a prethrombotic
Robert
D Rosenberg
The
last
and
decade
state
Kenneth
witnessed
exist?
vided
below
briefly
by basic
significant
of the
functioning
mans.
For
opment
the
summarize
major
advances
of the
blood-coagulation
a quiet
peptides;
transitions
these
ofspecific
to thrombin, as well
(release
the conversion
The activation-peptide pathways
have
taught
active,
albeit
assays,
converted
normal
level.
circulating
to thrombin,
tralized by natural wall, such as the
low
and
the
resulting
systems
(5).
assays
( 1-4).
fined
systemically
Prethrombotic
as occurring
by radioimmunoassays augmentation various
to fourfold
to thrombin
sufficient
free thrombin
in vivo
conditions
can
subsequent
platelet
surface,
thrombin events
governing
cascade
linked zymogen with little overall Thus,
the
ceptualized that (‘/in
by about
eration possible
Indeed, of
fivefold
above
pro-
The
concen-
event
hours
or
translocation
and
transitions step-to-step
process
cascade
Printed
to the
in converting
pro-
are
completely
un-
systemic
con-
that
factor
molecular
of the this
should
zymogen by normal in USA.
by the that
to the
action the
VII
to
pathway
is
IX with mmXI).
of factor
to production to convert
of
normal
XII-factor
concentrations
of factor factor
IXa
Xa by
X to factor
Thus, the intrinsic pathway is to thrombin generation, which
complete
of the
of existing
intrinsic
is responsible
absence
of circulating
factor
factor
for generating arterial
IXa
on
cascade-amplification
sufficient
or venous
factor
X.
event
It is
outlined
thrombin
to cause
thrombus.
normal
aging of humans predictably alters coagulation(9). Below age 40 y very few individuals exhibit concentrations of activation peptides. However, from
function
X activation
activation
numbers
of humans
who
are
otherwise
peptides
peptides. are due
These
altered
to increased
activaIX and
concentrations
production
rather
of than
decreased clearance of the markers, as shown by direct investigation of radiolabeled peptides (9). A remarkable correlation
coag-
series
of ‘From the Department of Biology, Massachusetts Institute of Technology. Cambridge, and Beth Israel Hospital, Boston. 2 Address reprint requests to RD Rosenberg, Department of Biology,
be conconversion
inhibitory
phase
under
normal exhibit elevated concentrations of prothrombin tion peptide as well as elevated concentrations of factor
controlled mechanism in enzyme genera-
mechanism regulated
enzyme
levels
to be due
factor-factor
are unable
recombinant
prothrombin
(factor
conditions. with regard
45 to 70 y, increasing
in minutes)
The
reveal
controlled
elevated
Xa under
(6).
at various
is a tightly amplification
of tightly
1992:56:787S-8S.
(over
of the
disease
blood-coagulation
are individually
days
comparisons
peptides
in health
of factor
VII)
with with
convert
the contact high
of patients monitored
functions
and
offactor
equivalent
factor-factor
formation
before
systemic
generation
from
been of the
with
for the activation
relatively
also
function
VIlla. It is surmised that the increased production offree thrombin via the tissue factor-factor VII-factor X extrinsic pathway is probably required to convert small amounts offactor VIII to factor VIlla, with the resultant amplification of thrombin gen-
modest
peptides.
be instrumental
for careful
as a set
Nuir
a more
of the generated
it may
of activation
ulation
-mii
the
In addition,
centration
A, show
of conversion
be a transitory
to thrombin
known.
excessive
translocation where
appears
de-
as quantitated
to elevate
contribution
Xa under ambient normally dormant
A.
is that
events
increase
of fibrinopeptide interesting
tion.
must
tissue
tissue
activation-peptide
offibrin
extent
is generated
Also
with
the
the
is then
are operationally
in activation
that
Furthermore,
(roughly
transitions the
thrombin.
and
the actual in vivo steps studies have demonstrated
VII pathway Xa
generation
thrombotic
normalized
factor
responsible
thresholds
investigations who have been
while
factor-factor
is continuously neu-
the
elevations elevations
cell surfaces. cascade have
to the overall
to generate
the
conversion as well are elevated by
which
example, deficiencies assays
Surprisingly,
blood-vessel III and protein
regard
thrombotic
small These
inhibitory
taught us much about cascade (7, 8). These
the tissue
imal
it appears
or overtly
certain
conditions
also mainly
acute
the generation
suggest
thrombin trations
ofthe
for fibrinopeptide
oftwostudies
de-
is normally
enzyme
with
states,
before
to
During
events, the rates ofprothrombin-to-thrombin as other zymogen-to-serine protease as measured
fibrinogen
proteins have the coagulation
consumption,
prothrombin
with
the activation-peptide etc)
example,
rearranged
mechanism. For various zymogen
that
anticoagulant mechanisms heparan sulfate-antithrombin
C-thrombomodulin
10-fold
For
to exceed
somewhat
IXa,
mechanism
reactions
devel-
on the biochemically
the blood-coagulation
of prethrombotic
in hu-
(prothrombin
or substrate
the
occurrence
then to be sequestered on specialized The actual steps in the coagulation
to monitor
IX to factor substrate
based
generation
at an extremely
0. 1% of the
allow
A or B) (1-4).
ofenzyme us that
proteases
ofthe
gen-
protein
are able
factor
probably takes place because of rather extent of systemic enzyme generation.
in the
blood-coagulation
Xa,
The
events in the
were
mechanism
to serine
X to factor
cesses.
its repro-
as by studies
occurred
for
of fibrinopeptide
fined
which
radioimmunoassays
in our
and sections
as well
revolution
zymogens
factor
as evaluate
fibrin
advances,
investigations
of radioimmunoassays
activation
that
these
biochemical latter,
is it?”2
A Bauer
understanding of the blood-coagulation mechanism lationship to arterial and venous thrombosis. The erated
If so, what
Massachusetts Institute of Technology. enue, Cambridge. MA 02139.
pro-
© 1992 American
Society
for Clinical
Nutrition
E25-229,
77 Massachusetts
Av-
787S
Downloaded from https://academic.oup.com/ajcn/article-abstract/56/4/787S/4715607 by East Carolina University user on 16 January 2019
Does
ROSENBERG
788S exists
between
the concentrations
of factor
IX and factor
tivation peptides in any given individual, with a somewhat correlation between these markers and the concentrations
AND
X acpoorer 2.
3.
from
fibrinogen.
The
critical
unanswered
question
these biochemically hypercoagulable individuals are more likely to have hypersensitive responses to environmental stimuli, with the production of small amounts of extrinsic-pathway-generated free thrombin because their blood-coagulation mechanisms are closer to the threshold of the inhibitory processes. The generated enzyme could then be used to mobilize their dormant intrinsic cascades, which tions of factor
are potentially
hyperactive
(elevated
4.
is whether 5.
6.
concentra-
IX activation peptide): to explosively generate large amounts of free thrombin: and to develop an arterialor venous thrombus. 13
7.
8.
References 9. I. Lau H. Rosenberg iS, Beeler DL, Rosenberg RD. The isolation and characterization of a specific antibody population directed against
the prothrombin activation fragments F2 and Fl +2. J Biol Chem 1979;254:875 1-6 1. Teitel JM, Bauer KA, Lau HK, Rosenberg RD. Studies ofthe prothrombin activation pathway utilizing radioimmunoassays for the F2/F1 +2 fragment and thrombin-antithrombin complex. Blood l982;59: 1086-97. Bauer KA, Kass BL, ten Cate H, Bednarek MA, Hawiger JJ, Rosenberg RD. Detection of factor X activation in humans. Blood 1989;74:2007-l 5. Bauer KA, Kass BL, ten Cate H, Hawiger ii, Rosenberg RD. Factor IX is activated in vivo by the tissue factor mechanism. Blood 1990;76: 731-6. Meade TW, Miller GJ, Rosenberg RD. Characteristics associated with the risk of arterial thrombosis and the prethrombotic state. In: Fuster V. Verstraete M, eds. Thrombosis in cardiovascular disorders. Philadelphia: WB Saunders 1992;79-97. van der Poll T, Buller HR, ten Cate H, et al. Activation of coagulation after administration of tumor necrosis factor to normal subjects. N EnglJ Med 1990:322:1622-7. Mannucci PM, Bauer KA, Gringeri A, et al. Thrombin generation is not increased in the blood of hemophilia B patients after the infusion of a purified factor XI concentrate. Blood l990;76: 2540-5. Bauer KA, Mannucci PM, Gringeri A, et al. Factor IXa-factor Vilacell surface complex does not contribute to the basal activation of the coagulation mechanism in vivo. Blood 1982:79:2039-47. Bauer KA, Weiss LM, Sparrow D, Vokonas PS, Rosenberg RD. Aging associated changes in indices of thrombin generation and protein C activation in humans. J Clin Invest 1987:80:1527-34.
Downloaded from https://academic.oup.com/ajcn/article-abstract/56/4/787S/4715607 by East Carolina University user on 16 January 2019
of
prothrombin activation peptide. These observations are interpreted to mean that certain individuals as they age exhibit increased function of the tissue factor-factor VII pathway with augmented activation of factor IX and factor X, which are variably manifest as more extensive conversion of prothrombin to thrombin with minimal elevation in the generation of fibrin
BAUER