Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by ... Forms in Chronic. Relapsing. Thrombotic. Thrombocytopenic. Purpura. By. Joel ..... blood obtained. 30 to 90 minutes after the transfusion of either normal.
From bloodjournal.hematologylibrary.org by guest on July 10, 2011. For personal use only.
1985 65: 1232-1236
Effects of fresh-frozen plasma and its cryosupernatant fraction on von Willebrand factor multimeric forms in chronic relapsing thrombotic thrombocytopenic purpura JL Moake, JJ Byrnes, JH Troll, CK Rudy, SL Hong, MJ Weinstein and NM Colannino
Information about reproducing this article in parts or in its entirety may be found online at: http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
From bloodjournal.hematologylibrary.org by guest on July 10, 2011. For personal use only.
Effects von
of Fresh-Frozen Willebrand Factor Thrombotic By
Remission
plasma
relapsing
thrombotic
contain thelial
to
of some von
those
frozen
plasma
(FFP)
in the
in
patients
with
patients
with
Three
remission
have
their
plasma.
with
FFP.
three
plasma
Two one
immediately
vWF
multimers
plasma
of
two
of
after
three (on
one
occasion). was
URING
the
immediately patient
in patients
patient
transiently
plasma
cular This
human During decrease
platelet may be
chronic
and attach
with
intravas-
thrombocytopenia. preferentially
to
platelets in vivo in the presence of a putative inciting cofactor released in association with inflammation or tissue necrosis. The unusually large vWF multimers then return to patient plasma as recovery occurs. The infusion of normal fresh-frozen plasma (FFP), often
in association
From
the
University
Boston
School
School;
the
Thorndike College
institutes
No.
of Health, June
Address tology.
reprint
Veterans
from
the
HL22355
and
HL13262
Bethesda,
Md.
Hospital-Mail TX & Stratton.
0006-497//85/6505-0027$03.00/0
1232
City University.
accepted
Houston,
Research
Rice
to Dr Joel
Methodist
by Grune
funds
77030. Inc.
Centers;
Nov
in
Boston
of Miami
Boston and
1 1. 1984;
The
Medical
Hematology Tex;
is effective
University
requests
Fannin,
© I 985
VA The
Laboratories, Waco,
by research
Submitted
Miami
Medicine;
Memorial
grants
plasmapheresis,
B. Castle
of Medicine, by
6565
and of
William
Supported and
with
Medical Laboratory.
Hospital;
Baylor
Houston. Administration
from
the
National
14. 1984.
L. Moake, Station
Medical 902.
Main
and
plasma
in a third
patient
who
HemaBldg.
was
multimers
to smaller results
fraction the
vWF
indicate of normal
metabolism
this
in partial
an
plasma
large in
& Stratton.
or preventing
harmful. The
have transfusion
contains plasma,
pernatant been found prophylaxis
in vivo chronic
in controland
relapsing
to
of normal
relapsing
normal platelets,3 of factor IX on be
ineffective
or
cryoprecipitate,
which
multimers present in normal Transfusion of the cryosu-
fraction of normal plasma, however, to be at least as useful as normal plasma against, or therapy for, TIP relapses
patients with chronic relapsing TTP.46 tant contains residual amounts of the multimers present in normal plasma. In this
report,
cryosupernatant on the plasma with chronic
we describe
remission. in order
between multimer
therapy forms.
Cryosupernasmallest vWF
effects
of FFP
and
The patients were studied during to allow a correlation to be made and any changes in plasma vWF It is not possible to make this correla-
tion during relapses relapses the unusually
in chronic TTP, because during large vWF multimer forms (and
even the in circulation)
in association
the
has for in
infusion, as well as plasma exchange, vWF multimer patterns in three patients relapsing TTP who were in complete or
partial remission
sometimes normally
phase.
multimers.
in chronic
reported
the largest vWF is also ineffective.46
fluid
Inc.
relapses
been
FFP large
cryosuperna-
vWF
TTP.2 In contrast, transfusions of albumin,4 -y globulin,5 or preparations fibronectin5
in the
some
in
abnormality Neither
in the
is involved
is defective
the
TTP
unusually
in vitro
of unusually
process
the
remission.
activity
its
disap-
from
relapsing
converted
forms
that
and
in vivo
multimers
reversed
fluids
or cryosu-
FFP,
rapid
chronic
directly
these
in
the
exchange
remisremoved
FFP
activity
vWF
with
cryosupernatant
controlling
purpura multimers similar to
endothelial cells in relapses, the unusuon disappear from
in association
agglutination because they
remission.
ling
large
patients
when
normal
an
plasma
patient
medium
cells, either
that
her
Unusually
from
culture
promoted
unusually
two
TTP patients. 0 1985 by Grune
infusions.
with
conclude
of
the
to
thereafter.
disappear
with
fraction.
of
returned
endothelial
in vitro
We
not
on
L. Hong,
persisted
or from
human
cryosupernatant plasma
did
samples,
incubated
that
plasma received
the
and
normal
tant
(on
who
after
multimers
were
These
trans-
after
relapsing thrombotic thrombocytopenic (TTP),’ von Willebrand factor (vWF) larger than those in normal plasma, and those produced by normal culture, have been found. ally large vWF multimens
patient
cryosupernatant
vWF hours
from
nor
large
from
following
or
on before
Unusually
serially
REMISSION
once
studied
disappeared
The
studied
in
Suchen
to 24
multimers
pearance
during
Fraction Relapsing
large
pernatant.
of
present
was
1 1/2 hours and
plasma
cryosupernatant
occasions)
occasions).
TTP
transfused
exchange.
1/2 to
two
were
patient or
vWF
sion
form
multimers
received
third plasma
within (on
cryosupernatant
D
two the
decreased
FFP
exchange
the
relapsing
patients
large
of TTP
relapsing
ten
mul-
fresh-
or prevention
vWF
within
endo-
(vWF) human
as normal
chronic
chronic large
the
and
samples
fusion
of
of
occasions,
and
treatment
unusually
(TTP)
cryosupernatant
effective
the
chronic
normal
of the
is as
Unusually
with purpura
factor
by
infusion
of
TTP.
normal
The
fraction episodes
patients
Willebrand
produced
in culture.
cells
John J. Byrnes, Joseph H. Troll, Christine K. Rudy, Mark J. Weinstein, and Noreen M. Colannino
thrombocytopenic large
similar
Moake,
L.
samples
unusually
timers
Joel
Plasma and Its Cryosupernatant Multimeric Forms in Chronic Thrombocytopenic Purpura
with
largest vWF multimers disappear from patient the
in vivo
that is the pathophysiologic organ ischemia.
Blood,
Vol 65, No
platelet
basis
5 (May),
found plasma
agglutination
for
the
1985:
multifocal
pp
1232-1236
From bloodjournal.hematologylibrary.org by guest on July 10, 2011. For personal use only.
EFFECTS
OF
CRYOSUPERNATANT
ON
vWF
IN
UP
1233
PATIENTS
hours
in 0.15
changes),
Patient
1
For
five years,
either
FFP
TTP
this
relapses.
She
et al.’
counts,
is described
were
to
335,000/ML)
U/dL),
present
she
as part
of her
study
and
Patient
gave
unusually
(vWF
antigen
with
2 units
mL)
of normal
prophylactic
large
of either
She
consent
on the
This
was
program
understood
the
to
at the
purpose
of
for it to proceed.
This
34-year-old She
woman
was
is patient
once
has
B in Moake
intermittently
et al.’
she gave
permission
then
30 minutes
after,
she
was
in
vWF
forms
She
for blood
were
found
hen
On
infusion. and
plasma
(vWF
of FFP
This
one
of those
At
before, the
time,
unusually antigen
21-year-old
recovered unusually
large
vWF
she
level,
the
relapsing
occasion,
when
(platelets had
had
383
reappeared
143
patient
TTP.
She
had
partially
she
I l0,000/zL),
a 3-L
antigen,
from
chronic
one
multimens
vWF
obtained
On
relapse
U/dL),
(postexchange
had
et al.’
a TTP
168
were the
woman
from
antigen,
human
vWF and
in hen plasma
exchange
U/dL).
before,
and
with
180
then
is
blood
7.4. samples,
IRMA,
were
were
applied
gels
were
soaked
mol/L
NaCI
lgG
changes
acetic
acid
for
hours
and
placed
procedure.
and
The
preparation
plasma
of
(PPP)
from
described.’
vWF
quantified
by
high
Colloids
antigen
was
(IRMA)’ rate
also using
Chemical
(100%)
rabbit
of the
Agarose
mol/L
Patient
and
same
vWF two
2#{188} to out
2/2
and
containing ing)
for
(Dako
and
NY)
plasma
mented
and
contains
100
assay
Cryosupemnatant lated was
method
of Gralnick backing
sodium
pooled levels
They different
were
origin
hrs at 100 electrophoresed rabbit 16 hours
in the
samples
in the
same
0.5%
second vWF
and
-35
into
0.5%
dimension
then
for cut
agarose
(Calbiochem-Behrwere
then
washed
to
in an oven
at 56 ‘C for six Rochester,
screens
(E.
NY)
I. duPont
Wilmington,
de
Del)
for
veins
in gelatin
dishes
containing (at
anti-human
isolated
does
for
not
by
Laboratories,
medium
56 ‘C,
vWF
were
(Difco
199
supple-
30 minutes)
react
with
fetal fetal
calf
was and
prepared
for transfusion from
three
from
single
normal blood
donors
units in
was
different
in acid-citrate-dextrose. made
from
anticoagulated made
from
normal
obtained
and
from
anticoagulated
from pooled
donated
single
donors,
Cryosupennatant units
of blood
by
acid-citrate-dextrose. units and for
the PPP
of fresh
anticoagu-
in vitro
citnated
PPP
prepared
from
studies of four fresh
in hepanin.
RESULTS Unusually
the
before
gel slab were
antibodies V. Gels
agarose
in two
glycenol/l0%
8.6.
dimension
gel lanes
in 2%
Dept.
8.0,
‘25l-anti-human
(Kodak,
umbilical
grown
heat-inactivated
plasma
collected
human
to
buffer first
human
was
pH
adjusted
running
pH
HGT
buffer
acetate,
were
first-dimensional
in the
SeaKem The
sodium
electrophoresed
anti-human at 10 mA
0.5%
barbital-acetate
wells
V. The
using
by a modifica-
dimensions.
mol/L
plasma
with
al7
both
barbital/0.080
normal antigen
et for
done
(Cohn
Louis),
for 48 hours
film
Products
and
individuals
different was
20%
Fresh-frozen
U/dL
albumin St
vWF).
normal
rabbit
from
(Rabbit
vWF
PPP
dried
of deionized bonate/0.I50
rabbit then
at I 00
isopnopanol.
serum
intensifying
Photo
35-mm
serum.9
Accu-
Plus
Inc.
cells
with
serum
rabbit
Calif).
Antibodies,
Westbuny,
pooled
Detroit)-coated
backing
immunoradiometnic
vWF
immunoelectrophonesis
electrophoresis. from
GelBond
La iolla,
been
calf
were
XAR-Omat
treatment
were
SeaKem
and
buffer.
hours
sodium
with
NaCI, gels
running four
Co,
pH 20 L
hours at -70#{176}C.
collagenase
antigen.
on GelBond
0.048
0.5% Me)
Corp.
Corp.
Normal
on
Rockland,
by solid-phase
Scientific
plasma
using
Corp,
has
normal
Aganose
anti-human
vWF.
vWF
FMC
quantified
Two-dimensional tion
(HGT)
platelet-poor
samples
and
(Calbiochem-Behring
and
‘25l-anti-human
blood
in patient
Co.
23 ‘C
SDS,
changes
in borate/NaCI,
The
with
two
mol/L
Chemical
at
mol/L
Lightning and
in
in 0.02 and
acid/lO%
bovine
Sigma
18 hours
hour.
‘/2
Endothelial
pooled
electroimmunoassay5
Div.
vWF
normal
venous
levels
temperature
anti-human
and
citrated
antigen Laurell
gelling
(Marine
patient
free,
of 0.15
Chronex
24 to48
METHODS
AND
for
hour
in 0.036
(1 x l0 cpm/mL)
Nemours MATERIALS
one
of
at 50 V and
I mg/mL
acid
three
after,
for
a
hour
and
plasma
I 5 minutes,
by 10% acetic
30 minutes
containing
vWF
samples
layer
V. fatty
(vWF
immediately
under
in the gels
pooled
urea/2%
gel
washed
incubated
mol/L
the
for
and
EDTA/8
for
fixed
normal
of
at 60 ‘C
was
mol/L
EDTA/0.l%
and
by dilution
incubated
V, protein
I .5 x
0.04
mmol/L
the
by electnoimmunoassay
15 U/dL
wells
1% of
gel slabs,
buffer,
in patient
quantified
for one
sulfate ‘251-antiusing
(1%)
running
were to
water,
the levels
mmol/L
dodecyl
in a modification
acetate/2
antigen to
electrophoresis
normal sample
rabbit
autonadiognaphy Aganose
in
sodium
vWF
Following
and
of the origin
with
system
Zimmerman.S
previously
samples
and
reproducible.
by sodium
by
formed
TRIS-HCI/2 The
patient
of patient
overlaid
analyzed
adjusted
the
same
the expeni-
of
always
matching
separated
buffer
were
The
plasma
fraction
FFP
and
mol/L
pH
8.0.
were
and
mm,
Under
gels
exact
in
photographed.
a continuous
when
normal
Venous
and
IgG,
and
for the
positions were
electrophonesis,
of Ruggeni
x
mol/L
large
and
acid,
samples
chamber.
individual
multimers gel
aganose
The
A in Moake
together, vWF
plasma
relative
after
(two
Feinbiochemiacetic
concurrently
patterns
Blue-stained
R, Serva
normal
the
superimposed
taped
Plasma
SDS,
3
patient
were
Coomassie
with
acid.
performed
vWF
water
stained
Blau
electrophonesis
plasma
Coomassie
wells,
80
U/dL).
Patient
Dried
and
always
in deionized
‘C,
methanol/lO% acetic
described,
TRIS-HC1/0.02
unit
to be taken
of the
normal
hours
0.1%
45%
patient
in the same
control
method
since
deficiency”
relapses.
308,000/.tL)
in
of TTP
a single
samples
completion
(platelets
episodes
T1’P
of
conditions
plasma
G plus in
was
mental
four
methanol/7%
(SDS)-agarose
“thrombopoitin receives
against
and
remission
periodic
to have
as prophylaxis
occasions,
had
believed
periods
for
at 37 to 45
Blau FRG)
dimension
time
vWF
(0.1%
in 25%
second
122
FFP
plasma.
Blue
Electnophonesis
C
(platelet
NaCI,
in an oven
Heidelberg,
destained
patient
levels,
transfusion
Center.
informed
and
remission
when
of
to prevent
2
infancy. and
and
Medical
transfusion weeks
in clinical
plasma
(-.400
regular
of Miami
required to four
5 in Bynnes2
was
transfused
fraction
University the
patient
in hen
was
has
three
as patient
the
cryosupernatant done
woman every
When
190,000
multimers 235
26-year-old
or cryosupennatant
Moake
in
Bnillant ca,
mol/L
dried
for 18
plasma longer tive
of two detected, amounts,
large
in citrated
blood obtained of either normal or FFP
vWF
multimers
in the
chronic relapsing TTP or were considerably
in patients
PPP
30 to 90 minutes cryosupennatant I and
2 (Fig
samples
remission
patients reduced
were no in rela-
prepared
from
after the in patient
transfusion 1 (Fig 1),
2). These
changes
in
From bloodjournal.hematologylibrary.org by guest on July 10, 2011. For personal use only.
MOAKE
1234
NP
EC
Pre
t5i
ET
AL
24h
Pre
__ ____
(.
...
.
+
n i
1.5 h Fig 1 . Following the transfusion of normal cryosupernatant (-400 mi), venous blood samples were obtained from patient 1 at 1 .5, 12. and 24 hours (1 .5h. 12h. and 24h). Analysis of patient plasma samples was by two-dimensional immunoelectrophoresis in 0.5% agarose (A). and by SDS-agarose (1 %) electrophoresis and autoradiography (B). (A) n. normal platelet-poor pooled plasma; p. patient 1 plasma. (B) NP. normal pooled plasma; EC. normal
.,.rt
12h
es
A
..
i-n 24h
circulating transfusion
vWF forms were of 2 units of FFP
cryosupernatant (on two 1 . Similar changes were the transfusion hours later the
W.
of I unit unusually
observed (on one
B
4.
following occasion)
the or of
of three occasions) in patient also seen immediately after of FFP in patient 2. Ten to 24 large vWF patterns were the
same as the pretransfusion patterns in patient I , and remained unchanged thereafter as long as the patient was in remission. Platelet counts did not decrease, plasma vWF antigen levels did not change detectably, and the clinical status of patients 1 and 2 was not altered following the transfusion of cryosupennatant or FFP. These results indicate that the disappearance of the unusually large vWF multimers was not the result of their attaching to platelets and Unusually
causing agglutination large vWF multimens
the plasma of plasma exchange during
a period
patient (Fig when
in vivo. not
were
present
3 immediately following 3). This procedure was her
platelet
count
was
in 3-L done
progres-
sively normal.
endothelial
cell
increasing and Disappearance
culture
her
medium.
clincal status of the unusually
had become large vWF
forms in patient 3 could have been the result both their physical removal and their conversion in vivo somewhat smaller multimens (as described below). Unusually large vWF multimers did in vitro from remission plasma samples when they were incubated with normal tant or normal obtained when were incubated vWF multimens
of to
not disappear of patient cryosuperna-
plasma (Fig 4). Similar results were remission plasma samples of patient 3 with normal plasma. Unusually large also did not disappear in vitro from the
medium removed from cultured human cells when this medium was incubated phase with normal cryosupernatant (Fig vitro results were not affected by the
endothelial in the fluid 5). These in presence or
absence ofcalcium (12.5 mmol/L), additional hepanin (14.3 U/mL) or proteolytic inhibitors (2 U/mL hirudin
+
100
fluorophosphate
U/mL
aprotinin (DFP)
+ +
2 mmol/L
1 zmol/L
diisopropyl-
p-amidinophenyl
Pre
+
Fig patient normal ma.
I
2. Venous blood samples were obtained from 2 before (Pre) and after the transfusion of 1 unit of FFP. n. normal pooled plasma; p. patient 2 plas-
O.5h
From bloodjournal.hematologylibrary.org by guest on July 10, 2011. For personal use only.
EFFECTS
OF
CRYOSUPERNATANT
ON
vWF
IN
UP
1235
‘e.,
-
-
.
-
-;
Pre
-.
r,’
+
___1i
Fig
3. Venous blood samples were obtained from 3 before (Pre) and immediately after a 3-i plasma exchange (Post). n. normal pooled plasma; p. patient 3
patient
Post
plasma.
80% I-TIP NP
0
20% 8h
20%
%
+ NP24h
EC
0
r
CS-
-TTP
24
8h
CS
80%
20% ‘
0
NP
8.i
Fig
4. Patient remission plasma (TTP) was with normal platelet-poor plasma (NP) or with normal cryosupernatant (CS) in the ratios indicated. The mixtures were either sampled immediately (0 time) or were incubated at 37 ‘C for eight and 24 hours (8h and 24h) before sampling. EC. normal human endothelial cell culture mixed
:
4.
medium.
!ctCs NP
Samples of normal human cell culture medium (EC) were removed and mixed with equal volumes of normal human cryosupernatant. The mixtures were either sampled immediately (0 time) or incubated at 37 ‘C for one hour (lh). Some of the mixtures contained calcium (Ca) or calcium plus additional heparin (Ca + Hep). as indicated. and all in this experiment contained hirudin + aprotinin + DFP + p-APMSF). NP. normal pooled plasma; and CS. normal cryosupernatant.
I_____ 10
Ca ii1IO
r
Hsp;;I $1I
W1NPIO
c 11,110
Hsp.Cal Th”O
Ih1NP
CS
Fig 5. endothelial
II
up
#{149}
+
From bloodjournal.hematologylibrary.org by guest on July 10, 2011. For personal use only.
1236
MOAKE
methanesulfonyl ing the time
fluoride of incubation
(p-APMSF), to eight hours.
FFP TTP were
30
to 90
minutes
after
or cryosupernatant patients in remission, present in relatively
disappeared, multimers patient, venous
into two unusually reduced
exchange
was in partial samples were
transfusions
with
on different
The
during patient
relapsing possible
that the contains conversion,
TTP remission explanation for
large
to the in vivo
cryosupernatant an activity that of unusually
plasma. these observations
fraction converts, large
corollary of this explanation of unusually large vWF circulation of the TTP cryosupernatant must
of normal plasma or potentiates the vWF multimers to This are A
would be that the turnover multimers already in the
patient at the be rapid.
time
of plasma
in the
treatment
pernatant
on the
forms indicates transfused was
of relapses
metabolism
in chronic
or
of unusually
that the short-lived
short-lived effect yet uncharactenized
is
smaller forms only on endothelial cell surfaces. may occur as the unusually large multimers secreted from endothelial cells into the circulation.
multimers from TTP patient are capable of distinguishing
that
may TTP
because they contain an activity that promotes the breakdown or removal of unusually large vWF multimers before they can attach to agglutinating platelets. The rapid dissipation of the effect of FFP or cryosu-
studies, the conversion of unusually large vWF forms did not occur in the fluid phase when normal cryosupernatant was mixed with ( 1 ) the medium removed previously from endothelial cells in culture or (2) with chronic One
vWF
these two possibilities are not yet available. FFP and its cryosupernatant fraction
be useful
the next ten to 24 who was studied
In contrast
large Techniques
Normal
when after
unusually
unusually plasma. between
large vWF of a third
at the time, immediately
FFP.
occasions.
of
chronic relapsing large vWF forms amounts, or had
remission obtained
multimers reappeared in the plasma of the
serially
transfusion
from their plasma. Unusually were also absent from the plasma
who blood
vWF hours
the
AL
A second possible explanation for our results, which cannot be excluded, is that the transfusion of FFP or cryosupernatant somehow accelerates the removal of
or by extend-
DISCUSSION
Within
ET
may
active in the
be an substance
large
vWF
substance that patient studied.
intrinsic in FFP
was This
property of the and its cryosu-
pernatant fraction. Alternatively, an autoantibody in the blood of the chronic relapsing TTP patient may have inactivated within a few hours the effective substance in transfused normal FFP/cryosupernatant, or interfered with its attachment to endothelial cell surfaces. Although this is speculation, it is compatible with clinical observations that normal FFP often must be infused
frequently
for days relapsing
(with
or without
plasmapheresis)
relapses It is also
in some compatible
in order to control TTP patients.2’4
reports that (glucorticoids,
agents with immunosuppressive vincnistine,’#{176}
beneficial effects with the chronic
in the relapsing
)
treatment of form of TTP.
chronic with
properties may have
some
patients
REFERENCES 1. Moake NM,
iL,
Azacan
plasma
factor
relapsing
VIII:
ii:
Harkness
purpura.
5.
DR.
Bynnes
Med ii,
punpura Miuna
Yamagami
Weinstein Deykin
Mi, D:
factor
multimers
punpuna.
infusion
M,
ii,
Assoc
Lian
EngI
Koizumi
E C-Y,
M: Treatment N EngI K, Nakamuna N,
Kinoshita
of
Hemostas
i
WD,
of thrombotic J Med
297:1386,
K, Ohno
9.
5, Abildgaand
Blood
thrombocy-
CF:
T, Investi-
in a young boy who responds
62(5):246a,
1983
HR.
Coller
of factor SL:
Effect
synthesis
in endothelial
umbilical
cord Gutterman
247:1433, 11.
Res
I 8:787,
Stevenson
purpura
TD:
with
multimenic
Blood
thnombin and
human defects
pig
57:1 140, on
aorta
com1981
prostacyclin and
human
1980 Treatment
vincnistine.
of i
Am
thrombotic Med
Assoc
Weinstein
Mi,
1982
Moake
Colannino
iL,
NM,
thrombocytopenic Hematol
Thnomb
calf
the
1975
complex
and
from
of
Qualitative
56:814,
factor.
of bradykinin
thrombotic
1982
Studies III.
The
Willebrand
LA,
thnombocytopenic
Invest TS:
cells
vein.
Y:
protein:
J Clin
Zimmerman
recurring
I 3:259,
Sultan
factor
VIll/von
with
i Hematol
BS,
disease.
ZM,
Hong
of a patient Am
Willebnand
Willebrand’s Ruggeni
10.
1977
T, Tatsunami
infusions.
plasma
Hensley
Studies purpura.
VIlI/von
position
1981
repeatedly
normal
1981
CS:
Gralnick
factor
8.
thnombocytopenic
plasma components and hemolytic anemia
to
Kitchens
thnombocytopenic 7.
Med
thrombotic
8:9,
Williams
in thrombotic
246:1931,
plasma.
treatment
Thromb
transfusion
Khunana with
in the
Semin
Bynnes
M, Taniguchi
1)
lange
in chronic
N
gation of the efficacy of several with chronic thrombocytopenia (suppl
6.
Colannino
Unusually
in von Plasma
of platelet i Am
topenic
Willebrand
purpura.
Hazard 4.
von
iH, SI,
1982
Byrnes
3.
Troll Hong
thrombocytopenic
thrombocytopenic GT:
CK, RH,
thrombotic
307:1432, 2.
Rudy
i, Seden
(in press)
Rudy Hong
CK, SL:
punpura
Troll
Therapy with
iH,
Schafer
ofchnonic prednisone
Al, relapsing
and
azathiopnine.
thrombotic Am
J