assay would disclose.
The seemingly appropriate adjustments in the rate of erythropoiesis would re-
sult in polycythemia when the curve is shifted to the left and anemia when
the shift is to the right.
Structural mutations involving the hemoglobin molecule may produce shifts
in the dissociation curve. These mutations, indeed, result in polycythemia when
the curve is shifted to the left, as in hemoglobin Chesapeake’ and hemoglobin
Yakinia.2 Presumably, in patients with these abnormal hemoglobins eryth-
ropoiesis has been regulated to that point that the PO’2 in the oxygen-sensor
reaches a normal level, although, because of the abnormal oxygen dissociation
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498 BEUTLER

0
0
z 90

0 80
-J
0 70
TO
Ui RIGHT N

I
60

I’-.
4

0 10 20 30 40 50 60 70 80 90 100

P02(mmHg)

Fig. 2.-A schematic representation of the oxygen dissociation curve of whole

blood. This curve describes the relationship between the oxygen tension (pOx) on the
one hand and the degree of saturation of hemoglobin with oxygen, on the other. The
sigmoid shape of the curve is of considerable physiologic importance in making pos-
sible the efficient delivery of oxygen to the tissues. As oxygen is added to normal
reduced hemoglobin the configuration of the hemoglobin molecule is altered as each
of the four heme groups of hemoglobin binds, in turn, a molecule of oxygen. This
results in changes in the affinity of the hemoglobin for additional oxygen, a phenom-
enon which has been termed the heme-heme interaction. The degree of heme-
heme interaction may be calculated from the shape of the dissociation curve.
Also shown are the positions of the oxygen dissociation curve when the affinity
of hemoglobin for oxygen is increased, “a shift to the left,” or decreased, “a shift to
the right.”

curve, the patient is now pobycythemic. The lack of severe anemia when it is
shifted to the right in hemoglobin Kansas3 is probably due to the marked
abnormality in the shape of the curve, resulting in a greatly lowered arterial
oxygen saturation.
It has also been suggested that variations in the degree of compensation in
different hemoglobinopathies associated with a moderate decrease in red cell
survival could be due to shifts in the dissociation curve.4
Alteration in the amino acid sequence of the hemoglobins is not the only
way in which the position of the dissociation curve may be shifted. A classic
means of shifting the dissociation curve is by altering the pH of the blood.
Recently, it has been clearly demonstrated that intracellular phosphate com-
pounds, particularly ATP and 2,3-diphosphoglycerate, can produce marked
displacement of the oxygen-dissociation curve.56 Apparently, these compounds
are bound to hemoglobin, the binding resulting in a lower affinity of the
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EDITORIAL 499

hemoglobin molecule for oxygen.7 Since the levels of ATP and 2,3-DPG within
the erythrocyte are subject to alteration by regulation of the rate of metabolism
by way of the Rapoport-Luebering cycle, the erythrocyte is provided with
an opportunity to adjust its own oxygen dissociation curve. Even relatively
brief exposure to high altitudes results in the accumulation of 2,3-DPG
within the red cell,8 and a right shift in the dissociation curve has been ob-
served in patients with erythrocytosis secondary to arterial hypoxernia of
chronic pulmonary disease.9 Although this may make it simpler for the red
cells to deliver sufficient quantities of oxygen to the tissue without too severe a
drop in tissue PO2, too great a right shift of the dissociation curve could be a
handicap, since the red cells would then fail to bind sufficient oxygen in the
lungs.
It seems entirely possible that alterations in the concentration of 2,3-diphos-
phoglycerate in erythrocytes may also affect the steady-state level of hemo-
globin by shifting the oxygen dissociation curve. A family with an increase in
red cell ATP levels, in which there was marked diminution of erythrocvte
2,3-DPG levels is of particular interest in this respect.’#{176} Since the sum of ATP
and 2,3-DPG levels was considerably lower than normal, one would anticipate
a left shift in the dissociation curve. Indeed, although there was modest short-
ening of red blood cell survival in this family, there was a statistically signifi-
cant increase in the hemoglobin level of the blood. It would seem very w’orth-
while to measure the erythrocyte 2,3-DPG and ATP levels and oxygen disso-
ciation curves of other patients with mild, and otherwise unexplained poiy-
cythemia.
Conversely, one would predict that elevations of red cell 2,3-DPG levels
would result in a right shift of the dissociation curve and anemia. Although
pyruvate kinase deficiency produces a marked increase in red cell 2,3-DPG
levels,1’ it is difficult to interpret the result of this shift, since marked shorten-
ing of red cell survival also occurs. It seems likely, however, that other
metabolic disorders of the red cell may exist in which a right shift of the dis-
sociation curve is not accompanied by shortened red cell survival and in
which anemia may be ascribed to the change in the oxygen-binding properties
of hemoglobin. One may speculate that pharmacologic manipulation of the
levels of red cell intermediates may indirectly change the rate of erythropoiesis.
Thus, it will be of interest to examine the effects of agents such as cobalt and
testosterone on the oxygen dissociation curve.
In 1954 it was demonstrated that the oxygen dissociation curve of blood
stored in ACD solution gradually shifted to the left.12 This observation initially
received relatively little attention, and its mechanism remained obscure. The
demonstration that 2,3-DPG and ATP levels markedly influenced the position
of the dissociation curve have now explained this finding.’3 Stored blood be-
comes severely depleted of 2,3-DPG in less than 2 weeks. It now becomes ap-
parent that massive blood transfusion with 2,3-DPG depleted blood might he
quite hazardous. The transfused red cells would lack the capacity to effectively
deliver oxygen to the tissues for some hours. If this is so, why has there not
been greater clinical recognition of such hazards? Most individuals who re-
ceive blood transfusions have only a fraction of their circulating red cell mass
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500 BEUTLER

replaced each day. Patients who are bleeding massively would ordinarily be
transfused with units of stored blood of various ages, some of it quite fresh.
Occasionally a massively bleeding patient might be transfused with sufficient
blood stored for over 2 weeks within a short period of time to cause severe
tissue anoxia. But such desperately ill patients often die, and it would not be
surprising if in the complex clinical situation surrounding massive hemorrhage
the death would not be ascribed to failure of transfused red cells to deliver
their load of oxygen to tissues.
It is apparent that during the next few years it will be necessary for the
hematologist in the laboratory and in the clinic to show more concern for the
position of the oxygen dissociation curve. It is entirely possible that many
patients who now have anemia or polycythemia of unknown origin may ac-
tually be suffering from a “shift to the left” or a “shift to the right.”

REFERENCES
1. Charache, S., Weatherall, D. J. and Benesch, R., Benesch, R. E., and Yu,
Clegg, J. B.: Polycythemia associated with C. I.: Reciprocal binding of oxygen and
a hemoglobinopathy. J. Clin. Invest. 45:813, diphosphoglycerate by human hemoglobin.
1968. Proc. Nat. Acad. Sci. 59:526, 1969.
2. Jones, R. T., Osgood, E. E., Brimhabl, 8. Lenfant, C., Torrance, J., English, E.,
R., and Koler, R. D.: Hemoglobin Yakima: Finch, C. A., Reynafarje, C., Ramos, J.,
I. Clinical and biochemical studies. J. Clin. and Faura, J.: Effect of altitude on oxygen
Invest. 46:1840, 1967. binding by hemoglobin and on organic
3. Reissmann, K. R., Ruth, W. E., and phosphate levels. J. Clin. Invest. 47:2652,
Nomura, T.: A human hemoglobin with 1968.
lowered oxygen affinity and impaired heme- 9. Edwards, M. J., Novy, M. J., Walters,
heme interactions. J. Clin. Invest. 40:1826, C. L., and Metcalfe, J.: Improved oxygen
1961. release: an adaptation of mature red cells
4. Bellingham, A. J., and Huehns, E. R.: to hypoxia. J. Clin. Invest. 47:1857, 1968.
Compensation in haemolytic anaemias caused 10. Z#{252}rcher, C., Loos, J. A., and Prins,
by abnormal haemogbobins. Nature 218:924, H. K.: Hereditary high ATP content of hu-
1968. man erythrocyte. Proc. Xth Congr. Int. Soc.
5. Chanutin, A., and Curnish, R.: Effect Blood Tranf., 1964:549, 1965.
of organic and inorganic phosphates on the 11. Busch, D.: Heredit#{228}re nichtsph#{228}-
oxygen equilibrium of human erythrocytes. rozytare hamolytische An#{228}mien.: Blut 13:
Arch. Biochem. Biophys. 121:96, 1967. 109, 1966.
6. Benesch, R., and Benesch, R. E.: The 12. Valtis, D. J., and Kennedy, A. C.:
effect of organic phosphates from the human Defective gas-transport function of stored
erythrocyte on the allosteric properties of red blood cells. Lancet 1:119, 1954.
hemoglobin.: Biochem. Biophys. Res. Com- 13. Akerblom, 0., de Verdier, C. H.,
mun. 26:162, 1967. Garby, L., and H#{246}gman, C.: Restoration
7. Garby, L., and de Verdier, C. H.: of Defective Oxygen-transport Function of
Binding of ATP and 2,3-DPG to hemo- Stored Red Blood Cells by Addition of
globin-Effect on erythrocyte glycolysis. Folia Inosine. Scand. J. Clin. Lab. Invest. 21:245,
Haemat. 49:421, 1968. 1968
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1969 33: 496-500

Editorial: "A Shift to the Left" or "A Shift to the Right" in the Regulation of
Erythropoiesis
ERNEST BEUTLER

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