THROMBOSIS RESEARCH 61; 311-314, 1991 0049-3848/91 $3.00 + .OO Printed in the USA. Copyright (c) 1991 Pergamon Press pk. All rights reserved.

THE PREDICTABILITY OR INSENSITIVE

OF BLEEDING PIVKA DURING

TO

H. Red

(Received 5.10.1990;

BY PROTHROMBIN INTENSIVE ORAL

Arnesen

Cross

and

Clinic,

P.

TIMES SENSITIVE ANTICOAGULATION

Smith

Oslo,

Norway

accepted in revised form 22.11.1990

by Editor U. Abildgaard)

ABSTRACT To

evaluate K

Vitamin tendency

the effect Absence or

of PIVKA Antagonism)

(Proteins on

the

Induced by bleeding

during oral anticoagulation, we studied consewarfarin treated with intensively cutive patients The level of anticoagulation was measured (INR>4.8). with the PIVKA-insensitive Normotest (NT) as well as (TT), and the PIVKA-sensitive Thrombotest with the cent coagulant activity. results are expressed as per The

NT/TT

ratio

was

determined.

Twenty

patients

with

episodes had a mean NT/TT ratio of 2.06 as without bleeding 2.20 in 143 patients to (p=O.O8). As the NT/TT ratio was not higher in with bleedings, we conclude that PIVKA are of during anticoagulation with importance for bleeding

bleeding compared episodes patients no vitamin

K

antagonists.

INTRODUCTION Vitamin K antagonists thromboembolic disease. gonists, various amounts Absence or Antagonism) carboxylation in their

are widely used in the prophylaxis of During treatment with vitamin K antaof PIVKA (Proteins Induced by Vitamin K (1,2) are formed. PIVKA lack gammaglutamic acid residues, thereby losing

procoagulant activity (3). Control of oral anticoagulation is predominantly undertaken with prothrombin clotting time assays. Assays with dissimilar thromboplastin reagents differ with respect to their sensitivity to PIVKA as inhibitors of coagulation. Thus, Normotest (NT)

Key

words:

PIVKA. Oral Prothrombin

anticoagulation. time.

311

Bleeding

tendency.

Vol. 61, No. 3

PIVKA AND BLEEDING

based whereas

on

rabbit thromboplastin Thrombotest (TT)

is

minimally on bovine

based

influenced by thromboplastin

PIVKA, is

highIy sensitive to these proteins (4,5). At increasing intensity of anticoagulation, the ratio between NT and TT has been found to increase, reflecting a higher amount of PIVKA (6). The potential danger of bleeding is inherent in oral anticoagulation. The relevance of PIVKA to this bleeding tendency has, however, not been established, although Furie et al. (7 1 found that the native prothrombin antigen correlated well with the bleeding tendency in 13 patients with bleeding episodes. In the and the clinical

present study PIVKA-insensitive bleeding

we

have

compared

NT

during

in

the

patients

long-term

MATERIALS From February 1983 through both Normotest (Nycomed, Oslo, Oslo, Norway) in patients on episodes or with Thrombotest performed using 25 1-11 blood

AND

PIVKA-sensitive

TT

with

without and anticoagulation.

oral

METHODS

October

1987

we

routinely

measured

Norway) and Thrombotest (Nycomed, oral anticoagulation with bleeding values < 5% (=INR>4.8). The NT was

instead of 10 1_r1 to render it suitable for low levels of coagulation activity, as recommended by the manufacturer. The majority of patients participated in a prospective trial on warfarin in the secondary prophylaxis after myocardial infarction (8). Some patients with previous venous thromboembolism were included as well. In sample TT a

NT

a

thromboplastin

I:10 are used, thromboplastin rendering used,

I:5 are venous blood according to are the

rabbit

of bovine

was the

expressed as NT/TT ratio

and

rendering and a it highly

used for instructions

the

a

dilution

of

it insensitive to dilution of the test sensitive to PIVKA.

analyses of the

which were manufacturer.

per cent coagulation between the two groups

the

test

PIVKA. In sample of Citrated

carried out The results Comparison of

activity. was performed

by

the

t-test. RESULTS Of 58 patients appearing with bleeding episodes 20 had measurthat is < 5X, but at the same time < 300 ably low TT values, seconds (3% ?? 290 set, corresponding to INR 7.5). There were 8 3 nose bleedings and 3 G-I hematurias, 6 larger haematomas, Of 168 patients with TT bleedings in this "Bleeding group". 143 had measurably prowithout bleeding episodes values < 5% (< 300 set) as well as measurable NT longed TT clotting times clotting corresponding

times to

(< 180 set) (in this INR 8.4). The latter

system constitute

5%

= the

184 set, "Control

group". of approximately the same Table 1 shows that the groups were the mean NT was 8.1% and the mean "Bleeding group" In the age. TT was 3.9% resulting in a NT/TT ratio of Z.O6(median 2.00). In the "Control group" the corresponding values were 8.3X, 3.7L and 2.20 (median 2.25). It should be noted that great individual variations, also in the NT/TT ratios, were found.

313

PIVKA AND BLEEDING

Vol. 61, No. 3

TABLE

NT,

TT

and

the

NT/TT

1

ratio

in

the

two

Control group (n=143)

"Bleeding group" (n=ZCl) Age

(years),

groups.

mean

(range) NT

(:A),

mean (range)

TT

(761,

mean (range)

NT/TT

(1.50-3.25)

(1.50-2.75)

(range)

*

2.20"

2.06

ratio,.mean

pzO.08

DISCUSSION If with

PIVKA high

play levels

any

role

for

the

of PIVKA would Also, levels. affected more

haemostasis

be a in

more PIVKA

low those with patients theoretically be in those without, resulting in a higher present study we found, on the contrary a the "Bleeding group" than in the "Control difference was statistically of borderline clinical studies vivo haemostasis. technique found

are reported on Furie et al. a good correlation

the (7)

in

with

the

patients

bleeding test

than would

bleeding

than

NT/TT ratio. In lower NT/TT ratio group", although significance.

importance by selective of

vivo,

prone to sensitive

amount

of

the in the Few

PIVKA for immunological of

the

in

native

prothrombin that ing

molecule with bleeding in 13 patients, also suggestrole in this respect. not PIVKA did play any There seems to be species differences in the sensitivity of various thromboplastins to PIVKA in vitro. This may have implications for the influence of PIVKA on the bleeding tendency antagonism in various species. In during vitamin K absence or this connection it may be of interest to recall that bleeding in cattle led to the discovery of the vitamin K antagonists and the of their mechanism anticoagulant effect (9). Bovine thrombosensitive plastin is undoubtedly to the presence of PIVKA. We conclude that the PIVKA-sensitive Thrombotest is not more predictive for bleeding than the PIVKA-insensitive Normotest during oral anticoagulation. This implies that PIVKA play no role for the bleeding tendency during oral anticoagulation. One speculate if anticoagulated patients with low levels of may PIVKA would be more intensively anticoagulated and thus more prone to bleeding, if controlled by a PIVKA-sensitive test.

PIVKA AND BLEEDING

314

Vol. 61, No. 3

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