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Variability
of the
Response
By S. Charache,
Blood
Homeostatic
to Altered
S. Achuff,
R. Winslow,
from
p,
J. Adamson,
and P. Chervenick
carriers
of hemoglobin
Osler
had almost
the same
oxygen
affinity
as that of carriers
of Hb McKees
Rocks (Hb MR) (Pso
1 mm Hg), but
Hb concentrations
were higher in male carners of the former
(21 .6 versus
7.2 g/dI)
.
Two carriers
of each Hb were
studied
to
oxygen
affinity
and
their
responses
to
phlebotomy.
All four were healthy,
and all
excreted
normal
amounts
of erythropoietin.
Carriers
of Hb MR had somewhat
lower mixed
venous
p02 than carriers
of
Hb Osler.
There was no suggestion
that
phlebotomy
impaired
ability
to exercise
compare
in either
( Hb Osler)
their
M
adaptations
to
altered
EASUREMENTS
of erythropoietin
highand
low-affinity
hemoglobins
range,’
suggesting
that
oxygen
normal
group
of patients.
excretion
in healthy
carriers
have
yielded
results
within
transport
is normal
and
equal
of
the
to
oxygen
consumption,
despite
the stress
imposed
by a shifted
dissociation
curve.
This could
be accomplished
by changes
in cardiac
output,
Hb concentration,
and/or
tissue
PO2: anemic
patients
increase
their cardiac
output,4
some
hypoxic
patients
become
we exercise
our
a strong
polycythemic,5
legs.6 In the
argument
has
been
case
and we all lower
of hemoglobins
made
that
adjustments
basis
of altered
hemoglobin
concentration,
slightly,
and that mixed
venous
P#{176}2 remains
ments
have cast some doubt
upon
or below
the lower
limit of normal
globins
in whom
oxygen
our femoral
with
altered
are
almost
that cardiac
normal.7’8
was
evaluated
P02
when
affinity,
entirely
on
the
output
changes
only
More
recent
measure-
this concept,
since mixed
in six of eight
carriers
transport
venous
oxygen
of
(Table
venous
PO2
abnormal
1).
Some
was at
hemoof
these
patients
probably
were not in a stable
state at the time of study
(see Comments,
Table
I but the data
are of considerable
interest
when
compared
with
those
reported
here.
We recently
had an opportunity
to study
healthy
carriers
of hemoglobins
),
Osler and
McKees
families
(p
10-12
Rocks.
mm Hg,
the men of one kindred
sumed
that adjustment
output
ferences
From
were higher
than
to altered
Pso was
the Department
of Medicine,
Branch,
University
University
of Pittsburgh
Submitted
December
6, 1977;
Supported
by Research
Grant
A ddress
for
5 MO-I
reprint
of Medicine.
© 1978
1156
was almost
but hemoglobin
b Grune
Johns
Hopkins
Grants
School
accepted
and
result
University
ofMedicine.
August
HL-02799,
/4,
the
those
in the
accomplished
same
in
concentrations
other
(Fig.
by changes
the
School
of Medicine.
Institute,
Seattle.
Pittsburgh.
two
in
1). We asin cardiac
we hypothesized
that
of different
combinations
National
Heart,
Lung
and Blood
of Washington
School
of Medicine,
of Medicine,
School
affinity
27.5),
and tissue
P#{176}2as well
as erythropoiesis,
in hemoglobin
concentration
were the
Clinical
Hematology
ment of Medicine,
Center
Oxygen
normal
Baltimore,
dif-
Md.;
Bethesda,
Md. ; DepartWash. ; and Department
Pa.
1978.
HL-14131
, and
RCDA
A M-70669
and
Clinical
Research
RR35.
requests:
1030
Dr.
Blalock
& Stratton.
S.
Bldg.,
Inc.
Charache.
601
Hematology
N. Broadway,
Division,
Baltimore,
Johns
Md.
Hopkins
University
21205.
0006-4971/78/5206-0009$0I.00/O
Blood,
Vol. 52, No. 6 (December),
1978
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HOMEOSTATIC
RESPONSE
TO
ALTERED
p
1 157
MALE
FEMALE
22
21
ti
HB
gm/dl
.
and
(t)
of these
the
.
Hematocrits
1.
Fig.
Osler
of carriers
Hb Mckees
Rocks
adaptations.
nature
of
patients
with
of
ref.
:; :
studies
differences
secondary
and
to
11-5 in ref.
port.
All
fects
and
23 yr at
17, ages
four
significantly
et al.,’8
data
using
exhypoxic
cedure
informed
Medical
after
consent,
baseline
at
that
least
were
were
2 had
who
but
to
partially
trans-
ventilatory
and
only
72
and
hematocrit
de-
had
mg/dl
measured
mainly
in the
measured
by
Osler
and
the
method
by
degree
59Fe
McKees
mild
and
his
did
not
Rocks
of
of automation
and
incorporation
have
Rossi-Bernardi
the
into
facility
of
hemoglobin
in the Clinical
presence
previously;
the
approved
by
the
Clinical
was
carried
during
for
P50
(mm Hg)
Research
impartial
(for
1000
Cardiac
Index
(liters/min/m2)
cc
and
the
of
of Abnormal
Mixed
process
of
and
removed
P#{176}2 were
and
Hemoglobins
P#{176}2
(mm Hg)
Ref.
Remarks
5.0
33
9
40
10
Hemolytic
10.9
3.7
41
11
Postphlebotomy,
12
Hemolytic
13
Pso corrected*
14
Prior
Little Rock
23.8
Yokima
18.6,
Postphlebotomy
P50
23,
17.3
22
3.2,
2.8
31,
12.2
7.2 (liter/mm)
36
12
2.6,
34,
2.3
29
35
17.1,
17.3
10.3
3.9, 6.4
26, 27
Osler
22.1,
21.1
11
5.3, 6.0
33, 33
Normal
15
26.6
3.7
to a pof
26.6
mm
Hg for
normal
0.3
blood.
34-49
anemia
treatment
This paper
This paper
15
anemia
corrected*
32P, p.O2
±
replaced
Venous
5.3
13.5
Hopkins
phlebotomy)
1 4.5
12.6,
pro-
of obtaining
34.5
K#{246}In
formal
the
Johns
effect
output
was
gave
had
of The
of the
Cardiac
blood
Patients
having
Committee
evaluation
of erythropoietin.
in Carriers
Unit.
witness,
methods,
Investigation
out
approximately
Transport
an
experimental
measurement
exercise,
of
8.7
18
0Corrected
and
to oxygen
deaf
was
in
2 (lI-I
1 6.6
Heathrow
Rocks
in
sons
and
restrictive
hemoglobin
of hemoglobins
twice
of urine
and
Hammersmith
McKees
clarify
proband’s
referable
was
his
(the
mild
haptoglobin
2),
was
hospitalized
in the
Hb Concentration
(g/dI)
Creteil
2
Rocks--MR-I
of symptoms
and
serum
blood
was
Table 1 . Oxygen
Hemoglobin
His
differed
Catheterization
collections
at rest
free
MR-2,
structure
of
catheterization
Institutions.
measured
of the
affinity
Patients
cardiac
explained
try
phlebotomy
mice.20
studies.
consent for
and
(Table
I and
McKees
OSL-l
defect.
erythropoietin
polycythemic
Clinical
to
of
of his brother.
Oxygen
Urinary
healthy
function.
a modification’9
handling.
out
effects
METHODS
study)-and
increased
Analyses
been published,’6’7
carried
the
Osler-OSL-
smokers;
obstructive
those
studies.
of this
tobacco
somewhat
from
Laboratory
time
pulmonary
was
AND
hemoglobins
25 yr)--were
a mild
normal
count
of
the
were
had
had
reticulocyte
39 and
patients
MR-I
diabetes,
differ
Carriers
22 and
were
evaluate
polycythemia.
summaries.
16, age
I 9
Hb
MATERIALS
Clinical
OSLER
#{149}MR
(U).
Hemodynamic
those
#{149}
L
20
with
calculated
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
CHARACHE
1158
Table
Data
from
C arriers
Rocks and
of Hb McKees
H ematologic
Hct
Retic
(%)
(%)
(mi/kg)
(g/dl)
(U/24
MR-i
53.0
3.8
4i
17.1
5, 3.3
14.6
MR-2
50.3
1.8
17.3
1.6-3.0
14.9
7.7
0SL.1
67
1.2
57.6
22.1
4
18.3
10.4
OSL-2
62
1.3
49.6
21.1
41-Si
0.8-2.5
Prephlebotomy
Patient
Normal
range
Mass
Postphlebotomy
Hb
-
25-35
AL.
Osler
2.
RBC
ET
Ep
hr)
Hb
Peak
EPO
(g/dl)
(U/24
hr)
14-18
16
19.0
-
P50
(mm
Hg)
10.3
11.0
-
2-6
(male)
with
plasma
repeated
protein
within
Patients
titled
was
and
were
by pedaling
no
while
lying
asjudged
by
consumption
and
measurements
at rest
complications
supine
ofthese
for
5 mm.
oxygen
consumption
cardiac
output
and
The
work
before
were
during
exercise
were
then
studies.
made
done
could
and
after
during
the
not
be
quan-
phlebotomy.
last
Mea-
minute
of
the
period.
Cardiac
output
nary
artery.
area
as a function
was
Cardiac
the Special
measured
index
capacity
or
was calculated
(dI/min)
measured
from
van
the
with
weight.2’
Model
arteriovenous
averaged
unless
there
pressures
165);
and
2)
agreed
and
calculated
in oxygen
red
cells;
was
upward
as
I mm
content
samples
trend,
(ml
the
taken
in which
ease
are
shown
clinical
Hg.
of
contents
content
and
consumption
measured
cardiac
blood).
Red
and
value
in
Chemistry
02
at 30, 60,
last
surface
Oxygen
from
product
the
pulmo-
electrodes
Oxygen
latter
being
02/dl
were
02
the
calculated
the
giving
with
in
within
were
of
nomograms
measured
3 Mk
values
was
autologous
a clear
were
saturations
catheterization
from
Laboratories
Cooximeter.
content
of expired
air, the
transport
difference
51Cr-labeled
after
calculated
BMS
Instrumentation
and oxygen
Oxygen
technique
was
Oxygen
technique,
with
an
the volume
Fick
(Radiometer,
Slyke
technique.23
and
measured
and
direct
output/m2)
Laboratories,
by the
the Scholander
the
Laboratory
(Corning
measured
by
(cardiac
of height
Hematology
Laboratory
results
There
reproducible
of oxygen
exercise
(Plasmanate),
15 mm.
exercised
but
surements
were
fraction
10
cell
mass
90 mm
was
by
output
and
was
the
used.
RESULTS
Oxt’gen
finity
was
dissociation
very
high
curves
nent was somewhat
almost
superimposable
1.00
.
of
in both
more
.
evident
at oxygen
.
whole
families,
blood
but
the
presence
in the carrier
saturations
in
of the
of Hb
in the
Osler.
range
Fig.
2. Oxygen
abnormal
af-
compo-
The curves
were
of mixed
venous
__
.7 5
SAT
/7 /
.50
I
ii
1/
--OSLER
1
----
McK ROCIC
NORMAL
.25
0
25
50
75
p02
100
125
150
Fig. 2.
blood from
Oxygen
carriers
Rocks, 37’C,
pH
oxygen saturation.
percentage
dissociation
curves
of
of Hb Osler and McKees
7.4, pCO2
40 mm Hg. Y,
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HOMEOSTATIC
RESPONSE
TO
ALTERED
1159
PRE
POST
PRE
POST
PHLEBOTOMY
PHLEIOTONY
OXYGEN
CONSUMPTION
A-V
O2DIFFERENCE
(mI/mIn/m2)
CARDIAC
(mI/dI)
INDEX
(dI/mln
MIXED
VENOUS
/m)
(mm
P
Hg)
02
So
Fig. 3.
Assessment
of oxygen transport
in carriers
of Hb
McKees Rocks (U, Ii) and Hb
Osler (*,
) before
and after
removal
of 1000
cc blood,
at
rest. See text for further
description.
Normal
ranges15
indicated
by vertical
bars.
to near-normal
excretion
Fig.
was
normal.
MR
The
was
there
(Fig.
was
no
30
only
postphlebotomy
consistent
4) even
suggestion
Hb
Osler
is similar
to those
published
within
the normal
range in the carriers
of highphlebotomy
and rose after
the carriers
were
bled
levels (Table
2). In carriers
of Hb Osler,
augmented
Data
lower
20
..
was
that in general
mixed
venous
a slightly
exercise
50
The curve
for
abnormality.2425
despite
transport.
3) showed
high, and
40
_______________
hemoglobin
g/dl.
Oxygen
60
j
excretion
before
occurred
50
40
blood (>60#{176}c)saturation).
for other
families
with this
Ert’thropoietin
affinity
hemoglobins
70
hemoglobin
obtained
during
oxygen
P#{176}2and
consumption
A-V oxygen
difference
between
mixed
venous
this difference
that phlebotomy
concentrations
cardiac
catheterization
in
disappeared.
increased
>18
(Table
1,
was normal,
cardiac
index
difference
were low or lowcarriers
P#{176}2
of
the
of
latter
Hb
Osler
and
patients.
Particularly
cardiac
work.
Hb
During
after
exercise,
DISCUSSION
These
hemoglobin
studies
were undertaken
because
male
carriers
of Hb MR
had lower
concentrations
than male carriers
of Hb Osler;
they also had lower
hematocrits
than did female
carriers
in their own kindred
(Fig.
1), although
all
had very similar
p.
The
difference
in mean
hemoglobin
level
between
the
males
known
was
statistically
normal
variation,
significant
conclusions
(p
<
0.005),
drawn
but
must
with
such
be circumspect.
small
samples
and
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CHARACHE
i 160
PRE
POST
PHLEBOTOMY
ET AL.
POST
PHLEBOTOMY
PRE
OXYGE N CONSUMPTION
A - V O DIFFERENCE
(mi/min/m2)
(sel/dI)
600
fr-a
5 00
400
300
CARDIAC INDEX
(dI/ale/m)
MIXED
P0
VENOUS
(mm
Hg)
2
100
::
:
70
30
60
4.
Fig.
transport
20
Assessment
during
of
oxygen
exer-
moderate
cise before
and after
removal
1000 cc blood. Symbols, same
of
as
in Fig. 3.
These
data
were
mechanisms
fective,
were
since
collected
used
to determine
by the
erythropoietin
and transport
consumption
two
and
is accomplished
changes
may be
such
have
MR.
been
since
most
their
interesting
these
Their
are
among
the
reported
adjustment
Their
altered
tissue
pronounced
to assess
oxygen
are higher
than
could
comparison
altitudes.
Quechua
to have
to very
of Peru
normal
high
not
can
be
Hematocrit
altitude
than
rather
among
than
is better
in
stress
to random
patients,
sons
because
of
of differences
have
been
studied.
the
among
be
due
variation.
small
size
residents
of
to
and
metabolism,28’29
Hb MR.
It would
the Sherpa
decreased
only
cause
ef-
genetic
We
cannot
our
sample,
of high
Hb
1).
be done.
hypoxic
may
of
drawn
between
our
levels
are higher,
sponses
to
were
that
oxygen
kidneys.26’27
transport
in female
carriers
of
those
ofthe
male carriers
(Fig.
has lived in the Himalayas
longer
than
of the difference
is important
because
in Peru
but not in Nepal.32
Differences
be due
of adaptive
adaptations
capillarity
in carriers
cause
man
ramification
is a problem
may
combinations
men.
lower
mixed
venous
PO2 (Fig.
3), suggesting
from
blood
in some
or all of their
tissues.
In
residing
at high
altitudes,
increased
oxygen
measurements
Another
interesting
persons
living
at high
altitudes,
Sherpa
by
more
hemoglobins
Unfortunately,
of
excretion
was
normal,
suggesting
were in balance,
at least in the patients’
Carriers
of Hb M R had somewhat
that more oxygen
was extracted
animals
(and
probably
in man)
extraction
if different
groups
both
patients
and
at equivalent
of Nepal.3#{176}The
oxygen
affinity.3’
respects,
perhaps
be-
in the Andes.
The medical
chronic
mountain
sickness
in the erythropoietic
reor
altitudes,
environmental
be sure
but
of
it seems
where
factors
the
or
latter
in our
unlikely
as
many
more
per-
a
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HOMEOSTATIC
RESPONSE
We wished
also to evaluate
men
but
were
not
bled
indications
There
was
TO
ALTERED
because
of concern
for such
treatment
no suggestion
that
exercise
pre-
exercise
(Fig.
phlebotomy-induced
very
over
are
the
effects
vague
4).
Our
was
the
Both
none
and
viscosity,
OSL-2
men
noted
and there
was
made
during
not
designed
or
that could
potentially
but
four
transport.33
of the
hemodynamics
symptoms
safe, and
OSL-l
blood
phlebotomy,
measurements
were
in either
patients
The
of oxygen
harmful:
measurements
had
was
hematocrits.
of elevated
in disorders
tolerance
after
and postphlebotomy
improvement
high
of adaptation
in our
in secondary
polycythemia.
phlebotomy
ance,
and none
of the patients
We concluded
that phlebotomy
with
1161
only to study
mechanisms
the effects
of phlebotomy
dyspnea
or decreased
little difference
between
moderate
Pso
to
show
exercise
have
useful,
toler-
been
alleviated.
in the patients
declined
such
treatment,
but their
45-yr-old
mother
has been
bled
regularly
to keep
her hematocrit
below
ss;. We have not attempted
to keep her hematocrit
in the normal
range,
and unpleasant
symptoms
were reported
in a carrier
of Hb Creteil
with equally
high
affinity
when
com m unication).
Others
have
common
flow and
he
used
types
of
decrease
work35
and
therapy
normal
in patients
hemoglobins.
was
bled
to
a normal
hemodynamic
secondary
cardiac
exercise
studies
might
(Poyart
as a guide
polycythemia.34
The
work.
Serial
noninvasive
capacity36
with
hematocrit
be
an
cardiopulmonary
to
C:
phlebotomy
goals
are to
measurements
effective
disease
Personal
way
as well
to
as
in more
improve
of
blood
cardiac
monitor
such
in those
with
in the
of
ab-
ACKNOWLEDGMENT
Dr.
E. A.
tients,
and
Murphy
provided
Patricia
valuable
Hathaway
and
advice,
Mollie
Jean
Jessop
Scott,
R.
performed
N.,
many
assisted
of the
care
laboratory
the
pa-
studies.
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I.
Adamson
JW,
poulos
G:
globin
Rainier:
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2.
and
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G,
Burger
ciation
marrow
1969
gen
Erythrocyte
function
pp6l3
Bethesda
8.
Invest
9.
CA:
with
Physiological
decreased
Seattle).
4.
man.
5.
J Med
CA,
Lenfant
EngI J Med
Balcerzak
polycythemia.
6.
Doll
cisc.
and
Keul
and
281:915-919,
JT,
286:407-415,
Hematol
J:
pH
femoralvenous
and
Sport,
blood
Biochemistry
vol
in
3. Basel,
the
Exer-
Karger,
Acid
1972,
E,
by
IDS,
White
JM,
caused
Heathrow,
Br Med
YS,
for
by
a
i 103
new
(G5)
FreAnn
White
the
JM:
severe
Com-
anaemia
Hammersmith.
Eur
J
1976
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H:
B,
Hemoglobin
1978
haemoglobin
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1978 52: 1156-1162
Variability of the homeostatic response to altered p50
S Charache, S Achuff, R Winslow, J Adamson and P Chervenick
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