Download Platelet Dysfunction in Glycogen Storage Disease

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Platelet
Dysfunction
By Emily
in Glycogen
E. Czapek,
Daniel
Deykin,
A
HEMORRHAGIC
has
deficiency
or
(GSD-I).
epistaxsis,
Affected
individuals
frequently
and excessive
bleeding
following
Previous
investigations
the
etiology
function
of
to
function,
lished.
times,
normal
of
to
been
observed
I glycogen
a
Linneweh
only
the
one
study
of
of newer
platelet
of
function
the
dys-
glycogen
assessing
GSD-I
in
platelet
platelet
of
et al.#{176}
described
abnormal
platelet
various
glycogenoses,
the platelet
dysfunction
was
not
discussed.
define
further
the nature
of the hemorrhagic
We were
afforded
the unique
opportunity
a course
relationship
platelet
and
in
with
disease
of easy
bruising,
surgical
procedures.
methods
function
In a brief
communication,
Corby
decreased
platelet
adhesiveness,
platelet
factor
3 in patients
with
GSD-I
during
investigate
the
of
patients
storage
attributed
deficiency
developn’ient
in
history
and
disorder
et al.
glucose-6-phosphatase
Since
I
W. Salzman
Type
have
a
dental
implicated
bleeding.’
platelet
accumulation.4’5
let
have
such
Edwin
Type
abnormality.
DIATHESIS
glucose-6-phosphatase
and
Disease
lipemic,
platelet
function
was
strikingly impaired.
Two patients
received
a course
of continuous
intravenous
alimentation.
As their
general
metabolic
state
approached
normal,
abnormal
platelet
function
was corrected.
We found
normal
platelets
to contain
no glucose-6-phosphatase.
There
was
no
consistent
increase
in platelet
glycogen
levels in patients
with GSD-I.
These
data indicate
that the bleeding
disorder
in GSD-l
is an acquired
defect
rather
than
a primary
platelet
A hemorrhagic
tendency
has been observed
in patients
with glycogen
storage disease
Type I (GSD-l).
We have
studied
the hemostatic
mechanism
in
six patients
with GSD-l who have mild
to severe
bleeding
tendencies.
All exhibited
abnormalities
of platelet
function (decreased
prothrombin
consumption, abnormal
aggregation
reactions,
prolonged
bleeding
time,
and
low
platelet
adhesiveness).
The degree
of
dysfunction
correlated
with
the patients’
general
clinical
condition:
when
patients
were
acidotic
and
severely
11
Storage
has
platebeen
pub-
prolonged
bleeding
aggregation,
and
but the etiology
Our
study
was
undertaken
diathesis
in GSD-I.
of studying
two patients
with
intravenous
hyperalimentation,
between
platelet
function
and
enabling
us
changing
metabolic
to
state.
From
the
Departments
of
Submitted
June
Supported
by
USPHS
Presented
in
part
Societies
for
Emily
E. Czapek,
M.D.:
Associate
Mass.
Blood,
Israel
1973
by Grune
HL
April
& Stratton,
Vol. 41, No. 2 (February),
August
1972;
and
M.D.:
HL
Meeting
Israel
2,
Hospital,
Boston,
Mass.
1972.
05422.
of
the
Federation
of
the
American
1972.
Beth
Medicine,
Salzman,
Boston,
Beth
1,
Memorial
Medicine,
of
Surgery,
11414
Annual
Children’s
of
Professor
Hospital,
56th
Biology,
W.
and
August
Grants
the
M.D.:
Edwin
Medicine
revised
NIH
at
Department
Boston,
©
1972;
Experimental
Coagulation,
Beth
15,
Hospital,
Israel
Chicago,
Hospital
Department
Professor
of
of
Boston,
Medicine,
Surgery,
Ill.;
formerly
Mass.
Beth
Department
Fellow
Daniel
in
Deykin,
Israel
Hospital,
of
Surgery,
Mass.
Inc.
1973
235
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236
CZAPEK,
MATERIALS
AND
DEYKIN,
AND SALZMAN
METHODS
Subjects
Six
patients
from
a
third
hepatic
from
two
families
with
family
was
studied
to
glucose-6-phosphatase
was
based
on
in a sibling.
had
All
although
patients
of
with
tests
(total
were
rhagic
derived
to
Blood
was
technique.
of
tions,
and
part
were
studied.
of
nor
the
1.5
and
one
one
controls
with
had
members
addition,
ml)
individuals
controls
Three
procedures
unaffected
In
Normal
trauma.
surgical
Five
gflOO
patients
deficiency
for
no
ingested
all
Type
IV
coagulation
history
any
patient
with
of
a
hemor-
drugs
for
10
a
double-syringe
days
Processing
or
scalp
vein
were
employed
collected
other
time
in
with
for
collection
assays,
were
(ACD)
collected
and
glycogen
acid-citrate-dextrose
samples
(Addendum
in
3.8%
proc-
determinaanticoagulant
sodium
citrate
(1
A).
Mechanism
(PT)
standard
needle
glucose-6-phosphatase
were
Clotting
and
activated
techniques.
previously
21-gauge
materials
platelet
All
blood).
prothrombin
methods
for
blood).7
9 parts
by
19glass
microscopy
5 parts
of the Soluble
Clauss
a
siliconized
Samples
electron
ACD:
The
partial
Factors
described.8
II,
Fibrinogen
thromboplastin
VII-X,
V,
was
time
VIII,
determined
by
(aPTT)
IX, and
XI
the
and
Ellis
were
were
assayed
Stransky9
or
methods.10
Platelet
Function
Platelet
Tests
factor
nique.12
3
and
1
were
patients
the
a modification
Ivy
Model
B counter,
machine
at
determined
of
and
sucrose.
It was
The
20
washed
specimens
to
at
dehydrated
were
method
(PPP)
et
by
al.’6
adhesiveness
were
counts
test,
and
by
lipid
the
O’Brien,’4
and
same
(Sigma)
(PRP)
individual.
during
plastic
prepara-
was
measured
times
were
performed
were
done
on
levels
phase
and
tech-
plasma
bf lipid
in
Bleeding
prformed
and
Hovigl5
from
clearing
Hardisty
Salzman
Platelet-rich
samples
Platelet
of
the
Born’3
of
consumption
counts
precluded
microscopy.
a
by
Coulter
an
accurate
Platelet
ATP
Totter.18
fixative’9
were
mm at room temperature.
temperature,
to separate
paraformaldehyde-cacodylate
mm
by
described
appreciable
Goldstein
Strehler
method
graphs
overnight
then
no
template.17
of
the
measured
bitartrate.
platelet
method
allowed
for
was
the
the
times
Micro
milliliters
plasma
centrifuged
pellet
by
of
Mielke
for
which
Electron
Nine
rich
a
the
as
prothrombin
method
except
count,
Platelet
the
using
on
tendon
plasma
was
Three-hour
of
technique
based
platelet-poor
to
was
epinephrine
there
blank.
beads
bovine
and
against
according
glass
performed
(Sigma)
hyperlipemia,
PPP
assayed
to
(ADP)
blanked
with
of
was
from
diphosphate
samples
was
was
prepared
adenosine
the
(PF3)
adhesiveness
aggregation
collagen
tion
activity
platelet
Platelet
using
lead.
lipids
four
enzyme
or
studied.
patient
biopsy-proven
minimal
bleeding.
(total
seventh
remaining
a proven
dental
also
A
had
following
following
were
population
patients
through
or
samples.
determined
by
the
drawn
citrate:
In
ml)
the
and
bruising
bleeding
family
g/100
a known
and
Plastic
essing
by
1.5
Neither
Collection
Tests
one
in
disease
detail.
patients
study.
Blood
part
marked
hyperlipemia
from
diathesis.
prior
of
lipids
the
life-threatening
siblings)
postprandial
hyperlipemia
of
and
experienced
three
marked
(1
had
and
a history
in
Three
diagnosis
with
epistaxsis
studied
degree.
The
compatible
had
frequent
none
(parents
course
were
limited
deficiency.
a clinical
a history
GSD-I
a
stand
for
3000
in
g,
40
room
0.01
M cacodylate
through
examined
alcohol,
in
a
Phillips
buffer,
fixed
Model
pH
in
osmium,
200
7.4,
added
to 1 ml plateletsuspension
was
the platelet
pellet.
The
This
containing
and
electron
7.8
finally
g/100
stained
microscope.
ml
with
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PLATELET
DYSFUNCTION
Platelet
Platelet
glucose-6-phosphatase
Platelet
fuging
at
0.04
in
One-half
tissue
homogenate
such
Lowry
ml
1
mM
was
times
activity.
than
nmoles
60
mm,
and
mm
15
tated
t’he
The
method
samples
phate,
and
Eibl
and
(2)
one
containing
(3)
one
with
were
Linneweh
Platelet
al.
Platelet
glycogen
PRP
then
fuged
represents
liver
glucose-6-
of
100
jmoles
to
were
incubated
After
to
remove
Ames.24
The
(1)
containing
one
of
of
15,
30,
standing
precipi-
(P1)
according
no
glucose-6-
following
instead
addition
at
at
TCA.
mm
of
contain
additional
glucose-6-phos-
glucose-6-phosphate.
digitonin-treated
platelets
All
by
the
method
release.4
g KH2PO4,
tube.
The
to
This
acetone
of
glycogen
Diazyme
(Miles
incubating
hr
of
experiments
platelets
lysed
six
of
the
platelet
no
glycogen
M
times,
subjected
thereafter,
with
to
in
glycogen
those
standard
Diazyme
to
of
confirm
taken
water.
to
Diazyme
solution
lysate,
containing
the
content
over
[200
mg
mixing,
and
glucose
was
distilled
performed
in
curve
was
no
major
platelet
preparations
glycogen
content
decreased
of
samples
range
was
workers.28’30
validity
of
the
once
other
care
water
duplicate.
derived
from
hydrolysis.
lysed
content
6.5)
recentri-
specific
sample
were
a
pH
was
freeze-thawing
ml
platelet
glycogen
there
added
the
determinations
incubated
decrease
0.9
Thereafter,
A
glycogen
platelets
suggesting
glycogen
to
with
by
One
decanted.
Gaintner’s
but
Diazyme
on
performed
of
in
KH2PO4]
to
total
platelets
significant
agree
All
modified
g NaCl/liter,
lysed
filtered
shaking.
based
The
of
commercial
venipuncture;
was
content
of
cold,
twice,
al.25
was
6.29
was
resuspended
et
PPP
resuspended
repeated
1 ml
Johnson
the
of
pellet
method.7
control.
also
was
then
0.1
ml
not
platelet
constant
were
number
showed
a
glycogen.
glycogen
of
as
control
to
ml
2
was
adding
(Worthington)
glycogen
The
100
content
platelet
was
by
of
4#{176}C,and
lipid,
pellet
the
It
method
at
g NaH2PO4’H20,
procedure
37#{176}Cwith
served
platelets.
studies
at
glycogen
portional
Recovery
ice.
in
commercial
determining
platelet
performed
Clucostat
glycogen
Calculation
Various
the
of
5.52
washing,
dry
was
11/2
by
of
and
the
5 mm
amounts
washing
Laboratories)
for
measured
purified
modified
0#{176}C.After
in
instead
the
large
after
g for
2700
by
preparation
times
determined
at
(0.65
hydrolysis
for
on
phosphate
glucose26
above.
the
was
centrifuged
added
as
keep
hr
determined
interference
without
were
3
the
4 mM
for
phosphate
jS-glycerophosphate
before
inorganic
content
was
minimize
buffer
six
also
measuring
:
homogenate
removed
80%
inorganic
of
controls
0#{176}Cthroughout
This
were
10
final
Folin-
6.8.
samples
cold
a
the
containing
pH
a
Glycogen
milliliter
To
duplicate.
for
to
by
platelet
assay
g for
was
of
4#{176}C.The
up
at
of
addition
ml
3000
method
zmoles
in
at
product,22
0.15
assayed
as
added
4 mm
made
samples
at
the
TCA
performed
was
et
then
100
80%
the
The
adding
were
simultaneously
Clucose-6-phosphatase
of
by
or
for
assayed
They
count
bottom
a buffer
to
by
above.
the
as
Lands
centri-
resuspending
platelet
and
at
necessary
milliliter
centrifuged
Lands23
incubated
determinations
stopped
gently
into
Boehringer-Mannheim
were
supernatants
of
were
phosphate,
was
of
X-100
initiated
one-half
by
a
ml
ml
glucose-6-phosphate.
and
samples
5.4
Triton
protein
the
moles
reaction
0#{176}C,the
protein.
to
the
at
of
were
0.1-0.2
to
tg
and
PRP
preparation
with
60
Eibl
of
as
rpm
protein
platelet
added
and
from
One
the
conducted
protein
1700
mg
the
and
homogenizer
30
of
ml
by
pipetted
at
the
keep
amount
mixing.
recentrifuging
was
from
reactions
P1/100
constant
homogenized
NaF,
repurified
10
with
was
mg
the
The
glucose-6-phosphate,
suspension
to
1 mM
twice
and
solution,
the
were
60
washed
6.5
sucrose-EDTA
taken
L-histidine,
pH
approximately
3-4
a modification
were
at
rinsed
Incubations
three
phosphatase
for
and
Care
approximately
37’C
of
approximately
7.3
and
237
approximately
platelets
the
contained
procedures.
EDTA,
less
DISEASE
by
from
EDTA)
of
quantitatively
that
representing
ml
homogenizer
method.21
above
M
milliliter
was
volume
The
0.001
0.7
determined
obtained
at 4’C.
(with
resuspended
motorized
were
5 mm
sucrose
performed.
was
pellets
g for
2700
M
were
the
STORAGE
Glucose-6-Phosphatase
technique.20
in
IN GLYCOGEN
of
0.2
slightly
X
lower
loss
during
was
of
our
was
for
i-i
proX
than
1010
that
repeated
100%.
platelets
slowly.
method
directly
The
of
lysis.
Time-course
assayed
within
normal
values
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CZAPEK,
238
Platelet
Acid
Platelet
AND SALZMAN
Phosphatase
acid
Sigma
DEYKIN,
phosphatase
was
measured
by
the
method
of
Zucker
and
Borrelli3l
using
reagents.
RESULTS
We were
unable
to detect
platelets.
Both
homogenized
glucose-6-phosphate
released
is approximately
mintlO1’
present
platelets.
in platelets,
phosphate
as
from
6-phosphatase),
revealed
32.5
Tests
implies
phosphatases.
is sufficient
of Soluble
Clotting
the
present.
/Lmoles
readily
account
glucose-6-phosphate
Pit
reported
to be
from
f3-glycero-
substrate
degradation
measurement
This
platelet
glucose-
at
pH
6.8
of acid
amount
Pi/mintlO”
platelets
for the 0.2
moles
as a substrate.
in our
Pi/mintlO”
Factors
the soluble
prolonged
in those
instances,
and it was thought
hyperlipemic
0.36
13-glyceromoles
phosphatase.3#{176}
Although
6.8 (the pH optimum
for
acid
phosphatase
platelets
to be
to liberate
therefore,
using
Results
of tests
of
PT was minimally
However,
normal,
of acid
at pH
amount
substrate,
of 0.25
that
This
equivalent
has
not been
amount
of Pi
glucose-6-phosphate
amount
active
an
another
in release
action
a large
is minimally
and can,
liberated
of
human
with
platelets.
from
resulted
of nonspecific
in normal
incubated
Pi/min/lO”
Pi released
Substitution
actual
platelet
Sigma
unitst1O
phosphatase
i.moles
0.2
of
activity
platelets
Since
f3-glycerophosphate
liberation
of the same
to the
Platelets
contain
acid phosphatase
system
platelets
only
amount
tissue
(Table
1).
for glucose-6-phosphate,
is secondary
The
the
1/30
of rat liver
phosphate,
glucose-6-phosphatase
and
digitonin-treated
plasma.
clotting
mechanism
only
in instances
specific
the PT
The
aPTT
levels
of
prolongation
was
not
are shown
in Table
of extreme
hyperlipemia.
factors
was
2.
II, V, and VII-X
were
due to an artifact
of
significantly
prolonged
in
any
instance.
Platelet
Studies
The
function
thrombin
platelet
count
was
impaired
consumption
prolonged
on
adhesiveness
with
at least
was
adenosine
was normal
(200,000-600,000)
in all patients.
to some
degree
in all patients
(Table
3).
was
uniformly
decreased;
the
bleeding
one
occasion
decreased
in
diphosphate
in five
six
(ADP),
Table 1. Tissue
of
of seven
seven
epinephrine,
(n=10)
‘Mean
±
SEM.
and
Glucose-6-Phosphatase
Tissue
Liver
(n=7)
Platelets
patients,
patients.
Platelet
prowas
The
time
and
Platelet
collagen
the
was
Activity
Activity’
4.7 ± 0.37 imoles
(3.2 ± 0.47 moles
0.2 ± 0.04 imoles
(0.12 ± 0.06 imoles
P,/min/g
P1fmin/100
P1/mln/10”
P,/min/100
platelet
aggregation
mg protein)
platelets
mg protein)
diminished
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PLATELET
DYSFUNCTION
c’J
IN GLYCOGEN
STOFAGE
DISEASE
239
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From www.bloodjournal.org by guest on August 3, 2017. For personal use only.
CZAPEK,
240
to a variable
Abnormalities
ADP
degree
in all cases.
ranged
in severity
to no
reaction
to any
DEYKIN,
Representative
tracings
from
disaggregation
reagents
used.
Addition
AND SALZMAN
are shown
in Fig.
with
5 X
10
of
one
part
of
1.
M
patient’s
platelet-poor
plasma
impair
aggregation
was
normal
in all
to four
parts
with
collagen,
patients;
platelet
of normal
platelets
did not significantly
ADP,
and
epinephrine.
Clot
retraction
factor
3 activity
was
normal
in five
patients,
The five
ATP
members
was normal
D. family
and platelet
unaffected
ing times
prothrombin
and
platelet
adhesiveness
consumption,
platelet
Both
the patient
IV hyperlipemia
Platelet
with
postprandial
had normal
platelet
glycogen
0.068
±
of washed
This was
not
the
determined
molest109
in
slightly
and can
of glycogen
stimulated
by
addition,
activity,
washing
Name
values
procedure.
b.
C.
G.M.
a.
b.
PD.
N.D.
a.
b.
C.
Pu.D.
a.
b.
C.
from
(mean
tested.
bleed-
Mrs.
D. had
and aggregation
the
15
patient
±
for
a damaged
or by the
In patients
Studies
Platelet
Adhesiveness
<7
>25
(#{176}/o)
with
a normal
studies.
with
Type
in GSD-l
Prothrombin
Consumption
(#{176}/o
Comsumed)
37
67
12
13.5
0
0
13
1
7.5
10
12
19
11
23
9.5
5
10.5
13
10
-
volunteers
The
0.02
by
i.moles/109
a variety
storage
<35
0
content
platelets.
of processes,
increased
platelets
disease,
plate-
Patients
Activity
PF3
(eec)
<45
25
16
27
was
glycogen
cell membrane,
rupture
of some
glycogen
>60
-
normal
SEM).
±
lower,
0.38
be accounted
Bleeding
Time
(mm)
12
8.5
4
a.
samples
through
washing,
Table 3. Platelet
Normal
SM.
In
3
hyperlipemia
and
function
studies.
platelets
platelets
was
unexpected
such
as leakage
glycogenolysis
during
tests.
factor
in the four
patients
studied
all had normal
Glycogen
Platelet
0.495
content
of the
-
Platelet ATP
(38.8 ± 0.7#{176}
X
10-’
moles/lO’
Platelets)
-
-
40.0
-
41.5
-
36.3
-
-
-
-
-
0.36
-
-
0.39
0
45
36.4
-
-
-
-
-
0.37
7
40.1
-
-
-
-
-
-
0.35
51
31.1
-
-
-
-
M.D.
a.
b.
R.J.
‘Mean
15.5
>20
4
±
SEM.
7
22
13
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PLATELET
DYSFUNCTION
IN GLYCOGEN
STORAGE
DISEASE
241
EPINEPHRINE
Fig. 1. Representative
gation tracings
in two
platelet aggre-
GSD-l
patients.
Platelets
from S.M. failed
to respond
to high
doses
of collagen,
ADP,
or
epinephrine.
Platelets
from
P.D.
showed
a primary
response
to ADP
only.
let glycogen
upper
range
varied
from
of normal
greatly
increased.
Life-line
Studies
Two
patients
tinuous
normal
with
intravenous
values
for
well within
(Table
4).
GSD-I,
to
be
J:
I
C02
content,
I
I
I
12345
MINUTES
the normal
range
to
In no instance
was
reported
hyperalimentation.33
pH,
PD NL
}-5xlc6M
IxKM
-
elsewhere,32
On
blood
this
lactate,
therapy,
plasma
slightly
platelet
were
above
the
glycogen
given
previously
lipid
level,
conabBUN,
From www.bloodjournal.org by guest on August 3, 2017. For personal use only.
242
CZAPEK,
DEYKIN,
2. Platelet
studies
AND SALZMAN
SERUM
LIPIDS
GM. LIFELINE
4
STUDIES
q//OOm/
PROTHROM8IN
80
-
CONSUMPT/QV
Zcon/rol
:iIiiIiiiii.-
16
minutes
BLEEDING
-
GLYOGEN//O’PL4TELETS
08
,jinv/es
TIME
04
C
Fig.
venous
therapy
values
-‘
I
L,
I
I
- -
I
I
DAYS
and
uric
serum
children,
feedings,
acid
were
restored
platelet
function
as evidenced
by
to
toward
normal
are shown
in
of the patient’s
16
g/100
ml
prothrombin
ness
increased
12
mm
in
both
2. Serum
lipid
general
clinical
to
approximately
consumption
from
0%
to 5 mm.
1 g/100
glycogen
Normals
(n=15)
GSD-l patients
G.M.
S.M.
Pu.D.
N.D.
M.D.
‘Mean
±
SEM.
normal
and
content
data
shown
as
As serum
ml
from
Table 4. Platelet
Subjects
near
levels.
to initiation
time,
decreased
Representative
levels
are
condition.
increased
to 42%,
Platelet
or
of
In
both
intravenous
prothrombin
of platelets
with
ADP,
epinephrine,
and
platelet
adhesiveness.
During
a 14-day
platelet
function
reverted
dramatic-
patients.
Fig.
intra-
hyperalimentation.
Duration
of
is indicated
by arrows.
Normal
are designated
by dotted
lines.
was
abnormal
prior
a prolonged
bleeding
consumption,
decreased
aggregation
collagen,
and in one child,
decreased
course
of intravenous
hyperalimentation,
ally
normal
during
over
0%
the
did
Glycogen
a period
to 55%,
bleeding
not
from
one
an arbitrary
lipid
levels
of
7-12
patient
indicator
fell from
days,
the
the
platelet
adhesivetime
shortened
from
change
significantly.
Content
Platelet
(molee/10’
0.38
(Range
Glycogen
Platelets)
± 0.02’
0.24-0.54)
0.55
0.39
0.44
0.40
0.22
The
From www.bloodjournal.org by guest on August 3, 2017. For personal use only.
PLATELET
DYSFUNCTION
IN GLYCOGEN
STORAGE
DISEASE
243
..
Fig. 3. Platelet aggrein G.M.
prior to
and
during
intravenous
hyperalimentation.
During therapy,
platelet
aggregation
became
normal.
gometry
improvement
MINUTES
in platelet
Prior
to intravenous
100 ,l collagen,
10
12 days
of therapy,
response
to
aggregating
therapy,
the patient’s
X 10#{176} M ADP, and
the patient’s
platelets
agents
platelets
5 X 10
reacted
is shown
in
Fig.
3.
failed
to aggregate
with
M epinephrine.
Following
normally
to all three
re-
agents.
Electron
Microscopic
There
with
was
GSD-I
normal
in Fig.
and
Studies
no difference
than
from
GSD-I
in
the
normal
platelets,
appearance
of
platelets.
before
and
the
platelets
Representative
during
life-line
from
patients
mmcrographs
therapy,
are
of
shown
4.
DISCUSSION
The hemorrhagic
diathesis
in patients
platelet
dysfunction.3
Abnormal
platelet
be secondary
to platelet
glucose-6-phosphatase
with
GSD-I
has been
function
has
been
defi&ncy
with
attributed
postulated
accumulation
to
to
of platelet
glycogen.4’5
Our
studies
confirm
the
presence
of a defect
in
platelet
function
in patients
with
GSD-I.
The prothrombin
consumption
was
decreased
in all patients,
and
the bleeding
time
and
platelet
adhesiveness
were
abnormal
epinephrine,
Impaired
in
most
and ADP
prothrombin
instances.
was decreased
consumption
The
response
or absent.
in the face
of
platelets
of a normal
to
collagen,
soluble
clotting
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244
CZAPEK,
DEYKIN,
AND SALZMAN
Fig. 4. Electron micrographs
of normal
and GSD-I platelets.
(A), normal
platelets; (B), platelets from patient G.M. before life-linetherapy; (C), platelets from
G.M. during
life-line
therapy
when
platelet
function
had returned
to normal.
system
indicates
prothrombin
most
platelet
likely
reflects
such
a
syndromes
on
other
the
heightened
and
the
and
occasions
phatase.
platelet
We were
also
glycogen
levels
exceed
the
our samples,
be explained
by
upper
limits
many
sections
of
Our
findings
are
patients
published
Because
of
platelets
previously
the
and
theory,
if
the
6-phosphatase
late
excess
The
in contrast
elsewhere,
variability
platelet
platelets
of
in platelet
were
able
to electron
showing
believe
this
reflects
test16
factor
activity
of
test.
normal
3
in
inorganic
residual
presence
Glycogen
have
dysfunction
consumption
platelet
phosphate
acid phos-
greatly
increased
determinations
did
to
our
patients
with
glycogen
granules.
find
platelets
micrographs
an increase
in number
of
areas
of
perhaps
there
glycogen
in
is no
GSD-I
reason
from
of
both
glycogen
very little
granules
is
GSD-I
also
In studying
of platelets
in platelet
the same
platelet,
have
been
due
dysfunction
data
indicate
to platelet
of
we
small
amount
of
action
of nonspecific,
confirm
the
with
GSD-I.
We
from
GSD-I
glvcogen.2
among
individual
the apparent
to a sampling
not
to expect
normal
granules.
glycogen.
increase
error.
In
secondary
to
the
to accumu-
platelet
glucose-
glycogen.
accumulation.
aspect
of
increase
we
deficiency,
above
secondary
and
prothrombin
patients
tests.
platelet
that
contained
a large
number
could
also be found
that contained
in different
reported
might
two
with
kaolin-activated
glucose-6-phosphatase
the
the
decreased
in our
of normal.
platelets,
patients
platelets
of
laboratory,
the
unable
to
in patients
electron
micrographs
to demonstrate
an
and
cases,
the
between
3 activity
patients
retarded
In
The
failed
subjects
In both
some
the
factor
sensitivity
in our
of
relative
insensitivity
of
were
unable
to demonstrate
platelets.
could
not
in
sensitivity
discrepancy
platelet
in the
discrepancy
human
produced
The
normal
a difference
observed
We
dysfunction.
consumption
Rather,
the
abnormal
that
the
platelet
glucose-6-phosphatase
the
platelet
metabolism
dysfunction
deficiency
dysfunction
of
appears
patients
with
in
and
GSD-I
platelet
to be
GSD-I.
is
not
glycogen
related
to some
Support
for
From www.bloodjournal.org by guest on August 3, 2017. For personal use only.
PLATELET
this
DYSFUNCTION
hypothesis
data.
years
is
Physicians
noted
that
improved.
derived
from
following
as the
challenged
by
surgery.
More
and
general
on
Both
for
S.M.
and
patients
showed
pH,
CO2,
BUN,
Following
cessation
of
and
family
over
their
general
tendency,
evidence
metabolic
manifested
for
state
prior
to and
almost
serum
total
lipids,
is
during
by
frequent
a bleeding
severely
was
a correlation
afforded
between
by
intravenous
correction
and uric
therapy,
laboratory
the past
several
clinical
condition
less pronounced,
although
hemostatic
mechanism
concrete
intravenous
245
observations
D.
hemorrhagic
G.M.
DISEASE
clinical
became
when
the
function
obtained
both
their
and easy
bruising,
was
still
evident
platelet
STORAGE
members
of the
children
grew
older
Concomitantly,
nosebleeds
diathesis
tion.
values
IN GLYCOGEN
the
of
acid
platelet
approached
platelet
studies
hyperalimentafunction
as
normal.
function
deteriorated
progressively.
None
uricemia,
and
of the specific
hyperglycemia,
pyruvate
to cause
metabolic
chronic
levels
platelet
found
with
uremia;
a disorder
prolonged
bleeding
aggregation.34’35
approach
glyceride
in patients
dysfunction.
to patients
both
have
of
In
the
GSD-I
as hyperlipemia,
and
increased
has
respects,
definitely
these
platelet
BUN
are
with
GSD-I
and
usually
dysfunction.
to decrease
adhesiveness.36
However,
in the
was
tion of the bleeding
of hypenlipemias,
time.
we did
not able
receiving
panying
to find
patients
with
therapy
directed
at
other
clinical
conditions
diathesis.
function
Finally,
in
within
hours
hypoglycemia,
in
the
S.M.
and
time
G.M.
of institution
are less likely
From
the above
studies,
patients
with
GSD-I
is
deficiency.
receiving
consequence
Instead,
the
hyperalimentation
of
the
finding
abnormal
individuals
tested
there
patients
platelet
with
function.
no
not
Tnplate-
prolonga-
other
forms
We
were
grossly
elevated
lipid
levels
who
were
not
their
hyperlipemia.
Hyperunicemia
accomhas not been
associated
with
a hemorrhagic
course
(several
suggests
days)
that
metabolic
of intravenous
to be related
we
not
of
a
does
uremic
patients
with
platelet
individuals
have
been
shown
In our limited
study
not observe
impaired
and
by
abnormal
seen
in
in normal
let
shown
analogous
chronic
acidosis
characterized
adhesiveness,
in patients
hyperlactate
been
patients
hyperuricemia
and
function
frequently
decreased
However,
such
acidosis,
with
some
both
have
platelet
time,
the levels
infusions
abnormalities,
metabolic
conclude
secondary
of normal
suggests
the
metabolism
to
correction
platelet
platelet
of
abnormalities
therapy,
such
the platelet
that
to
that
of
platelet
corrected
as acidemia
dysfunction.
and
the defect
in platelet
function
platelet
glucose-6-phosphatase
function
dysfunction
characterizes
in GSD-I
is an
this
patients
acquired
disease.
ACKNOWLEDGMENT
The authors wish to express their appreciation
to Dr. R. Field, Dr. B. Senior, Dr. H. Boda,
and Dr. A. Britten for their cooperation in various portions of this study.
We are grateful to Dr. W. Tse and Dr. J. Crigler for allowing us to participate
in their
studies of intravenous hyperalimentation.
These studies were carried out at the Children’s
Hospital Medical Center, Boston, Mass. under the support of General Clinical Research
Center Grant USPHS
NIH Grant RR 00128.
Dr. C. Con and Professor G. L#{246}hr
gave us
valuable technical advice. Mrs. Kiara Rev provided valuable technical assistance
in the
preparation of samples for electron microscopy.
From www.bloodjournal.org by guest on August 3, 2017. For personal use only.
CZAPEK,
246
DEYKIN,
AND SALZMAN
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1973 41: 235-247
Platelet Dysfunction in Glycogen Storage Disease Type I
Emily E. Czapek, Daniel Deykin and Edwin W. Salzman
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