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Formation
of C8-CI-Inhibitor,
Plasmin-a2-Plasmin-Inhibitor
By Yanina
Stimulation
of
clinical
the
classical
are
activated
Using
platelets
complement.
as
for
plasma
nary
was
hours.
pathways
neutrophil
was
The
these
their
complexes
formation
are
cleared
by assaying
plasma
blood
of
blood
prolong
the
loss,’
and
cell activation
bleeding
time,
may
lead
circulation
qualitative
and quantitative
ing thrombocytopenia,’3
ergic6
platelet
and
A2,8
aggregate
and
depletion
formation,5
of
a-granule
granule
enzyme,
and
human
for
during
formed
have
neutrophils.
and C5a’7’8
krein,’’6
and
elastase,”
vasculature
that
are
enzymes
degranulation.
Under
bypass
aggregates
in
Three
factor
the
poly-
now
XIIa,’3
neutrophil
investigate
seen
the
Thrombosis
Sections,
SchoolofMedicine,
and
the
New
Division
Philadelphia;
ofthe
Submitted
complement,
the
Ben
Franklin
ing.
San
Broad
reprint
Center,
St,
The publication
payment.
charge
“advertisement”
indicate
© 1989
requests
Society
1986.
and
the
of Sur-
19. 1988.
Grants
No.
and a grant from
of Hematology
published
to Robert
PA
& Stratton,
Health
MD.
Sciences
article
must
with
Meet-
in abstract
Inc.
section
1734
that
with
of
the
pathways
but
of
probably
neutrophil
activa-
bypass.
Inc.
3400
solely
bypass,
pathways
are
to produce
activated
neutrophil
ago-
AND
METHODS
components.
purified
dodecyl
of 85 .tmol
was
insoluble
urokinase.
purified
as described.
wt)
CI, was a generous
prepared
factor
sulfate
(mol
weight
was
XII
(SDS)
88 and
by
85 kilodalton
by
Cl-inhibitor23
of
of
On
a nonne-
as a doublet
(Kd)
pNa
activation
gift
of purified
fragments.#{176}’’
gel it appears
of D-Pro-Phe-Arg
prepared
activation
with
of
a specific
hydrolyzed/mm/mg.
purified
plasminogen
and a2-plasmin-inhibitor24
by
were
Purified
antibodies.
IgG was purified
from monospecific
antisera raised in rabbits against Cl-inhibitor,
a2-plasmin-inhibitor,
and
normal
serum,
respectively.
F(ab’)2 fragments
were prepared
by
digestion
of rabbit anti-human
IgG as described.25
Clinical
cardiopulmonary
bypass.
In nine adults with normal
function
tests,
formation
samples
from
whom
of enzyme
obtained
written
inhibitor
before,
during,
informed
after
and
consent
was
was measured
complexes
in
open-heart
sur-
for congenital
(one
patient),
valvular
(four patients),
or
ischemic heart disease (four patients).
Blood samples (15 mL) were
drawn
from
a radial arterial
catheter:
(a) before
induction
of
anesthesia;
(b) after anesthesia,
before hepanin; (c) after heparin,
before
CCB; (d) five minutes
after start of CCB; (e) 45 minutes
after start of CCB; (f) just before CCB ended; (g) 60 minutes
after
CCB; and (h) 24 hours after CCB. Plasma was harvested
from blood
samples
of all patients
that had CCB with a bubble oxygenator,
centrifugal
pump,
and arterial
line filter
as previously
described.”
gery
Thrombosis
Ctr,
by
sodium
plasma
N
were defrayed
in part by page
therefore
be hereby marked
18 U.S.C.
evidence
corn-
activation.
or fibrinolytic
Kallikrein
Plasmin
liver
19140.
costs ofthis
This article
in accordance
W. Colman,
and
1 nmol/L
±
no
cardiopulmonary
plasma
Bing.
obtained,
University
0006-497l/89/7302-0013$3.00/0
468
5-9.
this fact.
by Grune
and
1986.
Temple
Philadelphia,
Center
Philadelphia.
and HL-36579
indicate
contact
& Stratton,
human
David
activity
Fund.
December
68:342a,
York;
Department
of Health
nmol/L.
2
was
be associated
clinical
contact,
prekallikrein’9
of Medicine,
September
Institute
HL-24365,
Partnership
Francisco,
Address
accepted
in part at the American
in Blood
Research
1988;
by National
HL-19055,
Presented
form
22,
in part.
Harrison
ofPennsylvania,
there
results
cardiopulmonary
Purified
University
Research
New
2
±
from
Clinical
cardiopulmonary
bypass
(CCB)
circuits
contained
a
centrifugal
pump (Biomedicus,
Eden Praire, MN), bubble oxygenaton (BOS-102;
Bentley Labs, Irvine, CA), aterial line filter (model
I 331) and cardiotomy
reservoirs
(Extracorporeal,
Valley
Forge,
PA). Simulated
extracorporeal
circulation
(SECC)
perfusion
circuits (surface
area of 0.9 m2) included
a spinal coil membrane
oxygenator
model
0800-2A
(surface
area of 0.8 m2) and a venous
reservoir
(model R-500-4),
and were obtained
from Sci-Med
Life
Systems,
Minneapolis.
Silicone
tubing
was obtained
from Dow
Chemical,
Midland,
MI.
Beef lung hepanin
was obtained
from
Upjohn,
Kalamazoo,
MI. Linbro flat-bottomed
96 well polystyrene
E.I.A. microtitration
plates were obtained
from Flow Laboratories,
Inc, Handen, CN. Urokinase
was obtained
from Abbott Diagnostics,
Dr
Hematology-
Department
Center,
Surgery,
University
January
Supported,
the
Temple
21
rose
a
from
plasmin-a2-plasmin-inhibitor
and
may
Over
rose
Chicago.
the classical
the Thrombosis
Medical
of Cardiothoracic
Hospital
and
Medicine,
Sections,
Hospital-Cornell
HL-l8828,
Center
of
Hematology-Oncology
York
gery,
Research
Department
These
during
circulation.
complexes
to
However.
or in vitro
by Grune
molecular
From
nmol/L
complexes
nmol/L.
fibrinolysis,
duced
Oncology
I
±
complement
e 1989
kalli-
aggregation
whether
extracorporeal
MATERIALS
hydrolases,9”#{176} the
the azurophilic
form
stimulate
2
formation.
Colman
nists.
by surface
activation
of plasma
been identified
as in vitro agonists
all
plex
during
a2-adren-
recirculation.’2
Coagulation
We
is
with
circuit.
of thromboxane
contents.3
specific
peptides
proteolytic
there
decreased
lysosomal
lactoferrin,”
pulmonary
we
abnormalities.2
secretion
neutrophils
release
granule
constituent,
conditions,
5
±
W.
Cl 8-C1 -inhibitor
-inhibitor
and plasma
protein
increase
postoperative
pulmonary
receptors,7
fibrinogen
of
in vivo
tion
has been associated
with major
alterations
of platelets,
includreduced
sensitivity
to aggregating
Extracorporeal
agents,3’4
to
simulated
hours.
Bypass
levels
URING
CARDIOPULMONARY
BYPASS
extensive
contact
between
blood anticoagulated
heparin
and synthetic
surfaces
of the extracorporeal
alterations
25
not
in vivo.
their
baseline
classical
within
D
Consequences
in
concentration
to baseline
in vitro
of two
either
cardiopulmo-
increased
reverted
Jr. and Robert
period
to
assays
increase
clinical
Edmunds,
kallikrein-C1
complexes
a modest
after
complexes
Since
“sandwich”
-inhibitor
Cardiopulmonary
during
a
agonists.
and
During
L. Henry
during
or fibrinolytic
of
there
completed.
of enzyme-inhibitor
measured
that
complex
occurs
whether
kallikrein-C1
each
C. Harpel,
investigated
sources
found
of
bypass
We
immunosorbent
we
levels
Peter
neutrophils
contact.
potential
Cl 8-C1 -and
respectively.
24
and
bypass.
enzyme-linked
specific
Complexes
T. Wachtfogel,
cardiopulmonary
Kallikrein-CI-Inhibitor,
to
Simulated
assembled
extracorporeal
from standard
Blood,
circulation.
Perfusion
silicone
rubber
components,
Vol 73,
No 2 (February),
circuits
were
polycarbonate
1989:
pp 468-471
From www.bloodjournal.org by guest on June 12, 2017. For personal use only.
ENZYME-INHIBITOR
COMPLEXES
connectors,
and
described.4
Blood
carbon
dioxide
tons were
hundred
coil
spiral
and
IN CARDIAC
membrane
oxygenators
gas compartments
for I 5 minutes
primed
by applying
milliliters
of blood
before
were
priming
a vacuum
were
(3.3
mg/mL
blood).
system
before
barely
occlusive
lengths
with
drawn
from
The
carbon
temperature
was
blood
the
samples
reservoir
by
of 2.4
times
Plasma
during
was
the donor
recirculation
as
described.’
described,
measuring
C1,-Cf-inhibitor,26
complex
were
values
indicate
differences
the mean
as
kallikrein-CI-inhibitor,27
between
(ANOVA)
groups.2’
was
When either
Cl-inhibitor
can
be detected
sonbent
assays.
Similarly,
with a2-plasmin-inhibitor.
cific
assays
occurs
to document
during
inhibitor
nmol/L
hours
plasmin
We used
forms
three
10
±
postbypass
(Fig
a stable
sensitive
were
after
nmol/L
by 60 minutes
24
postbypass
hours
were
after
45
postby(data
not
extracorporeal
complex
During
formed
rose
SECC,
significantly
from a baseline
of 2 ± 1 nmol/L
to 1 1 ± 2
the first 30 minutes,
with a steady
increase
to
by 120 minutes
(Fig 2). During
SECC,
levels
(P < .00001)
nmol/L
within
21 ± 2 nmol/L
of kallikrein-CT-inhibitor
cantly
(P < .02) from
first
circulation.
of C1,-CT-inhibitor
two minutes
to I 5
by
a2-plasmin-inhibitor
increased
from
complex
formed
increased
signifia baseline
of 2 ± 1 nmol/L
within
the
120
1 .9
of 2.4
with
(Fig
a steady
2).
rise to 25
Levels
of
±
plasmin-
.
complex
formed
were not significantly
I 1 nmol/L
before recirculation,
with
±
±
4 nmol/L,
±
minutes
0.7
nmol/L
by
120
minutes
(data
a
not
shown).
activation
of these
enzymes
is performed
Stimulation
neutrophils
occurs
interaction.
prevent
the
The
consequences
of
application
of prolonged
as a direct
result
in approximately
of platelets
and
of
the
blood-surface
this cellular
extracorporeal
activation
recircu-
2
C
Levels
of C 1,-CTfound
to be 12 ± 2 nmol/L
45 minutes
ofbypass,
24 ± 4
postbypass,
and
1). The
concentration
8
±
I nmol/L
by 24
of kallikrein-
, Fl
I
bypass
annually.
complex
and spe-
bypass.
1 nmol/L
by 60 minutes
immuno-
circulation.
formed
complex
prebypass,
the enzyme
reacts
complex
that
enzyme-linked
cardiopulmonary
1.05
±
2 nmol/L
by
Cardiopulmonary
200,000
Americans
antibody
whether
extracorporeal
Clinical
0.5
±
postby-
DISCUSSION
kallikrein
or CI, is formed,
to form an enzyme-inhibitor
by double
by 24 hours
complexes
7.39
±
8 ± 2
by 60
In all cases
RESULTS
with
2.2
1 1 .4
the SEM.
±
2 nmol/L
±
prebypass,
5 nmol/L
shown).
maximum
and plasmin-a2-plasmin-inhibitor25
complexes.
Statistical
analysis.
An analysis
of variance
used to test for significant
and
pass,
7
prebypass,
nmol/L
of bypass,
5 nmol/L
forma-
performed
1.8
±
and
±
1). Plasmin-a2-plasmin-inhibitor
Simulated
ventilated
from
postbypass,
(Fig
levels
various
a rate
bath.
directly
9.5
shimmed,
at 37#{176}C
by immersing
water
pass
minutes
from the
for
at
Assays for measuring
plasma
enzyme-inhibitor
tion.
Enzyme-linked
immunosorbent
assays
±
reservoir
were
mixture
either
at various
directly into circuit
blood) and glucose
oxygenators
maintained
drawn
(who
I .0 L/min
bag in a constant-temperature
from
donors
the
Cl-inhibitor
complex
was 8 ± 2 nmol/L
nmol/L
after 45 minutes
of bypass,
14
minutes
Five
a precisely
of
dioxide
Oxygena-
were removed
by
at a rate
100%
gas port.
random
to enter
recirculation
up to 120 minutes.
Blood
previously
permitted
pump
oxygen-5%
the reservoir
harvested
or from
the
roller
of time
was
with
the circuit.
to the lower
and any air bubbles
starting
a 95%
L/min.
Blood
foaming,
without
as previously
flushed
had abstained
from any medications
for 2 weeks)
venous reservoirs
containing
hepanin (5.0 U/mL
gravity
469
BYPASS
I
2
‘S
0
C
.
E
0
L’-
E
‘C
0
0)
I-)
.
.0
2O
120
E
316
J
l2
,
uTj
::
0
J-T
‘C
ll6
;
l1’i:t
T
‘0
ANESTHESLA
#{128}P5R1N
#{216}YPSS$
POST
20
40
60
80
100
120
POST
Fig 1 .
C1,-C1-inhibitor
and kallikrein-C1-inhibitor
complex
formation
during CCB. Plasma
levels of C1,-C1 -inhibitor
and kallikrein-C1
-inhibitor
complexes
formed
are expressed
as nmol/L.
Each column
represents
the mean
±
SEM
of nine separate
patients.
TIME
(mm)
Fig 2.
C1,-C1-inhibitor
and kallikrein-C1-inhibitor
formation
during
SECC.
Plasma
levels
of C1,-C1-inhibitor
kallikrein-C1
-inhibitor
complexes
formed
are expressed
L. Each point
represents
the mean
± SEM
of eight
recirculations.
complex
and
as nmol/
separate
From www.bloodjournal.org by guest on June 12, 2017. For personal use only.
470
WACHTFOGEL
lation
to
the
addition,
membrane
treatment
of
anticoagulation
alterations
much
of
bypass.
the
In
mechanisms
activation
morbidity
this
of
pathways
pulmonary
with
chose
to
activation.
In
and
result
in
we
complexes
lation
occur
also
measured
Levels
contact,
and/or
fibribypass
would pro-
the
in a well-defined
system,4
in the
which
absence
allows
the
of hepatic
of the
activation
chemotaxin,
occurs
C5a.’7”8
to both
complement,29
Since
the
active
of C3a
to implicate
mask
classical
component
classical
levels
during
of the
plasma
is
has led
path-
alternative
complement
of
pathway
must
circulation
in both
and 2). It is apparent
that
full extent of the activation
components
coagulation,
ulate
human
the
plasma
kallikrein
elevated
CCB
Levels
and
SECC
in vivo clearance
acts
that has occurred.
intrinsic
kallikrein
and
(Figs
we cannot
exclude
CT,-CT-inhibitor
Levels
of
factor
of extracorporeal
stim-
complex
circulation
(Figs
that
postbypass
of 8
level
However,
to 20
levels
4 nmol/L
±
1 nmol/L
±
of both
a2plasmininhibitor
showed
Thus,
through
directly
contact
coagulation
XIIa
and kallikrein,
the
factor
directly.2#{176}
through
the classical
potential
to activate
Kallikrein-CT-inhibitor
the C1,-C1-inhibitor
complement
neutrophils.
complexes
1
complexes
bly due to a combination
order
rate
inhibitor
constant
complexes
C1,-C1-inhibitor
the rate
Second,
is 1.30
complexes
ofactivation
form
(Fig
of two
for
much
2). This
factors.
the
formation
x i0 mol/L’s’
is 0.44
x
for prekallikrein
is accelerated
by high molecular
of CT by activated
factor
XII
(C5a),
weight
is not.
has
faster
effect
First,
of
iO
the
by factor
kininogen
Therefore,
the
than
is probasecond
kallikrein-CTwhile that
mol/L’s’.37
60
to
postbypass
a
(Fig
and
1).
plasminrise
at
in vitro
complexes
complement
undergoing
is known
pathway.38
cardiopulmonary
to activate
Moreover,
bypass
the
two
of 48
in a prospec-
tive study,
presented
with a sudden
rise of airway
pressure,
acute
pulmonary
hypertension,
and systemic
hypotension
bubble
or membrane
levels
within
of C3a32’33’4’
the lungs.42
evidence
oxygenators
and causes
Although
of alternative
sharply
plasma
pathway
activation,43
most
investiga-
of C433’” and thus
by the alternative
the first evidence
that cardiopulmoboth the contact
and classical
comple-
ment pathways.
Presumably
both pathways
are initiated
by
activation
of factor
XII on the surface
of the bypass
circuit.
Activation
suggests,
of both
but does
contact
the
enzyme
previously
of
for
specific
pathways
definitively
system
are wholly
neutrophil
inhibitors
help
to delineate
nary
bypass.
during
cardiopulmonary
prove,
that components
observed
of factor
the
role
or partially
responsible
degranulation.”
XIIa,
of these
kallikrein,
pathways
bypass
of the
or
for
The
use
CT,
may
in cardiopulmo-
ACKNOWLEDGMENT
XIIa
while that
kallikrein
increases
sequestration
of leukocytes
Collett
et al reported
direct
pathway.
complement
factor
XII
system,
both
and indirectly
pathway
completely
com-
no significant
This study
provides
nary bypass
activates
classical
activates
not
urokiactiva-
returned
kallikrein-C1-inhibitor
complexes
factor
XII
pathway.36
the
also
and/or
system
but
by 24 hours
tors do not observe
a consistent
reduction
conclude
that
complement
is activated
activate
contact
did
possibility
in CCB.
rose significantly
within
and 2) indicating
that plasma
prekallikrein
has been converted
to the active
enzyme.
Kallikrein
activates
factor
XII
to factor
XIIa
and subsequently
to factor
XII fragments’9;
fragments
Surface
In
shortly
after protamine
injection,39
consistent
with activation
of the complement
and/or
kinin forming
systems.#{176} Previous
work
has shown
that cardiopulmonary
bypass
with either
Addiand aer-
of kallikrein-C1-inhibitor
as a result
the
contact
XIIa,
degranulate.’3’6
chemotaxis34
CT.
in turn
complex
of
classical
patients,
1
to mask
pathway
to aggregate
and
induces
neutrophil
obic glycolysis.35
are
of
neutnophils
tionally,
in SECC,
rin-protamine
be considered,
since levels of C1,-C1-inhibitor
complex,
unique
to the classical
system,
are elevated
as a result of the
extracorporeal
plasmin-a2-plasmin-inhibitor
of
which
any time postbypass
(Fig 1). The mechanism
of activation
of
the complement
cascade
is unknown,
but formation
of hepa-
now
Two
of
normal
of CS
CCB
that
C4
and prevent
detection
of elevated
levels.
Thus,
while
we found no evidence
of activation
of the fibrinolytic
system
to
cell
pathways
than
plexes
circu-
to the
and
activation
the
way.3#{176}33However,
the
alternative
elevation
investigators
in response
rapid
However,
in CCB the rate of clearance
may
the production
of plasmin-a2-plasmin-inhibitor
tion.
blood-surface
interaction
or reticuloendothelial
more
products,
such as tissue plasminogen
activator
nase, may explain
the absence
of fibrinolytic
above
extracorporeal
probably
in either
CCB or SECC.
This rules out fibrinolysis
SECC.
In this system
the lack of endothelial
cell
minutes
clearance.
Neutrophil
common
formation
simulated
is
C1 must then activate
C2 and
C3 and finally CS to form CSa.
change
during
duce agonists
capable
of causing
neutrophil
degranulation.
Due to the probable
in vivo clearance of the enzyme-inhibitor
complexes,
formation
addition,
activate
extracorporeal
examine
the possible
We postulated
that
complement,
cardiopulmonary
during
injury.
degranulation,
neutrophils
associated
study
we
neutrophil
of the classical
nolytic
severe
with heparin,
of platelets
and
ET AL
The authors
wish
to thank
John
Greenplate
for expert
technical
assistance.
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1989 73: 468-471
Formation of C1s-C1-inhibitor, kallikrein-C1-inhibitor, and plasmin- alpha
2-plasmin-inhibitor complexes during cardiopulmonary bypass
YT Wachtfogel, PC Harpel, LH Jr Edmunds and RW Colman
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