Use Of Viper Venom

From www.bloodjournal.org by on July 21, 2009. For personal use only.

1986 68: 869-874

The use of the dilute Russell viper venom time for the diagnosis of lupus anticoagulants P Thiagarajan, V Pengo and SS Shapiro

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Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published semimonthly by the American Society of Hematology, 1900 M St, NW, Suite 200, Washington DC 20036. Copyright 2007 by The American Society of Hematology; all rights reserved.

From www.bloodjournal.org by on July 21, 2009. For personal use only.

The

Use for By

We

describe

here

a modified

a test

Russell

amounts

for

viper

of phospholipid

patients

with

normal

a prolonged

activated

1 4 tested

by the

normal.

normal

L

ANTICOAGULANTS

against

when

with

of a lupus and

anticoagulant

recurrent

prevalence

of

lupus

since

inhibitor

have

not

been

clearly

activated

partial

miof

established.

by the finding

thromboplastin

time

of the

tissue

the

ever,

thromboplastin

TTI

can

test presence

inhibition

be negative

in the

using

diluted

phospholipid method,

venom

and

reagent.33 as well

We

as some

compared

concentration

describe

here

studies

the TTI lupus anticoagulants. ity

a limiting

to

prolonged

that

of lupus

described Russell

of

3.8%

tests.

trisodium

trifugation

prothrombin bin

time,

and

2,500

NJ),

tissue

Thrombin

in our

laboratory

Preparation

are

The

was performed

using

a

1:100

Diagnostic

seconds,

of

23 to 36 seconds,

to the method

tissue

to specific coagulation Assay.35 All test results

factors described

described

viper

previously.33

Wellcome,

Raleigh,

manufacturer

and

mol/L

0.02

Blood,

NaC1,

Vol

room

mol/L

NaCI,

glucose,

pH

0.02 7.5.

68.

venom

time

Briefly,

NC) further

mol/L

No 4 (October),

Russell

was

chem,

San

tration

of

Raritan,

NJ),

was diluted

I :200

Tris,

pH 7.5).

Diego,

and

tests

20 to 26 test

of Schleider The

et al,9 titers

1986:

was performed

pp 869-874

phospholipid

as

(Burroughs

as suggested

in Tris-buffered

substituted

for

mol/L

Tris,

-

were

to 2 mL

ionophore-treated

but

70 #{176}C for future

at a EDTA.

suspension

A23

five

platelets

mol/L

without

(giving for

of 0.15

0.005

of platelet

ethanol

incubating

washed

resuspended

ionophore

in absolute

were consisting

EDTA,

buffer,

of calcium and

at

mol/L

in the same

at I ,500 g for

platelets

platelets

by adding

Calif)

the

in a buffer

twice-washed

tmol/L,

temperature.

was centrifuged

0.001

Citrated

at room

1 87

a final

concen-

minutes

were

used

I

(Calbioat

room

immediately

use.

RESULTS

Effect sell

ofphospholipid

viper

venom

concentration

was

diluted

of lupus

achieved

lupus

on the

to give

RVVT.

a clotting

time

Rusin normal

25 seconds. At this dilution,

of approximately

separation than

at

anticoagulant

higher

and

venom

are antibodies

anticoagulants

the

slightly

normal

plasma

concentrations.

with

Since

immunologic

reactiv-

Cardeza of

saline

by the (0.15

reagent

Foundation

Medicine.

for

Jefferson

Hematologic

Medical

Research.

College

of

Thomas

Jefferson University. Philadelphia. Supported

by NIH Grants HL-09163 (555). HL-27278 and an Established Investigator Award from

in part

(PT), a Grant-in-Aid the

American

Award

Heart

Submitted

1015 charge

Association

of The Lupus

Foundation

The

centrifugation

in aliquots

were determined by the here were performed in

reconstituted

was

platelets,

platelets.

and

and

solution

The

or frozen

were

for these

venom

diluted

chloride using

was

I 5 minutes

supernatant

achieved

2.5

temperature.

Address

viper

platelets

was

of

for 30 seconds

calcium

ionophore-treated

of 8 x I 08/mL

of a 5 mmol/L

of

(RVVT)

mol/L

the

manner

RVVT mL

In experiments

temperature

The

March reprint for

Walnut

6. 1986; requests

Street.

payment.

“advertisement” indicate this fact. cc 1986 by Grune

(PT)

Foundation

Hematologic

The publication Russell

0.1

phospholipid

of 0.03

the

dilute

plasma,

partial

however, in

The

of

at 1 50 g for

by suspension

From

laboratory.

The dilute

washed.

plasma at

Department

Morris

inhibition

thromboplastin.

Other

The

respectively, ranges

thromboplastin

according

dilution

normal

of

minutes

twice

time and throm-

Systems,

IX.

a simple. method for

by cen-

Diagnostics,

Mich), The

tissue

obtained temperature.

thromboplastin

Kalamazoo,

I 2 to I 5

room

(General

previously.34

(TTI)

our

partial

was

at

of

Results).

recorded.

the

volume

one-tenth

saline.

determined

ionophore-treated

centrifuged

was

was

in

plasma

minutes

(Ortho

respectively.

antibodies Bethesda

15

(Upjohn,

as desribed

seconds,

collected

thromboplastin

Thrombofax

performed

was

VIII.

phospholipid.

Activation

METHODS

Platelet-poor g for

time, activated using

Plains,

Blood

citrate. at

AND

be

mL

mL

time

of the

details

be

Thrombofax;

0. 1 mL diluted

0.1

of calcium

to

(see

and

which

for

needs 0.1

the clotting

and

1:8 in Tris-buffered

reagent

venom,

is not

to factors

Inc.

be substituted

incubating

viper

better Coagulation

by

RVVTs.

RVVT

anticoagulants.

Thrombofax

for

performed

plasma

MATERIALS

each

of

patients.

dilute

of antibodies

& Stratton,

can

The

two dilute

RVVT appears to and relatively specific

was diluted

dilution

zL

and specificin the diagnosis of

aPTT

the

Grune

concentration

Howlupus

presence

the

by

remaining

normalized.

the dilute sensitive.

detection

the

phospholipid-dependent

or Xl. Thus. reproducible,

of its sensitivity

and

in the

ten

a

anticoagulants30’3’ and has been reported to be positive in the presence of some factor VIII or factor IX antibodies, as well as in the presence of heparin.32 In order to avoid some of these problems, we have employed a modified Russell viper venom time,

long

Shapiro

completely

The platelet-rich

(aPTT)

(TTI).9’29 of some

phospholipid;

nearly

of

corrected

plasma.

for very

of a

by addition of an equal volume of normal Corroboration is frequently sought by performance

is not

were

blood

coagulation

Suspicion

aroused

with

0. 1 mL

the to

difficult

been of this

S.

substituted

added

thrombosis’#{176}’8

Time

Sandor

at 37 #{176}C, after

presence

Nevertheless,

diagnosis

is usually

anticoagulant

prolonged

for

has

the

the

and

Thrombofax

individu-

that

Pengo,

thromboplastins

variety

a

Venom

Anticoagulants

a 1986

erythemato-

in

factor

anticoagulants for

was

reactive

normal

abortions.’928

criteria

were

Though

described

is a risk

of

prolonging

lupus

clear

a

were

antibodies

apparently

become

spontaneous

determine, lupus

it has

test

tests.’5

been

three

platelets

systemic

in

had

RVVT

thereby

Viper

both 29

29

and

dilute

are

sus, similar inhibitors have disorders and, occasionally, years

of the

inhibition the

on

limiting

studied

time

tested.

in patients

In recent

have

Five

coagulation

recognized

als.29

RVVT.

phospholipids,

phospholipid-dependent tially

using

ionophore-treated

anionic

Vittorio based

(RVVT). We

Russell of Lupus

anticoagulants

thromboplastin

1 9 patients

completely

UPUS

Thiagarajan,

thromboplastin

tissue

In 1 7 of

Perumal

venom.

dilute

partial

Diagnosis

time

and

Dilute

the

lupus

venom

of the

and

the

Sheryl

ofPhiladelphia accepted to

Dr

May

Philadelphia.

PA

S.

Shapiro.

Jefferson

Medical

costs ofthis

article

were defrayed

must

therefore

in accordance & Stratton,

with

Cardeza College.

19107.

This

article

Hirsch

12, 1986.

Sandor

Research.

N.

(555).

18

U.S.C.

in part by page

be hereby

§

1734

marked solely

to

Inc.

0006-4971/86/6804-O0I0$03.00/0

869

From www.bloodjournal.org by on July 21, 2009. For personal use only.

THIAGARAJAN

870

ity

towards

anionic

sensitivity

test

phospholipids,

further

phospholipid

we

by using

reagent

the

used

when

tested

in normal

plasma.

lupus anticoagulant Thrombofax dilution concentration

from

even

undiluted

normal plasma, I 4 fresh normal normal

range

using

fresh

We consider above

the

not

laboratory was

clotting

times

by

addition

this

test,

of such

were

prolonged

of

an

have

Of

therapy

aPTT

equal

the

the

remaining

time

fifth

patient

patient

had

had

Substitution

of

gated

as follows.

is variable

for

two

patients

but

titer

had

20

a

f

0

of 1:16; and

platelet

in

.

Ionophore-treated

the

of a

abortions;

phospholipid

the

.

PH OS P HO L I P ID

the

.

.

dilute

ionophore. was investiwere

diluted

of 23 to 28 seconds. to give this clotting

preparation,

Fig 2. Effect lupus anticoagulant

.

calcium reagent

platelets

giving an RVVT of platelets necessary with

i..-. 30 Q

ranging

.

to The time

between

50

l08/mL

and

stored

for

0

two

the

w

The

I-. c.:

::

one

4

0

The

by

2 0

the

does I:2

PHOSPHOLIPID Fig RVVT. patients.

1. Effect Bars are

of phospholipid normal controls

I :4

I :8

I:I 6

I:3 2

DILUTION concentration and closed

on circles

the are

was

R VVT

in

RVVT

VIII,

dilute lupus

IX,

in these addition

In contrast,

I :I

two

factor X levels below 0.4 receiving oral anticoagulants

0

not

-

at

70

not completely

of the

.

However,

Washed,

ionophore-

#{176}C without

2, in 17 of 19 cases

prolonged

factors

#{149}

Fig

was

.

.

O

or more in

very

dilute

VII,

108/mL.

in suspension at least during can be quick-frozen at least

had

dilute

cies.

x

be seen

RVVT

patients

addition,

.

200 stable and

the once loss of

tested

in

the RVVT was completely normal when perplatelets rather than phospholipid. In the other

with

cases

two

6 0

and phospholipid on the RVVT of Hatched areas are the 2 SD normal

I 2 months

As can

formed .

8

and

treated platelets are day they are prepared,

this manner

-

of platelets plasmas.

ranges.

activity.

I0 0

P L AT E L E T S

erythematosus.

The effect of substituting platelets for the phospholipid

a concentration concentration

is

normal

presence

study

(RPR)

of recurrent

lupus

platelets

-

F

patient

.

RVVT. . activated

SD

had a chloropromaan antinuclear antibody

one

a history

systemic

(

2 SD).

of

five,

of our

zine-related lupus syndrome with titer of 1:320 and a rapid plasma reagin

the fourth

period, ±

(>3.8

volume

40-

on The

referred to us because of the Of the 29 patients, only 24

at the

previously;

of

a single

a 3-year

2.6 sec (

or greater

diagnosed

an anticoagulant. aPTT.

on steroid

on

and make a presumptive when an abnormal test

in 29 patients

a prolonged

with

of variation

±

50

a

clearly

RVVT

over 25.6

of 30 seconds

we

were

range, determined 1 .5 sec ( ± 2 SD).

±

in our

at

phospholipid

replicates

normal 26.2

plasmas,

anticoagulant

suspicion had

The was

frozen

Using

lupus

0.8%.

this

normal

20

of

achieved

coefficient

observed

corrected

plasma.

The

mean) to be abnormal, of a lupus anticoagulant

diagnosis

a

by performing plasmas,

As

separation

was

At

had

reagent.

was

and

optimal

patients

some

phospholipid

of

activation.

plasma

anticoagulant

test, determined

this

However,

normal

though

the

was slightly inhibitory when at a dilution of 1:2 to 1:4,

of I :8 or greater.

lupus

abnormal,

increase

to

concentration

for prothrombin

necessary

be seen in Fig I , Thrombofax undiluted and was optimal

can

wished

minimal

ET AL

situations

of an

addition correct

XI,

equal

receiving

normal

or

XII.

dilute

oral

factor in

test

of normal

of

deficient

with

the prolonged

RVVT

deficien-

plasma

Plasmas

volume

in

anticoagulants.

U/mL and plasmas give a prolonged volume

These

and,

RVVTs

coagulation is

of an equal the

normalized.

dilute

factor

from dilute

patients RVVT.

is normalized plasma

of normal lupus

in

V or

(Fig

3).

plasma

anticoagulant

plasma. In fact, an occasional lupus anticoagulant plasma shows a further prolongation of the RVVT test on admixture with normal plasma (Fig 3), an effect previously referred to

as the “lupus

cofactor”

The dilute to coagulation

R VVT in the presence of heparin or antibodies factors. The presence of antibodies to fac-

tors

VIII,

phenomenon.36’37

IX, or XI does not prolong

the dilute

RVVT

(Table

From www.bloodjournal.org by on July 21, 2009. For personal use only.

LUPUS

ANTICOAGULANTS

871

Table

70

2.

Effect

of Factor

V Antibody

on the Dilute Dilute

Factor V Antibody . Concentration lBethesda

60

.

Phospholupid

(seconds)

66.3

a)

50 40

was

also

I-

tion

between

I0 .J U

68.9

59.2

66.9

57.8

6.63

61.9

56.7

0.663

38.5

40.1

0.066

32.3

29.2

0

25.4

26.9

normal

in the results

appears

RVVT

Platelets

U/mL)

663.0 U

RVVT

RVVT

TTI

test.

all

three

of

to be the

most

Thus,

although

tests

was

sensitive

the good,

correlathe

dilute

of the three.

30 DISCUSSION A

20

0 Fig

P+N

P

3.

(A)

Effect

factor-deficient

of

normal

plasmas.

V-deficient

plasma;

P plasma

0. factor

on

P+N the

X-deficient

#{149}.plasma

of

dilute

RVVT

plasma;

patients

on

0.

oral

of

number

anticoagu-

of

presence

correct

when

an antibody

V does

to factor

prolong

ionophore-activated

platelets

are

used

the not

(Table

As

shown

prolonged

in Fig

4, the

by therapeutic

to be less

appears Below

0.2

RVVT

is

U/mL

levels

sensitive

Comparison

with

of heparin.

The

the

aPTT

prolongation

ionophore-treated

(data

the aPTT

As

like

the

when

for phospholipid

inhibition test. had prolongations

RVVT,

than

of heparin,

corrected

substituted

dilute

the

aPTT,

and

immunologic thereby

tests.

may

show

reactivity

prolong

dilute

RVVT regard.

Nevertheless,

variable

of the

aPTT

phospholipid-dependent

sensitivity

and/or

specificity

the dilute

and

tests,

the quantity for

ity toward utilize any

of phosphatidylserine

has been shown

example,

lupus added

anticoagulants.4”42 One phospholipid, presumably

pholipid

originating

dust.”43’

Second,

the

different

tests:

in

from the physical the

present their

to affect

no

in such sensitiv-

test38 relying

does not on phos-

plasma or the “platelet state of the phospholipid

aPTT

and

the

RVVT

utilize

90

I

are

I

thromboplastin RVVT,

toward

lupus anticoagulants for several reasons. First, there are standards for phospholipid reagents used in coagulation

not shown).

and

anionic

dilute

platelets

and the tissue

used

phospholipid-dependent

V

I

be seen in Fig 5A, 25 of 29 patients

can

and

is

in this of the

proposed

towards

have

phospholipids

differs

2).

been

anticoagulants

tests

the

in contrast to the lupus anticoagulant, RVVT of factor V antibody plasma does

have

reflecting the their definition clear that lupus

reagents, 1 ). The

tests

for the diagnosis of lupus anticoagulants, difficulty in reaching a consensus concerning and mechanism of action.9’38’39’#{176} It is now

coagulation

factor

lants. (B) Effect of normal plasma on the dilute RVVT of lupus anticoagulant plasma. Equal volumes of patient (P) and normal (N) plasma were mixed and the dilute RVVT recorded. Hatched areas are the 2 SD normal range.

test. However, prolonged dilute

of different

0/

while Li

four

patients

aPTT. abnormal

patients TTI

with

an abnormal

dilute

RVVT

As shown in Fig 5B, I I of 14 patients in both dilute RVVT and TTI tests. with

while

potent

a third

1gM

lupus

patient,

with

anticoagulants a weak

lupus

had a normal studied were However, two had

/5

I

z

I

a normal

anticoagulant,

I-.

0 -A

1 . Effect

of Antibodies on the

to Coagulation

Dilute

‘V

Factors

0/0

RVVT

Titer (Bethesda U/mL)

Dilute RVVT (seconds)

FactorVlll

38

25.9

FactorVlll

87

26.3

FactorVIll

7

26.8

FactorVIll

23

25.7

FactorVlll

14

26.7

FactorlX

85

27.1

FactorXl

415

26.4

.

0

‘-,

Antibody

S

9/

0

Table

V

V

V

3

OOl

0.02

0.05

Ol

HEPARIN Fig 4. Effect of heparin three normal plasmas. Open RVVT.

02

05

10

(units/mI)

on the aPTT and the symbols. aPTT; closed

dilute RVVT of symbols. dilute

From www.bloodjournal.org by on July 21, 2009. For personal use only.

872

THIAGARAJAN

:

50

.

. .

I-

> > Li I-.

IX,

or XI,

by the and

by using

test

dilute the 20

RVVT, test

-I

but

prolongs

also

patient

0

is easy

these

this

whom

did A

30

50

p T T (

a

60

antibody a rare

.

and

C

0

U

a)

#{149} #{149} #{149}

C

and

be easily

test.

highly

platelets

correct

the

in one the

unlike

Furthermore,

factor

V antibody substitution reagent

findings

with

presence

a marked

The event,

phospholipid

the

the

with

by repeating plasma. rare

to study,

for

test,

is associated occurrence

excluded

opportunity

reproduc-

for lupus anticocan prolong the

and patient V. an extremely

However, the

of

phospholipid

of

lupus

a factor

prolongation

V

of the

PT,

with lupus anticoagulants. Nevertheless, definitive exclusion of a factor V antibody requires specific measurement of factor V inhibition in a mixture of patient

sec

50

40

not

anticoagulants.

)

can

to factors

the sensitivity of both

to perform

of normal to factor

we had

of ionophore-treated 2’0

of antibodies increased

concentrations

on a mixture of an antibody

presence

lO

presence further

limiting

This

venom.

have

ible. Nevertheless, it is not entirely specific agulants. Coagulation factor deficiencies

!#{149}#{149} #{149}.#{149}

#{149}L#{149}

0

30

.

it is unaffected

VIII,

and

#{149}#{149} #{149} #{149}#{149}

.

since

the test

0

::

40 a)

I

ET AL

normal Finally,

plasma. therapeutic

concentrations

dilute

RVVT,

although

aPTT

(Fig 4). 1-leparin

of heparin

to a somewhat

lesser

prolong

extent

the

than

the

in

.c:.

!;;

ment

3#{176}

>

ofthe

Li

thrombin

:

ever, occurs but rather

:

patients

IO

05

I 0 TTI

I RATIO

20

25

Fig 5. Comparison of the dilute RVVT with the aPTT (A) and the TTI (B). Open circles are patients with 1gM lupus anticoagulants. Closed circles are patients with IgG or a mixture of lgG and gM lupus anticoagulants. Dotted lines indicate upper limits of normal for the tests.

fled as a relationship

or

in micellar form, whereas time (PT) make use oftissue phospholipid is protein-bound.

in their

vary

antibodies factor

response

VIII

may

Finally,

there

related

to the

prolong

appear

for example,

lants

do not prolong

to

aPTT,

be

variations

the

forms.

in the plasma several lipids

as our

Since

presence

lupus of

some they

of lupus since

.

.

an increased

lipids,

to

The

anticoagulant

platelets

1.3,45,46

sensitive highly

1gM

anticoagu-

studies.

Second,

for the diagnosis

as

.

in

our

concentrations We have chosen of lupus

of thromboembolic

abortions)28

.

The

with

syphilis

some with

.

For example, positive are due to reactivity

to standardize

which

we

Moreover, than

the

aPTT

as

a

and

screening

both

describe

as we have

useful

has

have is less

if

serologic

of patient do not have

the

types

here

of tests.

is simple

demonstrated, TTI,

and

diagnostic

and

it is more thus

test

should for

be

further

other

be positive

of

rarely,

alone,37’8”5 to 30% of

for example, that are not associated

syphilis yet patients

RVVT

reproducible.

sensitivity

anticoagulants

use

is clear, antibodies risk.

it will be necessary

anticoagu-

activity the

history

spontaneous

.

thrombotic

dilute

test

of tests

anticoagulant which

an increased prevalence of lupus anticoagulants or of thromboembolic disease.48 For an adequate understanding of the biologic role of antibodies reactive with anionic phospho-

lupus

may

bleeding,

a

have

It

evaluated adequately. types of “anticardiolipin”

to

RVVT.

do prolong

patients

sensitivity

tests make use of limiting to increase their sensitivity.

test

the

in the

anticardiolipin antibodies, as measured by any immunologic techniques, has also been identirisk factor for thrombosis.5’2447 However, the between these two measurements has not been

ACKNOWLEDGMENT

in We wish to thank

the

has been advocated.

primary

in

of the

shown,

incidence

clearly established, one test and not another. Strategies to increase

not

although

and

antibodies

but

class

the TTI,

factors

instance,

the

not been

two

For

as we have

a result,

As

of clotting

factors.

immunoglobulin

lant; tests.

to deficiencies

to clotting

the TTI and the thromboplastin, in Third, the tests

is normal

test

by measure-

of a lupus

with

repeated

tests in patients with serum with cardiolipin, phospholipid prothrombin which the

this

presence

this antibody

with

presence of one ofseveral

out

as a result of the lupus anticoagulant in the fact that approximately 25%

phenomena,’#{176}8

B

since

be ruled

anticoagulant.

The significance of the does not lie in its association

20

can

time,

of a lupus

presence

a:

effects

E. BatIle

for expert

secretarial

assistance.

taken evident

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