Bleeding time, other in vivo hemostasis tests and the arrest of hemorrhage

THROMBOSIS RESEARCH Printed in the United

vol. 4, pp. l-23, Pergamon Press,

States

1974 Inc.

EDITORIAL

BLEEDING

TIME, AND

OTHER

THE

IN VIVO

ARREST

ALFRED

HEMOSTASIS

TESTS

OF HEMORRHAGE

L. COPLEY

Preamble Editorials appraisal of

the

and

are new

editors

policy

considered

publishers

on Editorials

on a topic rather

of his

brief

They

thought.

and

as vehicles

anEditor

choice

An

the

deals

made

it advisable

to extend

the usual

ial.

This

was

case

the Editorial

several

include

July

in THROMBOSIS

surprising

my

reasons

They

European

recent

contributions

in

two

chanisms Chief

on

decimal

entirely

at

the

of

the

by in

to write

a

topic,

with

the

which

it

for

this

our

colleague

our

Editor.

journal

this

(2).

Editorial.

(3),

reflections

on what

and

research

laboratories

in dif-

summer,

and

acquaintance

with

last

my

phenomenon

absurdity

places and

are not

RESEARCH.

discretion

is usually

length

September

views

published

to the the

personal

information

prompted

to clinical

of hemostasis

of THROMBOSIS

last

journal's

an article,

countries

comments

This

to reading

RESEARCH

at visits

the new

with

I was

reaction

ferent

My

and

p ublished

P. Fletcher,

For

ues

the

opinions

importance

of its

also

expressing

Editorial

complexity

Anthony

substance

Critical

to express

(1).

However,

article.

articles

conveying

of a publication.

invites

or her

are

for

made

of each

of blood

of reporting solely

in my It

my

should

bleeding

time of the

valme-

as Co-Editor-in-

be realized

individual

I found

clotting.

as a student

capacity

last

Editor

that

it is

of THROMBOSIS

ON HEMORRHAGE

2

RESEARCH

to accept

or reject

or authors.

Each

contribution

is accepted

of the

Editor

communication

THROMBOSIS

and

in vivo equacy ates

to lag

and

I developed

ledge.

Therefore,

which any

given

his

any

1939

use

contributions

on hemorrhage,

today

page

towards

aids

in view

which

my

to a large

and

of new

in

that

their

former

the ad-

associ-

extent,

the use-

fundamental

know-

theoretical

in determining

a brief

blood

to note

appear

the underlying

reason

is given

front

(4-10).

information

of hemostasis

on the

responsibility

tests

that,

upon

this

name

by an author

if a particular

surprised

to 1951

knowledge,

For

responsible

I was

published

new

submitted

or her

in general

the

Vo1.4,No.l

readers.

depends

such

test.

Editor's

the

appreciated

test

advances

and

from

It is generally of any

fully

its

tests

behind

fulness

remains

to laboratories

hemostasis

HEMOSTASIS

a contribution

signifies

RESEARCH

On my visits

AND

the validity

appraisal

and

of

of mechanisms

theoretical

clotting

contribution,

and the

experimental

genesis

of

thrombosis. In

when

1932,

I worked

laboratory

of Edgar

University

of Wurzburg,

the

physiology

phenomenon

WCihlisch he

of in vivo

of bleeding

of bleeding

time

and

time

on blood

coagulation

factory

answers

and

for

about

my

the

I did

subjects

mechanisms

of in vivo

a number

are

not

and

physicians

my

time

in Germany,

theoretical

I contributed

Although

from

that

was

could

of hemostasis.

(11-34)

pertaining

in certain

mechanism

of which

praisal

at

animals, and

for

hemostasis

recommendations, to the mechanisms

about

the values dis-

the

au-

not

to the

leading

give

me

bleeding

This

satistime

uncertainty and

experiment-

to which

of additional

communications,

to the

many

topic

years

will

tests

at present

as well

as from

from

my asso-

this

the work

benefit

of hemorrhage

of

on in vivo

that

article.

hemostasis of inves-

a critical

generally a new

and

the

hemorrhagic

considerations

I believe

surgeons

of

of hemostasis

pertinent

work

in the

students

paradoxical

to the

source

tigators,

seemingly

time

medical

puzzled

pertaining

became

in human

the

I was

thrombin Institute

the

questions

and

some

to teach

to my

phenomenon

and

and

of

Physiological

me

who

thority

ciates

the

coagulation

W8hlisch,

inquiries

purification

hemostasis.

Professor

al

at

asked

eases.

the

on the

look

ap-

employed at problems

hemostasis.

ON HEMORRHAGE

Vol.4,No.l

The

1.

Arrest

hemostasis

Hemorrhage

It is quite

blood.

of

integrity

what

is not

lar

integrity

HEMOSTASIS

3

of Hemorrhage

Hemorrhage, phenomena.

AND

the

obvious

generally

properties

surrounding

tissues

that,

with

circulatory

mammalian of at

the

the

clotting

that

organism blood,

hemorheological

extravasation

is the

of whole

occurs,

impaired.

blood

in close

on

the

vessel

the

However,

maintenance

depends

the

and

are

hemorrhage

system is

site

the

wherever

understood

the

of certain

blood

is identical

blood

in

and

of vascucombination

wall

proximity

and

the

of extrava-

sation. The by

the

the

highly

dramatic

formation

far

of blood

distant

past

fascination

with

tury

source

is

the

clotting

and

of

this

ed

to blood

their

role

in

Hemostasis

fibrin note,

part

ation,

then A

in

the

I pointed

out,

limited

tablishing

of

the

special

term

in

the be

study

limit-

of plate-

with

later,

the

of fibrinogen,

appears

to play

of hemorrhage,

large

blood

is used

a major as ap-

phases,

of platelets,

may

maintained

be

by to de-

the process

i.e.,

it occurs

vessels

collectively

formation,

in mammals

vessel,

the width to 20 p,

venules

since

of blood

clumping

to be mainly

monomer its

a cen-

of

the

polymerization,

in vivo

in whole

retraction.

This

gel-

blood process

in fibrinolysis.

blood

precise

smallest

latter

than

of thrombosis.

appears

in all

capillary"

minute

the

The

presence

terminate

"blood

and

and,

arrest

since primitive

longer

be dealt

(34)

or injured

to fibrin

of fibrin

to the

initiation

initiated

(35),any

ly be

the

the

no

proteins,notably

of clotting

leading

cross-linking

or plasma

of plasma

form

as

As will

more

approach can

stoppage

this

of students

latter

such

coagulation.

coagulation,

coagulation

may

aggregation,

in damaged

subsequent

interest

for

its

to man

It is

which

The

recognized

in

events

phenomenon.

adsorption

it does

in great

dramatic

and

known

times.

sophisticated

the processes

parently

probably

increasingly

to fibrin

as a newly

are

of irresistible

cellular

polymolecular

clots

of bleeding

of prehistorical

these

remarkable

and

lets,

occurrences

boundaries and

capillary

5 to 20 p

of these

since

is called,

in diameter.

capillaries

no morphologic between

arterioles. should

according

the

blood

only

not

exist

after

that

as

necessarifor

capillaries

I recommended

be used

However,

should criteria

to Landis

the

adequate

es-

and term identi-

4

ON HEMORRHAGE

fication

and

(l6,l7) when

case

the

when

seal

the

capillary

Vo1.4,No.l

acts

Such

single

hemorrhage

afflicts

vessels

are

wound

blood.

This

as a tamponade

a composite

capillary

one

severed.

of multiple

of clotted

tissues,

one

in capillary

traumatization

a mass

wounds.

if only

differ

is a composite

into

adjacent

vessel

seals

numerous

extension the

HEMOSTASIS

(28).

Hemostatic hage

AND

or merely

capillary

In

latter

the

thrombi

the

and

their

supported

closures

would

a few

single

mass,

on

structure

or capillor-

by

of the

be

less

formed,

vessels

are

trauma-

tized. French, thrombi pouch dy,

produced

microscopic

pica1

forms

aware

of

studies due

not

studies

on the

as well

as

count

the

process layer

proposed

upon

Ultimately, all

three

cesses and

by platelet 2.

Duke The

vivo the

arrest

phenomenon. term

stoppage

of blood

Time,

This

"hemostasis" of bleeding.

order,

ending Platelets

and

often

beginning

not

considered

in

Thus,

take

and

thrombi into

the

ac-

growth

molecules,

formation. seal these

with

plasma

plasma

involves growth

the

pro-

adsorption

proteins,

followed

coagulation.

Hemostasis

constitutes

is apparently is

thrombus

in fibrin

other

protein

Probably

other

not

formation

wound

of a hemostatic

clotting.

of hemorrhage

other

in sty,

experimental

not

which

fibrin

stuelec-

occur were

and

produced

initial

and

may

cheek

to look

investigators.

to be made

growth

was

their

was

other

and

made

of thrombus

therefore

of atypical

of fibrinogen and

fibrin

the

their

who

of fibrinogen

of fibrinogen

the normal

clumping

BleedinP

concept

have

in chronological

aggregation

the

constituting

processes

occur

will

in

concern

design

of experimentally

occurrences

layer,in

not

and

of wound in

apparently

did

of these

thrombi

of adsorption

However,

and

advanced,

structure

other

they

that

investigators the main

adsorption

studies

a study

p in diameter

investigators

Moreover,

yet

experimental

other

fibrin.

occurrences,

made

It is of interest

these

polymolecular

was

30-50

of thrombi,

typical

(26).Since

(36)

arteries

of many

studies

accordingly.

to the

Sanders

hamster. those

and

such

proteins the

as in

platelets

and

in small

of the Golden

as well

tron for

Macfarlane,

not used

by well

its

very

nature

appreciated,

strictly

to denote

an in since the

ON HEMORRHAGE

Vol.4,No.l

In can

1910

be no

cessary

been ing

question

tool

by

diagnosis

the

instance,

and

right

authors

same

in

bleeding

quate

100

(4)9

which

thod

on

will

the

meaningful to those

be

day,

be

secured

for

54

example

results with

seconds.

obtained

highly

problem

in which

information

gathered

to be appraised

with

ways

needs Duke

since

the

related bleeding

availability of what

and

Nearly

all

and

most

ous

and

comfortable

We

from

are

well

sampling

to

seal

Copley

for the

in

the

vessel

the

for

These

the

blood

is

It is well

results

organs

the

or

how compared to

research, test

al-

validity.

for

Ever the

formation

"clou

he/ma-

thrombus"(8).

is

in vivo

test

by

show-

(37).

platelets

in human

skin the

its

me-

appears

of a given

wounds

this

as

This

in vivo

"wound

tests

testing.

other

methods,

h&mostatique"

while

skin

an

method

arises

regarding

to blood

named

that

use

the

subject,

of experimental

scrutiny

"bouchon

condition.

a condition

by

on

by

with

question

by

inade-

time

as a test

ones.

on

little

supported

obtained

crude

other

drugs

such

bleeding

The

considered

organ,

of

use

me

areas

time

aware

one

authors

with

hemostasis

accessible

a hemorrhagic such

and

in vivo

est

reflect

was

called

Lalich

skin.

veal

time

(39)

the

results

bleeding

of platelets

Hayem

statique"

in different

the

so very

sophisticated

be a general the

from

1.3

the results

vary

Values

and

he and

of certain

be

left

in 20 tests

basis

cannot

time

Thus,

the

On

these

later.

from

why

pro-

bleeding

in 5 animals

to explain

bleed-

simple

Cent.

cent

this

have

the

similar

10 per

ne-

in patients.

tests

Copley-Lalich

to 204

or

time

effect

certainly

discussed

from

can

claim

controlled

same

ed variations

since

and

which

in repeated

investigators

tests,particularly

the highly

on the

data

There

determined

10 per

subjects.

is difficult

other

Their

who

bleeding

cent

in

the

about

about

papers

It

the

test.

conditions

time

to vary

in 17

many

as by

methods.

of

4 per

time.

as well

repeated

found

tests

published

Roskam

(38)

in rabbits

340

authors

within

time

is a valuable

the differences vary

animal,

time

bleeding

subject

5

bleeding

as meaningful

by many

that

Roskam

the

of hemorrhagic

the Duke

found

ears

same

cent

the

employing

They in

the

in

HEMOSTASIS

bleeding

past

for

use

the

the

reported

values

the

that

to accept

time

per

in

introduced

It is difficult

cedures.

in

(37)

Duke

AND

subjects

affect

largest,

tough-

the most

ubiquit-

known

hemostasis do not

of the

same

that may

the re-

necessarily subject.

6

ON HEMORRHAGE

What

is not

blood ic

generally

sample

does

not

mirror

subjects

the

testing

their

combined

praisals

usage

they

entirely

such

ceed

described arrest and

them

linked

without

depend

on

realize

anism

may

that

expressed

task

platelets and

apart clot

has

from

still

this

period

(42-44). and

number

cannot

be

that

explain-

need

to pro-

certain

facts

a significant

as well bearing

to caution

not

as newly on the

investigators

of hemostasis,

human

thrombocytopenia

mainly

although

or necessarily

to 5,000.

must

histologically patients

earlier to the

by

long

by

Zucker held

These

Jorgensen

concept

15,000

and

and

than

part

of

thrombi

in

doubt are

the

possibly

be-

defects

the marked

clots

contrary

platelets

of

considered

Borchgrevink

some

in hemo-

thirty-

earlier

hemostatic

hemostatic

part

spite

past

authors

causes

Thus, that

the

of wound

that

other Such

of platelets in

the

coagula-

an important

the

formation

thrombocytopenia (47).

in

"that

of blood

during

concluded have

role

"a

in the mech-

ascertained

to be below

count.

with

The

to be

concluded

to have

mainly

the

seems

of platelets

appear

in rats.

They

it

Macfarlane

(41).

found

that

as accelerators

I contributed

in the platelet

from

role

on platelets

of platelets

10,000

regard

extent

been

will

satisfactorily

produced

tween

reported

to the

have

of hemostasis

1941,

role

made

Htihn (45)

thrombocytopenia,

so found

there

scientif-

the view

do not

been

studies to which

Apitz

In

their

not

years,

cimens

ap-

any

may

exact

mechanism"

five

minution

for

conditions.

which

problem

1938

the

retraction,

extensive

critical

imperative

sciences

is written

in

to define

the haemostatic

stasis

condition,

that

to platelets,

of hemostasis"(40).

tion

of the

extra

is imperative

have

the

in hu-

them.

Tocantins hopeless

remains

of view

or ignoring

This

doubt

It

or thrombot-

of blood

the nature

facts

problems

which

and

hemorrhagic

points

taken

Although

in vivo

tests

certain

neglecting

a peripherally

circulation.

judging

views.

Vo1.4,No.l

a hemorrhagic

of the medical

the

phenomena

that

skin

for

obscure

of hemorrhage.

make

the

certain

regarding

without

the

of certain

fashionable

ic inquiry

of

fields

emphasizing

may

in

in numerous

of the nature

fashions

ed by

sites

prerequisites

In different

the

inevitably

all

remain

in

is

for

vivum

HEMOSTASIS

understood

situation

man

AND

were (46)

in di-

alin

spe-

to findings is cast the main

with re-

ON HEMORRHAGE

Vol.4,No.l

quirement ber

for

the

of platelets This

induced.

experimental

initiation is required

is a problem

approach

on a molecular Weiss

and

Rogers

genital

afibrinogenemia

primary

arrest

fibrinogen that in

these

and

may

other

examined

whether

brinogen

play

tion

in

tions the

a role

aim

1882,by of

this

findings,

it

capillary

vessel

not

due

ous

vessels

rhagic isms

and/or

factors

.

The

Ivy

Since

the Duke by

time

phenomenon.

Bucher

40 mm Hg

around

by increasing recommending illary

Ivy

tonus.

this

arm

test,

In my

time

Ivy

will

test,

Ivy

the

in

it is not of their

in a severed

traumatization Vascular and

which

and

conditions

be dealt

of nu-

in numerto hemor-

the mechan-

may

other

blood

defects,

lead

origins

with

ves-

observa-

the

the

vary.

Dif-

processes

with

test

time

application off

test,

developed

bleeding

later.

such

attempts

for

the

by Ivy,

effectively

to eliminate a procedure

the

have

bleeding

by Ivy,

of a cuff

the microvessels

thought

appraisal

blood

Hayem's

vessel

fi-

normally.

organ.

is a crude

to improve

to cut

pressure

to occur

size,

than

Modifications

the

suggested

and

to be

in addit-

Although

blood

the

of bleeding

other

appraisal

involved

hemostasis

named

the the

and

of

traumatized

different

which

authors

The

from

in the

It needs

hemostasis

in an

are

bleeding

several

(5l),was

(52).

Time

arrest

made,since

con-

concluded

proteins

found

hemorrhagic

clotting

Bleeding

made

Melnik

of

that

structure

these

They

(49,50).

in a given

in hemostasis

been

and

in

plasma

a critical

have

with

clarification

primary

been

greatly

can

a fresh

of fibrinogen

function.

was

proximity

of different

role

selectively

to give

of hemostasis

the

two patients

further

which

article

manifestations,

be

vivum

in afibrinogenemias,

have

differ

extra

afibrinogenemia.

investigators

may

in

in the

be realized

and

num-

submicroscopically.

for

on

to traumatization,

processes

both

many

in close

ferent

made

in hemostasis

studies

should

vessels

studies

extent

aggregation

cannot

attention

with

to which

a critical

more

studies

a role

that

needs

platelet

the microcirculation

in

merous

and

patients

Biomicroscopic sels

made

for

play

and

to platelet

hemostasis

which

to determine

requirement

fibrinogen

without

in vivo

of bleeding

7

and

which

(48)

HEMOSTASIS

of hemostasis

including

level

and

AND

Shapiro Nelson

and

pressure

of

venous

return

to 40 mm Hg. the

factor

is not

In of

cap.

desirable,

8

ON HEMORRHAGE

because

several

involved non

factors,

in hemostasis.

where

sels

vascular

the

is not

or other

arrest

in and

determinations

are

Moreover,

dependent near

HEMOSTASIS

other the

of hemorrhage

entirely

clot

AND

from

mechanisms

of hemostasis

blood

as well

the

vessels

ly important that

the

introduced

recently

as

artefact

is also

time

represent

of bleeding

This

of a cuff

the

the

of the

as

application

of this

so called

"stressed

the

with

the

by O'Brien

et al

of a cuff

pressure

of 80 mm Hg

so-called

"template

bleeding

time

ized

procedure It was

their

by Mielke

most

bleeding

authors,

who

Pollini,

unfortunate

time use

This

practice.

et al

values

the was

Ivy

and

to more may stop-

without

cuff

an

pressure.

bleeding

test

time",

involves

in performing

test",described

ap-

the

as a standard-

(54).

that

Ivy,

in places

Nelson

of two

and

time,

the

case

in

Mars

(3),

to which

(55)

described

the

Bucher

decimals,

continue

bleeding

also

Cortellaro

and

possible

of the

i.e.,

This

(53).

plication

equal-

values

initiation

physiologically,

is

are

leads

these

However,

status

of the

It is quite

of 40 mm Hg

time

in the

wall

them

it occurs

case

reported

values.

vesclump

Bleeding

The

surrounding

pressure

of numerous

interference

processes,

are

is a phenome-

vessels. no

tonus,

of a platelet

occur.

tissues

clotting

in bleeding

adequately

page

the

application

conformity not

as are

as

formation

in which

physiological

time

the wounds

traumatized

preferable,

capillary

bleeding

on the

the

than

Vol.4,No.l

paper

reported

since

to indulge by

Praga,

I referred

many in this

Malisardi,

in

the

pre-

amble. Secondary

4.

Bleeding

Borchgrevink condary they

bleeding

measured

wound

they

intention

was It

though

they

in

1942,

mice",

they

Waaler These

time".

about

is rather cited

failed that

of their

two

by

one

"neither

day

earlier

to cut

"one

did

the with

such

not

include,

tests

with

named

bleeding

which

formed

a surgical

blade.

nor

to cause

damages and from

to our work

they

the

crust

vessels

saline

what

renewed

by Copley

into

to refer

bleeding

new that

paper

time

they

authors

removing

dubious

on bleeding

regrettable ison

and

in minutes

set

mage".

Time

can

Lalich the

in their those

which in

the

Their

tissue

da-

be avoided. (5),

tail

on human

"se-

published

of heparinized It is

subjects. studies,

developed

Al-

a compar-

by us,

viz.,

ON HEMORRHAGE

Vol.4,No.l

the

Copley-Lalich

clot

resistance

quite

the wound bleeding nance

to our

thrombi time

made The

test

appears

must

have

taken

question

The

considered

solely

a piece

time

the

are

ject

and

the

vivo

hemostasis

consuming because

controlled nificance An tests

attempt

which

we

in

were

developed

are

is

both

the wound

was

which

time.

I do not test,

There

bleeding

but

is an-

time

and,

(54),

et al.

paper

is used

concerning the

person

to deter-

time

to them,

familiar tests

The

reasons

physicians or employ

the

with

the

test

for

this

to the

in performing

They

with and

performance

discomfort

required

altogether

the

performing

to them.

investigators,

known not

the

time

by Mielke

of certain

of

use

do

and the

sub-

in tech-

least

so to a large

availability their

of well

possible

sig-

conditions.

therefore

and

by

because

hemostasis

described.

clinical

rabbits The

they

both

their

procedures

in clinical

both

and

ignore

in vivo

reluctance

Many

merely

test. Ivy

(6).

Time

period

tests.

the

or filter

subjected

merely

increased

either

is with

found

the wound.

Bleeding

patient

not

as

the

healing

bleeding

as a hemostasis

from

tests

after

of

that

bleeding

not

wound

is

as we

limits

interval

recommended

considerable

as by

long

for

been

the mainte-

measures

secondary

of blotting

hemostasis

reluctance

extent

test,

of bleeding

is

of in vivo

nicians

this

the modification,

There

time

to this

normal

as well

this

for

decreased

22 to 24 hours

to be a measure

Copley-Lalich

as well

about

be

that

the

however,

of

with

mine

time,

usefulness

objection

namely,

within

during

test

or

appears

after

Copley-Lalich

always

bleeding

place

the

test

difference

minutes

is markedly

have

time

The

an acute

thrombi

would

bleeding

several

although

the

cannot

other

test

was

of hemostasis

but

.

This

the wound

test.

is made

hemophilia

secondary

secondary

represents

concomitantly

set,

also

and

9

a comparison

resistance

resistance

with

maintenance

Such

their

clot

of hemostasis.

in patients

it

since

(4,5,7) and

time

(4,6,8).

test

meaningful,

to be related

time

bleeding

AND HEMOSTASIS

made

to acquaint

In my appraisal

laboratory in human

they

investigations,

subjects

the

(4) and

readers

are

with

significant

since in mice

these

(5,7),

tests rats

(16).

Copley-Lalich

bleeding

time

test

into

physiologic

saline

10

ON HEMORRHAGE

is to my knowledge

the

measuring

the

controls siological cause

of the

setting

base

the wound,

and

infliction

the

sharpness can

paper

the

freely

or other

detection

directly

from

absorbing

as we

from

latter

the

also

prevents

of

vary

Values

subjects

these

values

peated

were

tests

er within

short

variation

may time

be The

les were nifies

17

to 340

to be

over

time

of

may

time

such

vessels

arterial

or arteriolar

remained

within

three

180

the

blood

shorten

no

filter

for

the

inter-

the

blood

bleed-

to flow saline,

to

from

time

of blood compared

were

traumatization, in healthy

not

the

such

human

such

repeated and

still

to differor arterio-

flow In

injured.

bleeding

eith-

time.

also

arteries

be

on re-

days,

seconds

to a non-pulsating

apparently

minutes

Thus,

permits

may

fingers,

of bleeding

small

of

traumatizing

or on different

test

can

above,

or of other

range

when

cent

There

Upon

30 to 180

the

174 healthy

(4).

six-fold.

for

latter

as mentioned

about

the normal

the

5 per

subject.

on one

made

in

and

seconds

finger

up

bleeding flow as

of the

and

blood-air

time,

seconds

human

index

vary

within

traumatized

37.5'C

shape

6)

precautions

values,

healthy

of the

Copley-Lalich

that

single

be approximately

a pulsating

these

determinations

periods

considered

entiate

of all

of 334

same

tests

at

struc-

physiological

bleeding

from

phalanx

into

bone

so that

the

Copley-Lalich

found

the

can

when needs

area

the

the

of the

on the wound

by permitting vessels

out

length,

the

cases,

finger

vessels;

7)

at

hemolysis.

in bleeding

in

terminal

bleeding

the

test;

several

spite

ranged

variations

in

minute

is placed

the

traumatized

determination

human

traumatized

be-

maintained

to injure

wound

of phy-

temperature,

a distal

a certain

The

is held

taken

for

(4).

in a bath

the

it is 4)

of a gaping

excluded

in

has

in

bath,

before

far

pressure,

because

so as not

during

subjects

finger

changes

saline

material

found

Nevertheless,

widely.

3)

thus

37.5'C

of the

avoided

stylet

the

at

of the wound;

production

is entirely

time,

phalanx

2 minutes

selected

of bleeding

which,

face,

is

automatic

for

flow

about

available

in hemodynamic

the physiologic

rapid

5)

changes

virtually

for

phalanx

temperature

terminal

for

ture;

must

1)

there

terminal

the

in human

kept

bath

wide

phenomenon

no

are

into

The

time

of the heart;

to be inserted

ing

test

2)

traumatized

Vol.4,No.l

controlled

follows:

saline;

the

height

as

HEMOSTASIS

best

bleeding

are

AND

time

subjects,

which spite

sigof

usually This

in-

Vol.4,No.

1

dicates

ON HEMORRHAGE AND HEMOSTASIS

a significant

regardless the

of the

automatic There

is no

shape

for

the

infliction

the

heel

of the

may

could

children

be

of

foot

for

the

that

selected

area

to the

bleeding could

length

for

time. be improved.

and

of differ-

could

be

and

small

children

setting

volar

region

by

site

selected

the wound.

area

of the volar

volar

of hemostasis,

traumatized

test

In infants

a suitable

or a suitable

be preferable

in vivo

a different

the wound.

in adults

of vessels

of smaller

and

be

initiation

Copley-Lalich

this

stylet

should

the

number

for

employed

and

elbow

well

used

the

a different

ent

the

and

question

instance,

near

type

stylet

For

large

phenomenon

11

of the

site

of

In

lower

arm

the hand

of a finger's.

terminal

phalanx. 6.

The

Wound

As the

stated

clot

tized

is also

The the

multiple

wound"

fills

the

multiple

of

gaps

different

part

trunk.

adequately after

the In

for

was

found

bleeding

the

severed

the

the

term

The

bleeding

traumatization,

the

to be appreciably determination,

in

consisting

surgical in

time

single

in

than

when

a skin

the

at

the

edges

tissues. the

protrude

extra-

the

clot

"ov-

which

with

composed

thrombi

of

and

be pictured

the

the

like

the

of roots

which

lead

therefore

not

picture

does

the

arrest

capillary

that

from

vessels,

selec-

a vessel

wound

obtained

wound

is

set

to

of hemorrhage

operations.

of bleeding

longer

and

contiguous

may

time

be affected.

with

wound

blood,

occurring

will

structure,

the multiple

seal

of hemostasis

thus

the

in which

surrounding

may

trauma-

bleeding

inside

ves-

following

extravascular

is

plug"

the

for

blood

are

form

connected

particular

"hemostatic

minute

organs

which The

of clotted

and

the

thus

introduced

procedures

occur

by earth,

time

for

which

tissues

viz,,

and

will

and

into

was

proximity

tissues

organ.

portions,

covered

skin

tissues,

This

mass

close

surgical

are

severed

the hemostatic

time

in

thrombi

thrombus"

thrombi

the

extend

in

large

studies

ted

vessels

thrombi.

of a tree,

the

case

formed

in

wound

comparatively

in

thrombi

special

clot,

era11

two

wound

traumatized

vascular

the

in

wound

wound

Resistance

of capillary

vessels

of additional

multiple

Thrombi

"wound

wounds

as many

of a gaping

This

term

numerous

microcirculation

These

the

simultaneously,

test.

Wound

the

seals

Since

infliction

of

and

above,

which

(8).

sels

Thrombus

for

the

and

wound

ON HEMORRHAGE

12

thrombi

occur

in numerous

the

formation

of the

ably

fibrin

coagulation

process,

.occurring

ant

the maintenance

that

for

and

but

In addition,

tized

vessel

sels

teins

initial

take

part

(34)

may

tribute

significantly

pictured

as follows:

at

the

occurs

at and

near

vascular

result

of this

altered

longer

an

distribution

the

this

initial

site.

followed

by a growth

of these

proteins.

then

followed

outside

the We

lular

ting

no

clumping

gation

which,

plained as

the

and

pertaining The

interpretation either design

and

It is

and

the trauma-

blood

ves-

plasma

pro-

will to the

but

plasma an

reinterpretation of new

of experiments,

both

with

the

viz.,

upon

layer is

clumping,

as well

inside

and

vessel. to blood the

as a form role

in

of hemostasis in

cannot

or fibrin regard

flowing

formation

include

which

be no

proteins,

coagulation

of findings

aggregation

may

as a

occurs,

plasma

increasing

findings

in

their

proteins

initiation

there

processes must

is i.e.,

that

of layer

blood

con-

disturbance

surmised

thrombus

fibrin

clotting

play

other

may

of bleeding,

process

and

damaged

formation

and

of clotting

proteins

adsorption

immediate

the

wound

onset

a dynamic

of the

other

situation,

subsequent

other

by platelet

wall.

or near

hemorheological

of platelets

limit

fibrin

re-

vessel

of the

process

the

plasma

the

rather

site

in my view,

of thrombosis. the

of

and

longer

of fibrinogen

of problems

and

process

affected

solely

inured

and

vessel

lesion.

of fibrinogen

formation

can

a major

of the

by deposition

as by fibrin

with

Consequently,

This

at

of the

This

hemorheological

adsorption

(15)

thrombi

to the wound

adhesiveness

of the

Immediately blood,

at

limited

of fibrinogen

site

of whole

blood

contended

the wound held

sites

in hemostasis.

extravasation

even

of were

thrombi

the

Copley

traumatized

to hemostasis.

the

and

the

constriction

of layers

occur

wounds

the

clotting

to be import-

also

of

both

prob-

appears

be

wounds the

latter

not

of the

and

in which

may

contraction

by

of

firmness

a property

aided

surroundings

the

adhesiveness

deposition

The

Lalich

the

and

clot,

of hemostasis.

become

(4,8,41,49) The

vessels,

may

of the vessel

the

to the vessel

However,

is. thus

involved. in

hemostasis

adhesiveness

sponsible. thrombi,

is mainly

capillary

maintaining

their

site

blood

Vol.4,No.l

Hemostasis

extravascular

predominantly

injured

HEMOSTASIS

vessels.

contiguous

of the in

AND

the

cel-

aggreof clotthe

study

as well

as

literature

be readily

formation, to laboratory

ex-

aS

Well

studies

ON HEMORRHAGE

Vol.4,No.l

and

clinical

new

form

other

investigators

it was

rinogen

(58).

in

issue

this

that

fibrinogen

can

polymerize

transglutaminase

It has

been

found

that

(59),

without

alteration

a few

in

of its

for

the

disulfide

of fibrinogen

evidence

into

account

is increasingly

that

system

polymers

approach

to take

shown

redoxin

found

This

have

13

this

being

made

by

(56,57).

It is known Recently

will

investigations,

of clotting.

AND HEMOSTASIS

the

can

Blombgck

presence bonds

gross

were

by

presence

thrombin.

directly

et al.,

clot

in fibrinogen

fib-

as reported

of thioredoxin

molecular

formed

without

reductase

are

structure.

reduced However,

on re-oxidation.

These

of a thioredoxin-like

authors

substance

in platelets. There the

may

We

platelets.

layers that

in

the

platelets

growth

may

considers

ness

my

time

values

prolonged

to the the

formation

fibrinogen

at

Wound test ing

time the

site

thrombi

by Copley

and

vessels.

tized

with

termination thrombi systolic

stated

an automatic of both

resistance. pressure

the

time

clots

in

to the

above, stylet

bleeding

is applied

initial

phase

of

he

Hartert

the

plateau

relates

to the

of findings

relates

(57) for-

thick-

patients,

may

not

the vessels, aggregation of the

formerly

of certain time

pressure

and

named

be primarily

of the

the

for

replenished vessels.

clot

resistance

measure

minute

due

for

and

test-

capillary

simultaneously

trauma-

dimensions

the

for

subsequently

of about

to the upper

of fibrinogen,

traumatized

in numerous are

in which

traumatized

is an in vivo

they

to blee

afibrinogenemia

by infusions

values

(4,6,8),

A cuff

of the

for

these

corrected

of hemostasis

As

In

of the wounds

Lalich

strength

thrombi.

congenital

(48).

resistance,

the maintenance

blood

with

were

but

suggest

of fibrinogen.

bleeding

test,

of surface

of rheo-simulation,

which

involving

findings

in the

an explanation

Rogers

of fibrin

the

of wound

reinterpretation

times

normal

bleeding

layers

and

bleeding

resulting

as

method

in patients

by Weiss

These

(60).

to be formed

as well

the

resistance

in increasing

to furnish

of

in hemostasis

viscous

rheo-thrombelastogram

example

obtained

the

proposed

of polymolecular

ding

a role

proposed

theory

in his

An

increased

of a thrombus newly

mechanism

of platelets

play

layers

In his

mation

found

presence

polymolecular the

be an additional

arm

20 mm Hg 5 and

de-

the wound below

15 minutes

the af-

14

ON HEMORRHAGE

ter

the

ing

into

the

pressure

newal

completion saline

impaired.

7.

Capillorrhape, Capillary

ces,

signifies

not

ment

cells

among

other of the which rin"

remain

toxins

affects

typical

membrane,

the

the

blood

vessel

the

endothelial

space,

these

and

The

suggested,

from

the base-

contain-

which

of

the

the

inner

of

sites

(61)

of

exendothe-

material

Palade

forms

site,

aspect

and

represent

or other

can

basement

remaining

of granular

well

fib-

membrane.

interendothelial

and

"cement

vascular

in

the

constituents

Hemorrhage

basement

localized

and

is fibrinolysin

at a given

by Majno might

for

lining

pools

observed

membrane,

of the

of the

agent

of the

the

be

disturban-

agents,

(26,28,31).

to be

in

studies,

authors

or more

fibrins,

layer,

viz,,

longer

(5,7,17,20,25$bacterial

in proximity

31).

microscopic

as

rin,

wall,

28,

Hemorrhagic

term

proposed

cells,

exoendothelial electron

was

no

composition

hemorrhagic

integrity

can

is

Test

space

hyperfibrinolysis

the

re-

versus

exoendothelial

on one

atypical

endoendothelial

(26,

spaces

and

from

fibrin

One

Fragility

basement

and

No

of hemostasis

the

chemicals act

in

and

valve.

to clotting

a defect

nature

as a generic

damaging

Cement

certain

minutes

the Ecchymosis

due

obscure.

membrane.

result

ultimately

lial

in

introduced

therefore

quite

of a needle

and

of bleed-

three

Capillary

the

The

(13,14,29),will

basement

was

by

of

traumatization,

always

(26,28).

others,

by

separated

Renewal

the maintenance

or necessarily

includes

layer

membrane

use

Petechiae

produced

solely

Hemorrhage

the vascular

the

that

Permeability,

to be

endothelial

with

Vol.4,No.l

(6).

a period

Pseudohemorrhage,

Hemorrhage, considered

time

during

is maintained

of .bleeding

HEMOSTASIS

bleeding

is observed

not

ed,

of the

AND

in the in

their

fragmented

of atypical

fibfibrin

(26). In addition may

contain

to the

the

following

mucopolysaccharides ate)

and

lexes. capillary

therefore,

permeability

preparations (29).

The

which made

gations-on-the

of

nature

these and

the vessel

are

basement

collagen,

hyaluronic

acid

membrane

elastin,

and

reticulin,

chondroitin

mucopolysaccharide-protein

observations

by injecting

of hyaluronidase, results

fibrin,

substances:

(chiefly

glycoproteins We,

cement

into

on capillary guinea

collagenase, studies

composition

emphasize of the

pigs

elastase the

comp-

fragility highly and

need

basement

sulph-

and

purified

lysozyme

for

investi-

membrane

and

ON HEMORRHAGE

Vol.4,No.l

how

its

components

orrhage

and,

rhage

which

can

augment

fected

blood

are

be many the

because

15

to the production hemorrhage

become

or

of hem-

capillor-

amine

do not

Their

of whole

blood

in

the

study

globin

the

through

ditions which

were

and

origins

lead

blood,

to ecchyof

tissues

the afor struct-

(31).

due

manifest

escape

of red

between

the

space

bleeding.

become

cells,

Majno to histwhite

endothelial

simulated

Therefore,

visible

where

basement can

they

cells.

extravasa-

I named

there

types

of

the

hemolyze,

with

this

be another

likewise

the

this

form

cells

an

electron of pseuremain

escape

of hemo-

inflammatory

form Such

be differentis an

red

in certain

as petechiae.

in which

cannot

One,where

membrane

still

and

unless

Two

lesions.

themselves

microaneurysms

subsequent

the

differentiated:

There

capillaries,

to hemorrhage

such

other, the

(23,24,28).

can

11pseudohemorrhage"(23,25,28,31). may

of

capillorrhages,but

of blood

a gap

true

captivity

dohemorrhage intact,

in blood

or

petechiae

microscopic

of the

mirror

exoendothelial

Pseudohemorrhages from

do not

surrounding

extravasation

through

blood

cellular

iated

of its

treatment,

platelets

captivity

tion

and

observed

serotonin

and

cells,

but

functions

necessarily

without

(61)

and

(14)

of different

impaired.

visible

Palade

wall

agents

count

hemostatic

vessel

not

hemorrhagic

petechial

the

Petechiae

are

leading

to capillary

in particular,

mosis,

and

affected,

HEMOSTASIS

(16,17). There

ures

are

AND

con-

of pseudohemorrhages pseudohemorrhages

basement

membrane

remains

intact. We and

found

capillary

scopic

contention, that

synonymous. to occur

in

illary

permeability which,because

capillary

those

capillary

at

the

cells,

about

p rovide

of our

where

same by

site.

certain

and

capillary

so-called

an

findings,

basement

fragility,and

(or

simultaneously

(61)

of the

The

permeability electron

as a manifestation

permeability

cases,

permeability

brought

of capillary

to be antagonistic.

A breakdown

to increased

properties

of pseudohemorrhages

capillary

portable,

physical

fragility

findings

creased the

the

The

is no

membrane

hemorrhagic

longer

is

supare

considered initially

increased

incontinence)

necrosis

for

fragility

hemorrhage,

capillary

of in-

explanation

capillary

excessively

micro-

due

capexist

of endothelial

agents,

may

contribute

ON HEMORRHAGE

16

to the

breakdown

As and

of

of the release

occur

and

Fluid-filled capillaries or gap

In

I developed

earlier,

pores,

would

or

and

lead

are

blood

largest

by the

chance

vessels

which

in

vessels

have

a predeliction

capillary certain

the walls

and

of blood

largest

the

concept

pore

chance

a large

op-

of fail-

in fracture

a stronger for

in

the

produced.

the

of having

found

to enhance

abundantly

link

proximity

We

to exudates

defect

formation

the

membrane.

"poresft penetrate

the weakest

have

of fibrin

steadily

basement

peptides

the

with

is determined

processes

may

capillary

represents

in accordance

anics,

these

(29).

plasminopeptides

release

channels

(62).

ago,

and

This

in which

membrane

in the

Vol.4,No.l

HEMOSTASIS

simultaneously

cell

(30).

situations

large

years

of fibrinopeptides

permeability

ure,

many

endothelial

ening

the basement

I contended

fibrinolysis

AND

mechAs

opening.

tendency

to

capillary

fragility(25,

no

the

28). In vascular bility that

characteristics the

surface

surface

widely

ity

of

defect

is gross

of the

and

closely

capillary and

olysis

We

from

found

the

permeability

in

capillary

or in animals

edema,

is an indication as

compared

In augmented order

to the

capillary

of 0.1 p

or more,

Contrariwise,

surface.

significant a few

structural

to hundreds

of capillary

cases

increased

with

permeability, we

produced

as

in fail-

of Angstrom

antagonism

in which

permea-

fragil-

capillary

in scorbutic

increased

fibrin-

(24).

whether

all

can

or not

practical

of blood

and

thus

tested

be

On gross

hemorrhage.

echia

total the

spaced

decreased

A petechia

tiate

small

permeability

in dimension.

guinea-pigs

the

of very

This

is negligible

the

capillary

and

defect

system.

fragility

for

the

maintained.

vascular

is minute,

units

are

with

entire

spaced

enhanced

a condition

of the

fragility,

ure

purpura,

be

site.

a capillary

examination a petechia

purposes

indicates

can

either

it is not mirrors

a petechia

that

possible

denotes

as a sign

Conversely,

or a pseudoto differen-

a hemorrhage.

hemostasis

considered

hemorrhage

ecchymosis

is not for

the

However,

extravasation

impaired.

adequate

signifies

A pet-

hemostasis impairment

at of

hemostasis. In Copley

1948, and

I first

Kozam

(10)

described reported

the

ecchymosis

findings

secured

test with

(9).

Later,

simultaneous-

ON HEMORRHAGE

Vol.4,No.l

ly performed were

made

methods

with

for

pressures

a needle

valve,and

The

cups

were

per

arm,

3 to 9 cm below

for

and,

regions

with

applied

petechial

of capillary

purpura,

petechial

sure

tests,

ion.

This

did

parisons

were

healthy,

adult

negative

pressures

petechial

the

(9).

made

ecchymosis.

mm Hg,

of 4.5

mm

brachial

of the

by

in diameter region

and

They

maintained

axillary

human

of

(9,lO).

the up-

fossa

(9,10)

infraclavicular

and

seen,

which

plaques

though

a petechia

manifestation counting lesions

are

the

area,

counts

and

We

4.5 the

may

petechiae

and

the

examination

directly

count

of three

of impaired

numerous

(9).

Under

not

be

from

petechiae

accurately

because

discretely

visible.

numerous

in

area. al-

to pin-head. of

the

test

The

ecchymotic illuminated permits

with

in a cir-

for

in certain

petechial

we of

adopted

instances

As we pointed

of many

A count the

pur-

plaques

of ecchymosis

comparatively

numerous

pressure,

hemostasis.

plaques.

to merging

mm Hg

ecchymotic

simultaneously

petechiae

of ecchymotic either

used

in

as a hemorrhagic

The

degrees

com-

For

petechiae,

literature

skin.

100

(10).

of an electrically

on the

in diameter,

ies

considered

use

of

produced

ecchymotic

single

pin-point

condit-

with

the produced

as a large as

the

and

press

Thereafter,

a slight

to

from

extravasation

are

is applied

appeared

the

patients

skin

of ecchymosis

or glass

negative

of graded

of the

size

extensive

counted

increments

regions

of vascular

ecchymosis

in

detection

be due

and

es-

development

three

in

mm

presence

in

the

hemorrhagic

hemorrhages.

be identified

by

and

to the

defined

placed

could

the

was

differentiation

cular

with

of lucite

not

led

counts

detection

facilitated

5X magnifier

ecchymotic

the

for

cases

positive

application

originally

varying

of the

counts

blanching,

should

with

In

characterize

subjects

by a sheet

be

Its

measure

diathesis.

obtained

in different

counting

area

an adequate

of petechial

puric

was

and

supraclavicular

is not

produced

to affect

they

apex

hemorrhagic

sufficient

mosis

the

cup

internal

of petechial

test

purpura

out

-100

adequately

failure

vascular

ease

to -600

counts,

not

ecchymosis

Such

from

a special

count

timation

can

count

17

(10).

The

the

HEMOSTASIS

petechial

to the

comparison,to

AND

small few

their

large

of more test

out,

petechiae

ruptured

considered

those

area

ecchyor to

capillarwhich

number

than

with-

may

although

30 petechiae

of 15.9

mm2.

A

18

ON HEMORRHAGE

two-minute and

test In

error.

of ecchymosis induced -300

period certain

at

-300

in normal

mm Hg was

good

for

Final

in vivo

article

important

tools

bleeding subjects

Such

comparative and

ploration, not

ion

for

This

that

simple

procedure

by

found

production

this

the

could

with for

clinical

of capillary

trial

not

and

be

below

capillary

test

can

blood

hem-

be put

to

vessels.

in

studies

1942

appraisal

of extra

employing

in vivo

possible,

with

different

forms

ties

of blood

sent

a great

They

may

the

various

hemostasis

extra

of clotting

tests. should

vivum

tests

the

that

research

pate,

if adequately

studied

extra

vivum

will

methods,

be

combined,

pertaining

studies as far

to the

combined and

with

hemostasis

and

phenom-

a critical

rheological

of bleeding

in patients

ex-

in connect-

Nevertheless,

investigators

to be

the

of other

to give

on phenomena

prove

re-

saline.

Such

in vivo

thrombi

described

different

to individual

wound

in

mammals.

to consider

Editorial

tests

and

we

into

(11,13,20,25,32,33).

challenge

conditions

which

of this

hemostasis

the

dif-

described

in other

of a number

of bleeding

scope

vivum

clots

find

article,

we

as

species.

employing

which

is advisable

tests

mammalian

be made

comprise

usefulness

in vivo

other

subsequently

also It

on the

other

those

applicability,

investigations in

and

tests.

and

studies

including

in this

and

in human

should

its

rethinking

time

comparative

mice

with

bleeding

methods

including

is not

clinical

Vol.4,No.l

produced

to initiate

hemostasis

ecchymosis

our

It

we

Since

ecchymosis

of the

and

dealt

with

less.

hemostasis

time

human

ena,

standard

conditions

and

is meant

It is recommended

sistance

as

to be pathognomonic

(10).

interpretations

ferent

mm Hg

HEMOSTASIS

Comments

This and

purpuric

considered

diathesis

8.

chosen

subjects,

orrhagic use

was

AND

important

when

to experimental

as

three proper-

studies their

and

teams.

its

tests

stop-

and

applied studies

pre-

with to

in an-

imals. The ported phasized but

can

simultaneous

by many in

authors,

1954,

have

these

cumulative

occurrence does

not

need

phenomena

may

action

and

thrombosis

(22).

learned

the

interrelationship

and

hemorrhage,

not

always

in clinical

A great which

oppose

deal

can

each

other,

manifestations

remains

exist

re-

As I em-

to be paradoxical.

resulting

of hemorrhage about

of thrombosis

to be

between

hemor-

ON HEMORRHAGE

Vol.4,No.l

rhage, ount

thrombosis

and

hemostasis

of investigative Fundamental

fibrinogen lation,

studies

and

with

of blood blood

studies

which

19

invites

its

clotting

cellular on the

of extravasation

and

needed

on hemorrhage

knowledge

HEMOSTASIS

substantial

am-

work.

aggregation,

together

AND

clumping blood

surrounding and

in its

its

and

vessel

tissues

three

will

forms,

fibrin

wall

viz.,

coagu-

at

the

advance

site

much

arrest.

REFERENCES 1.

BLOMBkK,

B. and COPLEY,

itors-in-chief.

A.L. Editorials, A note Biorheology.1, 231, 1973.

from

the

ed-

2.

FLETCHER, A.P. Editorial. Thrombolytic therapy in acute cardial infarction. Biorheology. 2, 233, 1973.

3.

P., POLLINI, C., CORTELLARO, PRAGA, C., MALISARDI, MARS, G. Bleeding time and antiaggregating drugs: Thrombosis Research.2, study in elderly patients.

M., and A controlled 13, 1973.

4.

COPLEY, A.L. and LALICH, clot resistance in men.

J.J. Bleeding time, lymph J. Clin. Invest. 2l, 145,

time, 1942.

5.

COPLEY, A.L. and LALICH, hemophilia-like condition a, 547, 1942.

J.J. The experimental in heparinized mice.

6.

COPLEY, A.L. and LALICH, J.J. The influence of blood transfusion and injections of Bursa pastoris (Shepherd's Purse) extract on the clot resistance in two hemophiliacs. Am. J. Med. Sci. 204, 665, 1942.

7.

M.H. and COPLEY, LALICH, J.J., LALICH, mice following the oral administration (4-hydroxycoumarin). Surgery.12, 316,

a.

LALICH, mechanism

J.J. and COPLEY, of hemostasis.

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A.L. Bleeding time in of 3,3'-methylenebis1943.

A.L. Clot resistance Arch. Sur~46, 224,

A.L. The ecchymosis Science.=, 201,

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10.

COPLEY, A.L. and KOZAM, G. Studies on capillary fragility and the ecchymosis test in man. J. Appl. Physiol. 4, 311, 1951.

11.

LALICH, cometer

12.

COPLEY, A*L* gic findings dogs. SW%*

of clot Med.=,

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the

9.

J.J. and COPLEY, A.L. A study tubes. Proc. Sot. Exp. Biol.

capillary

in mice 1943.

dia-

firmness in vis232, 1942.

STEFKO, P.L. and NAYLOR, J. Comparative hematoloin normal, splenectomized and Spleen-transplanted Gyn. Obstet.&, 646, 1947.

20

ON HEMORRHAGE

AND

HEMOSTASIS

Vol.4,No.l

13.

COPLEY, A.L. A new concept and studies of capillary haemorrhagSot. Haematol., 3. Internat. Proc. Internat. ic diathesis. Grune and New York: Congress, Cambridge, England, 1950. Stratton, 1951, p. 541.

14.

COPLEY, A.L. and CHAMBERS,R. Experimentally induced petechial hemorrhage and white embulization in the rabbit's nictitating membrane. Am. Heart J. &, 237, 1953.

15.

Hemostasis in sympathectomized COPLEY, A.L. and STEFKO, P.L, and adrenalectomized animals before and after total body XAm. J. Phvsiol.D, 295, 1954. irradiation.

16.

COPLEY, A.L. Capillorrhagic and antihemostatic effects in capillary hemorrhagic diathesis following ionizing radiation. Sot. Hematol. 4. Internat. Conpress. Mar de1 Proc. Internat. Plata, Argentina. 1952. New York: Grune and Stratton, 1954, p. 216.

17.

COPLEY, A.L. Effet capillorragique de la fibrinolysine et de l'antifibrinolysine sur la membrane nictitante du lapin normal et expose'aux rayons X. Arch. Internat. Pharmacodyn. Th& 2, 426, 1954.

18.

COPLEY, A.L. Thrombosis and thrombo-embolization in blood In: Thrombosis and Embolism I. Internat. Conf., illaries. Basel, 1954. T. Keller and W.R. Merz (Eds.) Basel: Benno Schwabe & Co., 1955, p. 451.

19.

COPLEY, A.L. and MAR.&HAL,J. Le taux de fibrinog&ne et la nume/ration des plaquettes dans le purpura vasculaire produit chez le cobaye par du sgrum de lapin antifibrine de cobaye. J. de Physiol. 9, 987, 1957.

20.

COPLEY, A.L. Thrombose.

21.

COPLEY, A.L. Vascular purpura in guinea-pigs and hamsters produced by guinea-pig antifibrin rabbit serum. Proc. 6. Congress European Sot. Haematol., Copenhagen, 1957. Basel-New York: 1958, vol.2, p. S518. S. Karger,

22.

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23.

COPLEY, A.L. Vascular integrity and the endoendothelial fibrin film. Proc. 8. Congr. Europ. Sot. Haemat., Vienna, 1961. 1962, ~01.2, 'NO. 357. S. Karger, Base1 and New York:

24,

V. The antibradykinin action of fibCOPLEY, A.L. and TSULUCA, rinolysin and other studies on capillary permeability employBiochem. ing different mediators and synthetic bradykinin. Pharmaco1.10, 67, 1962,

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cap-

und

ON HEMORRHAGE

Vol.4,No.l

25,

AND

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21

COPLEY, A.L. Le r&e de la fibrine et de la fibrinolyse dans l"integri6 de la paroie vasculaire. Hgmostase (Paris).l,

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27.

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28.

COPLEY, A.L. significance vessel wall.

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COPLEY, A.L. Capillary permeability, capillary incontinence, compaction stasis and basement membrane breakdown. Bibl. 148, 1965. anatomica.1,

30.

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Capillary permeability versus fragility and the of fibrin as a physiologic cement of the blood Bibliotheca anatomica.i, 3, 1964.

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On the capillary fibrinopeptides capillary wall.

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B.W. and ALLEN, Jr., R.L. J.P., LUCHINI, permeability enhancing activity of isolated and their role in the physiology of the-blood Bibl. anatomica.2, 475, 1967.

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22

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ON HEMORRHAGE

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AND

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HEMOSTASIS

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