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The
Activation
of the
in Plasma:
The
Contact
Effect
By K.A.
The
endogenous.
activation
gated
groups
either
coagulant
mas.
The
involves
activity
(VlIc)
The
can
be
contact
The
size
of the
large
and
ship
between
factor
VII
by
the
of
these
activity
(VIIc),
the incidence
5 years. The
between
of ischemic
same study
VIIc
and
the
the
both
at entrance
demon-
VII
to the
coagu-
study,
and
cholesterol
citrated
plasma
is incubated
in plastic
the
For
initiating
are
obesity,4
disease
as well
all of these
concentrations
stand
we
diabetes,5
all associated
the
use
as with
relation
have
high
levels
between
previously7
and
of oral
an increased
risk
examined
It is also
its
bar
artery
and
clear
to
the
flux
In
late
the
plasmas
in the
presence
as kaolin
complex,’6
XII
acts
as
and
by kallikrein.
activates
pathway.2’
cofactor
in
or
or
that is enzymaactivating
role
of prekallikrein’8”9
of factor
kininogen
plasma,
consists
the
surface
catalytic
the
the
in the
together
within
the
results
VIIc
in
proteolysis
XI2#{176}
and this (XIa)
intrinsic
coagulation
factor
weight
that
factor
hypercholesterolemia
relation
in
surface
the
HFa
factor
High
all
can
IX, thus
molecu-
these
reac-
lions.22’23
with increased
plasma
triglycerides.
To under-
hyperlipidemia
induced
contraceptives6
of coronary
of VIIc.
conditions
are associated
of cholesterol
and
the
rabbit
and
with
limited
activation
activate
increasing
tubes
vesicles.’7
HFa (the two-chain
form
active)
appears
to play the primary
cance
age,3
than
of certain
negatively
charged
surfaces
such
glass,’4
dextran
sulfate,’5
ellagic
acid-metal
reciprocal
instance,
induces
activation
women.
Inc.
through
disease.
that
women
charge
the
of nega-
of potential
& Stratton.
epidemiologic
observamay be of causal
signifi-
heart
of negative
carrying
density
from
concentration
by Grune
concentrations
in plasma.
Further
tions also suggest
that high VIIc
in ischemic
density
These
subsequent
plasmas
a higher
with
acid.
fatty
surface
the
pres-
increase
particles
contact
and
Vllc
of late
in the
to
added
a 1989
the
the
the
XIla
relative
tubes
at a sufficient
Moreover,
have
nonpregnant
sulfatide
tically
and
VII.
a higher
heart disease
within
the subsequent
has also shown a positive
correlation
triglyceride
provide
of factor
a satu-
incubation
Vllc
lipoprotein
acid
and
At
observed
in plastic
the
pregnancy
tubes.
liposo-
has
factor
could
factor
large
late
The
caused
of
fatty
the
of plasmas.
plasma
that
free
in the
in plastic
charge
sets
concentration
generation
and
similar
stearate
suggest
from
relation-
on the
Study”2
between
of
very
The
charge
sodium
pregnancy
range
was
incubated
or control
of
Vesicles
Esnouf
of negative
charge
the
Vllc
in both
appropriate
of
negative
(chylomicrons.
ence
tive
and
liposomal
is within
density
results
XII
activation
of
and
increasing
plas-
factor
density
Heart
measured
VII
and M.P.
similar
Surfaces
Liposomal
plasmas
pregnancy
hours
of subjects
lipoproteins).
Park
was
conditions
from
multilamellar
of negative
association
24
treated
for
rating
the
factor
these
groups
and
from
the
in the
particles
density
a strong
pregnancy
plasmas
at 4#{176}C
for
vesicles
NORTHWICK
strated
control
derived
large
intermediate-density
HE
vesicles
the
and
appropriate
lipoprotein
the
mal
investi-
under
in both
Reeves,
induces
is rate-limiting
plasmas
B.E.A.
was
The
of enzymes
surface
in the
carrying
low
lant
of
Martin,
that
tubes
assayed
J.C.
by Physiologic
Charged
factors
incubated
was
Negatively
surface
in late
age.
glass
supplemented
charge.
sizes
in
generation
VII
vesicles
T
or
activation
of factor
women
were
plastic
the
(Xlla).
from
of child-bearing
of subjects
in
Mitropoulos,
coagulation
taken
subjects
of Coagulation
of Large
charged
contact
in plasmas
control
two
negatively
of the
Phase
activation
formation
of a 52-Kd
of
factor
of an 80-Kd
heavy
by a disulfide
chain
bond.
and
The
XII
by
enzyme,
a 28-Kd
heavy
binding
domain,26
and the
domain.25
The heavy chain
light
chain
light
can
kallikrein24
HFa25
which
chain
held
contains
the
chain
contains
be further
split
coagulation
pathway.
In rabbits
fed a 1% cholesterol-supplemented
diet, the increase
in plasma
cholesterol
concentration
was associated
with an increase
in V11c7 and an increase
in
or 800-d,
each of which remains
disulfide
linked to the 28-Kd
light chain
of HFa.27
These
last fragments
(HF1 or f3XIIa)
the
the
of
is
have only residual
coagulant
activity,
contact
surface
binding
capacity.28
rate of thrombin
excess
cholesterol
associated
with
lomicrons,
very
generation
in vivo.8 The
in the hypercholesterolemic
the
large
intermediate-density
increase
from
particles
lipoprotein
lipoprotein
in VIIc
attributed
lipoprotein
low-density
in the
to the
(IDL)
reactivity
in the ratio
such
in chybomicrons
Late
pregnancy
has been
VII.’2
is also
attributed
the VLDL
associated
to
an
with
increased
of factor
and
1), 1989:
IDL
vert
fragment
factor
increased
and
finally
yields
V!!29’30 to aVIIa
VIIc
following
and
fragments
since they have lost the
However,
HF1 can con-
this can
the prolonged
3,000
be seen
in vitro
incubation
as an
of plasma
at low temperature.3’
be
arising
reactive,
plasma
caused
reactivity
pp 1525-1533
can
VII
more
increased
The plasma
proteins
factor
XII (Hageman
factor
XI, prekallikrein,
and high molecular
ogen constitute
the contact
activation
system
lation.’3
The contact
system
can be initiated
Blood, Vol 73, No 6 (May
the
The
rabbit
of the two-chain,
and
as chyand
fractions.
form of VII (aVila)
to the single-chain
form.9
Late pregnancy
is associated
with increased
centration
of triglycerides
and of cholesterol,
increase
part
rabbit
(VLDL)
hypercholesterolemic
increased
an increase
major
40-Kd
of either
the
to a
conby an
fractions.’#{176}
VIIc”
of
that
factor
factor
[HF]),
weight
kininof blood coaguin vitro when
From
wick Park
Biochemistry,
the MRC
Epidemiology
Hospital,
Harrow
The Radcliffe
and Medical
Care Unit.
and Nuffield
Department
Infirmary,
Oxford,
England.
North-
of Clinical
Submitted
March 15. 1988; accepted December 19. 1988.
Address reprint requests to K.A. Mitropoulos.
PhD. MRC Epidemiology and Medical
Care Unit, Northwick
Park Hospital.
Watford Rd. Harrow, Middlesex
HA! 3UJ, UK.
The publication
costs ofthis article were defrayed in part by page
charge payment.
This article must therefore
be hereby marked
“advertisement”
in accordance
with 18 U.S.C. section
1 734 solely to
indicate this fact.
©
I 989 by Grune
& Stratton,
Inc.
0006-4971/89/7306-0022$3.OO/O
1525
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MITROPOULOS
1526
Although
contact
blood
vitro intrinsic
activation
lished,
during
since
or high
potent
in contact
or they
concentrations
weight
unclear.
that
Some
factor
activity
are
activation
studies
studies
have
greatly
enhanced
XII
surface,
factor
that in the presence
suggested
that
its substrates,
the
present
the physiologic
surface
that
incubation
identical
incubations.
which
the
activation
vesicles
effect
these
negatively
of stearate
incubation
autoactivation
kininogen
prekallikrein.39#{176}
to identify
the
the contact
either
Moreover,
incubation
surface
are supplemented
size and negative
in supplementing
mixtures
has been
with
charge.
the negative
investigated.
AND
(PC)
from
an XM-lOO
A membrane
pressure
of
various
plasma
lipoproteins.
Late
pregnancy
from
in
for the
in
METHODS
frozen egg yolk (type XIII-E),
phosphatidylserine
(PS) from bovine brain, cholesterol
(CH), and
sodium
stearate
were from Sigma Chemical
Co (Poole, Dorset, UK).
No impurities
could be detected
in these lipids by thin layer
chromatography
using standard
solvent systems.
Dihexadecylphosphate (DHP)
was from Aldrich (Gillingham,
Dorset,
UK). Rabbit
brain thromboplastin
was obtained
from Diagen
(Thame,
Oxon,
UK).
Blood
samples.
A lO-mL
sample of blood was taken between
10:00 and 1 1:00 AM from pregnant
volunteers
attending
Northwick
Park Hospital antenatal
clinic. These women were in the last 6 weeks
of normal gestation.
The same volume of blood was taken at the
same time of day from control subjects
who were healthy volunteers
of child-bearing
age not on oral contraceptives.
The blood was taken
by a vacutainer
system into 10% (vol/vol)
of 3.8% trisodium
citrate.
The citrated
blood was centrifuged
at 3,000 g for I 5 minutes
at room
temperature.
The plasma was removed
with a plastic Pasteur pipette
and used without delay.
Preparation
ofliposomes.
PC:CH,
PC:DHP:CH,
or PC:PS:CH
liposomes
were prepared
either by using the procedure
described
by
Batzri
and Korn4’ for preparation
of single-bilayer
vesicles
of
relatively
narrow
range of small size, or by the procedure
of
Bangham
et a142 for preparation
of multilamellar
vesicles of relatively wide range of large size. For the single-bilayer
small vesicles,
the dilute suspension
in 0. 15 mol/L
NaCI was concentrated
and
washed free of ethanol
by ultrafiltration
on an Amicon
(Woking,
Phosphatidylcholine
N2
indicated.
plasma
was
and
Sigma
Preparation
from
MATERIALS
under
charge
or plastic
mixtures,
is rate-limiting
stirring
liposomal
Also, the
of
coagulation
in glass
rapid
used to isolate the various lipoprotein
fractions.
Chylomicrons were collected from the surface layer after centrifugation
at
22,000
g for 30 minutes.
This fraction was recentrifuged
at 205,000
g for 24 hours to obtain
the chylomicron
fraction
in the floating
layer
free
of the contaminating
lipoproteins
(d > 1.006).
VLDL
(d < 1.006),
IDL (1.006 < d < 1.019),
LDL (1.019 < d < 1.063)
and HDL (1.063 < d < 1.21) fractions
were isolated
from the
plasma by sequential
preparative
ultracentrifugation45
in a Beckman
L8-70M
ultracentrifuge
using a Ti70.l
rotor (Beckman
Instruments, High Wycombe,
Bucks, UK). Portions ofthe various lipoprotein fractions
and the various liposomal
vesicles were assayed
for
total cholesterol by an enzymic method with reagents
and standards
nature
the reactivity
of factor
pregnancy,
following
the
cold
with
Isolation
with the reactivity
offactor
VII in
women
of child-bearing
age after
charged
of factor
VII,
of the appropriate
other
of a negative
weight
activates
in the
tubes, and compared
these
plasmas
from nonpregnant
presence
undergoes
factors.
For this, we have compared
VII in plasmas
from women
in late
prolonged
proteolytic
In contrast,
using
tions
is
zymogens
reciprocal
molecular
factor
XI and
paper
we attempt
surface,
a weak
proteolytic
surface.
The reaction
the
device
and
in
activation
the
ultrafiltration
acts
to be
not present
contact
contact
in the
XII
of high
commonly
membranes
at low
charge
(ie, sulfa-
prekallikrein.38
that
estab-
known
either
of
by
and
suggested
not
is a physiologic
mechanism
of factor
have
charged
In
are
XII
and
prekallikrein
express
in the presence
of a suitable
rates
upon
do
in vitro
there
the
to be
UK)
Surrey,
(103 KPa). The average
diameter
of vesicles prepared
by this technique
is 25 nm.43 For the
preparation
of large size multilamellar
liposomes,
the lipid mixture,
dissolved
in chloroform,
was deposited
on the sides of a glass conical
tube by evaporating
the solvent under a stream of N2 at 37#{176}C.
The
dried lipid was then hydrated
with
50 mmol/L-imidazole/HC1
containing
100 mmol/L
NaCI buffer, pH 7.4 (glyoxaline
buffer)
and the mixture
was dispersed
by vigorous
shaking
with a vortex
mixer for 20 seconds
and allowed
to stand for 30 seconds.
This
process was repeated
ten times. The preparation
was then placed on
a reciprocal
shaker
(two cycles/second,
5 cm amplitude),
for 30
minutes at 37#{176}C.
The lipid concentration
was 60 mol/mL
of buffer
and this was diluted appropriately
on addition
to plasma.
The large
multilamellar
vesicles
had an average
diameter
of 1,320 nm as
determined
by negative
stain and I ,610 nm as determined
by
freeze-fracture
techniques.”
All lipid ratios or percentages
in the
liposomes
are expressed
on a molar basis. The sodium stearate
(1
mmol/L)
was suspended
with albumin
(60 mol/L)
in distilled
H20
and the suspension
was added to the plasma
in the final concentra-
prekallikrein,33
of the surfaces
are present
in mammalian
or low density
of negative
and
for the in
of contact
yet
XII,32
kininogen’
Most
activation
Assuming
identity
has
in factor
disorders.
blood
tides).37
in vivo
deficient
molecular
bleeding
is a prerequisite
the significance
coagulation
persons
exhibit
its
activation
coagulation,
ET AL
al”
Boehringer
(Mannheim,
of proteins.
Sweet
freshly
picked
sweet
The purified
inhibitor
FRG),
corn
respectively.
inhibitor
corn cobs by the
was a single-chain
was
method
protein
prepared
of Mahoney
et
with a molecu-
lar weight
(mob wt) of 12,000 on sodium dodecyl sulfate (SDS) gel
Human
factor XII was isolated from fresh frozen
human
plasma.47
The single-chain
factor XII was converted to HF,
by digestion
at 37#{176}C
with trypsin
for I 5 minutes at an enzymesubstrate
ratio
of 1:100 (mol/mol),
in 50 mmol/L
Tris/HCI
buffer,
electrophoresis.
pH
8.0, containing
75 mmol/L
NaCI.
The
reaction
was terminated
by the addition
of a twofold
excess of soybean
trypsin
inhibitor
and
the HF, was isolated by chromatography
on DEAE-Sephacel.
The
purified protein moved as a single band on SDS gel electrophoresis
(mol wt, 30,000).
Human
Cl inhibitor
(C1INH)
was prepared
as
previously
described”
except
that
DEAE-Sepharose
was
used
instead
of DEAE-cellubose.
The purified protein moved as a major
band on SDS gel electrophoresis
(mol wt, 104,000)
with two minor
contaminants
(mol
wt, 70,000
and 30,000)
that
were the cleaved
inhibitor.
Assay
of VIIc.
Bovine
plasma
depleted
of the
vitamin
K-dependent
proteins
was prepared
by two successive
additions
of
barium
sulfate
powder
(50 mg/mL)
to fresh oxalated
plasma.
Factor
VII-deficient
II,
IX,
and
plasma
was
prepared
by the
addition
of human
X to the barium sulfate-absorbed
plasma.
Standard plasma
was a pool of normal ciliated
plasma diluted to a factor
VII potency identical
to that ofstandard
plasma from Immuno
AG.
(Vienna).
Duplicate
coagulation
assays were performed
in an H.
Amelung
KCIO Coagulometer
(American
Hospital Supply, Didcot,
Oxon,
UK) at 37#{176}C.
To 0.l-mL
of a dilution
of the plasma sample,
0.1 mL offactor
VIl-deficient
plasma and 0.1 mL ofa 1:32 dilution
of rabbit brain thromboplastin
were added and the reaction was then
factor
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
ACTIVATION
OF THE CONTACT
COAGULATION
1527
FACTORS
started by the addition
of 0.1 mL of 25 mmol/L
CaCl2. The mean
clotting time for the duplicate
assays of each dilution were obtained
and activity
in the test plasma
as a percent
of that in standard
plasma
was calculated
by means of a microcomputer
program.
The
addition
to
plasma
unilamellar
of
either
large
multilamellar
the
or
small
or of the stearate
suspension,
at the concentramixtures,
did not influence
the
liposomes
used in the cold activation
measurement
of factor VII activity.
Other assays.
CIINH
antigen was determined
by electroimmuno
assay#{176}using rabbit
anti-human
C1INH
(Dako Ltd. High
Wycombe,
Bucks). Factor XII coagulant
activity
was measured
as
tions
described
previously.5’
1 shows
in 50 plasma
VIIc
samples
from
late pregnancy
and in I 8 plasma
samples
from
women
of child-bearing
age. VIIc is significantly
the
women
in
nonpregnant
higher
in
fresh
plasmas
from
late pregnancy
as compared
values
in the plasmas
from the control
subjects.
those
VIIc
is increased
further
in late
pregnancy
with
plasmas
or in
the plasmas
from nonpregnant
control
subjects
by incubation
in glass tubes, at 4#{176}C,
for 24 hours
(Table
1). The extent
cold
activation
higher
of
than
that
plastic
tubes
control
possibility
factor
of
but
in the
increased
that
VII
due
were
or
between
bate
C1INH
activity
was
plasmas
(P
control
<
two
the
(Table
1).
in the extent
and
sub-
groups,
VIIc
from
in
in the
pregnant
(either
in
glass
of either
C 1 IN H
In late pregnancy
and the factor
XII
0.001 ) of the corresponding
subjects.
However,
in
plasmas
from
diluted
I :1 with
and
plastic)
C1INH)
or
of purified
were
control
incubated
incubation
when the
between
subjects.
either
buffer
plasmas
coagulant
values
experiments
The
The
was
VII
same
plasmas
VIIc
was
Table
1
.
Vllc
in Fresh
in Late
(P
presence
of 12.5
steps
involved
Nine
late
volume
(N-50)
control
subjects
-
from
Vllc is expressed
tubes.
significant
the
nmol/L
corn
sweet
XII),
in the
activation
was
The
progressively
The fact that
both in plastic
vate”
in
sam-
tubes
in the
concentrations
of
caused
decreased
by
(Fig 2).
plasmas
of factor
(enzymes
plasma
in glass
in VIIc
by the cold
increasing
from
late
pregnan-
charged
surface
factors
and generate
XIIa.
further,
To explore
same
late
in plastic
or in glass.
cold
can
be seen
glass,
the
plasma,
the
VIIc
plasmas
The VIIc
the
dilutions
corresponded
samples
VIIc
decreased
with
contact
hypothesis,
same
for
were
dilution
the
was
nondiluted
(Fig
cold
3). It
activated
cold
that
would suggest
rate-limiting.
vesicles
made
50
75
in
of the
activated
by a factor
the dilution.
This
surface
becomes
of
either
to the dilution
that
liposomal
that can
factor
dilutions
conditions
of plasma
actithat
activated
at each
value
in the
the
cold
observed
under
observed
various
were
corresponding
in the
whereas
commensurate
dilution
the
possibility
activated
that
tubes,
this
this
pregnancy
with
the
the late pregnancy
plasmas
“cold
and glass tubes (Table
1) suggests
these plasmas
contain
a negatively
activate
the contact
coagulation
the
the
1). To confirm
pregnancy
of increasing
increase
concentration
of the inhibitor
The contact
surface
in
cy.
late
incubated
presence
inhibitor.
observed
(Fig
of
as is the
from the conversion
generation
of XIIa
nine
were
differ-
presence
0.001),
<
VIIc
HF,
The
in the
(P
The
of
was
in
not
that on
To test
negatively
700
500
0
pregnancy
plas-
buffer
Control
from
Subjects
0lIll
In Glass
In Plastic
160 (37)
1,163 (729)
1,423
94-271
119-3,350
410-3,236
101 (22)
104 (18)
63-141
79-142
467
0
as percent
in
of mean
some oups
activity
were
incubated
for 24 hours
(276)
Fig
the range
in plastic
125
on VIle in cold activated
late
nine women
in late pregnancy
were
diluted
1 :1 with
buffer
and incubated
in the absence
and in
the presence
of various concentrations
of HF, for 24 hours at 4’C.
VIle was assayed
and
expressed
as percent
of the activity
in
incubations
conducted
in plastic tubes in the absence
of HF,. The
mean
values of the corresponding
nine incubations
conducted
in
plastic (0) and that for incubations
conducted
in glass with no HF1
(#{149})
are given and the vertical
lines indicate
the so.
pregnancy
(SD) in a standard
at 4#{176}C
either
100
HF, (nM)
180-1,112
was not normal,
25
(541)
of values is also given.
The plasmas
factor
as above,
and
absence
;
18)
plasma. Since the distribution
glass
125
and
the
mixture.
of HF,.
absence
between
and
I against
in the increase
Plasma
or Nonpregnant
Fresh
Late pregnancy
(N
is highly
0.001)
diluted
Cold Activated
NOTE.
the concentration
in the
the increase
in VHc arises
to aVIla
catalyzed
by the
pies,
in Fig
incubation
00
in both
of glyoxaline
and in Cold-Activated
Pregnancy
Plasma
Nonpregnant
in the
400
ofbiochemical
of VIIc during
cold activation.
mas were diluted
with an equal
Women
=
of HF,
is plotted
>-
plasma
similar
with
difference
that
VII
and
present
observed
125 nmol/L
were
XII-deficient
mixtures.
The sequence
in VIIc
plastic
in
plasmas
of HF,
increased
ence
Cl INH varied
(by the
77% to 160% of that in
or factor
in glass.
activity
plasmas
plasmas
involving
plasmas
from subjects
in late pregnancy
there
no difference
in the rate of cold activation
of factor
addition
treated
compared
of activation
control
in the concentration
1 72%
from
taken
pregnancy
XII was considered.
was 77% (P < 0.001)
control
the
did not increase
plasma
considerably
differences
to variations
factor
from
of
is considerably
nonpregnant
plasmas
at 4#{176}C
for 24 hours,
VIIc
The
plasmas
from
of the
plasmas,
women
pregnancy
of plasmas
Incubations
jects.
bate
the
in
in plastic
tubes,
at 4#{176}C,
for 24 hours
in the
in the absence
of human
HF,. VIIc was assayed
concentration
derived
RESULTS
Table
and incubated
presence
and
‘
1.
Effect
plasmas.
of
human
HF,
Plasmas
from
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1528
MITROPOULOS
150-
charged
and
dilutions
I
>-
ci:
neutral
the contact
increasing
concentrations
<25 nm)
or
prepared
large
from
were added
to the plasma
activating
surface.
When
phospholipids
to supplement
of small
unilamellar
multilamellar
were
size,
50-
0
concentration
was repeated
size,
there
>25
was
tration
>
of liposomes.
ment
with
nm) prepared
from
an increase
in VIIc
of
liposomes
(Fig
prepared
also
from
increase
VIIc
above
Small
the
experi-
vesicles
(average
(0.85:0.15:0.5)
PC:DHP:CH
that depended
on the
concen-
unilamellar
vesicles
(0.85:0.15:0.5)
PC:DHP:CH
the
when
charged
4).
value
nm)
in plastic
with equal volume
in VIIc was seen at
However,
negatively
size,
>25
incubated
tubes with late pregnancy
plasma,
diluted
ofbuffer,
at 4#{176}C
for 24 hours,
no increase
any
(average
(average
( 1 :0.5)
PC/CH
ET AL
observed
failed
in the
to
absence
of
liposomes.
0-
--
I
0
10
0.5
Sweet
corn
inhibitor
1 25
(tM)
Fig 2.
Effect of sweet
corn inhibitor
on Vllc in cold activated
late pregnancy
plasmas.
Plasmas
from nine women
in late pregnancy were diluted
1 :1 with buffer
and incubated
in the absence
and in the presence
of various
concentrations
of sweet
corn
inhibitor
for 24 hours at 4’C. VlIc was assayed
and expressed
as
percent
of the corresponding
activity
in the incubation
conducted
in glass tubes
in the absence
of the inhibitor.
The mean values of
the corresponding
nine incubations
conducted
in glass (#{149})
are
given and the vertical
lines represent
the SD.
These
results
late pregnancy
teins.
However,
the late
produce
pregnancy
an increase
instead
effect
of negative
pregnancy
charged
of negative
charge
plasma
of a vesicle
tubes
or buffer
vesicle
concentration
of large
ratio
of phospholipid
failed
separately
and
suspension
vesicles
composed
to cholesterol
the
incubated
in plastic
the
of a constant
(1 .0:0.5)
to
amounts
one tenth
of the PC,
the VIIc
was lower
than
that seen in the late
On
(diluted
increasing
1:1 with
the
had
buffer)
content
been
added.
incubated
of DHP
late
vol-
contained
increasing
DHP
effect
VII, the
an equal
concentration
activation
of
to
vesicles.
To investigate
activation
of factor
were diluted
with
suspension
The
techniques
were added
large
charge.
on the
samples
as before.
plasma
100
plasma
by floatation
in VIIc when they
of the negatively
The
ume
suggest
that the contact
surface
present
in
plasmas
is provided
chylomicrons,
VLDL, byandthe IDLplasma
isolated lipoprofrom
At
a DHP
after
cold
pregnancy
in glass
in the
same
molar
which
5).
(Fig
phospholipid
to
20%, the VIIc
in the diluted
increased
to greater
than twice the value seen
plasma
incubated
in glass. A further
increase
in the
ratio
smaller
>-
molar
increase
of DHP
to PC
was
accompanied
by
a
in VIIc.
100
>
>
0
>
I
CD
I
I
0
0
100
Cholesterol
Percent
200
300
with liposomal
400
vesicles
500
(jM)
dilution
Fig 3.
Changes
in Vllc with
dilutions
in cold activated
late
pregnancy
plasmas.
Plasmas
or diluted plasmas
were incubated
at
4’C for 24 hours either in plastic
(0) or in glass (#{149})
tubes. Activity
in the diluted
plasmas
is expressed
as percent
of the activity
observed
in the corresponding
undiluted
plasmas.
Each point gives
the mean value of at least 25 comparisons
and the vertical
lines
indicate
the SD.
Fig 4.
The relation
between
the concentration
of negatively
charged
liposomes
and Vllc in late pregnancy
plasmas
diluted
1:1
with buffer
and cold activated
in plastic
tubes.
Relative
activity
of
1 00 is one-half
of the Vllc that was found in undiluted
plasma cold
activated
in plastic in the absence
of liposomes.
Each point is the
mean value of nine comparisons
and the vertical
lines indicate
the
so. Large size multilamellar
vesicles
(#{149})
or small size unilammellar
vesicles
(0) contained
PC: DHP: CH (0.85:0.15:0.5).
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
ACTIVATION
OF THE
CONTACT
COAGULATION
1529
FACTORS
4
E
E
-
>3
--
,
C
p
-C
2
a
..D
I
I
I
0
10
20
30
40
a
0’
E
S
E
,0
2J)”
F
C-)
10
>
20
,
.
20
30
C-)
40
30
40
in liposomal
phospholipid
When
the above experiment
was repeated
diluted
plasmas
from nonpregnant
women,
relationship
between
VII activation
was
negative
observed
used
to determine
the
regression
However,
we
have
inserts.
==
individual
plasmas
correlations
(n
ment
and
36, n
in Fig 5 and
From
these
charge
for the late
are identical
as shown
in Figs
pregnancy
than
in the
plasmas
required
from
tion-dependent
stearate
this
of the
densities
of 12.4
and
>
experi-
0
in Fig
17.5,
density
(compare
a)
>(
a)
0
of late
a)
0
of negative
a)
activation
the
a)
0
respec-
plasmas.
These
from the means
half-maximal
tubes,
0
inserts
in VIIc,
from
follows
at 4#{176}C
for 24 hours
with equal
Methods)
in
0
of late
volume
of an albumin
results
in a concentra-
which
control
concentration-dependent
shown)
The relation
between
the density
of negative
charge
in
vesicles
and Vllc in plasmas
from nonpregnant
control
subjects
diluted
1 :1 with buffer and cold activated.
Eleven plasmas
were diluted with an equal volume
of buffer and cold-activated
in
plastic (0) or in glass () tubes in the absence
or in the presence
of
large size multilamellar
liposomes.
These were made of phospholipid:cholesterol
(1 .0:0.5)
at the constant
concentration
of cholesterol (1 mmol/L
in the incubation
mixture)
and with varying
molar
ratios
of phosphatidylcholine
to dihexadecylphosphate.
VlIc is
expressed
as percent
of activity
in the corresponding
incubations
conducted
in plastic
in the absence
of liposomal
vesicles.
Each
point is the mean value of 1 1 comparisons
and the vertical
lines
indicate
the so. Figure insert is the same plot except
that log Vllc
(mean)
is plotted.
The arrow shows the density
of negative
charge
for half-maximal
activation
of VII.
the
followed
subjects
increase
a semi-logarithmic
saturation
also
showed
in VIIc
relationship
(Fig
in which
incubated
in plastic
tration
of stearate
late
pregnancy
or control
plasmas
tubes,
the VIIc at the maximal
used (0.3 mmol/L)
was always
50
100
Stearate
a
7),
like
that seen in Figs 5 and 6 for the relation
between
VIIc and
the density
of negative
charge.
In a number
of experiments
(not
Fig 6.
liposomal
positive
of negative
activation
a lower
subjects
in plastic
7). Plasma
increase
phospholipid
>
increase
(Fig
of
for the experiment
to achieve
control
of the
values
results
half-maximal
at
plasmas,
diluted
of stearate
(see
suspension
kinetics
6. The
in each
significant
we calculate
occurs
Fig 5 and Fig 6).
The incubation
pregnancy
the
for the
activation
5 and
that
seen
used
highly
0.960
=
slope
pregnancy
and the control
to the values
determined
plasmas
charge
but
44, r
n
for halfmaximal
tively,
values
also
0.950
regressions
using similarly
a corresponding
30
i n liposomal
charge
and the extent
of factor
(Fig 6). Four mean
values
are
obtained
=
20
% of d i hexadecylphosphate
Fig 5.
The relation
between
the density
of negative
charge
in
liposomal
vesicles
and Vllc in late pregnancy
plasmas
diluted
1:1
with
buffer
and cold activated.
Nine plasmas
were
incubated
in
plastic (0) or in glass tubes (#{149})
in the absence
or in the presence
of
a fixed amount
(1 mmol/L
with respect
to cholesterol)
of large size
multilamellar
liposomes.
These were made of phospholipid:cholesterol (1 .0:0.5)
at constant
concentration
of cholesterol
and with
varying
molar
ratio
of phosphatidylcholine
to dihexadecylphosphate.
Vllc is expressed
as percent
activity
in the corresponding
incubation
conducted
in plastic
in the absence
of liposomal
vesides. Each point is the mean value of nine comparisons
and the
vertical
lines indicate
the so. Figure insert is the same plot except
that log Vllc (mean)
is plotted.
The arrow
shows
the density
of
negative
charge for half-maximal
activation
of VII.
6).
10
>
% of dihexadecyiphosphate
were
concenlower or
(,uM)
Fig 7.
Effect of stearate
on VIIc in cold activated
plasmas
from
women
in late pregnancy
and from nonpregnant
control
subjects.
The plasmas
were
diluted
with
an equal volume
of buffer
and
incubated
in plastic tubes for 24 hours at 4’C in the absence
and in
the presence
of various
concentrations
of stearate.
Relative
activity
of 1 00 is one half of the VIIc that was found
in the
undiluted
plasma
cold activated
in glass tubes
in the absence
of
stearate.
Each point is the mean value of 1 1 comparisons
with
plasmas
from nonpregnant
control
subjects
(0)
or nine comparisons with late pregnancy
plasma
(0). Vertical
lines indicate
the
SD.
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1530
equal
to the
VlIc
in parallel
tubes
in the absence
presence
of the optimal
incubations
of the fatty
concentration
conducted
tions
conducted
in glass,
in glass
acid.
However,
in
of large multilamellar
liposomes,
with an adequate
negative
VIIc always
exceeded
the value obtained
The
the
charge
density,
the
in similar
incuba-
in the absence
The
data
plasmas
subjects,
presented
in
from
women
a negatively
exogenous)
can
and
initiate
generate
conversion
this
of liposomes.
the
activated
demonstrate
pregnancy
surface
contact
XII,
which
coagula-
also
late
leads
to
surface
offactor
XII,
and
Late
form
in VIIc after cold activation
of factor
VII. The likelihood
of activated
factor
XII
for this conversion
XIIa
derived
from
Plasmas
show
from
from
after
the addition
of HF, to the
addition
of a specific
inhibitor
of
sweetcorn52
of factor
VII. A similar
Ratnoff
and Moneme.53
control
abolished
conclusion
subjects
the
has
incubated
the plasmas
finding
that
had little
greater
in the late
pregnancy
is
associated
the
fail
to
plasmas
taken
under
the same
pregnancy
plasmas
mainly
to an
in the
increase
than
in
on VIIc,
suggests
that
that
presence
when
late
pregnancy
of a constant
for both
kinds
of
plus exogenous)
is
VII (Figs 3-7). This
the results
of Fig 3
plasmas
exogenous
are
contact
incubated
surface
in
(incu-
bations
in glass), VIIc decreases
linearly
with the dilution
of
plasmas.
However,
since the contribution
of the endogenous
contact
surface
diminishes
sharply
with the dilution
of these
plasmas
(see incubations
in plastic),
the composite
effect of
the exogenous
tions in glass)
correspond
to
various
dilutions
bated
in glass,
(P > .01) than
plus the endogenous
contact
results
in rates of activation
the dilution
of plasma.
of plasma
from control
the VIIc
observed
was
would
have been expected
When
these
same
plasma
samples
presence
ofan additional
glass surface
was
significantly
beads.
amounts
similar
raised
(P
=
.01)
surface
of factor
In contrast,
when
subjects
were incuhigher
in all cases
from the dilution.
were
incubated
(glass beads)
by
(incubaVII that
the
presence
in the
the VIIc
of
the
The results
(Figs
5 and 6) showing
that at optimal
of contact
surface,
the relative
increase
in VIIc is
in both kinds of plasmas
are consistent
with the idea
that the in vitro rate of factor
amount
of contact
surface.
VII
activation
is limited
by the
to identify
that
promotes
clearly
possible
that
them,
one
may
be
VLDL,
of these
seen
for
of the negatively
in
in
the
IDL
due
lipoprotein
fractions.’#{176} It is
or a combination
the
in late
particles
charged
increase
triglycerides
of large
and
components,
responsible
contact
activating
surface
sizes of these lipoprotein
size
an
and
population
like chybomicrons,
presence
of
pregnancy.
encompasses
the
of
raised
The range
of
the average
multilamellar
vesicles
success-
endogenous
contact
but of an average
than
supplement
the
endogenous
also show
since neither
that
the
the vesicles
unilamellar
nor
that
of
IDL
failed
to
surface.
Our
be negatively
experiments
charged,
multilameblar
large
the
pholipid
were
capable
contact
surface.
isolated
by
The
floatation
vesicles
made
of
supplementing
finding
that
techniques
the
did
bow molecular
weight,
surface.
size less
of neutral
phos-
the
endogenous
barge
lipoproteins
not
supplement
endogenous
contact
surface
was surprising.
possible
that the isolation
procedure
resulted
the
However,
in the
negatively
charged
it is
loss of
compo-
nents,
a view supported
by our finding
that
stearic
acid
stimulates
cold activation.
It is also well recognized
that the
plasma-free
fatty acid levels in late pregnancy
are considerably above those in the plasma
It had previously
been shown
taken
from control
subjects.
This, taken with the
the modulation
of either
factor
XII or C1INH
or no effect
with
of cholesterol
relatively
by
in VIIc.
Moreover,
the increase
in VHc
plasma
the contact
surface
(endogenous
rate-limiting
for the activation
of factor
would
appear
to be inconsistent
with
showing
activation
reached
in plastic
show considerable
increase
cold activation
in glass tubes,
is considerably
cold
been
a significant
increase
in VIIc whereas
subjects
in late pregnancy
incubated
conditions
following
reprethat a
(HFa
or HF,)
is the agent
is supported
by the observa-
responsible
tion that
VIIc
increases
plasma.
Conversely,
the
can
been
is particularly
concentration
not
we
has
in plasma
plasma
glass
shown),
report
pregnancy.
contact
should
assume
that the increase
sents the rate ofcleavage
reactive
of this
VIIc
after
cold
time-dependent
conducted
either
in
(results
more
aim
of the
in
is linear
to the
nature
aVIIa.
This
is seen
as an increase
activation.
Since
the
within-24-hours
increase
in VIIc
in these
incubations
tubes
VII
in
control
plus
of blood
principal
fully used to supplement
the
Vesicles
of the same composition
or plastic
factor
that
or from
(endogenous
phase
factor
of single-chain
other
physical
particles,
report
in late
charged
the
the activation
DISCUSSION
tion
ET AL
MITROPOULOS
factor
XII
containing
surface.’7’55
can
be
of nonpregnant
women.54
that the activation
of isolated
achieved
vesicles,
Liposomal
in
the
±
0.5 nm made
phosphatidylethanolamine
of 100%
35
tion of factor
XII, whereas
100% phosphatidylserine,
sulfatide
are capable
of the same
size are not.55
present
system
significant
activation
multilameblar
(0.15:0.85:0.5)
tively
charged
of sulfatideactivation
radius
of
or 42% sulfatide-58%
of promoting
activa-
100% phosphatidylethanolamine,
and 100% phospatidylcholine
We
des
large
presence
which
provide
the contact
vesicles
of a hydrodynamic
vesicles
(results
not
vesicles
may
vesi-
have observed
in the
of VII in the presence
of
made
shown).
of
The
PS:PC:CH
of the nega-
size
be of importance
in providing
binding
sites for all three proteins
(factor
XII, prekallikrein,
and high molecular
weight
kininogen)
for a significant
rate
of factor
XII activation.
This requirement
may be satisfied
by the
large
lipoprotein
particles
with
the
tive charge
provided
by free fatty acids
with the blood. However,
in view of our
strate
directly
that
large
lipoprotein
for the
present
factor
XII-dependent
experiments
with large
vesicles
or stearate
complex
represents
Stearate
from
added
nonpregnant
suggest,
are
contact
to late
pregnancy
women
in incubations
responsible
that
plasmas
in the plasmas
from
women
from
in late
plasmas
the
above
or to plasmas
conducted
the two conditions.
pregnancy
VII, the
liposomal
surface.
in plastic
tubes produced
an increase
in VIIc.
However,
the
concentration-dependent
increase
in VIIc followed
kinetics
negacirculate
to demon-
of factor
charged
do not prove,
the endogenous
also
inability
particles
activation
negatively
but
appropriate
that
the
stearatedifferent
In the case
increase
of
in VIIc
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
ACTIVATION
OF THE
CONTACT
followed
saturation
was rate-limiting.
kinetics
By adding
acquire
a negative
coagulation
factors.
nonpregnant
stearic
stearic
non
acid.
In this
acid concentration
may
plasma
explain
shorten
interact
in the
subjects,
in the presence
why
case
the
certain
appears
highest
fatty
time58
fatty
acids.
For instance
in diabetes,’62
women
using
oral contraceptives,”
and
charge
particles
with the contact
plasmas
from
the
to
be
concentration
the relation
is semilogarithmic.
the clotting
negative
more
surface
of the
1531
FACTORS
as though
the
sodium
stearate,
charge
and
In contrast,
control
even
limiting
COAGULATION
between
This
acids
added
or shorten
of
VIIc
and
phenome-
rabbit.7’8
induced
provides
In this
increased
the
experimental
animal
concentration
increased
of barge
concentration
model
lipoprotein
the
is due
Similarly
increased
plasma
to
an
in humans,
VIIc#{176}are
concentration
increase
in
of the contact
the
ratio
conditions
that are
also associated
with
of barge
lipoprotein
of
there
inhibited
poorly
changes
reflected
by
the
strong
concentration
shown
in epidemiologic
dietary
association
and
and
therefore
VIIc
and
could
small
pathway
will be
This is consistent
between
triglycerides
studies
fat intake
of
III,67
the coagulation
changes
in VIIc.
of
concentration
in the
there
is also an increase
in
argument
that aVIIa
is only
of
explain
and
the
cholesterol
the relation
VIIc.
ACKNOWLEDGMENT
in
with an
in the
and
of
in
diet-
aVIIa:VII.7’9
particles
increase
antithrombin
positive
plasma
between
surface,
associated
an increase
is an
in the flux
in measurable
particles
hence raising
the flux in the intrinsic
pathway
of coagulation
and therby
causing
an elevation
in VIIc.7
This increase
VIIc
where
the large
lipoprotein
particles
VIIc.#{176}It is also relevant
to this
with
to citrated
the thrombus-
formation
time of blood in an in vitro system.59
The above sequence
of events
may explain
the increased
VIIc and increased
hypercoagulability
in the hypercholesteremic
demia,65
in obesity,63
in hypertrigbyceri-
free
We wish to thank Dr A. Burgess for the human factor XII, HF,,
the sweet corn inhibitor,
and the CIINH.
We thank H. Gordon for
making available
his patients,
Y. Stirling and Dr i. K. Cruickshank
for organizing
the reception
of the blood samples,
and T. Jones for
typing the manuscript.
We also thank Dr T. W. Meade for support
and encouragement
throughout
this work and H. Wilkes
for comments on statistical
treatment
of the results.
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1989 73: 1525-1533
The activation of the contact phase of coagulation by physiologic surfaces
in plasma: the effect of large negatively charged liposomal vesicles
KA Mitropoulos, JC Martin, BE Reeves and MP Esnouf
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