From bloodjournal.hematologylibrary.org by guest on September 20, 2012. For personal use only.

1949 4: 1290-1297

THE CHAIN REACTION OF THE BLOOD CLOTTING MECHANISM IN RELATION TO THE THEORY OF HEMOSTASIS AND THROMBOSIS
J. H. MILSTONE

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From bloodjournal.hematologylibrary.org by guest on September 20, 2012. For personal use only.

THE

CHAIN

REACTION
TO THE

OF
THEORY ByJ.
THE

THE
OF
MILSTONE,

BLOOD

CLOTTING
AND

MECHANISM
THROMBOSIS

IN

RELATION

HEMOSTASIS

H.

M.D.
REQUIREMENT

PHYSIOLOGIC

F OCCASION
for the blood

arose
to

to
remain

invent
fluid

a blood
in the

clotting
vessels,

mechanism,it might
yet promptly

be arranged
congeal when mixed

with
punctures. difficulty

the

juice
However, might

of

freshly
as appear. this

cut
As the

tissue.
blood

This
was

would
tested flowed

probably
with through larger the

work
cuts, break,

well
an a

for
unexpected

small

mechanism

coagulated

film tissue
clotted.

would and

be deposited hinder
Therefore,

on
hemorrhage

the

cut of

surface. tissue
would

This juice
continue

layer with

would that
through

seal portion
a

over of

the blood

wounded not
lined

the

admixture

yet
by

passageway

freshly To
layer the juice could

clotted overcome
of blood be achieve coagulation would then

blood. this difficulty

was needed clotting, process only a hemostatic
it

a chain
would be to exert plug incite

reaction
the effect

might
neighboring from on would one the

be

introduced.
layer to to by the layer. accretion, clot.

Then,
Thereby and and next, The

as one
tissue which,

could

propagated its which

layer initial

mechanism

grow

in
might

this Thus,

respect, by
serve. Other

would

resemble conjecture,
functions can

the we
be

natural have
imagined.

plug arrived begin

depicted at some

by function
chemical

Tocantins.t a chain
reactions,

teleologic

reaction
be they

Ordinary

stoichiometric down.
reaction, creasingly

combinations when
with faster.* the

or reaction
that chain as

enzymatic, is involved,
more product may reactions

rapidly of
is

and products
the a lag

thereafter accelerates
reaction period,

slow the
goes but later in-

But,

a chain
result Hence,

one
start

the
formed with

are period,

apt

to but

proceed ensures

explosively. rapid
THE

This when

offers the

opportunity lag has been

for passed

control or

during overcome.

the

lag

action

BIOCHEMICAL

MECHANISM

Whatever
of blood. of
the work concept which by Co., throughout used in order reactions

its
An plasma
Laboratory was

prime
experiment

function,
in was

a chain
which described
Yale from the University James

reaction
the clotting by Gratia
School Hudson

does
1911.2

occur
in Once

during
was the

the
transmitted process

coagulation
through had

process

a series
From This sity
*

samples
of Pathology, by a grant reaction and themselves

of Medicine, New Brown in

Haven,

Conn. Fund of the Yale Univer-

aided of chain

Memorial with to Chemistry, reactionS various

i.

School The

of Medicine.
was

originally It
over and

introduced has been When, of to the

of

connection applied thereaction

the series
velocity

photochemical of D. consecutive Van is imeffect and autoreincreases

combination actions as plied are catalytic Nostrand described

of hydrogen repeat Inc., Glasstone

1946.

chlorine. over then

broadly in Physical

again.

addition,

(Glasstone,

S.: the possible

a special

Textbook is said Here,

group I 2.90

New ed. type and

York, which

P.

1083),

chain

nonstationary. be

It is this autocatalytic

the
are

present
regarded

discussion. other
as

terms besides
nonstationary

cJi
chain

autocatalytic reaction;

to include

mechanisms

a simple

reactions.

From bloodjournal.hematologylibrary.org by guest on September 20, 2012. For personal use only.

J. been seeding apparently experiments initiated

it

H.

MILSTONE

12.91

in

the of minor

first

tube,

each

tube

of

fluid

plasma

was

caused

to serial

clot passage

by

with
with

a few

drops
Gratias

of

serum
previous

from
in

the
discussion,

preceding
reported and results.

tube.

In
similar Gratia

1935,
was of

Fischer,
impressed

unaware

differences

technic

by Fischer

the

formal
of

resemblance
the clotting demonstrations autocatalytic

between
process were effect.

the
with

propagation
repeated new they in the separation

of

bacteriophage
formation

and
thrombin.

the

propagation

wrote
of (a)

of
these the

blood

coagulation

as

an

endlessly

transmissible
were nineteenth not

chain
the century,

Although dications

spectacular, Beginning

reaction. infirst
two

complementary
nism: Separation

approaches
of

have
coagulation

been

made
factors;

to
(h)

the

analysis

of
of

coagulation
individual

mechareactions.

w
w z I U
U-

0 I-

z
0

FIG.

1.-SOME

EVENTS

OCCURRING

WHEN

BLooD

CLOTS

IN

GLASS

The TUBE. chain and the limit help illustrate

reaction the the

is

the

kind The

of process decreases

which in and or synoptic

could

cause

the

growth activity, respectively.

of a hemostatic thrombin Such appear are case text. for (Figure to the and reactions have The three

plug fibrin

propagation
growth

of a thrombus. antithrombokinase,
of a

thrombokinase fibrinolytic of a diagram necessary

less pertinent

antithrombin hemostatic This will

is

effects, thrombus. does as more than in

may to

plug, type of

not data is the the

been broken

attempted line by Armin curves.

before representing The

Hemberger.)

and

modifications changes and

probably
on

become
observations

obtained.

platelet historical

based

continous

experimental

background

is outlined

prepared Mr.

By

1904,

this

twin

approach Thrombin.
Fibrin. before separated concept
1904,

had

developed In the

far enough presence

of into separated And

to

engender

the

classic

two-

stage
i. i.

theory:

Prothrombin
Fibrinogen
-*

-s

of
thrombin. the all

thrombokinase
present, reactions along the results which line

and

calcium.
have been that have the been

In

the and factors

presence continuing and be modified.

But, obtained simple

beginning with two-stage

show there

must

repeated
which followed the

intimations
coagulation by a in period a glass

of

autocatalysis.
products of tube. accelerated appear.

Many
A

studies
frequent the complete

have
finding events

been
has of experiment

made
been a that chain

of

the
a lag re-

rate
period

at

production-characteristics which such outlines a

action.
blood

This
clots

is illustrated

in

figure
,

occur has

when never been

Actually,

From bloodjournal.hematologylibrary.org by guest on September 20, 2012. For personal use only.

1191

CHAIN

REACTION

OF

BLOOD

CLOTTING

MECHANISM

done;
ways. During is

and

the
the the

diagram
performance impression

is a tentative,
of is the routine

rough
test that

summary
for very clotting little

of

data
time,

obtained
and when

in
the takes

various
blood place

normal,

gained a solid

physical This gross

change

until
viscosity

the

end
rapidly

pint finer

is
increases

imminent.
and

Then,
clot

in

comparatively of fibrin

brief
impression

interval,
has

the
been

forms.

confirmed

by

methods; At the time to polymerized

and the

the solid fibrin.

fibrin

production clot As

is accordingly than half the of fibrin

Then, as can or more inactive be developed contains only to the may full. be complex partially potential state. to enough fibrinolytic

represented fibrinogen continues,

on standing by blood. of enzymes, of As the a result potential understood, in detail,

in the diagram. been converted

clotbecomes many weighing. and disease ing the The degree. fibrinolytic explanation fibrinolytic represents the or artificial activity Normally, hours, the This

appears, less this production

more, theclor somewhat, of the part activity blood one in normally For developed fibrin curve reasons an can fibrinolytic

has the

firmer. amount last only enzyme

Aftera effect a partial is kept manipulation, to liquefy is the is

haif-houror of the due for fact its rarely, shape to the the that own if of ever, the

retracts.

diminishes action of most

be determined

development fibrinolytic clot.

a surpris-

It is a remarkable potential for

but the thrombin

further
Soon

main to
noted
amount

reason for its late clot the fibrinogen.

the the accelerated
of

start is that, This delay

production of further,

up until that time, there was reported 1901 inby Arthus,6

thrombin just delay must Collingwood time they into to period an by different the a prompt work technical unanimous comprises in these the production basic mechanism is involved that show and and of was called three that the rapid Collingwood approaches, on the spent stages, period in before the

is not
who clot

enough
appeared. is

the
Carrying to

thrombin
sufficient
experiments a large

dwindles-the
one step thrombokinase
on part

antithrombin
the activity blood, clotting which process been possible latent noted The reaction,

effect.
thrombin first be and in formation developed. MacMahon developing carried in of by loss of and the followat least of three a factor can be interthromboout ac-

discussion that
simple

due
Reasoning

the
from

fact in by

whole
ofthe

concluded thrombokinase Recently,

three succesive

I9I2.

that from an

inactive the

precursor coagulation
it

prothrombokinase. thrombokinase

separating
sets of test

tubes,

has
i.

activity celeration seeding kinase MacMahon. These pretations ing distinct that can Contemporary broad

develops still experiments. activity, are of reactions. accelerate not

as

shown in a There

figure chain was

suggested another isolated recent (a) (b) the literature, A

interpretation corroborated

further foreshadowed Using

result findings.

several

investigators9 The chain however, coagulation reaction of

are

virtually

conclusions:

activation

prothrombin. shows findings

elaborated
partly are used from in

with
the different

greater
fact ways that

diversity
terms and that

than
like several

might
new

be
terms

supposed.
and have

The
thromboplastin been

diversity
introduced.

stems
More

thrombokinase

From bloodjournal.hematologylibrary.org by guest on September 20, 2012. For personal use only.

J.

H.

MILSTONE

12.93

important

is

the

uncertainty

concerning

which

and really

how

many

factors

participate

in as

the

direct
now

activation
thought to

of

prothrombin.
activate prothrombin,

Beyond thrombokinase.
evidence autocatalytic reaction

this
do

is many
been

the

question
else,

of
such

which

factors, reactions against

something

accelerate
occur? the not

the
To occurrence

development
date of no a simple

of
convincing

How
has

different
presented x accelerates

chain
either the for or

(e.g.,

production
although

of x accelerates

x).
quite

Scegers
conclusive,

and

his of

associates
in favor

have
of

brought
a more

forth
complicated

impressive,
chain

evidence

( e.g.,
of ities
I
.

the
to

production
the

y,

which
situation

in

turn
so as

accelerates
to emphasize

the

production
the similar-

x).
It is possible summarize present

of

individual

viewpoints
Complex

rather
-s

than chain this

presence of

their reaction conversion.

of

differences:
Complex. An autocatalytic

Prothrombokinase

Thrombokinase

or of
2..

results
the active

in

the

acceleration
corn-

Prothrombin
Fibrinogen is an

-s

Thrombin. Fibrin. In the

In plex.

the presence

thrombokinase

3. This the

thrombin. details, calcium, and which between that are is demonstrably from conversion time concerned required with the present inactive is of for the of the further blood development the in, different by grouping may this necessary and form signifito clot in a from to the be in found formulasubobtainable

oversimplification, complex

attained all factors,

by

neglecting including

thrombokinase

to tion

participate
For the present

directly
discussion

in

the

activation
there are may It blood the part effect blood, off to the a good biochemical blood,

of
important be complex conversion This of

prothrombin.
differences emphasized

and
for the form in tube. when get

the

old
these

two-stage
three The complex; been stages

theory.
of and a large the autocatalytic prothrombokinase

stances from, the active cance glass can, and Thus can process.
*

coagulation

blood. has that it Moreover,

thrombokinase

followed

experimentally.8

consumes

the is

of thrombokinase
mixed the we take place clotting have

activity.*
with rather entirely process

As a consequence,
unclotted detailed within start

a small
accelerate in evidence and which the

amount
the first fresh of can

of coagulating
three of reaction the portion a chain propagate blood.

blood
reactions, which clotting

To

avoid precede
of

undue the and for future plasma leave

for a

complexity, three
thence

this

discussion and
inthe

does the

not principal
of

deal

with locus

the of the

possibility autocatalytic This blood decision MacMahon, plasma Whether

that

one effect

or might not

more be

reactions
in one

enumerated,
reflected

that

them, main the would

development

thrombokinase the of in the

activity.

would is in on is obtained the

change Also platelets,7 question forth with contain

the left

argument. elucidation (Lenggenhager intact

prothrombokinase

is the the essential and

question cited contribution a three-stage

whether in

prothrombokinase of the 8),or in both. When euglobulins. Any and

1936, 1940,

reference mechanism

this who brought

Collingwood
1912..

evidence

only

ordinary prothrombokinase

precautions, is

prothrombokinase uncertain.9

is found

plasma

platelets

From bloodjournal.hematologylibrary.org by guest on September 20, 2012. For personal use only.

12.94

CHAIN

REACTION

OF

BLOOD

CLOTTING

MECHANISM

THE

ROLE

OF

THE

THROMBOCYTES

This the will

advance, thrombocytes. proceed in

although On the the absence

not of

yet whole

consolidated, side it platelets.

is appears This

already that does

reaching the not chain prove

out that

to reaction

include material

experimental

derived
when impression will lead

from
they are that

platelets
present.

is not
In they platelets his

involved,
review cause to alter, will

or
on

that
platelets,

whole
in so on. the

platelets
Tocantins6 plasma,

are
states which

not

concerned
the in general turn

changes and

neighboring

not the
was

The platelet simply by presence

demonstrated

lysis contact of
by name but it platelet

and fusion with glass factor

and Wright has

observed in the found

Minot

in coagulating presence of calcium, in

1917. in

blood but
on

are brought about require particularly The

the factor, the other the

a heat-labile

the
may this the indirectly

serum
Brinkhous,8 be is serum related

globulins.
the can exerts same to change

serum
basis and factors platelets. of

factor
has

different suggested is In tion A tinuously formed supplied ceivably thrombokinase; mately hinder A in not turn, on reaction

considerations, the known; the the

recognized
, ,

what How or whereby

thrombocytolysin.
gives the means

material of shuttling metamorphosis and to be there reaction eddying a is how is cannot not

directly thrombin. between of platelets. blood, of to they be known. are

a pronounced could thrombus and in platelets Condevelopment effects platelets as well are the the plug, platelets. chain result might

accelerain be would be of intihelp as or the con-

production series, renewed flowing

platelets Thus where nidus the related, The suggest of chain that fresh

and

plasma, plasma

a white metamorphosed concerned the and two whether hemostatic

continuously this related. the further chain might but Exactly complexity

stationary much

independent

ignored.

white
clot, tionately very that be
it it

thrombus
or little). the high is absolutely even by in that curious red

formed
thrombus content Although the of the necessary.

in

flowing
in is fibrin,

blood,
stagnant along probably suggestions need congenital than is with

differ
blood. some a useful

appreciably
The fibrin that former

from
have it (sometimes,

the

test
a disproporapparently,

tube

formed platelets, fibrin of with have component Various

constituent, transformed this fibrinogen . . with of if two a separate the upon adhesive of the case

is

not

certain may

platelets connection,
. .

sticky, is

absence abnormality

to usually that

be

corroborated. In

patients their

absence alterations

are

less
21

incapacited Phylogenetic represent formation are And platelet used, as it yet, has

comparisons a primitive been not facts the does

suggested of Be that two compel the as it entirely us to

thrombocytes which materials to chain apply reaction them. for fibrin

hemostatic may, postulate even different

mechanism, mechanisms

superimposed. necessitate do not

metamorphosis.
THE PROBLEM OF REGULATION

How to We be are

the brought likewise

chain to

reaction an effective ignorant

starts, intensity of the

or precise

whether or critical mode

it

is always It

in

progress is still is likely

and a mystery. that

needs the

only control

concentration, of control.

From bloodjournal.hematologylibrary.org by guest on September 20, 2012. For personal use only.

J.

H.

MILSTONE

12.95

mechanism when it is

exerts already

not under

merely way.

a static Otherwise,

inhibition, why

but would

can not

also

dampen

the

process plug or a

a hemostatic

fresh vascular

thrombus system?
phenomena or active

continue
are of

to

grow
known their

until
which products. of great

it incorporated
result Mere importance. in the In

all

the

blood
of coagulant tube

in

the
the

cardioclotting products rapid loss

Several reactions by an

retardation of the test

disposal circulation

dispersion

may

be

the

of
is

thrombokinase
If, as link an important

activity
Quick2 in the

is
and

striking;
Ware, reaction,

and
Murphy

here
then

the
and both

way
Seegers4 the

is

open
believe,

for

its

further

investigation.8

thrombin

chain

antithrombokinase and

antithrombin may accomplish effect, and uncertain

blood,
it

effects more in some whether

appears

offer than

means is now

for

breaking appreciated.

the

chain.

The

fibrinolytic the in anti

enzyme(s) thrombin

Heparin

augments

ways delays the heparin occurs

activation of prothrombin. in significant quantity been

in of platelets, renewed blood a degree converted in this clotting the The propagation failure, of in formed. the limit clotting of dynamic factors figure i, the balance. Depending process growth or of a thrombus. must They on
it when was

Althoughis still it normal circulating other shock and anticoagulant

blood. indihas slowly to removed been maintain fast and coagulant relations, under plug action to the enough inferred the proceeding

total
secretions

body
are these are

to reach irradiation.

a highlyanticoagulant There have

steadily the are in This blood, turnover completely the implies for As take slow help excessive already the part been up to necessity. usual or

level after suggestions

to every

anaphylactic that
changes few days. balance be in

discharged data on factors consumed

response

the It

Suggestive cate that in to the prevent fluidity antithrornbin products this way. requirements might contribute kind Such which of that they of

prothrombin and reactions,

fibrinogen

circulation. circulating gross effects have action action of to

coagulation. could could could physiologic the

illustrated

antithrombokinase inactivate quantitative already hemostatic such

overpowering, of

It is quite ment of

possible

that

the activity.

critical But
TO

juncture detailed
THROMBOSIS

of study

the

entire of this

system has just

is the begun.

develop-

thrombokinase

RELATION

Undoubtedly,
Nevertheless if we it and state are guides For
to

there
it to is clearly understand theoretical of of thrombosis. thrombosis patients on the factor in administration this Among

are

many
necessary why

who
a thrombus

hope
to are

that
starts, fundamental

few
how efforts attempt

factors
it to are to prophylaxis of the tests

remain
analysis

to
of and

be disclosed.
coagulation what prophylaxis to estimate the makes

continue

a detailed the being

are therapy in based in the

propagates prognosis, made a and coagulation are the detect

stop.

These

questions For from blood. 22.

23

the tests Modern view

present, which

likelihood the

hypercoagulable therapy system used that the beckon chain is as a

anticoagulant that and and noted the question the coagulation dicumarol. only some of state

prevailing thrombosis, of outline these

significant

extensively prospects to which

the future

heparin has is

of the

the

investigator.

extent

From bloodjournal.hematologylibrary.org by guest on September 20, 2012. For personal use only.

12.96

CHAIN

REACTION

OF

BLOOD

CLOTTING

MECHANISM

reaction

furnishes

the and

biochemical

basis

for

the

propagation

of

thrombus.

In studdifferent

biochemical
the formation
24

experiments
propagation speculate brought might are

the

chain
of what

reaction
a thrombus the and blood of outcome extended.

has

long
has will The to

been
been be occur The as chain

in evidence.
the these reaction whenever would to be relative remains subject data

In pathology
of from is so usually importance be evaluated. of its a thrombus classic intimately

One

disciplines

together

a part
forms, play contribution

of the
unless some

coagulation
the part in in the individuals the genesis

mechanism
extension of in various

that is likely it
is the types circumstances unusual. thrombus. of

Consequently, it thrombi

There
were

may
no

be
chain

some
reaction;

conditions
some

where case, might

is far of of stagnant. tissue fresh

a thrombus
propagation

would a mural
myocardium;

propagate
might

even
impossible

if there into the

without chamber
Here blood fibrin depend the

one. Of the latter of the left ventricle

growing hardly by repeated surface be called diffusion formation could sustained on

the
from

extension of be an example.
the Is injured the factor coagulant continued through

thrombus
and the of at the

far

ventricular platelets Or free to the to experithe thromchain do does surface, and it

deposition the substances thrombus?

through he found
or in the suppose nature with ments that reaction, bosis.

operation in
that, degree suppressing state but of does the not subsequent

of statement
once of the

the

chain of Solandt,

reaction? Nassim
have tissue platelets

Anticipation and
covered will The by important. sine qua non success This of an have

of

this

question
region, or nothing pioneer anew include mural

is

to

the

Best21: seems It
little of

reasonable

agglutinating underlying of the mural growth cardiac clotting yet

injured their may cardiac

damage

thrombus. thrombosis is very as the

heparinization emphasized

system singleit out

SUMMARY:

WORKING

HYPOTHESIS

Detailed during
development

evidence the coagulation

of in reaction in its reaction countermechanism. been and

has
thrombokinase

been of

accumulating blood.
appear

that the
involved. be of

at

least
The

one

chain of

reaction platelets
effect

occurs and
may

Both
to

metamorphosis
autocatalytic

the offers
that plays an

serve
advantages the some The adequate long thrombin

a function
the chain part chain since

in making
physiologic occurs propagation. is a

possible
control in most

the

growth
the

of a hemostatic
clotting where a mechanism. thrombus

plug.
It forms, which

It also
is likely and demands

instances explosive materials

potentially With which can

phenomenon from help to blood, maintain thrombokinase activity, may

derived reduce

reactions inactivate the

have fluidity of

demonstrated liquefy fibrin.

These

reactions

the
*

circulating
This question for
4:

blood
has been publication. 1949.
5-7, July

by removing
raised

the
intwo

products
articles

of
which by

smoldering
appeared

clotting
since the present paper A.
page

reactions.

independently It was idea For and a step briefly toward

was

submitted : 739-746,
Insur.

mentioned of the its same

B. Alexander, presented reference i, see

deVries by J. H.
74.

and

R.

Goldstein:

Blood

The
1949.

a discussion

implications ere w idea,

Milstone:

J.

Med.

From bloodjournal.hematologylibrary.org by guest on September 20, 2012. For personal use only.

J.

H.

MILSTONE

1197

Such

effects
it
is

could of
now

help a thrombus.
possible

to
to

delimit
correlate

the
in

growth this way

of the

a hemostatic data on blood

plug,

or coagulation

to

end

the

propagation

While with
standing

present
still

knowledge
remain.

of hemostasis

and

thrombosis,

critical

gaps

in

our

under-

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