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A SURVEY
OF
THE
SIGNIFICANCE
By
LLOWING
blood
brilliant
transfusions
gradually
However,
groups
of cases:
transfusions,
and
intragroup
(0
patients
women
(2.)
demonstration
of the study
opened
by the
hitherto
discovery
description
that
and
agglutinins
on the
reactions
FACTOR
I9oo-19o1”
whole
were
isoagglutinins
an entirely
of the
interest
differences
other
the production
of the
2
a safe
still
and
four
routine
observed
in two
role
than the 4 blood
groups
were
of new antibodies,
but the
was very seldom
new field of clinical
of fetal
blood
observed.
importance
in isoimmunization,
In the
was
a subject
only.
HISTORICAL
In ioo two other
fetalis
were made.
the phenomenon
of
to many
species
of
within
any particular
in
became
transfusion
of immune
of this material,
of theoretical
Rh
who
had previously
received
a series
of uneventful
at the very first transfusion
associated
with
pregnancy.
It was for a long time suspected
responsible
for isoimmunization
actual
course
THE
M.D.
LEVINE,
Landsteiner’s
groups,
procedure.
PHILIP
OF
DEVELOPMENTS
discoveries
pertinent
to isoimmunization
and erythroblastosis
The first was the description
by Ehrlich
and Morgenroth3
of
isoimmunization
in goats
and later extended
by other
workers
animals.
In general,
the procedure
used was cross-transfusion
species
which
resulted
in the appearance
of immune
iso-
or isohemolysins.
This
work
led
to the
concept
of the
individuality
of animal
blood
by virtue
of combination
and permutation
of a number
of antigenic and hereditary
substances
in the red blood
cells.4 In I9oo, the Mendelian
laws
of heredity,
published
Correns,
Tchermak
and
and P, in 192.8,
the
human
blood
also,
heteroimmune
In 1939,
agglutinin
(1937)
had
o
concept
although
sera.5
Levine
and
held
delivered
35 years
de Vries.
previously,
With
the
were
description
independently
rediscovered
of the human
factors
M,
of the individuality
of blood
was
in these
discoveries
Landsteiner
Stetson6
offered
an explanation
for
the
extended
and
origin
by
N,
to include
Levine
used
of an atypical
to be responsible
for a severe
transfusion
reaction
in a recently
woman
at her very first transfusion.
The serum of this patient,
who
just delivered
a maccrated
individuals.
The intragroup
temperature,
and
agglutinins
Levine.7
(anti-A,,
in this
fetus,
agglutinated
the cells of 8o per
agglutinin
was at least as active
at 370
respect
anti-O,
it differed
and
widely
anti-P),
studied
from
the
extensively
normal
cent of group
C. as at room
atypical
by
Landsteiner
isoand
Levine
and Stetson
assumed
that
the fetus
inherited
a dominant
agglutinable
factor
from the father,
but not present
in the mother’s
blood.
Isoimmunization
could
then
result
from
the transpiacental
transfer
of minute
quantities
of fetal
red
blood
cells and/or
tissue
cells into the maternal
circulation.
The authors
were led to suggest
transplacental
isoimmunization
Ortho
From
the
Read
at the
Research
International
Foundation,
Hematology
Raritan,
New
Jersey.
and Rh Conference,
3
because
Dallas,
Texas,
Nov.
i,
1946.
of paral.
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4
SIGNIFICANCE
Id
observations
mutual
made
by
isoimmunization
parabiosis.
Gorer
strains
finding
and
9
in back-cross
of two
of mice following
transplantation
was reported
by Lumsden
in rats.
of a mouse
The latter
transplants
host
the
in certain
of immune
animals,
which
isoagglutinins
subsequent
findings
on
the
and Stetson
described
hitherto
known
blood
was assigned
to this
produced
discovered
property
these
from
described
Later
in
scribed
and an identical
noted
necrosis
of
to
which
several
factor
not
suspect
identical
in
times with
was probably
the
development
Stetson.
In each
case
or,
as we
and
that
in
the
the
way
for
At
the
same
know
at present,
Wiener”
were
ing
incidence
of
the
high
that the phenomenon
transfusion
reactions,
morbidity.
or another
form
It is of interest
compatibility
test
that
these
When
the
that
sera
all their
incubation
contained
several
was
the
the
time
poorly
at icebox
and
revealed
sera
agglutinin
it
were
of the
antibodies.
was derived
of knowing
Wiener
and
who
had
similar
to the
one
transfusion
was
these
suggested
As in the rethan
at lower
referred
of women
to them
as
were strik-
morbidity,
“cold”
In the
variety
light
infants
and
suffered
that
and
of our
the
the
present
de-
reaction
it
with
fetal blood,
responsible
correlated
with
the fetal and
that
fetalis
temperature.
neonatal
de-
antibody
now suspected
that
factor
previously
or fatal
and Katzin’7
of this group
identical
in sera
factor
was
indicated
a
in human
isoim.mune
who
had recently
delivered.
were more active at 370C.
of fetal
anti-Rh
cases
a severe
of immunization
was directly
histories
blocking
heteroimmune
with
Burnham
histories
of erythroblastosis
with
red
investigating
Stetson.
Because
the serum
and Wiener
had no way
Later,
in 1940,
however,
antigenic
in Rh-individuals
studied
in a woman
these agglutinins
Levine,
obstetrical
because
their
specificity
there
temperatures.
Accordingly,
“warm
agglutinins.”
The
suggested
intra-group
in
factors
paved
Rh+
blood.*
These workers
identical
with
the unnamed
by Levine
and Stetson.
1940
Levine
and Katzin’5
with
by
certain
a new blood
factor
which
was independent
of the
properties
such as A, B, M, N, and P. However,
no
new blood
factor
which
was antigenic
in the same
did
was
at the very first transfusion
markable
case of Zacho,’6
probable
sarcoma
workers
cell of the rhesus
monkey,
related
to but not
In the course
of their
studies
of the antibodies
workers
animals
been transfused
the human
Rh
*
2.
of erythroblastosis.
found
in the patient
studied
by Levine
and
from
the experimental
animal,
Landsteiner
that
their
factor
was important
clinically.
Peters’4
observed
that
the Rh factor
was
natal
joined
in
in animals
injected
with
rhesus
blood,
another
human
blood
which
they called
Rh.’2.
‘ As in the case
of the M factor
it
in rhesus
blood
related
to but not identical
with
the factor
first
rived
red blood
M factor.
demonstrated
of doves
antigenic
isoimmunization
species
(isoimmunization),
but not antigenic
antigenic
in animals
(heteroimmunization).
At about
the same
time (1937),
Landsteiner
a factor
in the
with
the human
‘#{176}frqj
isoagglutinins
against
pathogenesis
.
species
attributed
was
directed
cells of the donor
transplants.
It was this concept
of placental
blood.
At
Lumsden
hybrids
of immune
the
described
FACTOR
appearance
the
Levine
other
name
Rh
OF
from
was
for
neoone
intra-uterine
authors
suggested
knowledge,
a
it is
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PHILIP
blood
which
destruction
found
their
infants’
Rh+
was brought
about
way into the fetal
blood.’8’
by the action
of the maternal
circulation
to react
with
and
The proof of the concept
statistical
differences
pared
with
a random
presented
in a series
white
PROOF
is indicated
of mothers
in table i which
of erythroblastotic
with
anti-Rh0
shows
the strikinfants
as com-
population.
Further
proof was supplied
in a demonstration
that
in any given
population
depends
upon
the incidence
test
antibodies
destroy
the
19
STATISTICAL
ing
5
LEVINE
(anti-D)
the incidence
of the
of Rhindividuals
agglutinin.
TABLE
*_Statistical
I.
Proof
Per
cent
Rh+
Random
population,
350
mothers
2.04
husbands
539
affected
After
*
of
male
or
infants
infants
10
mothers
of Rh-
Rh-
8
female
erythroblastotic
of Rh-
disease
in the
mothers
90
ioo
-
ioo
-
Levine20.
TABLE
Race
Number
1*
Incidence
.1.
tested
of
Eryihroblaslosis
felalis
(()7
#{176}
#{176}
White’9
334
8.o
Negro”
2.64
95.5
4.5
52.0
99.2.
o.8
Chinese2
150
99. 3
0.7
very
rare
Japanese2’
150
98.0
a.o
very
rare
American
*
After
Indianl3
i.o
1.1
5.7
?
Levine21.
In 1941-1943
facts:
i.
In the
Levine
and
his
8 per cent Rh+
coworkers
mothers
established
of erythroblastotic
the
following
infants,
the
additional
isoimmuniza-
tion was attributed
to finer differences
of the Rh factor
(antiC),*
to a new
factor
called
Hr (genetically
related
to Rh),
and to the factors
A and
2.. The
Rh factor
was presumably
limited
to red blood
cells.27
Certainly
affected
infants
the Rh factor
could
not be demonstrated
in the body fluids.
3. Anti-Rh
agglutinins
could be demonstrated
in less than oper
cent of the
mothers
the
of erythroblastotic
hemolytic
*
For a discussion
process
of the
infants.’9
was
induced
terminology
It was
by the
see page
7.
action
assumed
that
in the
of an antibody
remaining
of another
blood
B.’926
in the
Rhcases
variety
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6
SIGNIFICANCE
not detectable
and Diamond3’
4. Intra-group
Rh5
and
and
blood
Anti-Rh
.
anti-C
anti-Rh’
with both
6. The
to Rhpatients.’9
sera differ
in specificity,
(anti-Rh’)
(anti-C)
sera
final
them
2. of
was not
statistical
found.
study
the
were
of either
serum
hemolytic
called
The
since
greater
the
D (Rh0)
superior
factor
was more
to the experimental
was largely
abandoned
process
in the affected
(anti-Rho)
serum
failing
importance
or human
13
anti-D
anti-Hr
a blood
revealed
rhesus’2’
far
and 1945,
Race,29 Wiener3#{176}
antibody.)
by the administration
of
now
giving
4 types
of reactions.32
gave only 3 types of reactions,
by injections
experimental
8. The
FACTOR
by methods
hitherto
employed.28
(In 1944
independently
described
the blocking
transfusion
accidents
could be prevented
serum,
presumably
because
7. Human
anti-Rh
sera
animals
Rh
OF
(anti-c)
to react
of the
ariti-D
antigenic.’#{176}’ 22
serum
produced
blood.33’
in
Accordingly
‘
at a very early date.
infant
could
be treated
more
the
effectively
by transfusion
of Rh
blood since the transfused
Rh+
blood
as well as the infant’s
own Rh+
blood
were still subject
to hemolysis
in
the neonatal
period.’9
Several
factors
of safety
were
listed
which
were
responsible
for the com-
.
paratively
low
incidence
of erythroblastosis
fetalis
in spite
of a high
frequency
of incompatible
mating
(8 X 15 = 12..75
per cent):
(a) the current
tendency
to
small families,
(b) a high incidence
of heterozygous
fathers
and (c) the failure
of
many
Rh
women
to produce
anti-Rh
antibodies.
It was suggested
that
the
capacity
to produce
antibodies
is dependent
upon one or more genetic
factors.’9’
38
In the 6 year interval
since the description
of the pathogenesis
of erythroblas-
tosis
Race
fetalis,
some notable
and their
colleagues,
workers,
mainly
Wiener,
with finer
contributions
Taylor,
Diamond,
methods
were
Coombs
Witebsky,
for detection
Chown,
Hill
of immunization,
of Rh-Hr
system,
attempts
to enlarge
the
nostic
purposes,
and replacement
transfusion
GENETICS
Reference
has
already
been
sera (anti-D
and anti-C)
testing
several
hundred
significance
of these
facts
infants,
while
40In the latter
fied the
affected
specific
and
anti-C
and anti-c
relationship
by Landsteiner
Rh-Hr
contrast
anti-C
their
and
bearing
anti-c
(anti-Hr’)
case the husband
Haberman.
These
dealt
theories
on the genetics
of reactions
to 3 types
and anti-c.
3 types
sera
for
diag-
on the
given
linkage
was observed
was Rhbut
of reactions,
of factors
C and c (Rh’
and
and Levine
for M and N.,
Hr’)
i.e.,
by two
anti-Rh
of reactions
observed
on
Because
of the historical
theory
by Rh-
of Fisher,
mothers
table
of eryth-
in an immunized
the mother’s
serum
i.e., a factor
in the blood
mother’s
blood,
and causing
only
workers,
Fisher,
by the American
SYSTEM
of these 3 sera, is reproduced.
and anti-C
were produced
gave
British
and
supply
of human
anti-Rh
of the affected
infant.
to the 4 types
criteria
of isoimmunization;
infant,
not present
in the
antibodies
by the mother.
Because
genetic
served
made
THE
in striking
bloods
with
3, showing
the relationship
Two
of the 3 sera, anti-D
roblastotic
mother.’9’
OF
made by the
and Mourant,
it
was
Rh+
satis-
of the husband
the production
suspected
was analogous
2. allelomorphic
that
to that
genes
and
of
the
obat a
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PHILIP
7
LEVINE
particular
locus on a chromosome.4’
It is for this
were reversed
to yield the term “Hr”
for the new
3 serologic
heterozyous
types
and
positive
third
the
cent).
It is true
but
the
with
70
anti-C
Levine,
mined
Levine’s
original
by
Race42
and
was
with
on Tests
t
for
per
anti-c
anti-Hi’
serum
sum
to explain
(anti-D)
(anti-c)
was
factor
second
(about
and
8o
of weak
per
activity,
by taking
into
account
which
was maximally
the genetics
or the
of the
or anti-Hr’
have been calculated
reactions
with
anti-C
with
334
Mrs.
Random
M.F.
3.*_The
Bloods
anti-Rho
Cross-Roads
(White)
Mrs.
MS.
of the
factor
E discovered
D, deter-
independently
Experiment
Carried
anti-Rh’
Rh,
+
+
Rh,
+
0
Rh’
o
+
Rh-
0
0
After
the
Wiener.43
Terminology
of Wiemer
and Landsteiner
*
and
with
unable
anti-Rh0
TABLE
Based
cent)
reactions
factor
could
and negative
however,
by reactions
(about
of positive
the incidence
of the
incidence
of positive
active.
“Rh”
the
3 genotypes:
(I)
CC, homozygous,
(2.)
Cc
The sum of the first 2. gives the incidence of
number
that
that the 2. letters
factor.
Accordingly,
correspond
to the
cc, homozygous.
()
reactions
gives
reason
blood
out
Mrs.
in April,
K.F.
May
and
June,
‘94’t
Incidence
(per
anti-Hr
oor±
of type
cent)
71
+
7’
oor±
2.
+
13
Levine’9.
At the
inclusion
request
in the
of Dr. Wiener,
third
edition
the scheme
of his book,
of the
“Blood
reactions
Groups
indicated
was
and Transfusion.”
made
available
to him
pp. 2.53-2.54
(CC.
Thomas).
Without
taking
of reactions
could
after the description
into
account
the
Hr
factor,
Wiener
suggested
be explained
on the basis of multiple
of the E factor,
6 genes
alleles,
that
at first
the
4 types
3 genes
and
of linkage
theories
at
are
.“
Subsequently,
Fisher
and Race45 suggested
3 different
loci on a particular
chromosome.
illustrated
below:
the alternative
theory
The two
contrasting
Multiple
Alleles
Linkage
D1
R’R’r#{176}.
.
R’R”r
Id
C
c
E
Wiener44
Fisher
position
*
For
produced
intermediate
a discussion
some
of this
genetic
between
theory
see
evidence
to indicate
D and E.
Wiener.44
Fisher
that
& Race43
the
gene
C is located
in a
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8
SIGNIFICANCE
Accordingly,
Fisher
extended
include
genes for the 2. remaining
late the existence
of 2. additional
Rh
OF
the concept
of the MN type
Rh factors
D and E. In doing
Hr genes d and e allelomorphic
genes D and E. One of these, e, was subsequently
described
a new human
antibody
which
gave
negative
reactions.
As will
be shown
these
values
derived
from
third
variety
of anti-Hr
definitely
This,
established.
by transfusion
produce
anti-Rh
Apparently
These
varying
not
destroy
of
anti-d,
the
incidence
of the
almost
gene
has
validity
ex-
frequencies.
not yet been
of the
theory
by the much
smaller
individuals immunized
per cent Rhmothers who
for D(DD)
can produce
anti-d.
92.
several
antibodies
observed
is an index
of the corresponding
factors,
since
the number
of
differ for factors determined by allelomorphic
genes.
are illustrated below:
Immunized
8%
does
when he
4 per cent
correspond
all anti-Hr
sera can be produced
mothers of affected infants or Rh+
of antigenicity
matings cannot
considerations
92.%
however,
of relationship
to
so he had to posturespectively
with
by Mourant49
positive
and
figures
a calculation
antibodies,
of Hr+
blood. In contrast to the
antibodies,
only those homozygous
the
of the degree
incompatible
discovered
96 per cent
below,
actly
to the theoretical
The existence
of the
since with
rare exceptions,
group of 8 per cent Rh+
FACTOR
Mothers
A nlibodies
Produced
Rh-
(cde)
anti-D
(also
anti-C
and
anti-E)
Rh-
(Cde)
anti-D
(also
anti-E
and
anti-c)
Rh-
(CdE)
anti-D
(also
anti-c
Rh+
DD
anti-d
Rh+
CC
anti-c
Rh+
EE
anti-c
This scheme
is simplified
since the Rh+
zygous for a particular Rh factor.
The incidence of matings incompatible
mothers
and
are represented
for the 3 Rh
and Hr
anti-c)
as being
factors
homo-
is given
as
follows:
Rh
of Mother
(anti-D)
Husband
X
Incidence
Types
Wife
of
Incidence
Mating (/)
(%)
Antibodies
duced
Pro-
Incidence
of Antibody
-
D
X
d
8
X
i
i
anti-D
frequent
+
C
)(
c
73
2.7
2.0
anti-C
rare
+
X
X
e
D
30
70
2.1
anti-E
occasional
+
E
d
X
X
63
)(
37
2.3
anti-d
+
c
X
C
8o
X
2.0
anti-c
rare
+
e
X
E
i6
3
anti-c
very
Wiener’s
view44 expressed
X
in numerous
was based on a series of multiple
rare
papers that the genetics of the Rh factor
alleles at
existence
of the Hr factors.
Furthermore,
tiple
allelic
theory
such
new
Rh genes
and Race47 (C”).
The complex
antigenic
readily explained
3
I’
i
locus does not
take
into
account
the
is difficult
to incorporate
into the mulas those
described
by Stratton46
(Du)
structure
of the Rh factor
can be more
it
in terms of linkage at several loci along the length of the chromo-
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PHILIP
9
LEVINE
some.*
It must be stated, however, that geneticists
entiate multiple alleles
from closely
linked
genes.
Because
locus,
the
genetic
linkage
Accordingly,
always
usage requires
variations
of a symbol
theory
necessitates
a departure
from
Fisher
arbitrarily
selected
c, d, e for the corresponding
Rh and Hr as blood
factors.
the
Hr genes.
letters
There
find
it
for allelic
the term
C, D, E for
is no reason
difficult to differgenes
“Rh”
the
at a given
as a gene.
Rh
for discarding
genes
the
and
terms
In a sense the choice
of D for the factor described
nate.
The student
in this field can readily
orient
by anti-Rh0
serum
himself
since the
already
important
serum”
is clinically
the most
of the D factor.
In terms
of the
referred
one
linkage
indicated
theory,
an Rh+
by a positive
Such individuals
i.e., either
DcE
sented
his
By the same
with
anti-D.
individual
reaction
with
is one whose
blood
contains
the
anti-D,
the diagnostic
serum
factor
D as
(anti-Rho).
may also possess
the factor
C, i.e., DCe or Rh,, or the factor E,
or Rh2 or all 3, i.e., DCE
or Rh1Rh2.
An Rh0 individual
is repre-
as Dcc since
Hr sera.
act
to in the literature
as the “diagnostic
because
of the greater
antigenicity
is most fortuanti-D
serum,
blood
token
The
will
an Rh
several
react
with
possibilities
Rh-
only
individual
-
anti-Rh0
is any
are given
dCe
Rh”
Rh’Rh”
dcE
dCE
Rh
dcc
In this paper the term Rhindicates
refers to the absence
of all Rh factors
Hr factors.
whose
and
blood
with
2.
fails
antito re-
below:
Rh’
negative
serum
one
the composite
group
while
“Rh negative”
and by the same
token
the presence
of all 3
TABLE
4
anti-
anti-
D
d
or
C
c
or
E
These
the
of Rh+
prognosis
heterozygous
incapable
locus
types
*
heterozygous
0
homozygous
o
+
homozygous
an
are important
husbands
for
the
clinician
as homozygous
(DD)
is far
for
in pregnancies
better
since
50 per cent
of the offspring
of immunizing
the Rhmother
(Dd
serologic
(serologic
For
+
+
considerations
entiation
e
+
excellent
tests for the corresponding
types)
corresponding
summary
of
the
Fisher
theory,
since
they
or heterozygous
matings
in which
will be Rhx dd). With
aid
(Dd).
2.
the
Race.4#{176}
differ-
Obviously
husband
is
(dd) and, therefore,
genes at a particular
blood factors
reveal
directly
to the 3 genotypes
as shown
see
in the
the 3 phenoin table 4.
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10
SIGNIFICANCE
The
Johannsen
formula
genetics
of the MN
there are 2. allelic
OP
previously
Rh
used
factors,
is generally
genes
and 3 types
FACTOR
by
Landsteiner
applicable
corresponding
and
for
Levine4’
the
for all genetic
systems
in which
to 3 genotypes.
This useful
formula is based on the application
of the binomial
theorem
to the gene frequencies.
The frequency
of any one gene is equal to the square
root of the percentage
of nonreactors
The
who must be homozygous.
brilliance
of Fisher’s
contribution
formula
positive
to Mourant’s49
reactions
and
populations.
of homozygous
formula
The
the
70
per cent containing
and the remainder
30
EE
gives
of genee
Frequency
of gene
EE
fEe
.
Remarkably
TABLE
#{176}
enough
the data obtained
very significant
/o
=
E
10-8.36
=
=
(5.64)2
=
i
=
(8.36)2
derived
X
=
8.36
=
1.64
X
values
8.36
are
=
2.7.3
=
70.
in almost
of Gene
F equencies
for the Rh-Hr
X
=
Incidence
one
dominant
x
=
Incidence
of the
other
j30/0
perfect
These
the3ry.
Systems
(C-c,
agreement
dominant
constitute
D-d,
E-e)
Xx+x2
=W0
0
100
0
I
19
8z
2.-l-
8
4
p.
64
3+
7
9
42.
49
4+
6
i6
48
36
5+
6+
5
2.5
50
2.5
4
i6
3
36
49
48
7+
42.
9
8+
2.
64
32.
4
8i
i8
i
0
0
i
0
the first anti-Hi
C was obvious,
considerations,
100
isoagglutinins
that
a particular
give maximally
and
gene
20+2
immune
with
findings
9
with
per cent
American
gene
10
surprising
will not
30
2..7
=
1.64
1+
9+
a more
potent
Historically
to the British
of Johannsen’s
the E factor
consist
of a certain
percentage
are heterozygous
or Ee. Application
of the
=10
50+
is not
the time,
these
-Determination
0+
In dealing
an application
by Mourant
for anti-c,
i.e., 96 per cent.
evidence
in support
of Fisher’s
linkage
X+x
it
from
of the e factor.
Anti-E
gives
reactions
in both English
and
following.
Frequency
97.3
is seen
recent
discovery
per cent negative
of human
origin
which
antibody,
perhaps
the
potent
reactions.
Although
only
occur
very
rarely,
one available
at
this occurred
with
serum (anti-c)
nevertheless
its genetic
relationship
with the factor
since anti-C
gave
maximally
potent
reactions.
Because
of these
the writer
hesitated
to publish
at length
on the Hr factor
until
serum
was
workers
it
became
available.
of interest
that anti-D
and the rare
(Race
and Taylor)
for their first
anti-c sera were available
studies.5#{176}Somewhat
later
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
PHILIP
an anti-E
agglutinin
was
found
late in 1943 and published
tities
of potent
specimens
in
and
LEVINE
I I
curiously
in I944.’
of anti-D,
enough
Fortunately,
anti-C
and
anti-C
Levine
a weaker
serum
was
first
used
had available
large quananti-c
in his first studies
1941.
Until
anti-d
sera
become
entiation
of homozygous
This is possible
because
available
and
there
there
is no choice
heterozygous
is a high degree
but
to use anti-c
CC for the 71 per cent of Rh+
individuals
of type DCe and DCE
As first pointed
out by Levine5’
anti-c
cannot
be used for the
individuals
of types
DcE (Rh,)
or Dcc (Rh0).
For this group
in the
specific
approximately
the
twice
hemolysis
antiserum
hemolysis
SOME
With
per
92.
the
aid
cent
contains
of anti-D
of all cases
(Rh, and Rh,Rh,).
per cent of Rh+
an anti-d
serum
is
anti-Rh
PRACTICAL
the
diagnosis
mother’s
antibodies
in heterozygous
until
an interval
CONSIDERATIONS
of erythroblastosis
blood
(agglutinins
to disappear
of another
and
Rh+
immunization
of several
for a “rest”
fetus in the
will
years
fetalis
is negative
is established
(Rh-)
or blocking
elaspse,
period
for the
next pregnancy,
not be so intense.
bloods.
showed
bloods.
and
antibodies).
Should
long
enough
periodic
tests
workers
become
for residual
antibody
producing
it is possible
that
show
serum
smaller
to special
not
in
if her
In the
group of 8 per cent Rh+
mothers,
the blood should
be submitted
in the field for testing
with the other anti-Rh
and anti-Hr
scra.
The mother
who has already
delivered
an affected
infant
should
nant
serums
in the
have been able
“
of homozygous
and heterozygous
(anti C, D or c) homozygous
cells
observed
if the
differ-
mothers.
DD and
14
essential.
Through
the use of the hemolytic
effect of anti-Rh
and anti-Hr
presence
of whole
blood
and complement,
Hill and Haberman63’
to show
a difference
In the presence
of the
for
Rh+
husbands
of Rhof correlation
of genotypes
preg-
antibodies
cells. In the event
the degree
of isoan increasing
anti-
body production,
many
authorities
believe
that labor should
be induced
in order to
shorten
the period
of intra-uterinc
blood
destruction.
Since
antibodies
have
been shown
to persist
for a number
of years,
further
pregnancies
are to all intent
and purposes
excluded
especially
for the older Rhwoman
whose
husband
is homozygous.
With
another
gress
when
antibodies
residual
from
the preceding
appeared,
it will
be very difficult-if
not impossible-to
from residual
antibodies,
particularly
if the husband
will
be made
but
test
this
Until
our
later
to the
value
of the
can be applied
only after
knowledge
is extended,
immunized
limited.
factors.
In practice
this is equally
applicable
Even
though
some of these infants
is always
In the case of Rh-
transfusions
the
women
already
globulin
test
on the
delivery
(see page 13).
the number
of pregnancies
already
fusions,
there
kernicterus.
by
anti-human
pregnancy
increasing
in general
and/or
in pro-
pregnancy
have
not yet disdifferentiate
newly
formed
is heterozygous.
Reference
previous
cord
of Rh-
pregnancies,
women
should
to Rh+
women
immunized
will recover
with
replacement
danger
the
of later
number
complications
of pregnancies
blood
be
by other
transbecause
to be
recom-
of
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
SIGNIFICANCE
12.
mended
will
routine
group
testing
of Rh-
mentioned
depend
the
upon
the
ease
with
for antibody
women
who
production
are readily
capacity
antibody
for
Rh
OF
FACTOR
which
antibodies
with
each
immunized
are
produced.
With
pregnancy,
the much
can be selected.
As
production
is determined
by
one
smaller
already
or
more
.genctic
factors.
In any event,
the incidence
of erythroblastosis
fetalis
can be lowered by prevention
of isoimmunization
in all of our Rhfemale
population
who
may be candidates
for transfusion
or intramuscular
injection
of blood53 (see page 17).
In view of the high fetal morbidity
in intensively
immunized
Rhwomen
whose
husbands
.abortion
are homozygous,
seems justified.39
made,
nancies.
had
For
the RhExcept
one
this
termination
In the several
patient
for those
had potent
immunized
or more normal
group
of cases
Rh+
either
of accidental
cases in which
antibodies
by previous
children
artificial
pregnancies
by therapeutic
this recommendation
was
residual
from
the
transfusions,
these
and had lost
insemination
one or more
or adoption
preceding
women
pregalready
affected
infants.
may be recom-
mended.
AGGLUTININS
In the
initial
study
on
the
AND
BLOCKING
pathogenesis
ANTIBODIES
of erythroblastosis
fetalis
anti-Rh
.glutinins
were observed
in less than 50 per cent of the Rhmothers.*
vious
that the remaining
Rhmothers
were immunized
because
their
hemolytic
symptoms
and these mothers
were equally
subject
to severe
reactions.
cannot
The view
be demonstrated
was
ag-
It was obinfants
had
transfusion
expressed
that
“antibodies
capable
of reacting
because
of limitations
in the sensitivity
of the
in vivo
technic
mployed.”28
It is of interest
that time-honored
suspended
in saline
after previous
enough,
the logical
step of testing
in vivo, i.e.,Rh+
In 1944,
Race,29
methods
washing
the mother’s
for testing
were used, i.e.,
to remove
serum
elements.
serum under
the conditions
cells suspended
in plasma,
was not
Wiener’#{176}and Diamond3’
independently
“blocking”
or “inhibiting”
failed
to agglutinate
saline
employed,
so that 3 reagents
taken.
described
Rh+
cells
Curiously
existing
“incomplete,”
antibodies produced by Rhmothers
suspensions
of Rh+
cells.
The indirect
were required
for their demonstration.
whose serum
method
was
The mother’s
serum
now
In
of a
ther
presumably
coated
the Rh+
cells suspended
in saline
and such treated
cells
became
resistant
to the action
of anti-D
agglutinins.
a number
of sera, titration
with
saline
suspended
cells revealed
the presence
prozone
in the higher
concentrations
and increasingly
strong
reactions
on furdilution.
In the light of present
knowledge
these sera contained
a weak
block-
ing
antibody
and
a stronger
agglutinin.
It was
shown
that
under
certain
by absorption
of undiluted
sera the blocking
antibody
could be specifically
and the anti-Rh
agglutinin
could
be recovered
almost
quantitatively.30’
The indirect
test, however,
was tedious
and time-consuming
because
periods
*
on
of
Undoubtedly,
the
the
were
required
this
so
figure
addition
of an excess
blocking
antibody.
that
it
is probably
of serum.
Under
is no
too
high
these
longer
since
conditions
employed
in
several
the
effect
as a routine
cases
could
weak
be
reactions
attributed
conditions,
removed
“
2. incubation
procedure.
were
to
elicited
the
action
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
PHILIP
A direct
reaction
when
they
quently,
for the
given
by blocking
recommended
developed
cells and
it
test
the
LEVINE
sera was
slide
that serum
that the test
test
discovered
and
by Diamond
concentrated
or plasma
was
could
be carried
cell
contribution
bovine
albumin
‘
since
bumin,
globulin
direct
is no
evidence
indicating
fibrinogen
in the form
In this connection
it may
Le Page’s
glue
No.
7 (by
virtue
of its
other
nonprotein
material
these
are not as satisfactory
rouleaux
formation.
With
of saline,
Wigod59).
disappear
Subsemedium
making
unfortunate,
proteins,
serum,
are essential
concentrations
content),
it
polyvinyl
al-
for the
of
alcohol,
may be used
to elicit
the reas bovine
albumin
because
of
the addition
of minute
amounts
the specific
reaction
still
remains
(Levine
and
*
Another
when
and
many
X protein
that certain
acacia
pectin
and numerous
action.58
59
However,
their
tendency
to form
the rouleaux
Abelson,’5
was made by
was suitable
appears
‘
‘
that
so-called
be cited
and
reactions.
acacia,
there
and
suspensions.
essential
as a suspending
out in test tubes,
thus
possible
to carry out quantitative
studies.’6
A notable
Diamond
and Denton57
when
they demonstrated
that
for suspending
the test blood.
Wiener’s
application
of the
term
‘conglutination’
particularly
3
I
notable
they
contribution
showed
blocking
Presumably
that
antibodies
a layer
was
after
made
prolonged
by
Coombs,
washing
with
are specifically
agglutinated
of antibody
is fixed to the
by
surface
Mourant
saline,
and
Rh+
precipitins
of the red
cells
Race60’
coated
61
with
for human
blood
cells
serum.
and on
addition
of the anti-human
globulin
serum,
the specific
union
with
the coated
red
cells results
in varying
degrees
of agglutination
depending
upon
the intensity
of
the coating.
The British
workers
and Haberman
and Hill63’ 63* found
this test to be
most
useful
in determining
sensitized
successfully
whether
with
mother’s
applied
this
or not
the
blocking
antibodies.
test to differentiate
infant’s
cells
In a number
Rh+
cord
at delivery
of instances
blood
from
had
been
the author
genetically
Rhblood exposed to but not damaged
by maternal
antibodies
residual
from the
preceding pregnancy.
The degree of coating can be determined
by quantitative
studies
to determine
the greatest
agglutinate
the washed
blood.
cells, the
a routine
anti-human
procedure
could safely
replacement
Attempts
toms
In
original
for severe
kernicterus
titration
Rh+
suspended
solution
test is by far the most
the red cells obtained
for testing
globulin
which
will still
to detect
coated
Rh+
sensitive
and it should
cord blood.
This
method
as
those
(z
of
blocking
cells.20
both
of
in
2.5%
general
toxicity
and
end result
of thrombi
antibodies,
Under
(plasma
obtained
part
jaundice,
was the
the
human
these
as
the
a diluent
modified
albumin
author
conditions
and
test
and
uses
much
in
pooled
higher
suspending
which
agglutination,
in the
parts
kernicterus.
(consisting
male
titers
serum
are
oxalated
employs
human
reaction
affected
Hemolytic
sympwere held to be
The claim
was
of specifically
as
a diluent
obtained
medium).#{176}#{176} The
Wiener
become
from
be used as a guide for therapy
and in the event of intense
transfusion
should
be carried
out.
were made by Wiener44
to correlate
the clinical
picture
responsible
made
that
good
of anti-human
several
procedures
with
the presence
of agglutinins
or blocking
antibodies.
were associated
with
blocking
antibodies,
while
agglutinins
infant
*
globulin
dilution
Of the
for
plasma).100
than
results
the
and
albumin
by
Wiener’s
are
first
time
at
least
albumin
as
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
14
SIGNIFICANCE
agglutinated
plied
the
were
Rh
OF
cells)
in the arterioles
of the
characteristic
coloring
to certain
likewise
plugged
with
FACTOR
liver causing
severe
icterus
which
supareas of brain
tissue
whose
arterioles
agglutination
thrombi.
Although
these
thrombi
found
in numerous
organs,
harmful
effects were assumed
to be specifically
in the liver and brain.
The consensus
is that
the agglutination
thrombi
by
Wiener
changes.
Many
with
and
Brody
exceptions
strong
represent
to these
anti-Rh
not
claims
agglutinins
the
have
and
specific
lesion
occurred,
i.e.
no symptoms
but
the
rather
severe
suggestive
were
localized
observed
postmortem
anemia
associated
of kernicterus.
The
latter
condition
has now been observed
in a number
of cases in which
blocking
antibodies
alone
were found.
It is of course,
established
that maternal
blocking
antibodies
in contrast
to antiRh agglutinins pass into the fetal circulation and specifically unite with fetal blood.
Remarkably
these cells remain
enough,
circulation although
unagglutinated
they are in continuous
in
contact with
the
fetal
or
infant’s
in a medium
antibodies
of plasma and, in a number of instances the antibody concentration in the infant’s
circulation
is sufficiently
great
to indicate
a state of equilibrium
on both
sides of
the placental
barrier.
In any event there is no justification
for the use of the terms
“univalent”
tively.
and
Since
ence
seen
both
sorts
both
in vitro
“bivalent”
sorts
for
blocking
of antibodies
exert
would
seem
of antibodies
and
to become
are associated
agglutinating
their
less
with
antibodies
harmful
effects
significant.
The
the
identical
respec-
in vivo,
fact
the
differ-
is that
clinical
entity
in vivo
of intense
blood destruction. The fact that blocking antibodies are frequently demonstrated
in the infant’s serum, does not necessarily indicate that they are of smaller molecular size than
agglutinins.
It was further
claimed
by Wiener
that
agglutinins
exert
their
harmful
effect
mainly
at delivery
and
not
during
the
to accept the view that a concentration
latter
part
of the
of maternal
pregnancy.
agglutinins
It is difficult
sufficient to induce
severe symptoms
of blood destruction or icterus gravis could be attained from the
process
of parturition
and delivery.
Certainly
it can not be expected
in the case of
infants
delivered
by Cesarean
section.
Furthermore,
the clinical
picture
is almost
identical
in many
anemic
infants
of mothers
with
either
agglutinins
or blocking
antibodies.
In a number
dilution.
of instances
qualitative
This
obviously
is a serious
with
the aid of the anti-human
due to a mixture
of agglutinins
presence
confirmed
On
tions.
for blocking
antibodies
with
source
of error
which
and
with
titration
Accordingly
Rh
+
of the
one
may
can
readily
globulin
test. As in the ealier
reports
and blocking
antibodies,
these findings
of two varieties
of blocking
antibodies.
More
by the results
of specific
absorption
experiments
treatment
moved
tests
albumin
cells will be entirely
negative,
but titration
in normal
human
serum as
will
reveal
a prozone,
i.e., gradually
increasing
reactions
on further
suspended
a diluent
but
not
absorbed
assume
with
Rh
serum
that
blood
-
now
the
reveals
antibodies
the
recently
by Levine
prozone
gradually
in the
be detected
on prozone
indicate
the
this view
was
and Wigod.62
is specifically
decreasing
course
of their
rereacpro-
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
LEVINE
PHILIP
duction
by the
immunized
mother
immune
globulin
which
still
On the basis of discrepancies
human
globulin
a third
These
order of antibodies.
authors
classified
ing
test
antibodies
and
the
do
not
for coated
(those
cells,
the
that
but
Hill
antibodies
saturate
“cryptagglutinoids”
block,
represent
and
changing
Haberman63
on the
the Rh
(those
will
an ever
basis
antigen
antibodies
be demonstrable
of saline
that
by the
disease
of symptoms
serum
and
process
and
therapy
will
As first
suggested
THERAPY
by Levine,
OF
THE
test”
to
a somewhat
Burnham,
Katzin
hemoglobin
In some
level
above
per
65-70
cent.
repeatedly
until
viving
donors’
the
Rh-
In any event
injured
one and
the infant’s
red cell
is not apt to survive
underestimate
transferred
is temporarily
infant
or in aluse
more
of the
accurate
study
serum
of the
of the
cord
studies
of the
subject.
on the
several
Vogel’9
the
affected
infant
with
Rhblood which
is not
It is essential
to maintain
a
cases
it
by
virtue
is necessary
of
the
to transfuse
normally
sur-
blood.
the degree
of blood
maternal
antibodies
In one severely
times,
maternal
Rh-
the
INFANT
and
transfused
antibodies.
in saline,
test
of the mother’s
the intensity
by serologic
of an Rhmother
should
be vigorously
subject
to the action
of stored
maternal
of
block-
agglutinate
globulin
AFFECTED
anti-
agglutination),
blood,
particularly
on the red blood cells. However,
more intensive
serological
and physico-chemical
properties
of purified
preparations
varieties
of antibodies
are required
for a fuller understanding
of the
SPECIFIC
the
existence
agglutinins,
do not
anti-human
be determined
the
causing
in the infant
and antibody
content
red blood
cells. In the final analysis
the
of the
and
assumed
without
bumin
and serum).
They
applied
the term
“developing
anti-human
globulin
serum
on fetal erythrocytes.
In conclusion,
serologic
tests are now available
for
correlation
and infant’s
configuration
retains
its characteristic
specificity.
in the behavior
of blocking
antibody
affected
blocking
after
long
exposure
to maternal
antibodies
in the infant’s
circulation.
One
destruction
resulting
from
stored
presumably
in the
infant
reported
elsewhere,
who
antibodies
were still demonstrable
is an
cannot
the action
of passively
infant’s
tissue
spaces.
was
on
transfused
several
the twenty-fifth
day of life. At this time the infant’s
blood
was Rhby virtue
of the surviving
transfused
cells. On the thirty-fourth
day of life, the infant’s
blood
for the first
time was agglutinated
by anti-D
serum,
but it was still a mixture
of about
onethird
Rh+
and
More
recently
two-thirds
Rh-.
several
workers
carrying
out replacement
large
quantities
of Rhwithdrawing
the infant’s
administering
of infant’s
*
special
The
the
blood
method
plastic
donor’s
are
of choice
catheter,
(Wallerstein,64
Wiener,65
Diamond66)
have
been
transfusions
by washing
out the infant’s
circulation
with
blood.
Wallerstein,64
Wiener65
and Vogel67
have
been
blood
either
from the fontanelle
or the radial
artery
and
blood
withdrawn
seems
as suggested
to
into
and
be the
one
replaced
use
by Diamond.66
of cord
of the
with
veins
superficial
2.0
which
veins.*
cc. Rhcan
blood
be cannulized
Units
and
with
of
2.0
cc.
the procthe
aid
of
a
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
I
6
OF
SIGNIFICANCE
Rh
FACTOR
ess is continued
until
the infant’s
circulation
is washed
out with
I liter
of Rh
blood.
An additional
quantity
of Rhblood
corresponding
to 10 cc. per pound
should
then be administered,
preferably
at the beginning
of the transfusion.
In less
red blood
severely
affected
infants,
as indicated
cells, smaller
volumes
of Rhblood
that many
placement
intrauterine
From
affected
infants
recover
after I or
should
be reserved
for those infants
blood
destruction.
the point of view
of prognosis
by the serological
may be used. Past
-
tests on the cord
experience
reveals
single
transfusions.
The radical
rewho have been exposed
to prolonged
2.
the most
significant information
will be
derived
from a study of the cord blood
carried
out soon after delivery.
The presence
of maternal antibodies in the cord serum is not as significant as the presence of
maternal
antibodies
fixed to the infant’s
red blood cells.In several cases the increase
of antibody content in the mother
shown
to be Rh-.
The mechanism
to be investigated.
from specifically
proved to be misleading since the infant was
of such nonspecific
antibody
production
is still
As indicated
above,
coated
Rh+
cells with
Race.
Assuming
the infant to be Rh+
and cord blood
is of some prognostic
genetically
Rhblood
the aid of the reaction
can be differentiated
of Coombs,
Mourant
and
the ratio of blocking
significance.
With
nization
of long duration
a state of equilibrium
can be
the placental
barrier,
in which
case the prognosis
is
duction
of labor a more favorable
ratio
may be obtained.
that the same conditions
which
favor
passage
of fetal
circulation,
i.e., gradual
thinning
of the placental
pregnancy,
are at the same time more favorable
for
antibodies
into the fetal
The author
has recently
tissues.
studied
a number
of cases
antibody in the maternal
more
intensive
isoimmu-
established
on both sides of
not favorable.
By earlier
inThere
is reason
to believe
elements
into the maternal
barrier
in the last third
of
passive
transfer
of maternal
in which
the
infant,
delivered
by early induction of labor and given an immediate
replacement
transfusion, recovered
completely
from the anemia,
although
the infant
in the preceding
pregnancy
had died
of erythroblastosis
fetalis.
The prognosis,
however,
so far as
freedom
from symptoms
since the damage
to the
due to kernicterus
is concerned,
brain
may not become
manifest
several
years.
In at least one such instance
the infant,
not require
more
than one transfusion
at birth
and
life.
Although
completely
symptoms
the cause
indicative
may
be,
antibodies
acting
The
seem
recovered
from
of kernicterus.
is determined
during
the
neonatal
recent criticism by Darrow68
valid,
the mildly
despite
the
at least
not
for
delivered
4 weeks
early,
did
another
in the fourth
day of
the anemia,
However,
the
by intrauterine
must
always
be guarded
for many
months
or even
this
damage
action
infant
is now
to the
rather
brain,
than
developing
whatever
by stored
period.
and others of the use of Rh
the
severely
affected
infant
will
transfusion
of Rh+
recover
blood.
affected
either
One
infant.
-
It is highly
blood
does not
probable
without
benefit
of transfusions
is not justified
in assuming
that
that
or
the
burden placed on the mechanism
for the disposal of large quantities
of destroyed
blood does not exert a deleterious effect on an anemic and jaundiced infant. To a
lesser degree perhaps the same objections are applicable also for the replacement
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
PHILIP
transfusion
with
Rh+
blood.
LEVINE
Undoubtedly
17
the
because
of the residual
antibodies
in the
survive
as long as Rh
blood.
It is advisable
to take the erythroblastotic
replacement
tissue
is never
spaces,
the
complete
Rh+
blood
and
will
not
-
Rh
antibodies
are frequently
present
infant
in the
off breast
mother’s
milk
milk
because
(Witebsky94).
anti-
This
pee-
caution should certainly be taken for the more acutely ill infants even though
it
is not definitely established that maternal antibodies are absorbed from the intestinal mucosa, at least in appreciable
amounts.
In the series of affected
infants
delivered
by immunized
should
be transfused
with
group
compatible
Rh+
blood
type as the mother. If the isoimmunization
is induced
Rh+
mothers,
the infant
of the same Rh-Hr
subby factors
A or B (e.g.,
mother 0, infant A or B), the infant should be transfused
with
along
with
the soluble
group
A and B substances
of Witebsky.95
PREVENTION
All
only.
will
Rh-
OF
individuals
ISOIMMUNIZATION
requiring
Rh-
OF
blood
mains
out
by
potentially
Levine,38’
immunized
transfusions
once
a patient
the
remainder
for
0
blood
INDIVIDUALS
should
In this way isoimmunization
will be prevented
be spared
the trouble
of treating
the patient
for
unsuccessfully.
As pointed
group
receive
Rh-
blood
and if present
the
transfusion
anuria,
is immunized,
of his
or
the
her
clinician
perhaps
individual
natural
re-
life
time.
This is most important
in the case of young
girls,
even as infants.
If Rhgirls arc
transfused
indiscriminately
as they have been in the past, their chances
many years
later for having
I or 2. normal
Rh+
children
are considerably
diminished.
These
women
are thus deprived
of the several
factors
of safety
which
tend to reduce
the
incidence
lost
of erythroblastosis
as a maccrated
fetus,
fetalis
erythroblastosis
fetalis.’3
There
is reason
to believe
several
instances
have
so
stillbirth,
that
received
that
those
women
intramuscular
the use of vitamin
of erythroblastosis
published
Rosenfield,69
Levine
and
their
have
who
were
blastosis fetalis in the firstborn has some
the more
not
infant
may
be
severe
forms
of
may
in
transfused,
of blood,
K, or for prophylaxis
fetalis
in the first
histories
elicited
in several
instances.
Regardless of the influence of previous
Rh+
first
may
injections
dure in the days preceding
In a larger
series of cases
by
even
or the infant
a routine
against
measles.
born,
soon to be
of intramuscular
injection
transfusions, the occurrence
bearing
proce-
on the mechanism
were
of crythroof transpia-
cental
isoimmunization.
Wiener
70 had assumed
that fetal blood entered the maternal circulation only during labor and delivery. Although
there
may be another
antigenic stimulus at delivery, the transfer of minute quantities
of fetal blood
in
the latter half or third of pregnancy must be the determining factor even in those
Rhvals
women
of 9-14
pregnancy,
by residual
immunization.
who
years
one may
antibodies
On
may have been transfused
many
between
the antigenic
stimulus
well
assume
which
renewed
that
the damage
are evanescent
contact
with
years previously.
of a transfusion
to the fetus
in character,
this
antigen,
or infant
With
interand the first
is not
caused
but rather
by renewed
many
years
later
the
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
SIGNIFICANCE
antibody
producing
cells
(anamnestic
reaction).
It is obvious
that
of the
the
OF
Rh
FACTOR
reticulo-endothelial
biologic
test,
system
as recommended
respond
more
by Wiener,7’
rapidly
i.e.
the
ad-
ministration
of small
quantities
of Rh+
blood,
will
also serve
to immunize.
More
sensitive
tests are now available
for detection
of immune
antibodies
specific
for differences within the Rhand Rh+
group, or new blood factors other than
Rh. Incompatibility
can be excluded if the patient’s serum does not agglutinate
the donor’s
in his own
cells suspended
serum,
plasma
or bovine
albumin.
A woman
who has delivered
an erythroblastotic
infant,
if transfused many years
later may tolerate one transfusion of Rh+
blood.*
In any event this transfusion
will
restimulate
antibody
production
so that
the following
transfusion
may result
in
a severe
anamnestic
reaction
perhaps
reaction.
with
anuria.
6.-Erythroblastosis
TABLE
Fetalis
This
in th
is another
First
Rh+
example
Infant
of the
in Rh-
Transfusion
Women
History
Positive
No.
cases
of
9
disease
mild
i
severe
6
fetal
death
Since
fetalis
is the
result
the number
of immunized
RhIn other
words,
an Rhwoman
infant may
be entirely normal,
blood destruction. However,
ably with
an unexpectedly
of prolonged
because
the next Rh+
severe
form
of
women
are always
subject
to severe transfusion
even many
years after their last pregnancy.
Intra-group
transfusion
reactions
in Rhbecause,
as a rule,
will have a slight
serve
after
chill
a series
or mild
as a warning
0
women
may have
started too late in the course of the pregnancy
should
4
12.
erythroblastosis
struction
infants.
Rh+
Negative
19
Severity
so-called
intrauterine
exceeds
anti-Rh
the antibody
out
Rh
de-
of affected
and yet her
production
to allow for much
may
have
if any intrauterine
infant will certainly be affected probthe disease.
In any event
these Rhreactions
male
should
patients
tests
and
they
require
can be readily
of uneventful
transfusions,
the
jaundice
following
a particular
to carry
blood
the number
antibodies
if found
blood
prevented
patient
eventually
transfusion.
This
to be Rh-,
only
Rh-
blood
should
be used for all future
transfusions.
Unless
these precautionary
measures are taken
the following
transfusion
will result
in a severe,
if not fatal,
hcmolytic
reaction.72
73 On
the whole
the transfusion
risks
are far greater
in women
than in men.
For transfusion
rather than
*
In
produced
one
instance
by
purposes
the 4 blood
there
a transfusion
was
it
is preferable
groups,
a delayed
4 years
with
reaction
previously.’8
to
the
probably
think
provision
attributable
in terms of 8 different types
that
Rh+
to
traces
individuals
of
residual
may
antibodies
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
PHILIP
receive
munized
either
Rh+
or Rhblood.
by the subtypes
of the Rh
rarely.
In any event,
differences,
at least
Rh+
should
individuals
Rh-
blood
not receive
should
In
immediately
1941,
roblastosis
fetalis
by the
Board
health
In
i.
of Medical
PUBLIC
These
receiving
have
been
subsequent
an
Rh
No
2..
fetus
noted,
donor
woman
with
and
then,
Rh
negative
serum
if her
donor
at
370
shall
whose
Rh
factor
practical
in the
drafted
Blood
consideration
pathogenesis
rules
2.
Transfusion
factor
to
blood
shall
prove
red
transfusions
Rh
be given
red
fctalis,
blood
account
all
However,
PROGRAM
writer
of the
repeated
an obstetrical
or erythroblastosis
for the very
patients.
of the
the
for the
shall
whose
blood
Rh-
HEALTH
role
to take into
requirements.*
which
of eryth-
were
discussed
Association
and
public
follow:
tests
transfusion
negative
the
Control
authorities.
individuals
for
established,
all
reactions
No
after
was
is not feasible
for transfusion
it
Rh-
be reserved
A
19
Although
certain
Rh+
patients
may be imfactors
(C, E) or by the Hr factors
(d, c, e),
this occurs
very
possible
antigenic
that
LEVINE
cells
whom
untoward
be performed
any
such
are
shown
recipient
found
characterized
by
habitual
a transfusion
unless
tests
cells
negative,
shall
have
such
been
be
Rh
transfusion.
negative
the
except
recipient’s
abortion,
for the
transfusion
subsequent
with
transfusions
shown
any
to
to be compatible
history
be Rh
(intra-group)
before
receive
to
blood
in
shall
stillbirth,
Rh factor
shall
be
to be compatible
been
made
only
with
the
made;
from
intravenous
anti-Rh
serum
would
of our present
knowledge
or
the
“No
intramuscular
second
serums,
taneously
she
The
general
The
must
from
negative
Rh
of these
and
been
program
of Rh
For
example,
sideration.
may
negative
the
blood,
perhaps
read
infancy
on,
in tests
with
blood,
influence
now
it
may
be carried
It remains
for skin
large
the
or tissue
number
donor.
to be seen
transplants
of antigenic
out
standard
necessary
unless
she
diagnostic
it be given
rules
will
a striking
encouraging
testing
public
and
there
result
to
has
b:en
anti-Rh,
intravenously,
in a reduction
reduction
health
in several
is the
of serious
whether
will
or not
give
diffcrences,
identity
successful
more
the
of antigcnic
satisfactory
success
of the
of the
and
authorities
states
the
(or
subcu-
experience
factors
results.
transplant
reported
a compreunder
by
con-
Lee,
many states
already
authority
is required,
should
be done
Theoretically
cells
at least,
depend
upon
of
intra-group
is now
in red blood
will
incidence
fatal
to adopt
measure
Saun and Brown,74
in Passaic
County,
NewJersey.
Since
compulsory
premarital
and prenatal
tests,
no statutory
cept perhaps
to obtain
financial
support
for the program.
All workers
in this field are agreed
that
the Rh test
*
of indiscriminate
becomes
as follows:
potent
whether
action
quan-
injection.”
fetalis
reactions.
has
only
of
it
age,
to be Rh
receive
adoption
writer
hensive
of any
If found
or by intramuscular
erythroblastosis
transfusion
so that
in a female
Rh factor
be available.
regarding
injection
proposal
transfusions
for the
anti-D)
an
recipient’s
C.
tities
of potent
In the light
tested
at
maccrated
have
Although
these preventive
measures
were generally
approved,
no official
could be taken
because
no assurance
could be given at the time that sufficient
modify
from
serum
Van
have
ex-
routinely
of donor
and
given
a suffciently
proper
selection
host
of
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10
SIGNIFICANCE
on the prenatal
has been unduly
indication
for
is RhThe
immunized
by
In addition
.
tests
tests
for the
should
especially
Rh
OF
FACTOR
rather
than the premarital
specimen.
alarmed
regarding
Rh incompatibilities.
Unfortunately
the
There is almost
lay public
never any
a couple
to break
their engagement
solely
because
the young
woman
only exception
applies
to those
Rhwomen
who had already
been
transfusions
of Rh+
blood.
to routine
screening
tests for the selection
ofRh+
and Rhmothers,
presence
of active
also be performed
those
with
isoimmunization
in a state-wide
large
obstetrical
should
program,
services,
be carried
out. While
these
all hospital
laboratories,
should
be prepared
to carry
out
these comparatively
simple
procedures.
Unfortunately
there are altogether
too few
workers
with
sufficient
experience
or background
in this new and clinically
important
field. Certainly
each of the larger
hospitals
should
have
at least
one or
more of their workers
specially
trained
in all aspects
of this field. It is further
suggested
that
smaller
laboratory
hospitals
to serve
the
pool
their
interests
interests
of their
in organizing
local
a properly
community.
Such
equipped
a program
can
conveniently
be organized
in conjunction
with
a central
blood
bank.7’
In recommending
a public
health
program
it is pertinent
to mention
that
the
morbid
effects incidental
to isoimmunization,
i.e. erythroblastosis
fetalis
and intragroup
transfusion
accidents,
are observed
far more frequently
than those resulting
from
syphilis.
isoimmunization.
races
and
Obviously
the
The potential
is directly
element
danger
proportional
to the
of contagion
is not
of Rh incompatibility
incidence
of Rh-
present
in the case of
varies
in different
individuals
in any
given
population.
A SUPPLY
OF
POTENT
ANTI-Rh
SERA
If Rh tests are to be done on a broad
basis in all pregnant
women
and all patients
prior
to transfusion
requirements
it is important
to maintain
a continuous
supply
of potent
human
anti-Rh
sera. Unfortunately
the experimental
serum
animals
injected
with
rhesus
or human
blood
is not sufficiently
potent
was largely
abandoned
soon
after
the description
of the phenomenon
placental
will
still
the other
antibodies
In the
favorable.
should
munized
isoimmunization.
be necessary
Even
to collect
if an animal
and
store
large
Rh and Hr antibodies,
and any other
of unusual
specificities.
past the outlook
for large
quantities
More
recently,
however,
a number
solve
Rh-
the
problem
of supply.
women
will become
women
to submit
to periodic
Rhblood.
In selected
women
bleedings,
who do
reactions
port the
(Hill
and
immunization
of Rh+
blood.
When
Both
donors
antibodies
of the
containing
very
sera
containing
rare
a greater
should
be maintained
insufficient
to appear
future
sera
by replacement
further
pregnancies
Wiener77
and
on a voluntary
begin
in the
of human
of human
anti-Rh
of steps
have
been
followed
not plan
men,
the potency
of the antibody
can
of minute
quantities
of Rh+
blood,
Haberman76).
of Rh-
is produced
With
routine
testing
available.
Physicians
munized
injection
tration
serum
quantities
produced
in
and its use
of trans-
to
sera was not
taken
which
number
encourage
by the
induce
dosage
of imthese
transfusion
of
and in isoim-
Diamond,78
and
basis,
by repeated
the
it
intravenous
unpleasant
others,
readminis-
is appreciably
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
PHILIP
reduced
so that
tions.
Undoubtedly
of other
there
varieties
bodies).
Two
sources
(anti-C,
of potent
ofconcentrating
weak
prozone
sera. The
and were therefore
latter
sera
considered
antibodies
sera
in such
siderable
Rarely,
degree
some
immunized
test
by repeated
tubes.
For
out
carried
sensitive
Recently
released
words,
may
content.
as not
their
may
corresponding
be derived
and by certain
Hr
from
anti-
the
treatment
recent
of so-called
blocking
antibodies
and agglutinins,
for diagnosis.
However,
the blocking
be specifically
absorbed
without
affecting
of the recovered
agglutinin
(Levine
mentioned
above may be applicable
procedure
small
Chown
in my
as the test tube
the National
be such
sera
sera,79
is appropriate
by employing
the
this
and
from subsequent
injecout for the production
to any
Con-
and Wailer’4).
also to patients
transfusions.
for distribution
a serum which
must
anti-Rh
anti-Rh
to mention
that anti-Rh
sera may be used
capillary
tube method
of Chown
instead
of
it
by Dr.
reactions
be carried
anti-E
contain
both
not suitable
the activity
of the measures
In this connection
more economically
2.1
is no danger
of untoward
all these procedures
will also
of antibodies
additional
program
LEVINE
to diminish
has
it
of
i
human
(6 per
is the
has
for
that
of a group
agglutinin
i
no
30
is active
as
serum
be
In other
the diluent
but
of the
normal
albumin
cent
on blood
tests
:32..
i
per cent
per
the
is almost
anti-Rh
AB or bovine
and
which
and
method
of at least
io times,
below
agglutinins
be used,
his
ruled
content
serum
cent
may
that
a titration
value
:32.0
may be diluted.
the protein
normal
be used as the diluent
antibodies)
*
The reagent
of choice
of sera
show
method.8#{176}
Institute
of Health
unless
has a titre
Accordingly,
quantities
laboratory
for
cells
may
blocking
suspended
in saline.
the
More
red
recently
blocking
cells to be tested
bovine
albumin.’’7
than the slide test.
greater
availability
blocking
antibodies
have
must be suspended
test”)
but
serum
or
antibodies.
Levine
1939
or tissue
mother’s
late
(slide
plasma,
For large scale work
it is preferable
to use test tubes rather
The main advantage
in the use of blocking
antibodies
is their
since most Rhmothers
of erythroblastotic
infants
produce
OF
MECHANISM
In
been recommended,
either
in their own
the
cells)
blood
mother
and
Stetson
containing
could find
to produce
TRANSPLACENTAL
suggested
that
a dominant
their way into
specific
ISOIMMUNIZATION
products
of the fetus
hereditary
the maternal
antibodies.
(red
blood
property
not present
circulation
and thus
When
the
pathogenesis
cells
in the
stimu-
of erythro-
blastosis
fetalis
was described,
experiments
were
or not the Rh factor
was present
in a water-soluble
it was established
that the Rh factor
unlike
the
carried
form.
secretor
was limited
anism which
the question
arose as to the mechof a red blood
cell, to penetrate
*
leased
The
on
to the red
permitted
Minimum
Requirements
December
i6,
5946
blood
formed
cells. Accordingly
elements,
the
for
from
the
Blood
National
Grouping
Institute
size
Serum
of
and
Health,
out to determine
whether
Using
saliva
as an index,
types of groups
A and B,
Anti-Rh
Washington,
Typing
Serum
D,
C.
were
re-
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2.2.
SIGNIFICANCE
the
placental
barrier
in sufficient
part of the mother.
If the Rh factor
were
OF
quantity
present
also
from uniting
with
the Rh
nature
of erythroblastosis
and Katzin
water-insoluble
but
that
the Rh factor
form.
Possibly
this observation
Witebsky8’
showed
tities
in the
servation
can have
the affected
infants
It does not seem
which
with
would
an Rh+
fluid
to stimulate
antibody
soluble
in sufficient
passage
into
of Rh soluble
production
form,
quantity
the fetal
material,
the
material
is present
in the red blood
cells, presumably
the Rh factor
may also be present
in tissue
Dodd8’
material
of some,
to recur
but not
could
cells. Accordingly,
the
the finding
of Levine
but
not
is still
may
all,
to be confirmed.
be present
in very
Rh+
fetuses.
and become
operative
with
an Rhfetus.
in a
cells,
small
However,
no bearing
on the pathogenesis
of erythroblastosis
belonged
to the so-called
non-secretor
type.
necessary
to assume
the presence
of gross lesions
have
fetus,
on the
to immunize.
In that
circulation,
would
be
thus preventing
the
factor
in the red blood
fetalis
substantiates
of Boorman
and
that Rh soluble
amniotic
FACTOR
in a water
readily
enter
the maternal
circulation
event
the maternal
antibodies,
after
completely
inactivated
by the excess
antibody
hemolytic
Rh
quanthis
since
in the
in each succeeding
It is significant
that
ob-
each
of
placenta,
pregnancy
in the vast
majority
of the cases the course
of the pregnancy
and the delivery
of these mothers
is entirely
normal.
Although
there is no direct
proof
that the fetal red blood
cells
(a large, formed
element)
find their way into the maternal
circulation,
nevertheless,
the
statistical
data
other
conclusion.
If one assumes
on
that
the
pathogenesis
minute
of erythroblastosis
quantities
of fetal
blood,
fetalis
either
as intact
cells or as stroma,
pass
nancy.
Isoimmunization
the placental
may occur
is genetically
capable
fluous
to assume
the
of producing
antibodies.
Accordingly,
existence
of genes
determining
placental
formed
barrier,
this must occur
only if the fetus is Rh+
permit
in every
and the
red
blood
normal
pregRhmother
becomes
permeability
it
of no
superto
elements.”
It is well
known
to the
genie material
(soluble
to induce
immunization.
immunologist
that
proteins,
suspensions
In recent
experiments
remarkably
minute
amounts
of bacteria
or red blood
in rabbits,38
distinct
of anti-
cells) suffice
increases
in
agglutinin
titre were observed,
following
14
daily
injections
of 2. cc. of a i: ooo
suspension
of human
blood,
the total volume
of which
was o.oo56 cc. whole
blood.
The corresponding
value for a woman
weighing
12.0
pounds
is only o. 13 cc.
It will
be recalled
tion is believed
maternal
sinus,
that,
in the
latter
to begin,
the blood
and separated
from
part
it
of the
pregnancy,
lated
by Dodds83
and Dees-Mattingly84
human
term placenta
exposed
to maternal
.
*
by
Cf.
the
Haldane.96
Rh
factor
are
observed
isoimmuniza-
that
the total
area of fetal
sinuses
is 70-12.0
sq. ft. and
of these villi,
if laid end to end, would
measure
ii
miles.
the fetal blood
is outside
the fetus and in the placenta.
In this connection,
it is significant
that the pathological
tion
when
vessels
in the fetal villi are adjacent
by a single
layer of cells. It has been
exclusively
in the
fully
One-fourth
effects
villi
total
to the
calcuof the
length
or more
of isoimmuniza-
developed,
or almost
of
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
PHILIP
fully
tion
than
developed,
fetus.
by the Rh factor
normal
incidence
may
possibly
any
from
properties
second
property
and third
months
of antigenicity
in the
factor
have
certain
conditions
of the
which
observation
that
in all succeeding
pregnancies.
It has
observed
value
(2.)
is out
matings;
dence of heterozygous
tion which
should
born,
At
particularly
present
there
peculiarly
the
suggestion
may
alone
fathers.
decrease
father
the
i.e.,
slow
with
the
the condition
is likely
is Rh+.
Apparently,
the
between
severe
erythroblastosis
fetalis
in the
Accordingly,
current
tendency
antibodies;
and
will
made
prevent
Oc-
the
extraction
prevent
or delay
the experimental
responds
with
is also
rather
trial
it
of such
the
injection
per cent
is neces-
to small families;
the high
inci-
to a recommendafetalis
in the first
the
on the
extracted
of antibodies
as they are formed.
antibody
formation,
but are capable
difficulties.87
recently
that
13
it
()
either
or the formation
of antibodies
of serologically
active
haptenes
However,
a fair
mother.
already
has been
of erythroblastosis
fatal
forms.
measure
which
many
technical
has been made
of antibodies.
It
serve to stimulate
of pregnancies
x Rh-
Reference
the incidence
in its more
is no specific
is to be given
Rh
when
and are in intipregnancy
offers
is compatible
that
the
by the
of several
years
elapses
is likely
to be increasingly
to the number
Rh+
the course
of pregnancy
may
the Rhmother.88
However,
mixture
of numerous
antigens,
multiplicity
material
pregnancy,
to isoimmunization,
mother
is immunized,
in which
the fetus
agglu-
more fundamental
may be inherent,
the maternal
sinuses,
area. Incidentally,
factors
of safety:
(i)
the
Rhwomen
to produce
antibodies.
and
between
isoimmunization
of the
preg-
fetus,
that the
antibodies
half
favorable
evidence
preceding
old fetus1
of the
a long
period.86
of isoimmunization
of proportion
blood
may neutralize
the action
lack the property
of stimulating
neutralizing
latter
even if an interval
erythroblastosis
fetal blood
across
the placenta,
mother.
Possibly
the injection
material
presents
The suggestion
the
438 deliveries,
if Rh tests are done in all cases of fetal and
can assume
an incidence
of about i :io
to i : ioo deliveries.
i.e.
to assume
several
inability
of many
blood
Nevertheless,
the
approach
surface
on clinical
curs about
once in every
neonatal
morbidity,
one
sary
cells.
once an Rhpregnancies
in successive
of susceptible
in the
until
are
is renewed
Furthermore,
this
red
of the antigen,
over
of the mechanism
been
from
85
initiated
isoimmunization
pregnancies.
Even
demonstrated
in the villi gradually
over an ever-increasing
administration
This
concept
clinical
to recur
of isoimmunization
There
is reason
to suspect
and the capacity
to unite with
.
is not
vessels
contact
effects
been
forerunners
probably
blood
mate
the
rate,
this subject
merits
further
investigation.
can be observed
in the yolk sac in the 4 weeks
tinable
even
2.3
More recent
data do not support
the view that isoimmunizaper se plays
any role in early fetal death.
If there is a higher
of miscarriages
in mothers
of erythroblastotic
infants,
this
result
nancies.
At
Erythrocytes
LEVINE
haptenes
of typhoid
transfer
of
part of the
from Rh+
Such haptenes
of specifically
from
Rh+
vaccine
in
antibody
formation
on the part
animal
when
injected
with
the production
of a corresponding
of
a
conceivable
that
injection
of nonspecific
than to depress
antibody
formation.
If this
is preferable
to inject
the
Rh-
women
with
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SIGNIFICANCE
2.4
such
antigens
as tetanus
mothers
are
their infants.
low
and
at the
and
same
diphtheria
time
Rh
OF
FACTOR
toxoid
producing
and
pertussis
antibodies
vaccine
which
will
so that
the
be beneficial
for
Erythroblastosis
fetalis
assumes
importance
altogether
out of proportion
to its
incidence
because
it is the first example
in any species
of a new cause of fetal
neonatal
morbidity;
i.e., genetic
differences
involving
a particular
blood factor
which
has a normal
incidence
in any
will
be found
in veterinary
medicine,
terized
by
The
a placenta
essential
which
feature
does
of this
racial
group.
Undoubtedly,
at least in those
species
not
form
differ
radically
of fetal
from
or neonatal
many
examples
which
are charac-
that
in man.
morbidity
is its selective
effect on Rh+
offspring.
Thus,
in the case of twins
only one of whom
is affected,
the normal
member
is always
Rh-.
Undoubtedly,
the mechanism
of isoimmunization
may
be operative
As examples
may
of selective
in cases
be cited
intrauterine
of selective
fetal
the observations
death
in pigs
and
births
in uteri which
are normal
in all
ma! fetuses
lying
side by side. On the
ferrets.
genesis
cedure
is mainly
whether
or any
blood
factor)
may
employed
or may
many
animal
Robinson’0
workers
not
the
evidence
statistical.
Accordingly
or not isoimmunization
a role
dead and norone is tempted
for the
from
their
patho-
the same proby fetal blood
in complications
or other
conditions
of the fetal
and neonatal
period.9’
Some
on the role of A and B factors
in causing
stillbirths
other
than
cause
multiple
blood
property
derived
of the normal
fetuses
and
to supply
play
species.
on the
described
respects,
and yet they harbor
basis of the findings
in man
have a particular
from
the blood
(Rh
in
and
These
to speculate
that
the dead fetuses
the male parent
which
is absent
mother.
It is significant
that the method
of erythroblastosis
fetalis
may be used to determine
death
of Corner’9
of pregnancy
preliminary
that due
findings
to erythro-
blastosis
fetalis
have already
been published.86
In this connection
mention
may also
be made
of the recent
findings
of Yannet9’
and Snyder93
on the high
incidence
of
Rh negative
mothers
of infants
and children
affected
with
the so-called
mental
insufficiencies
of the undifferentiated
group.
The possible
relationship
of these
cases to the after-effects
of kernicterus
is still to be determined.
ADDENDUM
In
this
contribution
appeared
after
the
this
paper
author
was
made
delivered
reference
at Dallas
to
several
(November,
1946).
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2.6
SIGNIFICANCE
S.,
63’HABERMAN,
AND
A. S.,
WIENER,
P.,
LEVINE,
ET
P., N.
VOGEL,
F. P.,
WIENER,
78
80
CHOWN,
BOORMAN,
E. F.
JAHN,
Paper
J.
Clin.
Rec.
M.:
S.,
M.,
M.
AND
Heredity
ET
Am.
J.
H.:
Bull.
L. H.,
Section
E.,
AL.:
J.
M.,
100
P.,
LEVINE,
AL.
:J.
M.
944,
1946.
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From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
1948 3: 3-26
A SURVEY OF THE SIGNIFICANCE OF THE Rh FACTOR
PHILIP LEVINE
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