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The
B 140 OD
VOL
67,
NO
The
J ournal
Society
American
of
of Hematology
JUNE
6
1986
REVIEW
Thromboly
By Marc
tic Therapy
Verstraete
W
HEN A FIBRIN
thrombus
impedes
blood flow in an
artery or a vein, subsequent
events partly depend on
the fate of the thrombus,
which may fragment
and embolize,
undergo
organization,
or lyse. There is deceivingly
sketchy
information
on the first two processes.
However,
knowledge
of the intricate
system of physiological
fibrinolysis
is rapidly
growing
and, as a result, a new generation
of thrombolytic
drugs is being developed.
THE
MAIN
COMPONENTS
OF THE
FIBRINOLYTIC
SYSTEM
The human
fibrinolytic
system comprises
a proenzyme,
plasminogen,
which can be activated
to the active enzyme,
plasmin,
by several types of plasminogen
activators
(Fig I).
Inhibition
of the fibrinolytic
system may occur at the level of
plasmin
or at the level of the plasminogen
activation.
Although
plasmin
is known
to possess
a multiplicity
of
functions,4
only its role in fibrinolysis
and thrombolysis
is
dealt with in this overview.
Plasminogen.
Human
plasminogen
is a single-chain
glycoprotein
with a mol wt of -90 kd; its concentration
in
plasma
is 20 mg per deciliter
(2.2 mol/L).
The molecule
consists of 790 amino acids; it contains
24 disulfide
bridges
and five homologous
triple-loop
structures
or “kringles”
of
-10 kd each.’5 These kringles
are disulfide
structures
contaming the lysine-binding
sites which mediate
its interaction
with fibrin,’6 with a2-antiplasmin,’7
and with histidine-rich
glycoprotein,’8
but also with the synthetic
amino acids such
as 6-aminohexanoic
acid (EACA)
and tranexamic
acid.’9
Native
plasminogen
has NH2-terminal
glutamic
acid
(“Glu-plasminogen”)
and can occur in two major variants
(I
and II) that differ
in carbohydrate
content20’21;
the two
molecular
forms appear to be synthesized
in liver parenchymal cells.22 Glu-plasminogen
can easily be converted
by
limited
plasmic
digestion
to modified
forms
with NH2terminal
lysine, valine,
or methionine,23
commonly
designated “Lys-plasminogen.”
During this degradation
process,
a 8-kd peptide is removed
from the NH2-terminal
end of the
Glu-plasminogen.
The conversion
of single-chain
Lys-plasminogen
to plasmin
is due to cleavage
of a single Arg
560-Val
561 bond.24 The resulting
two-chain
plasmin
molecule is composed
of a heavy chain (A chain) originating
from
the NH2-terminal
part of plasminogen,
and a light chain (B
chain) constituting
the COOH-terminal
part.25 The B chain
was found to contain
the active catalytic
site similar to that
of trypsin.’5
Blood,Vo167,No6(June),
1986:pp
1529-1541
in the Eighties
and Dsir Collen
ce2-Antip!asmin.
This inhibitor
is a single-chain
glycoprotein with a mol wt of 67 kd26’27 and its concentration
in
plasma
is 6.9 mg per deciliter
(I zmol/L).
a2-antiplasmin
belongs
to the same protein
family
as antithrombin
III,
a,-antitrypsin
and ovalbumin.2’
In purified
systems26’27 and
in plasma29’3#{176}a2-antiplasmin
forms
a I : I stoichiometric
complex with plasmin by strong interaction
between the light
(B)-chain
of plasmin
and the inhibitor.
The complex
is
devoid of protease
or esterase
activity.
The time course of the
inhibition
of human plasmin by a2-antiplasmin
is compatible
with a kinetic model composed
of two successive
reactions:
a
very fast, reversible,
second-order
reaction
followed
by a
slower,
irreversible,
first-order
reaction.31’32
The former
is
among the fastest protein-protein
reactions
so far described.
In spite ofthe presence
ofother
plasmin
inhibitors
in plasma
(eg, a2-macroglobulin)
the inhibition
of this enzyme is solely
and instantaneously
carried
out by a2-antiplasmin.
Plasmin
molecules
which have a synthetic
substrate
bound to their
active site or 6-aminohexanoic
acid bound to their lysinebinding site(s)32 either do not react or react only very slowly
with a2-antiplasmin.
The first step of the process
is thus
clearly dependent
on the presence
ofa free lysine-binding
site
and active site in the plasmin
molecule.
Tissue-type
plasminogen
activator.
Tissue-type
plas-
minogen
activator
(t-PA)
is a serine protease
with a mol wt
of -70 kd. t-PA obtained
from Bowes melanoma
cells
appears
to exist in two variants,
with an apparent
mol wt
difference
of 3 kd.33’34 The concentration
of t-PA in human
plasma is ‘-5 ng per milliliter
(-0.1
nmol/L).
Human
t-PA
consists ofone polypeptide
chain containing
527 amino acids
exhibiting
serine as the NH2-terminal
amino acid.”
Upon
limited plasmic
action, the molecule
is converted
to a twochain activator
linked by disulfide
bonds.3’3’
This occurs by
cleavage
of the Arg 275-Ile
276 peptide
bond, yielding
a
heavy chain (36 kd) derived
from the NH2-terminal
part of
the molecule
and a light chain
(32 kd) comprising
the
From
the Centerfor
silly ofLeuven,
Submitted
Address
Thrombosis
versity
Thrombosis
and
Vascular
Research,
Univer-
Belgium.
Dec 12, 1984;
reprint
and
ofLeuven.
© I 986 by Grune
accepted
requests
Vascular
to
Dr
Dec 2, 1985.
Marc
Research,
Herestraat
& Stratton,
49, B-3000
Verstraete,
Campus
Leuven,
Center
Gasthuisberg,
for
Uni-
Belgium.
Inc.
0006-4971/86/6706--000l$03.OO/OO
1529
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1530
VERSTRAETE
AND COLLEN
PLASMINOGEN
,
:“i.’”
.
-
,,VATO.
PLASMIN
PL ASMINOGEP4
P
tONAU
SmtO’NA
St
A.,iSOOAS
-.
STAtPTO.,NA
SI
.
Fig 1.
Schematic
representation
of
activation
pathways
of plasminogen
to plasmm
(-‘),
and site of action of inhibitors
(---..)
and of cofactors (“ “.-). Pro-urokinase
.PLASMNtCjN)
is synonym
plasminogen
PLASMINOGEN
COOH-terminal
region.
The heavy
chain
contains
two
regions that share a high degree of homology
with the five
kringles
of plasminogen
and with the single
kringle
in
urokinase
(Fig 2). The molecule
contains
an NH2-terminal
region which is homologous
with the finger domains
responsible for the fibrin-affinity
of fibronectin39
and another
sequence
having
a certain
analogy
with human
epidermal
growth
factor.
The catalytic
site is located
in the light or
B-chain
of t-PA; it contains
the three typical
amino acids
common
to all trypsin-like
serine
proteases:
histidine
in
position
325, aspartic
acid in position
374, and serine
in
position
48 1 and is highly
homologous
to corresponding
parts of trypsin,
thrombin,
plasmin,
and elastase.35’#{176}The
one-chain
and two-chain
forms of t-PA have different
amidolytic activities
towards
low mol wt substrates.4’
They have,
however,
virtually
the same fibrinolytic
activity
in a purified
system;
the plasminogen-activating
properties
are also similar.37’42 As explained
more in detail in the next section,
is a poor enzyme in the absence of fibrjnbut
the presenco.f
,
ftbi’ii’nstrikingly
enhs
the activation
rate of plasmen.
This can be explained
by an increased
affinity
of fibrinbound t-PA for plasminogen,
resulting
in a ternary
complex.
This high affinity of t-PA for plasminogen
in the presence
of
fibrin allows efficient
activation
on the fibrin clot without
significant
plasminogen
conversion
by t-PA in circulating
plasma in animals.36’42
Several
laboratories
have obtained
evidence
for the existence of rapidly acting inhibitor(s)
of t-PA at low concentrations in plasma of healthy
individuals4
or at higher levels
in pathological
plasma
samples.479
The complex
formed
between
t-PA and its specific inhibitor
has a mol wt of I 10 kd
and is formed very rapidly
(second-order
rate constant
iO
mol/L) m
_i),5O
Urokinase
and
single-chain
urokinase-type
plasminogen
trypsin-like
serme protease
composed
of two polypeptide
chains (20 and 30
kd) connected
by a single disulfide
bridge.
There are two
molecular
forms, designated
5, (31 kd) and S2 (54 kd), the
lower mol wt form being a proteolytic
degradation
of the
latter.5’
Urokinase
is isolated
from human urine or cultured
human embryonic
kidney cells.
activator
(pro-urokinase).
Urokinase
is a
of single-chain
urokinase-type
activator.
Several
groups have reported
the isolation
of an inactive
single-chain
precursor
(pro-urokinase)
of urokinase
which,
following
limited digestion
with plasmin,
is converted
to fully
active
two-chain
urokinase.5258
Pro-urokinase
is a true
enzyme,
as addition
of a plasmin
inhibitor
(aprotinin
or
a2-antiplasmin)
abolishes
the conversion
of pro-urokinase
to
urokinase
but not the activation
of plasminogen
to plasmin
in
purified
systems.59
Consequently,
the designation
singlechain
urokinase-type
plasminogen
activator
(scu-PA)
for
this single-chain
precursor
form of urokinase
was proposed
by the International
Committee
on Thrombosis
and Haemostasis
instead
of pro-urokinase
(annual
meeting,
San
Diego,
Scu-PA
is, however,
inactive in human plasma
due to the presence
of a competitive
inhibitor#{176}(Fig 3). If
fibrin is present,
this inhibition
is abolished
and plasminogen
activation
occurs, resulting
in formation
of fibrin-associated
plasmin.6’
The apparent
fibrin-specificity
of scu-PA
thus
seems
to be due to the fact that fibrin neutralizes
this
competitive
inhibitor,
and not to a fibrin-enhanced
activation
of plasminogen
as is the case for t-PA.
The gene coding for urokinase
has recently
been cloned
and expressed
in E coli.62 However,
if proteolytic
degradation is carefully
avoided during purification,
scu-PA
may be
obtained
from the same expression
system.63
Natural
and
recombinant
scu-PA
can induce more clot-selective
thrombolysis than natural or recombinant
urokinase
in experimental thrombotic
models.53’”’
Inactivation
by plasma
protease
inhibitors
does not seem
to play a significant
role in the inhibition
of urokinase
in
vivo,65 although
recently a new fast-acting
inhibitor
of urokinase has been detected
in low concentrations
in the blood.67
Streptokinase.
Streptokinase
is a nonenzyme
protein
with a mol wt of 47 kd, produced
by Lancefield
group C
strains
of fl-hemolytic
streptococci.
Streptokinase
initially
forms a I : I stoichiometric
complex
with plasminogen
which
then undergoes
a transition,
allowing
formation
of a complex
that possesses
an active site in the modified
plasminogen
moiety. This complex enzymatically
converts
plasminogen
to
plasmin.68
Human plasma contains
antibodies
directed
against streptokinase,
which most probably
result from previous
infec1985).
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
THROMBOLYTIC
IN THE
THERAPY
1531
EIGHTIES
)#{174}©
©
0#{174}#{174}©220
, 25
A
S
c
s
X5iy
_p
--V
A
V
!‘K1A,C,,,
-.
‘S’.
ti
,
,00
NS.12
Fig 2.
plasminogen
Structure
(C).
of single-chain
urinary-type
plasminogen
activator
(ecu-PA)
(A),
tissue-type
plasminogen
activator
(t-PA)
(B) and
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1532
VERSTRAETE
AND
COLLEN
Fig 2. (Cont’d)
tions
with
f3-hemolytic
is immunogenic
with
antibodies
sufficient
streptococci.
in humans.
and
tralize
the
obtained.69
REGULATION
biochemically
inert,
be infused
to neu-
apparently
must
before
OF THE
Different,
rendered
of streptokinase
antibodies
fibrinolytic
FIBRINOLYTIC
divergent
and
minogen
in situ
colleagues7#{176} were
is adsorbed
activation
the
SYSTEM
to fibrin
first
when
of fibrin-bound
reacts
activation
concepts
devel-
in the vicinity
of
antiplasmins.
Alkto propose
that
plas-
the latter
is formed.
plasminogen
was
The
consid-
scu -PA
-_______
competitive
plasminogen
inhibition
by
plasma
plasmin
2
urokinase
plasminogen
--.-
generating
thrombus,
from
plasminogen,
circulating
shown
diffusing
plasmin
antiplasmins.
which
was
is generated
to have
from
environment
More
particularly,
from
a higher
the plasma
in an
the native
affinity
Glu-
for fibrin
in
a purified
system7’
and in plasma.72
The lysine-binding
site(s) of plasminogen
mediate
its binding to fibrin’7 and are
also responsible
for the plasmin-a2-antiplasmin
interaction.
It thus appears
that by competing
with fibrin for the same
lysine-binding
the
sites
binding
Sakata,
a2-antiplasmin
plasminogen-binding
ing
in plasminogen,
of plasminogen
a2-antiplasmin
to fibrin.
cross-links
capacity,
of plasminogen
with
resulting
to fibrin.73
inhibits
According
Previous
to Aoki
fibrin
primarily
adsorbed
was dependent
affinity
of
Chesterman
in an indirect
conflicting
type
a specific
for
fibrin
plasminogen
was
of
plasma
demonstrated.7
activator
(t-PA)
may have
Glu- and
in techactiva-
for
fibrin.
plasminogen
Purified
binds
rate of
plas-
a relative
activator
affinity
bindreports
and that the
of circulating
et a177 demonstrated
streptokinase-plasminogen
Subsequently,
activator
onto fibrin,
on the level
and
but still has a
concerning
the uptake of plasminogen
by thrombi
been due to a lack of distinction
between
the
Lys-forms
of plasminogen
as well as to differences
niques and substrates
used.776
Another
school of thought
held that plasminogen
minogen.7743
plesmin
Fig 3.
Hypothetical
mechanism
for the activation
of plasminby single-chain
urinary-type
plasminogen
activator
(scu-PA).
ogen
by activators,
the
tors were
fibrinolysis
ant iplasmin
scu-PA
to be achieved
into
Lys-plasminogen,
is
been
ered
shielded
IN HUMANS
have
oped to explain
why plasmin,
formed
thrombi,
is not inactivated
by circulating
jaersig
streptokinase
streptokinase
is thereby
amounts
Moreover,
Because
specifically
tissue-
to
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
THROMBOLYTIC
THERAPY
fibrin’245
or
to
Quantitative
fibrin
ogen
have
on the
by t-PA.’’8
It was
fibrin
higher
No
of
found
in these
kinetic
pidlt
to
seem
previously
fibrin
are
not
has been
by
but
0.16
PLASMINOGEN
a much
PLASMIN
I ‘ PA
u2-ANTIPLASMIN
zmol/L).
parameters
clearly
which
to be at variance
been shown
inactivated
R
affinity
for
origin36 or obtained
by recombiThe
structures
involved
in the
of t-PA,
sites
defined.
to the
implicated,39
with this
tj.Lplasmin
but
FIBRINOGEN
FIBRIN
recent
hypothesis.89
is extremely
but.j,lasmin
s inactivated
L
The
is homologous
a2-antiplasmin,
occu]it#{235}dlysine-bind
to
of either
fibrinogen,
was
of fibronectin,
observations
It had
has a weak
(Km
region
binding
of plasmin-
in the absence
is present
t-PA
finger-region
t-PA
fibrin
the t-PA of melanoma
DNA
technology.35
NH2-terminal
that
zmol/L)
t-PA
activation
when
difference
binding
in the
shown
65
fragments.45
on
or a CNBr-digested
affinity
either
nant
fibrinogen
obtained
of fibrin
(Km
1533
EIGHTIES
been
role
for plasminogen
solid-phase
THE
CNBr-digested
data
and
IN
with
50 times
slr
aiitasm-in--
Reversible
blocking
of [he active
site of
plasmin
with substrate
also markedly
reduces
the rate of
inactivation
by a2-antiplasmin.
A molecular
model
was proposed
for the regulation
of fibrinolysis
in vivo that retains
elements
of each
noted
above,
absence
of fibrin
present.
Moreover,
fibrin
has
Mmol/L).
a
high
Fibrin
concentration,
of t-PA
an
t-PA.86
the
local
on
the
sJ.
thrombus
Liberated
plasmin,
by a2-antiplasmin
dissolution
replacement
at
new plasminogen
MAJOR
in
the fibrin
molecules.
CLINICAL
vivo
thus
surface
result-
of plasminsurface
has
occupied
[half-life
and
is
(t’/2)
is very
quickly
ms). Effective
requires
a continuous
of consumed
plasmin
WITH
by
about
the optimal
other
complications
streptokinase
STREPTOKINASE
and
urokinase,
as
was
apparent
at
an
agents,
particularly
in the postoperative
of
of
NIH
period,
after injury
and stroke,
and in patients
who have undergone
invasive
procedures.
The observation
that there appears
to be
a poor
systemic
degree
correlation
fibrinolysis
of thrombus
A well-studied
major
tokinase
massive
pulmonary
between
the laboratory
parameters
and the incidence
of bleeding
or
resolution
indication
embolism.
is also
for
Timely
and urokinase
results
pulmonary
emboli
and
of
the
vexing.92
thrombolytic
administration
cardiopulmonary
heparin
trials
dose and, above all, fear
result
in an underuse
Consensus
Development
Conference.9’
It is mainly
the risk
versus
a too uncertain
benefit
assessment
that is hampering
clinicians
in making
a more liberal
use of presently
available
thrombolytic
hemodynamic
treatment
urokinase
and
tutes of Health
UROKINASE
Uncertainty
bleeding
and
-m2-ANTIPLASMIN
COMPLEX
Fig 4.
Schematic
visualization
of the molecular
interactions
regulating
fibrinolysis.
On the fibrin surface.
plasminogen
is efficiently
converted
to the proteolytic
enzyme
plasmin
by bound
plasminogen
activator.
The plasmin
generated
is partially
protected from inactivation
by a2-antiplasmin.
whereas
free plasmin
in the blood is very rapidly inactivated.
The lysine-binding
sites of
plasminogen
( ) are important
for the interaction
between
plasmmn(ogen)
and fibrin and between
plasmin and a2-antiplasmin;
active site of plasmin
( p’).
with
ACHIEVEMENTS
AND
PLASMIN
between
bridge,
fibrin
however,
(V/2 of -100
of a
fibrin
plasminogen
interaction
fibrin
its lysine-binding
sites and active
site
only slowly inactivated
by a2-antiplasmin
of
10
inactivated
0.14
on the
for the activation
formed
is
and
(Km
plasminogen
a cyclic
constant
Plasmin
fibrin
to be the result
additional
through
ing in a low Michaelis
both
thus
and
DIGESTION
As
by t-PA
plasminogen
appears
FIBRIN
ACTIVATION
in the
when
formed
increases
creating
and its substrate
by
for
affinity
essentially
affinity
complex
affinity
4).
for plasminogen
higher
binary
This increased
surface.
concepts’7’32’#{176} (Fig
affinity
a much
the
assembly”
ogen
former
has a weak
but
“surface
t-PA
of the
t-PA
PLASMINOGEN
was,
reduction
included
in a greater
resolution
of
greater
improvement
of the
as was
streptokinase
(NIH).9395
too small
however,
in mortality.
as compared
shown
in the trials
sponsored
by the National
The number
of patients
to demonstrate
Moreover,
in the NIH-sponsored
only
trials
a significant
10%
were
with
Instiin these
of the
patients
in shock;
compar-
ative trials
limited
to patients
with pulmonary
embolism
in
shock
may reveal
a lower mortality
rate in patients
treated
with thrombolytic
agents
without
requiring
an exceedingly
large number
of patients
in the trial. A long-term
benefit
of
thrombolytic
complete
treatment
resolution
in major
A multicenter
gram
dose
treatment
has
reduced
trial was set
with 4,400
per hour and a 24-hour
in patients
with
recent
angiographic
significantly
pulmonary
of thromboemboli,
nary microcirculation,
pulmonary
hypertension.’
12-hour
therapy
is
of strep-
measurements
alone,
results
different
embolism
also
the
from
incidence
is that
the pulmoof chronic
up in France
to compare
a
CTA
U urokinase
per kilo-
treatment
pulmonary
and bleeding
between
the
with
half this
embolism.97
complications
two regimens.
hourly
The
were
not
However,
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
VERSTRAETE
1534
either
treatment
comitant
deep
days
of
intense
recurrent
tested
would
be too short
to dissolve
thrombi
effectively,
which
requires
vein
thrombolysis.9
pulmonary
graphic
clearance
of deep
In the presence
embolism
in
is indeed
vein
a
patient
in charge
must
to begin
thrombolytic
could
At
guide
least
with
cardiovascular
collapse,
a rapid
as to whether
streptokinase
been
physicians
or to mobilize
conducted
pretation
in decision
patients
with
in which
findings
were
Marder.92
critically
reviewed
trial
to determine
both
An aggregate
of six randomized
was
used
to
efficacy
assess
thrombolysis
was
nase-treated
0.001),
but
deep
was based
and
achieved
and
safety
well
more
Attempts
patients
than in heparin-treated
was 2.9 times greater
to recanalize
with acute
intracoronary
urokinase,
patients,
than four
assumption,
(IV)
rate
The
artery
hours after onset
based on earlier
by
size
75%
<
group
of
artery
with
of symptoms).
and later trials
or
of the
likely
relatively
early
to
(less
in salvage
of contractile
mortality,
and
myocardium,
improve
the
decrease
quality
of life
acute
myocardial
infarction.
This
investigation
in several
multicenter
Europe
and in the United
THE
HAS
ADMINISTERED
STREPTOKINASE
by the
(45% in those
high
NIH
receiving
and 27% in those
medical
community
pulmonary
was directly
ate site
protocol.
WITH
urokinase
nrooer
attention
jyc
treatment
with
HAMPERED
to details,
due
on
to this
cause
and
been
When
infusion
of coronary
dial
infarction
obstructed
observation
of
infusions
given
at 24-hour
250,000
U
level oscillating
concentration.”3
of streptokinase
intervals,
of
a
streptokinase
regimen.
in patients
a short-term,
To
of strepto-
between
20% and
Variations
with
administration
mdi-
with the routine
angiography
enabled
hemorrhagic
administration.”2
intermittent
tried.
a dissatisfaction
tion
between
of thrombolytic
treatment,”
levels rise progressively
after
streptokinase
drawback,
in a fibrinogen
pretreatment
and schedules
of
50%
The applica-
with
direct
acute
myocar-
perfusion
of the
vessel with thrombolytic
agents
as well
of the desired
thrombolytic
effect.”4
as direct
A mean
-
total dose of -.200 #{216}#{216}()
U of streptokinase
is administered
in
the coronary
artery over #{246}h
hour to 90 illjg.ues;
hemorrhagic
complications
are generally
confined
to the site of
.
angiocatheter
insertion.
shorter
perfusion
Nevertheless,
time
even
are still
this
associated
patients.”7”8
Spurred
coronary
eral
infusion
arterial
resulted
by the
occlusions
in a high
to catheter
placement
shorter
dose
and
5,000
of previous
antibody-binding
must
The
has
dura-
besides bleedantistreptokinase
streptococci
capacity.
intra-
a low bleeding
incidence
IU streptokinase
per
with streptokinase,
have significant
of streptokinase
and
the
of periph-
a considerably
treatment,
exceeding
as a result
loading
with
perfusion
rate,
An additional
problem
ing, is that most patients
titers,
gained
local
accessible
success
dose
a fibrino-
value,”5”6
in 7% of
experience
of streptokinase,
lower
with
gen decrease
to 83% of the preinfusion
bleeding
requiring
blood
transfusion
with
pulmonary
or streptokinase
ini’civn
bleeding
strentoki#{241}i#{232}
and
urokinase
>0.9
circulating
lumbar
infections.
be given
required
Thus,
to saturate
initial
dose
antibodies.’23
pain
during
of streptokinase,
#{176}C
occurs
in
treatment
tions
to streptokinase
reported
at a frequency
by the
and
throiiibo
is at Dresent
with
Minor,
leucocytoclastic
transient
transferase,
rise
in the
alanine
reported
during
remains
unclear’27
Some
rapid
dose
a
the
can
and
be
with
purified
allergic
and
Serum
rare
reac-
have
been
sickness
complication
reaction
precipitated
streptokinase.’25”26
serum
transaminase
aminotransferase)
Stoichiometric
elevation
highly
major,
is another
hypersensitivity
foreign
protein
com-
of a high
a temperature
even
are not uncommon
of 1 .7% to I 8%.I24
streptokinase
patients
infusion
but occasionally
vasculitis
attributed
to delayed
by exposure
to the
the
of patients,
25%
preparations.”2
requested
nrocedures
during
of
embolism
Admittedly,
bleeding
mainly
at the immedi-
procedures
to overcome
initial
in the trials
heparin)9395
has impressed
the
than the faster
resolution
of the
invasive
nonessenhitil
this
have
plain
UROKINASE
of bleeding
emboli
in the first group.
traceable
to and occurred
..with
with
SYSTEMICALLY
AND
incidence
in patients
receiving
more
of the multiple
yydin
late
hypothesis
is now under
trials,
conducted
both in
CONSIDERABLY
TREATMENT
sponsored
in patients
program
calculated
after in vitro titration;
however,
from a practical
point of view, large doses of streptokinase
are generally
given
THROMBOLYTIC
The comparatively
and
States.
OF BLEEDING
FEAR
early
to
throni1blyic
are the main
of streptokinase
to be a relationship
tion of thrombolytic
at dosages
not
It is a reasonable
with intravenous
and
intracoronary
fibrinolytic
treatment,’#{176}3’#{176}5that
reopening
of a thrombosed
coronary
artery
will result
timely
-1%
wpateii
and
advanced
directly
complications
for the use
of continuous
dosages
(P
of resolution
is more
begun
died
and the duration
fact that fibrinogen
30-minute
cated
in streptoki-
of streptokinase
and 45%
appears
resulted
and
treatment
when
daily
agents
as compared
function
and reduce
has yet to be prov-
or systemic
administration
resulted
in a reperfusion
of
the coronary
kinase
these
that
patients
in the first
There
complications
despite
the
inter-
power.
the infarct-related
coronary
myocardial
infarction,
either
respectively.’02
reopen
often
patients
treatment.”#{176} The bleeding
of the lack of enthusiasm
24 hours
revealed
is the
even
strokes.
recent
1% of the
circumvent
phlebography
treatment
(P < 0.04).’#{176}#{176}
Whether
the increased
deep vein thrombi
with thrombolytic
with heparin
will preserve
valvular
long-term
chronic
venous insufficiency
en.’#{176}’
in
adequate
hvnertensinn
concern
COLLEN
urokinase.
expounded
in which
hemorrha2e.
with
of sufficient
with
trials
3.7 times
upon
radiologists;
a major
of cerebral
have
studies
thrombosis
had a sample
thrombolytic
patients
bleeding
vein
by uninformed
No individual
heart-lung
controlled
the efficacy
of phlebograms
the
making.
and
Nevertheless,
3%incidence
with
severe
iFiokinase,
embolectomy.
No trial has
setting;
the results of such a
randomized
in
decision
IO3.IO6-IO8
cerebrovas#{231}Iar diseases
are excluded
from
treatmcjitL
In a postmarketing
surveillance
pulmonary
make
treatment
seven
of
phiebo-
life-threatening
surgeons
to perform
an urgent
been conducted
in this dramatic
trial
prevention
complete
thrombosis.
of a massive,
physician
best
The
embolism
con4 to 5
AND
(aspartate
levels
treatment;
complexes
its
mechanism
of
A
aminohas
been
streptoki-
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
THROMBOLYTIC
nase
with
THERAPY
IN THE EIGHTIES
plasminogen
are
still
1535
antigenic
and
immunogenic
in humans.’28
As compared
tage
of
with streptokinase,
being
nonantigenic;
depends
on
requires
an initial
possesses
the
little
discriminate
purity
its
of
high
urokinase
the
for
between
pyrogenicity
dose
fibrin6”29
circulating
more
rapidly
Because
t-PA
hood of induction
reactions
to
number
than
like
and
therefore
does
and
have
human
reactions
not
not
fibrin-
low.
specific
fibrin
reported
in
the likeli-
bleeding
Untoward
t-PA
the
The
TOWARDS
described
above
ment
of
available
MORE
SPECIFIC
THROMBOLYSIS
model
for
has
the
important
regulation
implications
for the
novel
thrombolytic
agents.
Indeed,
thrombolytic
agents
streptokinase
develop-
be neutralized
for thrombolysis.
reduced
plasmin
proteolytic
rapidly
When
is less
effect
by a2-antiplasmin
the a2-antiplasmin
rapidly
neutralized
on several
plasma
the
coagulation
components
VIII are the most
important.
concentration
of these
blood
combined
with
the inhibitory
degradation
products
polymerization
gerous
bleeding
systemic
on
and
correlate
proteins,
among
aggregation
its laboratory
which
and
fibrin
with
treatment,
bleeding
without
do not
manifestations.92”#{176}7”24
apparent
Table
danof
derangements
Thus, in one study it was shown that fibrinogen
ogen decreased
to lower levels after streptokinase
urokinase
be lost
are held responsible
for the potentially
tendency.’31’33
However,
the magnitude
fibrinolysis
necessarily
and
level is markedly
and can exert its
fibrinogen
and factors
V and
Excessive
lowering
of the
coagulation
factors
in plasma
effect
of some
fibrinogen
platelet
evaluation
and plasminthan after
difference
1 . Main
Charac
in
teristics
animal
value.
It was
activation
of
activation
fibrinolytic
Circulating
inhibitors
Antigenicity
Bleeding
Allergic
risk
reactions
effects
Bolus or infusion
Other
side
Trade names
plasminogen
for
between
the
fibrin
around
plug.
models
on
Nonetheless,
not
evident
Experience
is limited
plasminogen
with
scale
to -500
that
when
of thrombosis.’3’38
a small
shown
bleeding
for
initial
patients
systemic
with
that
were
of the
50%
activation
of
on the dose and infusion
the kinetic
parameters
of
by
t-PA.
This
fibrinogen
decrease
might
be due in part to in vitro fibrinogen
degradation.
The
fibrinogen
level dropped
(also
by I 1%) in the
placebo-treated
patients,
zation and
Hematoma
hemodilution
at catheter
ture
combined,
sites
indicating
that
were
treatment
compared
ative trial.’43
Further
half
as
to streptokinase
experience
(Table
In the two
increase
from
Y,
trials
with
degradation
the
The fibrinogenolytic
ation
This
stantial
reduction
breakdown
hypothesis
decrease
the
measured
by the
of Presen
tly Available
during
t-PA
in a comparto substantiate
when using t-PA
with streptokinase
for
or
sodium
Thrombolyt
StreptokinasePlasminogen
the observed
was
less
than
of circulating
fibrinogen.’”
may be limited
to the gener-
is further
in fibrinogen
t-PA,’43””
products
of the early degradation
products
which
are slowly
coagulable
or
clots.
catheteri-
1).
European
in fibrinogen
anticipated
frequent
treatment
is required
whether
less bleeding
is encountered
therapeutic
thrombolysis,
compared
urokinase
coronary
could also be partly responsible.’”
site and prolonged
bleeding
at punc-
fragments
incorporated
supported
during
sulphite
t-PA
X and/or
in fibrin
by the
less
treatment
precipitation
subwhen
method,’47
ic Agents
Recombinant
Tmsue-Type
Plasminogen
Activator
Single-Chain
urokinase-Tpe
Plasminogen
Activator
+ or
Streptokinase
Urokinase
+ + +
+ + +
+ +
+ or
Yes
No
Yes
No
No
Yes
with
fibrinogenolysis
antibodies
less
of the
system
Circulating
plas-
fibrinogenolysis
at
However,
a fibrin-
was
system
is dependent
be anticipated
from
Acylated
Systemic
cause
activator.
(gI 1021)
in
plasmin-
myocardial
infarction.’3’”
With the doses
a drop in fibrinogen
was noted to be about
the
the presently
and urokinase
to
wounds
produced
be
as tissue-type
a systemic
effective.
surgical
would
results
urokinase-type
expected
plasminogen
the fibrinolytic
rate,’45 as could
of fibrinolysis
agents
in a hemostatic
fresh
t-PA,
preinfusion
have no specific
affinity
for fibrin and will therefore
activate
circulating
and fibrin-bound
plasminogen
relatively
indiscriminately.
Any plasmin
formed
in the circulation
will thus
initially
platelets
from
was used in various
acute
used,
AND
be
system
is not expected
to differentiate
occluding
thrombus
and
the
recombinant
RAPID
molecular
agent
the
in
clinical
MOVING
may
explanation
single-chain
resulting
from
are therapeutically
Tissue-type
limited
so far treated.
and
activator
complications
doses
that
A plausible
thrombolytic
activator
aggregated
protein,
is very
been
Fibrin-specific
minogen
ogen
streptokinase,
is streptokinase.’#{176}
of allergic
t-PA
and,
of bleeding.’
activated
systemic
fibrinolytic
of hemostatic
plugs.92
and
also
in systemic
activation
of
is cleared
from the circu-
is a circulating
of patients
low
Urokinase
plasminogen
bound
plasminogen,
which
results
the fibrinolytic
system.
Urokinase
lation
is
preparation.
loading
affinity
has the advan-
incidence
that
the
dissolution
and
-
No
Yes
No
Yes
Yes
No
Yes
No
Yes
Yes
Yes
Minor
Yes
No
Yes
No
No
Yes
Infusion
No
Infusion
Yes
Bolus Injection
No
Infusion
No
Infusion
Streptase;
streptokinase-Kabikinase,
activator-Activase;
-
for acylated
for
urokinase-Abbokinase,
streptokinase-plasminogen-APSAC,
Actosolv,
Iminase.
Ukidan,
and Persolv;
No
Minor
for recombinant
tissue
type
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1536
VERSTRAETE
injection
of 30 mg of BRL
achieved
bleeding
in 86%
episodes
latter
dose,
of the
usually
fibrinogen
preinfusion
observed
ofacylated
can
26291,
coronary
of 57 patients
(Fig
were reported
in most
levels
were
be given
as
n singlelV
with
an
ogen
5.
General
complexes
which
assesses
Y, rather
than
Acylated
structure
as BRL 26921
of acylated
streptokinase-plasminand BRL 33575.
both
the
with
a coagulation
fibrinogen
and
the
rate
The
fragments
X and
complex.
pTasminoj
(BRL
ThacU’ticals,
Surrey,
center
located
26921
is functionally
in the heavy
tokinase-human
can circulate
either
and
separate
from
its
A-chain
of plasminogen,
plasminogen
in the vascular
plasma
inhibitors
fibrin-binding
acylated
is catalytically
system
without
or
740
of
site
strep-
inert so that it
reaction
with
plasminogen,
but
still
bind
to
fibrin
through
the unmodified
kringle
domains
of the plasminogen
moiety.
These
compounds
deacylate
under
physiological
conditions
following
first-order
kinetics,
with halflives
of 40 minutes
hours
(p-anisoyl
(p-aminobenzoyl
derivative
derivative
pIe of a thrombolytic
agent
fibrin and a prolonged
siderable
interest.
In a thrombotic
fibrinolytic
model
geivas
significantly
fiedSK-plasmipogen
having
The
the
properties
effect
has
in the rabbit,
more
both
I7
princi-
to bind
attracted
to
con-
given
the
as bolus
unjjJ-
SK-plasminogen
fibrinogen
at a dose
acylated
whereas
the two
5K
doses
were
mbolytic
;i:Ti.i:c
7fn
mpound
tern;
little
on a molar
reductions
yet
used
thrombolytic,
at equivalent
but also.niarkedlv
human
volunteers,
had
streptokinase,
fibrinogen
not
and
effect
basis,
this
on the
dose
which
produces
plasrninogen.’53
were
observed
in
plasminogen,
and a2-antiplasmin.
The clinical
indication
for
ogen complexes
infarction.
With
2692
rates
1 or above,
of 75% were
have been best
an intracoronary
the
is equivalent
a
significant
At doses >5
which
or
ColleaguesTM
90 minutes
than three
Gurewich
effect
of
dogs
with
and
with
hours
and
co-
scu-PA
of
pulmonary
scu-PA,
respectively.
Infusion
by systemic
fibrinogenolysis,
fibrinogen
times
more
nadiolabeled
agents
were
thrombus
infused
later
the
experiment.
only
with
similar
of recombinant
(rec-UK),
compared65
results
were
scu-PA
(rec-
and natural
unin rabbits
with a
vein. The thrombolytic
of four hours,
and two
of thrombolysis
was
measured
the radioactivity
introduced
in the vein segment
at the
Significant
UK was
associated
degradation.
Dogs
sensitive
to human
otherwise
in the jugular
IV oven a period
extent
between
recovered
of urokinase
whereas
scu-
obtained
a marked
thrombolysis
with
as the
in the clot
end of the
nat-UK
and
nec-
with
240,000
lU/kg;
this
was
systemic
activation
of the fibrino-
lytic system,
as evidenced
by consumption
of plasminogen
and a2-antiplasmin
and fibrinogen
breakdown.
Infusion
of
nec-scu-PA
induced
thrombolysis
at a dose
of
60,000
associated
activation
of the fibninolytic
syst-PA induced
a comparable
degree
of throm-
100
level
N
57
80
a
a.
of
systemic
plasma
in rabbits
scu-PA),
recombinant
urokinase
nary urokinase
(nat-UK)
were
reduced
5 mg
and
urokinase.
urokinase
than
rabbits,
but
obtained
as in rabbits.
The thrombolytic
properties
hours
Sumi
within
was greater
thrombolytic
cause
significant
to be about
ten
found
difference
and that
activator
dose.’#{176}
In a femoral
vein thrombosis
model
in dogs,
resulted
in a deep fall to 20% of the original
that was
comnoun.d.s
were
advantage
h4 thaftIey
tfl
In rabbits,
the mean
extent
of thrombolysis
after
was 6%, 1 7%, and 53%
following
infusion
of saline,
lU/kg
without
tern. However,
.#{231}yjatedSK-plasmin-
thrombolyticili#{225}n
complex,
I ) and
BRL-2692
BRL-33575).
embolus.
five hours
cell origin
PA did not
33575, Beecham Phi’
5). Because
the catalytic
BRL
UK)’49”#{176}(Fig
kidney
with
the
urokinase,
and
was accompanied
Stable
acyl-derivatives
of an equimolar
streptokinase-plasminogen
complex
have been
prepared
by
the Ser
residue
locai.e4ijthe cata1vtijenter
of the Iiht
B-chain
treated
main
of only 3,000
IU of
of body weight
in dogs
thrombosis,
studied
human
assay.’48
streptokinase-plasminogen
group
workers58
as 80%
plasminogen
complete
thrombolysis
whereas
the lysis time
in the
Fig
by as much
efftc
inje’tieisn_
urokinase-type
experimental
was
minor
with the
cPPmS
pro-urokinase.
By IV administration
scu-PA
or of urokinase
per kilogram
obtained
scu-PA,
reperfusion
side
SK-nlsminAge-’cniplevP
“SThjle-chain
COLLEN
6). Several
cases and,
reduced
value.’55
Other
after strenfnkinae.’
AND
levels
acylated
BRL
60
26921
fibrinolytic
sys-
to 178,000
IU
decrease
mg, progressive
of
of
40
2
V
YN: 3
20
fibrinogen,
-i--
SK-plasmin-
studied
is acute
myocardial
bolus of 10 mg of BRL
angiographically
determined
obtained
in 74 patients.’54
C
.2
a
reperfusion
After
IV bolus
15
Dose
Fig 6.
Reperfusion
a single.
BRL
rates
infarction
given
derivative
of streptokinase-plasminogen.
20
26921
in patients
intravenous
25
30
( mg
with
acute
injection
BRL 26921
myocardial
of
the
.
acylated
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
THROMBOLYTIC
THERAPY
IN THE EIGHTIES
1537
6.
bolysis
without
systemic
activation
of the fibninolytic
system
at twoto fourfold
lower
concentrations.
Although
this
difference
could result
from different
reactivity
of the rabbit
toward
both
obtained
types
in a human
the conclusion
thrombolytic
plasma
infusion
kidney
kilogram
minutes
fibninolytic
cell
systemic
minute
of
line
Scu-PA
fibrinolysis.
has
minutes
been
to support
a higher
isolated
at
specific
from
a rate
minutes,
in four
Infusion
given
of
9.
thrombolysis
dose
myocardial
in
over
infarction
60
and
of scu-PA
was
no systemic
directly
by oncogenic
viruses.
the
of
the fibninolytic
system
in five patients,
but in one patient
fibninogen
level fell to 25% of the pretreatment
level.
the
cleaving
10.
Strickland
and
Foltman
B,
Enzymes
and
lytic
agents
over
the
last
in the understanding
of
properties
of thrombo-
decade,
thrombolytic
not ingrained
in medical
practice.
Most
with the less fibnin-specific
thrombolytic
nase
and
urokinase,
circulation.
The
thrombolytic
risk
uncertainty
urokinase,
DB,
use
of
in the
these
clinical
on the
and
optimal
is due
S: Studies
early
other,
Their
patients.
depends
first
clinical
trials
Nature
Vassali
1 3.
RL,
of blood
Edgington
TS:
with
trials
in the
United
thrombolytic
being
studied
States
and
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1986 67: 1529-1541
Thrombolytic therapy in the eighties
M Verstraete and D Collen
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