1. No category

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Acquired
Circulating
Anticoagulants
“Collagen
Auto-immune
the
G.
HE OCCURRENCE
disseminatus
and
term
“collagen
with
in
scnil)ed
case
is
was
K.
WEIMER
that
patiemit
the
repom’ted
a
similar
This
whom
miot
has
first
were
never
and
heemi
classification
of
(‘ase
was
for
possible
used
samples
the
were
Department
supported
was
amid
The
atmthor
lupus
An
term.
by
disease”
a woman
case
amid Wemickert.6
acquired
climiical,
erythematosus
disease,”
additional
Nilsson
with
whose
demomistrate
openia
(‘ase as “(‘ollagen
published
char-
throsnbocyt
circulat-
laboratory
and
disseminatus,
typical
L.E.
hut
(‘elis.
all
Metabolic
is
indebted
of
She
in
gave
volume
National
Dr.
of
grant
Institutes
I)avitt
syringes,
(leterminatiosi
on
the
October
5, 1954;
accepted
Felder,
for
publication
691
test
of
test
to
the
tubes
venous
in plain
glass
0.1M
sodium
be
performed.
of anticoagulant.
University
research
coated
the
depending
solution,
b
Silicone
for
test
which
were
performed
Plasma
was prepared
with
2C.
(‘Orate
Diseases,
serum.
except
wit Ii 1/10
l)art
METHODS
and
consumption
Arquad
Medicine,
iii
to
plasma,
experiments
with
mixed
AND
Minnesota
A-26l
from
of Health,
St.
Paul,
who
Hospitals,
the
Public
gave
,January
15,
Minneapolis.
National
Health
Iermission
2.
Subniitted
a
positive
disease
amid
this
“(‘ollagemi
to
of blood,
for
tisne and the prothrombin
The sicedles
were treated
or 3.2 per
cent
sodium
Arthritis
multisystem
of this
use
beemi
(‘ases
typi(’al
processing
were
studs-
the
reported
the anticoagulamit
ii’as demonstrated
over a period
of
birth.
The
second
patient
developed
the anticoagulant
while
owsi
observation
after
a drug
reaction.
The third
patient
had lupus
disseminatus
with hemolytic
anemia;
this is the only case where
cells were found.
pipettes
From
de-
after
Collection
1)100(1
already
imi which
albuminunia,
The
specifically
MATERIAL
oxalate
he had
lupus
in whom
to ami infant
seven
weeks
under
oum’
erythematosus
typical
L.E.
clottisig
tubes.
the
of
co-wom’kers4
asit icoagulamit
re(’esitby
three
The
it has
birth
the
did
concerns
findimigs
and
arthralgia,
anticoagulant.
circulating
justifies
abmiormalities
m’epom’t
autopsy
a
author
anticoagulants.
under
cases
syndrome
Ley
with
a circulatimig
with
the
of which
of Libman-Sacks
temporarily.
two
kidney
changes
which
were
indistinguishable
from
of dissemiiinated
lupus
erythematosus.
rrhe failure
of the
time to m’espond
to l)lOOd tramisfusions
stromigly
suggests
Barkhani5
though
with
had
patient
by
evemi
only
one
erythematosus
grouped
presented
in 1952,
a case
hypoprothromnbinemia
with
postmortem
loop”
lesions
prothromhin
a(’t e5’iZ i rig
Conley’
inhibitors
present
imi lupus
conventiomially
rare.
reported
the “wire
prolonged
serology
(‘ase
M.kmey
anticoagulants
conditions
rather
clotting
of idiopathic
This
of
of circulating
Hitzig3
1948.2
amiticoagulamit
All
FRICK
assistance
related
disease”
erythematosus
and
Deficiency
I
T
big
PAUL
technical
Systemic
Disease”
Thromboplastin
By
With
in
1955.
Institute
of
Service.
to
stu(ly
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692
CIRCULATING
ANTICOAGULANTS
IN
“COLLAGEN
DISEASE”
Ba804
plasma
was prepared
by adding
100 mg.
of Ba504
(Merck
& Co.,
Rahway,
N. J.)
to 1.0 ml. of oxalated
plasma.
The
mixture
was
gently
shaken
for 5 minutes
and
Ba504
removed
by centrifugation
(2000 rpm for 10 minutes).
48 hour old serum
used
as source
of stable
prothrombin
conversion
factor
was
obtained
by
centrifuging
hours
normal
in plain
glass
Labilefactor
for
10-12
under
plasma
under
factor
this
collected
was obtained
conditions.
plasma
was obtained
deficient
days
Stable
of
blood
sterile
conditions
storing
normal
and
left
37 C.
at
for
48
tubes.
by
oxalated
plasma
at 20-24
C.
sterile
deficient
from
a patient
with
a congenital
deficiency
factor.”
Difco
rabbit
brain
Armour’s
dissolved
in
buffer
thromboplastin
I served
bovine
9.5
with
fraction
ml.
a PH
of
0.9
per
was used throughout.
as fibrinogen.
One
cent
NaCl
solution
hundred
and
0.5
rng.
ml.
of
of
1.72
dry
powder
per
cent
were
imidazole
of 7.2.
Bleeding
time. Method
of Ivy.7
Clotting
time of venous
blood. Modified
Lee White
method:
One ml. of blood
was
placed
in each of two
glass
tubes
(75 x 8 mm.)
which
were
tilted
every
minute.
The
first
tube
was started
10 minutes
after
venipuncture.
The
second
one was started
when
the endpoint
of the first was reached.
The endpoint
of the second
tube was recorded
as clotting
time
of
venous
blood.
Capillary
clotting
time. Method
of Nicholson.’
Prothrombin
time.
One-stage
method
of Quick.9
Recalcification
time.
Determination
of the time interval
between
the addition
of 0.1 ml.
of 1/40M
CaC12 solution
to 0.1 ml. of citrated
plasma
and the appearance
of a clot.
Platelets.
Method
of Rees and Ecker.’#{176}
Capillary
Rumpel-Leede
fragility.
Prothrombin
determination
and Seegers.”
bovine
serum
in
determination.
Van
Slyke’4 and
0.1 ml. of plasma
into
of
dry
at
37 C.
a series
a water-bath
second
tubes.
The
tion
(2000
r.p.m.
0.2
mixture
for
ance
dilutions
a clot.
with
normal
Michigan)
was
used
Protamine
titration.
and
was collected
intervals
for
3.2 per
highest
cent
for
all
at
the
first
were
sodium
then
method
of BaCO,
citrate
time
to 0.1
of
Commercial
method
fibrin
amid
each
interval
of oxalated
sample
prothrombin
with
addition
and
the
a clotting
succes-
of 0.1
appeartime
& Co.,
Davis
of
Detroit,
experiments.
tenth
5 and
compared
to
centrifugadetermi-
of serum.
the
gave
(Parke,
isi
intervals
added
plasma
solution
thrombin
placed
30 minute
between
and
from
distributed
were
obtained
by
and a two-stage
time
thrombin
at
Cullen
and
tubes
ml. of various
concentrations
of protamine
100 mg. per cent were added
to 0.9 ml. of citrated
time and recalcification
time were performed
on the
a control
in which
0.1 ml. of 0.9 per cent NaCl
solution
One
of Ware
treated
obtained
were
serum
on
ml.
bovine
All
solution
the
of
clot
syringe
2 ml.
performed
of the
solution
the
the
hour,
with
a glass
rod and
A one-stage
prothrombin
concentration
plasma.
to
on
in a siliconized
calibrated
of thrombin
The
between
of
of the two-stage
the addition
according
determination
and
Zuazaga.’5
Determination
times.
of
stage
ml.
stirred
minutes).
five
10 seconds
ranging
20 minute
fibrin
x 8 mm.)
concentration
clotting
of various
(75
was
of prothrombin
Thrombin
tubes
At
hour,
sive
ml.
glass
and
omitted.’3
was
of Ma
Blood
test.
Modification
defibrinated
of
nitrogen
micro-Kjeldahl
with
the method
consumption
nation
ml.
Precipitation
Prothrombin
the
per
Citrated
plasma
was not
as a source
of Ac-globulin
Fibrinogen
for
test.”
units
sulfate
solution
plasma.
A onevarious
mixtures
was
used
instead
of protamine.
Thromboplastin
plastin.
Difco
One-stage
titration.
The
undiluted
thromboplastin
prothrombin
thromboplastin
in 4.0
ml.
solution
of 0.9 per
CASE
Case
Hospitals
1.
A
for
36 year
a period
old
housewife,
of four
cent
times
with
was
prepared
NaCl
solution
various
by
dilutions
of thrombo-
incubating
at 48 C. for
150
mg.
10 minutes.
REPORTS
who has been
years,
originally
followed
noticed
at the University
menorrhagia
and
of Minnesota
subcutaneous
of
From www.bloodjournal.org by guest on January 12, 2015. For personal use only.
hematomas
after
minor
to have
a positive
while six months
husband
had
positive
serologic
she
developed
third
child
In 1950
in
prior
blood
the
it was
the
24,
of
found
third
baby
of
lowed
by
a
and
tubes
expire(l
paralytic
ileus.
during
the
administration
oil
Jumie
13.
The
the wall of the small
of both
kidneys
was
the majority
of the
their
wall.
The
first
per
6700
small
studies:
gramnilar
casts
cu.
scattered
mm.
the
weeks
of life.
developed
Past
one
and
with
the
a false
in
history
1948,
includes
a
complications.
were
replaced
point
by large
“wire
organs
albumin
1 to 4 l)lImS, occasional
Hemoglobin
Gm.
normal.
the
surface
examination,
fibrinoid
deposits
in
disseminated
lupus
erythrocytes,
leucocytes
per
Total
patient
The
histologic
of
fol-
throughout
hematoma.s.
revealed
lesions”
6.0-13.8
consistently
antibiotics
On
internal
pain
decompression
hemorrhages
hemorrhages.
loop
abdominal
and
intramural
typical
count
found
was
pregnancy,
pregnamicy
intestinal
electrolytes
of the
Differential
age
acute
with
vessels
sediment.
at
hemorrhagic
showed
Urinalysis:
in
pin
She
dealing
was
second
suction
glucose,
adrenals
first
diseases.
contimiuous
with
her
.
19 without
Patient
plasma,
Both
1946.
of
infant
one
patient’s
seven
at age
revealed
studded
in
The patient
delivered
her
blood loss was rather
copious
this time.
anticoagulant
which
was also present
autopsy
bowel.
the
that
etiology
of blood,
glomeruli
thematostms.
Laboratory
and
Despite
Since
the
postpartum
a circulating
child
trimester
assumed
undetermined
tomisillectomy
at age 8 and an appendectomy
There
wa.s no family
history
of hemorrhagic
Final
admission
: On May
31 , 1954,
the
first
last
negative.
. The
to have
1951
was
of her
the
it was
course
syndrome
693
FRICK
during
test,
During
December
of
delivery
Wassermann
test.
patient
the
since
to conception
a nephrotic
on
G.
(Wassermann)
a negative
the
the
trauma
serology
PAUL
cent.
Leukocytes
serum
cry-
4350-
proteins:
5.5
Gm.
per cent,
globulin
nitrogen
albumin
2.5 Gm. per cent, globulin
3.0 Gm.
per cent, a globulin
1.0 Gm. per cent,
0.8 Gm. per cent,
globulin
1.2 Gm.
per cent
(Method
of Milmie).’6
Illood
urea
10 mg. per cent.
Serum
bilirubin:
prompt
direct
0.1 mg. Per cent,
total
0.3 mg
per
Cephalin
cent.
cholesterol
12 tmnits. Serum
cholinesterase
misiutes.
urobilinogen
titer
Urine
1:7.
Coomhs
test
flocculation
1.36
1.4
4 plus.
pH/hour.
mg/day.
negative
direct
Thymol
Bromsulphalein
Heterophil
and
7 units.
turbidity
retention:
antibody
indirect.
Blood
titer
1:7.
serology
2 per
Zinc
turbidity
cent in 45
Cold
agglutinin
tests:
Wassermann-
quantitative
Kahsi
40 units,
Kline
1 plus, Hinton
negative,
Cerebrospinal
fluid serology
tests:
Wassermann-Kolmer
negative,
VDRL
siegative.
Bone marrow
examination
showed
a slight
depression
of normobla,stic
activity.
No typical
L.E. cells were encountered,
although
several
heavier
staining
inclusions were present
in some neutrophils.
Attempts
to demonstrate
LB.
cells in the huffy
coat of the patient’s
plasma
or clotted
blood
and to induce
the formation
of these
cells in
normal
marrow
mixed
with the patient’s
serum
failed
repeatedly.
The majority
of the tests
of hemostasis
were
abnormal:
Bleeding,
clotting,
recalcification
and prothromhin
time were prolonged
and the Rumpel-Leede
test was positive.
The results
4 plus,
Kolmer
VDRL
weakly
Kahn
3 plus,
positive.
1.-Tests
TABLE
Test
Case
of
I
hemostasis
Case
2
Case
3
Normal
Bleeding
time-minutes
11-15
4
time-minutes
time-
42-101
21-82
5
22
0-6
Clotting
Prothrombin
19.8-74.0
17.4
17.0
12.0-13.0
270-1380
480
480
90-180
mm.
142,000-252,000
Normal
Positive
110,000-204,000
Normal
Negative
172,000
Normal
Negative
150,000-250,000
%
300-560
340
360
250-350
54-69
165
186
250-380
12-20
seconds
Recalcification
seconds
Platelets-per
Clot retraction
Rumpel-Leede
Fibrinogen-mgm.
Prothrombisi
tration-units
timecu.
concen-
per
ml.
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694
CIRCULATING
2.-Effect
TABLE
Patient’s
ANTICOAGULANTS
of
normal
Patient’s
plasma
blood
plasma
Normal
plasma
IN
on
O.9’
1.0
the
“COLLAGEN
abnormal
coagulation
Clotting
minutes
NaCI
0.1
1.0
Prothrombin
time--seconds
0.1
0.1
0.1
3.-One-stage
prothrombin
Labile
deficientfactor
Normal
plasma-mI.
in
case
1
Recalcification
time-seconds
66
0.1
Plasma
of case
i-ml.
time
tests
64
0.1
TABLE
DISEASE”
times
of
Stable
factor
deficient
plasma-mi.
plasma-ml.
various
67.0
870
64.6
820
plasma
Dicumarol
mixtures
O.9
plasma-ml.
NaCl
Prothrombin
time-seconds
ml.
0.1
71.0
0.1
0.1
69.6
0.1
13.0
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
14.8
64.6
48.2
0.1
46.8
14.6
0.1
0.1
0.1
0.1
0.1
0.1
68.5
62.0
13.6
0.1
0.1
0.1
0.1
52.8
0.1
57.8
0.1
14.8
of these
tests varied
appreciably
over a period
of four years
(table
6) and
the figures
presented
in table
1 represent
the maximal
range
of fluctuation.
Very early
in the course of
this study it was noticed
that the addition
of normal
plasma
had no effect on the abnormal
tests
(table
2). This observation
led to the suspicion
of a circulating
anticoagulant.
Demonstration
The
of circulating
failure
3) strongly
was
or
of normal
suggested
mainly
any
of
anticoagulant.
caused
its
demonstrate
plasma
that
by
very
a clotting
conversion
in fact
to affect
the
that
the
addition
patient’s
Control
of 0.1
prothrombin
value
and
inhibitor
factors.
the
prolonged
not
of the
time
patient’s
own
by a deficiency
studies
presented
ml.
of normal
(table
plasma
of prothrombin
in
the
plasma
same
had
table
a nearly
corrective
effect
ficient
in stable
mixture
0.1 ml.
on the prolonged
prothrombin
time
of 0.1 ml. of plasma
defactor,
labile
factor
or prothrombin.
It was also shown
that
the
of 0.9 per cent NaC1 solution
prolongs
the prothrombin
time of
0.1
plasma
ml.
normal
only
of 1.8
seconds.
The
value
of
64.6
seconds
obtained
with a mixture
of equal amounts
of normal
and patient
plasma
was evidently
the
result
of an inhibitory
effect
of the patient’s
plasma
on the prothrombin
time of
normal
plasma.
The anticoagulant
also influenced
the clotting
time
of normal
blood
and recalcification
time
of normal
plasma
(tables
4 and 5). The lowest
dilution
in which
the inhibitory
effect
could
be demonstrated
was 1: 100. Anti
Hemophilic
Globulin
(AHG)
deficient
plasma
which
had
a prolonged
recalcifica-
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PAUL
4.-Effect
TABLE
Plasma
Normal
Clotting
of
plasma
of
G.
case
1 on
of case 1-mi
hlood-ml
time-minutes
AHO deficient
plasma-mi
Normal
blood-mI
Clotting
time-minutes
5.-Effect
TABLE
of abnormal
of case 1-%....
piasma-%
Plasma
Normal
Recalcification
100
0
640
of
Plasma
3rd
infant
Normal
Recalcification
Plasma
of case
Normal
plasma-%
Recalcification
2-%....
blood
0.05
1.0
31
0.075
1.0
32
0.1
1.0
33
0.125
1.0
35
0
1.0
17
0.05
1.0
16
0.075
1.0
15
0.1
1.0
17
0.125
on recalcification
60
40
20
40
60
20
80
10
90
630
610
540
620
620
time
of
normal
5
95
2.5
97.5
1.0
99
330
210
1.0
16
plasma
0
0.5
99.5
100
600
140
145
0
60
20
0
40
80
100
720
700
695
120
100
0
60
40
20
10
20
40
60
80
90
100
0
465
450
450
360
330
150
80
60
40
20
20
40
60
80
.
480
of case 3-%....
plasma-%
Recalcification
80
time-
seconds
100
0
10
90
0
100
time-
seconds
480
deficient
100
Normal
plasma-%
Itecalcification
0
630
in the
effect.
concentration
method”
the curve
ranged
(fig.
480
460
460
380
170
80
60
40
20
lOi
20
40
60
80
90
95
100
160
160
165
155
150
155
150
5
0
time-
seconds
tion time
inhibitory
490
plasma-
%
The
normal
time-
seconds
AHG
of
0
1.0
17
80
100
plasma-%
Normal
time
of
1-%
Plasma
clotting
time-
secon(Is
case
plasmas
695
FRICK
range
of the
patient’s
of prothrombin
between
1) obtained
54 and
with
plasma
determined
69 units
per
this method
was
used
with
as
the
ml. of plasma.
indicates
that
control:
modified
it had
no
two-stage
The short
slope
of
there
was no de-
ficiency
of prothrombin
conversion
factors.
This
was verified
by the fact that
fresh
normal
BaSO4
treated
plasma
and normal
48-hour-old
serum
added
as
sources
of labile
and stable
prothrombin
conversion
factor
respectively,
had
no
effect
on the curve.
The one-stage
prothrombin
time was not influenced
either
by these
two-stage
illness,
seconds
two sources
of conversion
method
were remarkably
the one-stage
prothrombin
(table
6). This discrepancy
factors.
constant
While
the results
obtained
during
the course
of the
times
showed
a fluctuation
is most plausibly
explained
with the
patient’s
from
19.8 to 74.0
by a fluctuation
From www.bloodjournal.org by guest on January 12, 2015. For personal use only.
696
CIRCULATING
ANTICOAGULANTS
IN
“COLLAGEN
DISEASE”
80
C
0
C.)
0)
60
ci)
Di
0
.5O
-o
o4Q
I
0
FIG.
1. Two-stage
6.-Variations
TABLE
2
Incubation
3
time
prothrombin
of
abnormal
4
(minutes)
determination
tests
in
5
in l)lassia
1 over
case
6
a
four
year
period
Date
4-23-50
Clottisig
time-minutes....
Prothrombin
5-26-50
7-il-Si
11-26-51
3-29-52
12-16-52
33153:
2.15.54
6-5-54
101
50
56
51
59
57
60
42
116
20.1
20.5
20.9
19.8
63.0
74.0
29.2
26.0
29.8
54
69
57
69
69
time-see-
onds
Prothrombin
concentration
-units
per ml
Recalcificmttiomi
time-seeonds
in inhibitor
the
two
activity
tests.
method
hibitor
The
and 3:10
was diluted
55
640
and
final
the
540
difference
dilution
iii
of the
for the one-stage
out to the point
tested
811)
plasma
1380
dilutiomis
plasma
is 1:300
-.
87()
27()
applied
for
imi rumining
the
method.
It is probable
that
the
of ineffectiveness
in the two-stage
two-stage
clotting
in-
method,
while
the moderate
dilution
applied
in running
the one-stage
test did iiot appreciably
influence
its activity.
Further
supportive
evidence
for this explanation
was presented
above
(table
5) when
it was demonstrated
that
the anticoagulant
was effective
up to, but not
countered
with
the one-stage
flects
degree
The
changes
in the
last
test
beyond,
method
in inhibitor
recalcification
activity.
times,
is notoriously
the
but
least
a dilution
of
over a period
1: 100. The fluctuation
of four years
probably
enre-
This
fluctuation
was reflected
to a certaimi
not in the clotting
times
of venous
blood.
sensitive
test
of
hemostasis
amid
the
most.
From www.bloodjournal.org by guest on January 12, 2015. For personal use only.
PAUL
G.
I
40
5
120
I
Prothrombin
consumption
Two-
;
I
20
60
-;
I
stage
method
Casel.
-
I
697
FRICK
::::l0a5e
:
1#{247}
1/10 vol. normal
,
#
One -stage
plasma
method
0
:‘
-
0
Case
Case
--
0
0
to
sul)ject
clusions
times
were
The
I
I
I
40
60
90
a period
(fig.
of two
To
serum
activity
patient’s
the
in
addition
The
year
period
observatiomi
thromiibin
plasma
of normal
of
had
the
normal
a deflmiite
blood.
direct
the
conclotting
osie
This
values
blood
the
(fig.
inhibitory
is imi striking
had
to
58
the
with
this
normal
plasma
of prothrombin
effect
3).
The
addition
of
effect
on
when
Hemophilic
amid
blood,
Plasma
PTC
shown
corrective
during
An
1:10
con-
have
consumption
ef-
the
interesting
of
volume
of prothrornbin
AHG,
rate
in nor-
a prothronibin
throughout.
on the
rate
Anti
has a complete
did not fluctuate
mimiimal
the
obtained
(PTC),
plasma
with
on
un-
concentration
with
patient’s
in
remains
values
patiemit’s
of
rise
a
present
with
o’er
units
shortenimig
of prothrombin
bloods
the
69
no
Componemit
comitrast
from
suggesting
studies
deficient
it remaisied
of
C.
phenonienomi
with
Comitrol
observed
37
of prothrombin
compared
(PTA)
at
a progressive
This
prac-
tubes
fell
plasma
Thromiiboplastin
of the
effect
higher
was
method
progressed,
amount
alomie.
of observatiomi,
was
any
that
two-stage
showed
normal
when
of 1: 10 i’olusiie
consumptiomi
patient’s
drawstate
imi glass
factors.
small
tested
Plasma
ramige
mnethod
slightly
Antecedent
sumuption
four
The
the
coagulation
comiversion
methods
was
(AHO),
the
as
for the
both
blood
Thromnboplastin
only
of prothromribin
omie-stage
(omisumptiOmi.
with
with
of 1: 10 volume
addition
accoumits
Globulimi
that
the
or its
plasma
to
can
coagulation
concemitratiomi
of prothromiibin
encoumitered
the
the
times
The
hazardous
6. One
tested
spontaneous
surprise
of prothrombin
mal
During
prothromhin
explained.
be
test
prolomiged.
hours
our
nil.
the
it would
in table
120
in minutes
cosisumption
of prothrombin
2).
venipuncture
Prothrombin
times
comisistemitly
nil
after
hence
clotting
plasma
i
2.
errors,
the
consumiiption
tically
per
technical
from
vol. normal
20
Time
FIG.
I.
I + 1/10
pro-
patient’s
consumption
and
PTA
deficient
From www.bloodjournal.org by guest on January 12, 2015. For personal use only.
698
CIRCULATING
ANTICOAGULANTS
IN
“COLLAGEN
DISEASE”
3001
I
--.-.
Prothrombin
Two-stage
t
200
-
consumption
method
Normal
blood+l/I0
09%
NaCI solution.
volume
Normal
bloodi-I/lO
volume
Normal
blood+I/lOvolume
I
----
-
io:
20
Time
Fm;.
3. Effect
plasmiias
which
rnal
prothronibimi
Site
of action
The
of the
any
were
an
this
fate
to
The
if one
affect
November
blood
effect
on
nor-
ii
t imne
recalcificatiomi
have
and
the
group
by
capable
of
elevated,
was
of
of the
that
was
amid
induced
labile
caused
the
labile
Comitrol
prothrombin
this
amid
in spite
factor
of prothronibin
factor
by
normal
a combined
is highly
time
1)100(1
of the
caused
recalcification
with
that
recalcificatiosi
Dicumnarol.
by
pro-
(osi(eIItmatiomi
(lotting
by
for the
unlikely
studies
be
prothrombin
by
part
a theo-
heparin
or
(omiversion.
of
clotting
protamine
times
(table
questionable,
of 19.8
presemice
Fromii
thromnhiii
concentrations
and
also
it is very
could
excluded
various
prothrombin
assumption
1951
type
failure
but
the
the
hypoprothm’onibisiesnia
imi mimior
their
of abnormalities
heparin
the
of a inhibitor
26,
all,
was
The
time.
that
deficiemicy
or of the
patient’s
the
shown
if at
inhibitor
time,
in which
Dicumarol
factor
The
decreased
prothronibi
time,
blood.
accounts
and
U/ml.
of the
7)
presence
makes
method
of thromboplastin
anticoagulant
(table
siorn1al
amiticoagulant
clotting
blood.
normal
prothrombin
moderately,
standpoint
times
of
an accelerating
the
the
one-stage
with
stable
that
patient’s
two-stage
50
only
indicate
in
omi (lotting
treated
inhibitor
An
on
the
a complicating
retical
of the
patiemit’s
approximately
times
consuniption
evemi
prolonged
abnormalities
effect
patients
was
of
of the
far
and
time
same
with
lomigation
in minutes
prothronbisi
or occasionally
thus
recalcification
encountered
venipuncture
1 on
anticoagulant.
presented
the
case
mio effect,
consumption
inducing
from
after
of
consumiiption.
tests
it had
plasnia
have
prothrombin
and
of
seconds
hypoprothrombimiemia
sul8).
because
observed
and
From www.bloodjournal.org by guest on January 12, 2015. For personal use only.
I’AUL
G.
7 .-i’h
TABLE
699
FRICK
rombin
clotting
times
Clotting
Concentration
of thrombin
case
Undiluted
factor
accoumit
which
19.8
15.4
21.0
1/8
40.6
44.4
on
the
the
times
obvious
tive
by
600
600
0.02
71.6
0.04
72.6
0.1
74.0
well
far
imihibitor
results
not
be
thromboplastin
plasma
with
in
not
low
are
to those
plasma
plasma
was
also
ineffective
made
imiability
of demonstrating
imply
the
that
some
reserve.
plasma
are
in our
an
results
omi PTA
the
the
imihibitor
one
directly
t:he
acted
and
PTA
against
with
values
figure
3 where
blood.
The
imi the
three
the
conditions.
patieiit’s
factors.
pa-
patient’s
blood;
in both
activity
shown
results
to exclude
on AHG
and
time
amid proand actually
thrombocytopenic
these
been
necessary
4 and
the
is presump-
abnormal
was tested
clotting
surprising,
was
quite
with
This
give
in normal
with
control
plasma
It appears
obtained
therefore
plasma
abnormal
was not
tests
realize
It has
plasmas
was
should
plasmas.
pronounced
and
comi-
comparable
starting
values
control
in table
same
deficient
PTC
over
here.
First,
the
It
more
timnes
presented
miot
deficient
patient.
a case
Alexander’8
prothrombin
anti-thromboplastin.
PTC
abnormalities
AHG,
amid
because
the
presented
to imihibit
to study
and
prothrombin
A snore cosnparable
time
of 20.2 seconds.
with
inhibitor
all the findings
is an antithrombodemomistrate
an antithromboplastin
thromnboplastin
for
and
case
plasma
than
weak
of prothrombimi
seconds
time
and PTC.
The patient’s
It had no effect
on the
of any of them.
This
shown
it
not
of
longer
AHG
of the
was
contrary
does
patiemit’s
encountered
in view
tient’s
with
a
opportumiity
with
in the
would
explaimi
test devised
to
evidence
an inhibitor
of AHG
PTC
deficient
blood.
thrombin
consumption
expected
as
the
the
cases
abmiormal
normal
such
a consumption
timiie of 29.8
recalcification
dilutions
al.’9 that
had
similar
are different.
a prothromiibimi
much
conclusive
et
recesitly
with
that
and
timiie,
imiterpreted
with
conceivable
have
620
625
a prothromhimi
as
which
of the
obtained
plasma
We
with
615
!
of 51 mninutes
clotting
by
to
scar(ely
documnemited
whose
Lamigdell
is
time
nil.
deficiency
that
sisiiilar
it
a clottimig
obtained
but
time-seconds
70.0
for
1
i
0.01
times
patient’s
Recalcification
of case
620
have
umidiluted
Dicumarol
time-seconds
time
68.2
omily
The
4)
recalcification
69.8
were
(fig.
Prothrombin
and
0.005
three
that
per
time
prothrombin
0
secomids
The
plastin.
in mg.
mixture
practically
suniptiomi
10.0
20.0
factor
reported
9. 1
1/4
inhibition,
was
of labile
control
14.0
Concentration
of protarnine
ml. of 5)lasma-protamine
could
in seconds
1
1/2
TABLES.-Effectofprotamine
labile
time
solution
on the
The
plasma
AHG,
PTC
From www.bloodjournal.org by guest on January 12, 2015. For personal use only.
700
CIRCULATING
ANTICOAGULANTS
700
IN
-
I
S
-
Normal
plasma
Dicumarol
plasma
-----
Case
‘a
I. plasma
,__#“
.4O0
‘I
/
0)
E
30O.
I,
200
1
-
I
1/10
FIG.
PTA
activity
can
thromboplastin
turn
activity
cursors.
In
effect
on
each
convincing
and
cursors
is
cannot
tion;
it
how
or
the
results
by
one
of
the
are,
in
should
consumption
the
Assuming
a weak
and
that
inhibitor
recalcification
figure
also
4:
consider
delay
in
and
an
tested
had
this
could
time.
due
not
deficient
a period
a prothrombin
was
account
for
from
the
PTC,
account
the
sake
or
in
have
with
stable
grounds
our
patient.
Hy-
prothrornbin
it was
on November
or stable
prolongation
for
of com-
of the
normal
Furthermore,
seconds
treated
argument
AHG,
to
observed
marked
matter
on theoretical
of prothrombin
patients
same
prothrombin
bloods
of 19.8
forma-
of an
excluded
of 2 hours.’3
time
to an inhibitor
Blood
of
be
pretime.
no
The
For
consumption
factor
over
can
A more
prothrombin
of anticoagulant
inhibitor
This
different
deficiency,
time.
type
a multi-
of thromnboplastin
antithromboplastin.
prothrombin
stable
the
elimination
The
one
an
conversion.
when
patient
only
three
factors.
PTA
prothrombin
activity.
leaves
and
pre-
had
of thromboplastin
phase
PTC
in
thrombo-
actually
on
in the
AHG,
blocks
plasma
inhibitor
anticoagulant
a normal
platelet
inhibitor
prothrombin
marked
have
of
the
an
to form
which
inhibitor
were
three
ability
thromboplastin
the
there
of the
against
that
that
that
one
a disturbance
fact
all
poprothrombinemic
that
by
in
presented
pleteness
factor
or
against
of
plasma
unlikely
NaCI
thrombin
which
of non-formed
precursors,
effect
inhibitor
platelet
testing
their
to
anticoagulant
it is highly
1/10,000
determnining
conversion
An
argument
known
by
prothrombin
acting
explained
they
an
PTA
three
retarding
be
severe
excludes
all
absolute
well
is
titration
Thromboplastin
demonstrated
the
case
of them
the
4.
fibrinogen.
present
inhibitors
1/1000
dilution
be
precludes
the
1/100
Thromboplasfin
induces
coagulates
plastin
lateral
omily
which
finally
This
I
/
$
and
DISEASE”
I
1
600
“COLLAGEN
factor,
of clotting
Dicumarol
shown
26,
1951.
such
time
or from
From www.bloodjournal.org by guest on January 12, 2015. For personal use only.
PAUL
patients
with
19.8
seconds
congenital
have
only
G.
701
FRICK
stable
factor
deficiency
a nioderate
prolongation
with a prothrombin
of the clotting
and
time above
recalcifica-
tiomi time.
rfhe
rather
pronounced
in the
comment
lancet
prolongation
light
of the
applied
for deterniination
and
vasocomistriction.
stab
thrombus
of
comiclusiomi
the
bleeding
drawn
which
involved
the
thromboplastin
prepared
that
time.
accoumited,
be excluded
the inhibitor
It canmiot
strated
The
stroyed
plasma.
was
table
of
thromboplastin
acetone
dried
at least
however,
inactivated
at 70 C. for
of the anticoagulant
study
9 she
BaSO4
of this
had
the
baby
same
in
girl
did
the
several
abnormalities
tests
It is believed
10 minutes
the
tissue
therefore
of the
fragility,
third
and
bleeding
demonfor
role.
30
completely
inhibitor
from
de-
oxalated
child.
imiterestimig
as her
was
only
reported
with
played
a contributory
heating
at 60 C.
adsorb
patient’s
revealed
clotting
not
All
performed
prolongation
capillary
may have
It resisted
a
by a platelet
upon
prompt
of thrombin
inhibit
not
to
well.
brain.
in part,
for the
that
increased
Rumpel-Leede
test,
not dialyzable.
partially
as
were
a special
following
is afforded
depends
the formation
appeared
rabbit
was
at 70 C. for 30 minutes.
Demonstration
The
from
by the positive
anticoagulant
minutes,
use
deserves
Hemostasis
of the bleeding
time
Platelet
agglutination
availability
of thromhin.2#{176} Iii the present
case
markedly
delayed
by the amiticoagulant
which
plasma
thromboplastimi,
but
tissue
throsnboplastin
herein
time
above.
features.
mother
with
AS
the
seen
in
exception
of the bleeding
time
which
was normal.
The
anticoagulant
could
be demonstrated
during
the first seven
weeks
of life. At the end of seven
weeks
there
still
was a definite
prolongation
of the recalcification
time and the prothrombin
time
was two seconds
lomiger thami the normal
comitrol
plasma.
At the end of three
9.-Laboratory
TABLE
tests
the
on
third
infant
Age
of case
1
of infant
Test
three
Clotting
time-minutes
Bleeding
time-minutes
Plasma
prothrombin-timeseconds
Recalcification
time-seconds
Platelets-per
Cu. mm
Clot retraction
days
weeks
six months
16
15
20.2
14.1
720
255
12.0
105
162,000
Normal
Normal
Normal
20.8
29.5
69.0
Wassermann-Koimer
4+
4+
4+
Kline
Negative
Serum
hours
seconds
prothrombin
time
37
4
seven
one year
302,000
two
after veni-puncture-
Blood
Kahn
Cephalin
tion
-
cholesterol
-
Negative
-
Anticompiementary
Negative
Negative
Negative
2+
Negative
floccula-
4+
3+
3+
From www.bloodjournal.org by guest on January 12, 2015. For personal use only.
702
CIRCULATING
months
all
tests
ANTICOAGULANTS
were
a positive
cephalin
remaining
laboratory
Urinalysis:
Very
normal.
The
cholesterol
IN
infant
also
flocculation
tests
were
occasional
as
“COLLAGEN
had
which
follows:
leukocytes
DISEASE”
abnormal
serologic
persisted
for
Hemoglobimi
in the
six
18.0
sediment.
Serum
tests
and
niomit.hs.
The
Gmii.
per
biliruhisi
(ent.
: prompt
direct
0.1 mg. per cent,
total
0.5 mg. per cent.
Thymol
turbidity,
4 units.
Zinc
turbidity,
1 unit.
Total
serum
proteins
5.4 Gm. per cent,
albumimi
3.4 Gm. per
cent, globulin
2.0 Gm. per cent. The analogy
with the matermial
findings
can only
be explained
by the transpiacental
transfer
of the anticoagulant
amid the factor(s)
which
gent
behavior
gests
for
hand,
the
that
the
caused
the
in respect
the
positive
that
and
both
serology
of them
could
be dialyzed,
adsorb
them
with
BaSO4.
developed
normally.
turbidimetric
time
cannot
Wassermann
positive
and
to survival
anticoagulant
it is of interest
false
serologic
be
cephalin
in the
had
similar
heat resistance
The child never
The
circulation
strongly
baby’s
identified
with
cholesterol
anticoagulant
abnormalities.
and
the
factor(s)
plasma
physico-chemical
sug-
accounting
flocculation.
the
diver-
Omi the
componemit
characteristics.
was similar
and
it was
had any hemorrhagic
not
other
causing
None
possible
symptoms
to
amid
Case . This
57 year
old white
male
was hospitalized
twice
because
of symptoms
of
arterial
insufficiency
in his lower extremities.
He underwent
a right lumbar
sympathectomy
in February
1953 without
any
hemorrhagic
complications.
Iii October
1953 he was readmitted
for a sympathectomy
on the left side and an endarterectomy
of the right common
iliac artery.
Shortly
before
the second
hospital
admission,
the patient
developed
an itching
skin rash secondary
to aureomycin
and penicillin
therapy
for a pyelitis.
The
patient
did
not have any unusual
blood loss at the time of surgery
on October
5, 1953. He was started
prophylactically
on penicillin
and streptoniycin
on the day of surgery,
but
these
drugs
had
to be discontinued
on the sixth
postoperative
day because
of recurrence
of the itching
rash
which
was
accompanied
by blood
eosinophilia.
The
preoperative
bleeding
time
was
2
minutes
45 seconds,
the clotting
time
(capillary
method)
was 5 minutes
50 seconds.
A clotting
time
done
24
hours
after
surgery
as
reference
for
future
heparin
therapy
was
repOrte(1
as
“longer
than 7 minutes.”
A Lee White
clotting
time
done
on the same
day
was
21 minutes
(normal
range up to 20 minutes)
. Heparin
therapy
was deferred
and three days after surgery
the clotting
time was 29 minutes.
There
was a progressive
spontaneous
rise up to 82 minutes
on the 8th postoperative
day. Two weeks
after surgery
the clotting
time was 50 mimiutes.
To the surgeons
surprise
and delight
there
was only
a small
wound
hematoma
and the
operative
result was excellent.
Unfortunately,
it has not been possible
to follow
the patient
after discharge
from the hospital
because
his residence
is more than 500 miles away.
In a recent
letter
he did not mention
any episodes
of bleeding.
There
was no past personal
or family
history
of hemorrhagic
diathesis.
Laboratory
data preoperatively
(before
October
5, 1953): Hemoglobin
15.0 Gm.
per cent.
Leukocytes
5500 per cu.mm.
Differential
count
normal
except
for 6 to 9 per cent eosinophils.
Urinalysis:
Specific
gravity
1.016, albumin
trace,
occasional
leukocytes
and erythrocytes
in
the sediment.
Mazzini:
Negative.
Laboratory
data
postoperatively
(between
October
6
and 20, 1953): Mazzini
2 plus, Wassermann-Kolmer
4 plus,
Kline
negative,
Kahn
2 plus,
VDRL
weakly
positive.
Cephalin
cholesterol
flocculation
4 plus.
Total
serum
proteins
7.1
Gm. per cent,
albumin
2.8 Gm. per cent,
globulin
4.3 Gm. per cent,
a globulin
1.4 Gm.
per cent,
globulin
1.1 Gm. per cent,
y globulin
1.8 Gm. per cent.
Coombs
test:
Negative
direct
and indirect.
Routine
tests
of hemostasis
are presented
in table
1. Prothrombin
consumption
was minimal;
as in case
lit
was noted
that the one-stage
values
became
progressively
shorter
as blood
clotted
spontaneously
in glass
tubes.
While
the plasma
prothrombin
time was
17.4 seconds,
the
serum
prothrombin
time
was
13.8 seconds
3 hours
after venipuncture.
The thrombin
titration
was normal.
The patient’s
plasma
prolonged
the
recalciflcation
time of normal
plasma
(table
5). Even
though
time
limitations
did not
From www.bloodjournal.org by guest on January 12, 2015. For personal use only.
PAUL
permit
as extensive
gests
that
the
a study
clotting
an antithromboplastin
dialyzable,
it was
heated
to 70 C.
as
case
in
abnormality
and
G.
1, the
of
the
703
FRICK
identity
two
of the
cases
was
a mild
hypoprothrombinemia.
to 65 C. for 30 minutes
and
resistant
results
the
obtained
same,
The
progressively
strongly
i.e.,
it was
anticoagulant
lost its
sug-
caused
by
was
not
when
activity
Case S. This 33 year old housewife
was
November
1952 because
of arthralgia
in
hemostasis
and
were
referred
to the University
of Minnesota
Hospitals
and anemia
of one month
duration.
Studies
of
imi December
1953.
The physical
examination
revealed
pallor
The patient
had menorrhagia.
performed
hepatosplenomegaly.
Laboratory
cytes
tests:
The
per
cu.mm.
2,330,000
Reticulocytes
Coombs
7.1 per
negative
test
prompt
direct
pltms.
contained
Leukocytes
cent.
Fecal
direct
and
0.2 mg.
Thymol
urine
per
turbidity
cent,
12
noalbtsmin.
with
urobilinogen
2048
Ehrlich
indirect.
Cold
agglutinin
total
units.
1.7 mg.
Zinc
Wassermann
negative.
normol)lastic
The
hyperpla.sia.
The
cu.mm.
per
cent.
turbidity
per cent., albumin
3.0 Gm. per cent, globulin
fi globulin
1.2 Gm. per cent and y globulin
Kolmer
4 plus, Hinton
4 plus, Kahn
4 plus,
fluid
Hemoglobin7.7
per
3100
Cephalin
15
percent.
Erythro-
units.
cholesterol
Total
flocculation
serum
proteins
4
7.4
Gm.
4.4 Gm. per cent, a globulin
1.3 Gm. per cent,
1.9 Gm.
per cent.
Serologic
tests
omi blood:
VDRL
positive
in dilution
1 :32. Cerebrospinal
patient’s
bone
diagnosis
Gm.
a normal
differential
count.
units
PCF 100 Gm.
of stool.
titer
1:112.
Serum
bilirubin:
marrow
of lupus
showed
typical
erythematosus
with
LE.
cells
associated
and
hemolytic
anemia
was hence
established.
The patient
was transfused
and given
peroral
Cortisone
for six months.
When seen in December
1953,
the patient
felt much better.
Hemolysis
and
anemia
had disappeared,
and it was not possible
at this
time
to demonstrate
any
L.E.
cells.
The abnormal
serologic
tests
and
the
positive
cephalin
cholesterol
flocculation
persisted
however.
Tests
of hemosta.sis
are presented
in table
1. Clotting
time and prothrombin
time were slightly
prolonged:
the recaleification
time was 480 seconds
and there
was
moderate
was
at
hypoprothrombinemia
the
inhibited
lower
the
limit
recalcification
(table
5). The
inhibitor
found
in case
1.
by
of normal.
time
was
not
the
two-stage
Thrombin
of
method.
titration
normal
plasma
dialyzable
and
as
had
Prothrombin
was
normal.
observed
the same
with
heat
consumption
The
patient’s
the
plasma
other
resistance
two
cases
characteristics
DIscUssIoN
The
appearance
of circulating
anticoagulants
in the
various
conditions
con-
ventionally
grouped
under
the term
“collagen
disease”
adds
a new facet
to the
already
diverse
and metamorphous
clinical
and laboratory
picture
of this disease
group.
The occurrence
of clotting
inhibitors
in patients
with
manifestations
of
hypersensitivity
may
have
some
bearing
on their
mechanism
of development.
The
tendency
of patients
with
lupus
erythematosus
disseminatus
to develop
antibodies
is
a
well
established
Coombs
test are frequent
able that
the mechanism
in type
as
and
the
The
analogy
diphtheria
duces
well.
The
association
transpiacental
antibodies
unknown.
that
Only
antibiotics
the
may
the
antigens
the
case
positive
above
1 tend
listed
to
serology
and
immune
mechanism
his
own
antigen-antibody
substantiate
of maternal
This
of
false
positive
of this disease.
It appears
highly
probof the anticoagulant
is immunologic
transfer
is obvious.
against
in
in
transplacental
measles
Ehrlich’s
dictum,
but there
bodies
can occur:
auto-immune
The
antigen
which
induces
ing
with
transfer
to the
and
fact:
manifestations
of development
implies
plasma.
This
reactions
this
assumption.
antibodies
that
is
in
against
a patient
pro-
conflict
with
is good evidence
that
the production
of such antihemolysins
constitute
the most typical
example.
antibody
formation
in collagen
disease
is usually
case of periarteritis
play an antigenic
nodosa
role.2’
are there
It appears
some
quite
leads
suggestpossible
that
From www.bloodjournal.org by guest on January 12, 2015. For personal use only.
704
CIRCULATING
case
ill
2 the
t.unately,
production
it has
not
anticoagulant
to see
the
inhibitor.
whether
mechanism
resistance,
shared
by
earlier,
abnormal
was
much
factor(s)
the
shorter
with
reveal
The
In the
original
this
It
appears
the
both
quite
clear
the
anticoagulant
report
occurred
that
the
two
the
by
is
BaSO4)
are
mentioned
As
Blood
causing
infant
of
fromii
several
a luetic
case
infectiomi
did
the
second
by
reported
Frick
normal
imi-
in
1953.22
mother
with
mio
The anticoagulant
was
precursors
of thromboplaswere
probably
1
imi-
flocculatiomi.
pui)hshed
anticoagulamits
was
on
cholesterol
was
against
amitibody(ies)
in
in an otherwise
of development
triad
of anticoagulant,
blood
serology
was
necessarily
imply
bination.
this
Cases
study
the
by
complete
From
triad.
a clinical
severely
afflicted
diatheses
fewer
symptoms
tests.
these
riot
idemitical
immunologic
a positive
standpoint
did
not
not
evemi
in
for
analogy,
individuals
also
inhibitor
Component
had
was
of thromboplastin
1 and
2 is much
influencing
prothrombin
prothrombin
an
to
act
at
type
in
the
second
of labile
add further
supportive
anti-thromboplastin.
first
The
with
phase
or stable
the
in
the
evidence
2 who
herein
case
with
where
the
phase
of normal
coagulation,
hemorrhagic
symptomatology
was excluded,
assumption
involving
hence,
that
i.e., the
of cases
clotting
conversion
that thromboplastin,
this phase.
On the
phase
of
labile and stable
basis
of laboratory
these
the
or
abnormal
reported
the
had
(AHG)
transfer22
i.e.,
niost
hemnor-
comparable
deficiencies
of
the
were
Globulin
previously
of
it was
presented
presented
with
hot
com-
course
to congenital
transplacental
congenital
factor
to
1 and
patients
the
occur
without
resorts
false
does
or where
inhibitor
Hemophilic
of coagulation,
It is well known
factors
influence
evidence
the
and
This
during
finding
cases
If one
than
the
comparable
that
deficiency
with
formation.
more
to thrombin.
conversion
inhibitor
hemorrhages
always
flocculation
clotting
Anti
(PTC)
anticoagulant
believed
phase
factors
fewer
circulating
encountered
an isolated
with
with
cases.
do
was
cholesterol
patients
flocculatiomi
three
been
it is remarkable
more
symptoms.
it appears
that
have
Thromboplastin
They
have
serology
all
of all
abnormalities
cephalin
versa,
cholesterol
feature
laboratory
positive
than
acquired
cephalin
disease”
false
Vice
rhagic
positive
a commomi
of “collagen
anticoagulant.
Plasma
that
where
aceonipamiied
tests
caused
cephalin
evidence
of “collagen
disease.”
but inhibited
one of the plasma
mechanism
the
.
of
characteristics
serology.
amitibody(ies)
first
forniatiomi
directed
adsorbed
time
if the
imistruc-
instances.
The
positive
an
with
survival
reaction
of
he
be identified
or abnormal
case the transfer
to
see
very
the
probably
Unforto
been
induce
is
positive
Wassermann
penicillin.
emiough
physico-chemical
failure
other
by
have
would
its
its
of the
The
it would
off
long
a false
because
transfer
case
that
cannot
phenomenomi.
patient
amiticoagulant
and
that
a positive
clinical
or laboratory
anti-thromboplastie,
tin.
the
DISEASE”
set
the
antibiotic
cause(s)
tests
transplacental
of
though
of
inhibitor
than
the
remarkable
amiy anticoagulant
stance
were
of the
which
serologic
dividuals
not
action
“COLLAGEN
was
follow
non-dialyzability
the
however,
the
to
doses
is rather
iN
anticoagulant
If this
of
It
the
possible
small
thromboplastin.
(heat
of
been
disappeared.
tive
The
ANTICOAGULANTS
clinical
inhibitor
data
was
an
From www.bloodjournal.org by guest on January 12, 2015. For personal use only.
PAUL
Very
little
comment
can
G.
be made
705
FRICK
in regard
to therapy.
In
case
1 a course
of
Cortisone
in small
doses
for two months
had no effect
on the anticoagulant.
Comisidering
the spontaneous
fluctuation
of inhibitor
activity
observed
in this
case, it would
be rather
difficult
to assess
the value
of any therapeutic
agent.
It
is possible
however,
that prolonged
treatment
with larger
doses of Cortisone
may
influence
the
anticoagulant
antibodies
like
The incidence
; the
hemagglutimiins
of anticoagulants
total
of thirty
patients
tus with positive
L.E.
presence
only
and
periarteritis
of the
allergic
nodosa
this
drug
on
other
could
appears
clotting
immune
rather
low.
A
disseminanodosa,
three
beyond
lupus
No
of
unclassified
The three
be demonstrated
total
group : two had
reaction
to penicillin.
revealed
types
cases of lupus
erythematosus
nimie cases of periarteritis
reaction
to penicillin,
and
two
of hypersensitivity
were studied.
of an anticoagulant
10 per cent
one had an
of
been well established.
in “collagen
disease”
including
sixteen
cell phenomenon,
cases
with
a systemic
multiple
manifestations
the
effect
has
cases
with
cases where
doubt
represent
erythematosus
disseminatus,
case of histologically
proven
inhibitors.
SUMMARY
1. A circulating
anticoagulant
germ disease.”
and
In
a four
plus
all
was demonstrated
was associated
with
cholesterol
flocculation.
cases
in three
it
cephalin
a false
patients
with
positive
blood
“collaserology
2. In one instance,
the amiticoagulant
was transferred
to a newborn
infant
it persisted
for seven
weeks.
The infant
also demonstrated
the abnormal
logic amid turbidimetric
3. The anticoagulant
4. The
tests during
the first six months
probably
acted
as anti-thromboplastin.
occurrence
of a clotting
tions of hypersensitivity
mechanism
of development
5. This
disseminatus
“collagen
study
and
disease.”
and
inhibitor
1. Esseva
demonstrate
anticoagulante
associate
con
le neonate
serologia
In
infante
sanguinee
del
“morbo
other
manifesta-
suggest
Illac
ageva
positive
inhibitor
indice
per
illo
t.hat
de que
como
coagulamento
e le tranferimento
su mechanismo
le presentia
de
e un
durante
esseva
flocculation
cho-
transplacental,
un
periodo
de 7
anti-thromboplastina.
in
association
transplacental
disveloppamental
con
es de
altere
de ille
charac-
immunologic.
5. Le studio
hic
presentate
includeva
the
term
cent.
circulante
transferimento
persisteva
probabilemente
de
collagenic”
le anticoagulante
falsemente
patiente.
de un inhibitor
hypersensibilitate
forte
casos
4 plus.
se trovava,
4. Le occurrentia
manifestationes
de
es un
con
omne
septimanas.
3. Le anticoagulante
ter
strongly
INTEIILINGUA
3 patientes
in
circulante.
un
IN
lesterolic
a cephalina
de grado
2. In un caso le anticoagulante
in
with
transfer
in type.
included
a total
of thirty
patients
with
lupus
erythematosus
associated
conditions
conventionally
grouped
under
the
The incidence
of circulating
anticoagulants
was 10 per
SUMMARIO
Un
of life.
in association
its transplacental
is immunologic
where
sero-
un
total
de 30 patientes
con
disseminate
From www.bloodjournal.org by guest on January 12, 2015. For personal use only.
706
CIRCULATING
ANTICOAGULAN’ps
lupus
erythematose
“morbo
collagenic.”
e un associate
Le frequentia
IN
‘
‘COLLAGEN
DISEASE”
condition
conventionalmente
de anticoagulantes
circulante
classificate
esseva
como
10 pro
cento.
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1
C.
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L.
CONLEY,
621-622,
2
H.
W. H.,
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B. AND GOLDSTEIN,
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‘
on
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18
AND
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17
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8 NICHoLSON
16
A.,
associated
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15
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LABHART,
6
13
II,
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prothrombinemia
P
: A hemorrhagic
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G. G., SORENSON,
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a
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3 HITZIG,
‘4
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in
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S
AN!)
G.:
Some
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7:
& Clin.
disease
anticoagulant.
observations
with
200-210,
hypersensitivity
serum
sickness
K.
Med.
reference
M.:
41:
Effect
of
637-647,
on
the
to a case
antiheniophilic
1953.
blood
clotting
of congemsital
mechaafibrino-
1946.
in
and
periarteritis
sulfonamide
following
Blood
pregnancy
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J.
From www.bloodjournal.org by guest on January 12, 2015. For personal use only.
1955 10: 691-706
Acquired Circulating Anticoagulants in Systemic "Collagen Disease":
Auto-immune Thromboplastin Deficiency
PAUL G. FRICK and MARY K. WEIMER
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