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

Does a prethrombotic state exist? If so, what is it?

a prethrombotic Robert D Rosenberg The last and decade state Kenneth witnessed exist? vided below briefly by basic significant of the...
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