A Modified International Normalized Ratio as an

Effective Way of Prothrombin Time Standardization in

Hepatology
Laurent Bellest,1 Valérie Eschwège,1 Raoul Poupon,2 Olivier Chazouillères,2 and Annie Robert1

International Normalized Ratio (INR), which standardizes prothrombin time (PT) during
oral anticoagulation, has been extended to standardize PT in liver diseases and is included in
prognostic models such as the Model for End stage Liver Disease (MELD). However, mech-
anisms of PT prolongation in liver diseases differ from those involved in oral anticoagula-
tion, and the thromboplastin reagents differ in their sensitivities to these 2 mechanisms. Our
aim was to determine whether, in the calibration model for thromboplastins proposed by the
World Health Organization, the use of plasmas from patients with liver diseases instead of
plasmas from patients on oral anticoagulation could lead to a new INR specific for liver
diseases (INR “LD”), achieving a real standardization of PT. First, 5 thromboplastins were
calibrated against an international reference using 60 plasmas of patients with liver failure
and, in a second step, the variation of PT reported as seconds, the ratio of patient PT to
normal PT, INR, and INR“LD” was assessed in 34 other patients. MELD scores were
calculated with the INR values obtained with the 5 thromboplastins. Only INR“LD” elim-
inated variability in PT results observed with the different thromboplastins. The discrepancy
between MELD scores were up to 4 and 7 points in 52% and 17% of the patients, respec-
tively. Conclusion: INR “LD” may provide a common international scale of PT reporting in
hepatology. Its adoption would be an important step because of the significant impact on
MELD score induced by interlaboratory variability in INR determination. (HEPATOLOGY
2007;46:528-534.)

boplastins contain recombinant tissue factor. PT is influ-

See Editorial on Page 295
enced by the levels of the following coagulation factors: I
(fibrinogen), II, V, VII, and X, all factors being synthe-

P
rothrombin time (PT) is the usual test for moni-
toring oral anticoagulation by vitamin K antago-
nists1 and is widely adopted to assess the severity of
acute and chronic liver injury.2 PT is the recalcification
time of citrated plasma in the presence of a thromboplas-
tin reagent.3 The term thromboplastin refers to a complex
mixture of tissue factor and phospholipids prepared from
tissue extracts of animal or human origin. Recent throm-
Abbreviations: INR, international normalized ratio; ISI, international sensitiv-
ity index; LD, liver disease; MELD, Model for End stage Liver Disease; PT, pro-
thrombin time; WHO, World Health Organization.
From 1AP-HP, Hôpital St Antoine, Unité d’Hémostase; and 2AP-HP, Hôpital
St Antoine, Service d’Hépatologie; Université Pierre et Marie Curie, Paris, France.
Received December 27, 2006; accepted February 9, 2007.
Address reprint requests to: Annie Robert, AP-HP, Hôpital St Antoine, Unité
d’Hémostase, 75571 Paris Cedex 12, France. E-mail: annie.robert@sat.aphp.fr;
fax: (33) 1-49-28-30-46.
Copyright © 2007 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.21680
Potential conflict of interest: Nothing to report.
528
sized by the liver and, among them, 3 (II, VII, and X)
being vitamin K dependent. Thromboplastins can vary
markedly in their responsiveness to the defects induced by
vitamin K antagonist therapy. As a result, the poor agree-
ment between PT in different laboratories whatever the
methods of reporting results4 has led to important differ-
ences in oral anticoagulant dosing.5,6 Standardization of
PT reporting in patients on oral anticoagulation has been
improved by the calibration model for thromboplastins
proposed by the World Health Organization (WHO).7
This system defines, for a specific thromboplastin reagent,
the International Sensitivity Index (ISI) obtained by a
calibration using plasmas of patients on stable oral anti-
coagulant doses, against a WHO international reference
thromboplastin.7 The ISI is a numerical value that reflects
the responsiveness of a given thromboplastin to reduction
of the vitamin K– dependent coagulation factors; the
lower the ISI value, the greater the sensitivity of the re-
agent. The recommended scale of reporting PT results is
HEPATOLOGY, Vol. 46, No. 2, 2007
Table 1. Characteristics of Thromboplastin Reagents
Number Name Manufacturer
1 Neoplastin CI Diagnostica Stago (Asnières, France)
2 Simplastin Excel BioMerieux (Durham, NC, USA)
3 SimplastinExcel S BioMerieux (Durham, NC, USA)
4 Thromborel S Dade Behring (Marburg, Germany)
5 RecombiPlasTin Instrumentation Laboratory (Lexington, MA, USA)
*ISI values were those provided by the manufacturers for photo-optical instrument except for thromboplastin 1, for which no instrument was mentioned.
the International Normalized Ratio (INR), calculated as
follows: INR ⫽ (patient PT/mean normal PT)ISI.7,8 This
standardization allows safe and effective dosing of vitamin
K antagonists, independently of the sensitivity of the
thromboplastin used.1
Thromboplastin responsiveness also varies widely with
respect to the coagulation defects induced by liver failure.
This variability may lead to large interlaboratory differ-
ences in PT results.9,10 Because of its omnipresence for
monitoring oral anticoagulation, the INR/ISI system has
been inadvertently extended to standardize PT in liver
failure.9 The INR/ISI mode of reporting is now widely
recommended for the evaluation of acute liver failure11
and is incorporated in different models to predict signif-
icant fibrosis in patients with hepatitis C12,13 and survival
in patients with severe liver disease, such as the Model for
End stage Liver Disease (MELD) score.14-16
However, the INR/ISI system has been meant and val-
idated for monitoring oral anticoagulant therapy only.
Some studies have previously reported that the use of INR
for reporting PT in patients with liver disease fails to yield
standardization.10,17-19 A recent study has shown that
variability between laboratory methods in determination
of INR has a significant impact on the MELD score in
patients listed for liver transplantation.20 In 2000, both
the National Academy of Clinical Biochemistry and the
Practice Guidelines Committee for the American Associ-
ation for the Study of Liver Disease (AASLD) have made
the following recommendations: “PT in seconds rather
than the INR should be used to express results of PT in
patients with liver disease, however this does not stan-
dardize results between laboratories” and “Additional re-
search into standardization of PT reagents and use of
derived indices in liver disease is needed.”21 We have pre-
viously demonstrated that, in liver failure, reporting PT in
terms of percentage of normal could provide a common
international scale of PT reporting.10 However, this mode
of PT reporting has gained little popularity outside Eu-
rope, presumably because of the difficulties of the calibra-
tion system.
We hypothesized that the use of plasmas of patients
with liver disease instead of plasmas from patients on oral
anticoagulation in the calibration model for thromboplas-
BELLEST ET AL. 529
Source ISI* ISI (“local”) ISI“LD”
Rabbit brain 1.72 1.67 0.98
Rabbit brain 1.69 1.54 0.94
Rabbit brain 1.07 1.05 0.70
Human placenta 0.98 1.03 0.84
Human recombinant 0.80 0.83 0.85
tins proposed by the WHO7 could lead to a PT standard-
ization specific for liver disease. The aim of our study was
to determine whether, in a new INR/ISI “liver dis-
ease”(“LD”) system, INR“LD” would achieve a real stan-
dardization of PT in liver diseases compared with INR or
other modes of reporting.
Patients and Methods
Blood Samples. Blood samples were collected into
Vacutainer tubes containing 0.109 M tri-sodium citrate
(Becton Dickinson, Plymouth, UK). Platelet-poor
plasma was prepared by centrifugation at 2,500g for 15
minutes at 20°C, aliquoted and stored at ⫺70°C until
assayed.
Calibration Procedure of Thromboplastins for the
Definition of the Parameter ISI“LD”. Calibration was
performed according to the WHO guidelines for throm-
boplastins and plasma used to control oral anticoagulant
therapy,22 with the following differences: the use of frozen
instead of fresh plasmas and the use of plasmas from pa-
tients with liver disease instead of plasmas from patients
on stable oral anticoagulation.
Sixty patients with chronic or acute liver failure were
selected on the basis of their PT report as a ratio of the
patient’s PT to that of normal plasma and their level of
factor V obtained with the routine thromboplastin of the
laboratory (Thromborel S, Dade Behring). To cover the
whole range of PT in liver failure, the selection of patients
was as follows: 20 patients with a 1.16 ⱕ PT ratio ⬍ 1.45
and with a factor V level ⬍ 75% (level 1); 20 patients with
a 1.45ⱕ PT ratio ⬍ 1.90 and with a factor V level ⬍ 65%
(level 2); 20 patients with a PT ratio ⱖ1.9, and with a
factor V level ⬍ 50% (level 3). Twenty healthy subjects
were selected among volunteers from hospital staff.
The 3rd International Standard for human, recombi-
nant plain thromboplastin (rTF/95, ISI ⫽ 0.94) was ob-
tained from a WHO laboratory for biological standard
(Central laboratory of the Netherlands Red Cross blood
transfusion service, Amsterdam, The Netherlands). Cali-
bration of the 5 commercial thromboplastins described in
Table 1 was performed according to the WHO guide-
lines22 with the rTF/95 as the reference thromboplastin
530 BELLEST ET AL.
on 10 working sessions, using for each session a different
set of 8 plasmas (2 healthy subjects and 6 patients with
liver failure).
PT of each plasma was determined with rTF/95 by the
manual tilt tube technique and with the 5 commercial
thromboplastins on an automated photo-optical coagu-
lometer ACL TOP (Instrumentation Laboratory). For
each commercial thromboplastin, an ISI“LD” was calcu-
lated as described in the WHO guidelines.22 PT of the 20
healthy subjects plus the 60 patients with liver disease
were plotted on a double logarithmic scale with rTF/95
on the vertical axis, and the commercial thromboplastin
on the horizontal axis. The slope of the orthogonal regres-
sion line was used as ISI“LD.”
Study of the Influence of PT Reporting on the Test
Standardization. Thirty-four patients with liver failure
different from those selected for the calibration procedure
were included. Thirteen, 11, and 11 of these patients
belonged to the previously described levels 1, 2, and 3,
respectively.
PT were performed for each plasma sample with the 5
commercial thromboplastins on the coagulometer ACL
TOP.
The mean normal prothrombin time was determined
for each thromboplastin reagent by calculating the geo-
metric mean of the PT results of 40 plasma samples col-
lected from healthy individuals.
PT results were reported in seconds (PTs), in the ratio
of the patient’s PT to mean normal prothrombin time
(PTr), in INR, and in INR“LD”. To take into account the
thromboplastin/coagulometer combination in our labo-
ratory, “local” ISI were determined for the 5 commercial
thromboplastins. This was achieved by means of a lyoph-
ilized plasma calibration set (AK-Calibrant; Techno-
clone, Vienna, Austria) consisting of 1 normal and 3 anti–
vitamin K pooled plasmas with assigned INR values. PT
of the calibrant plasmas measured on the ACL TOP with
1 of the commercial thromboplastins were plotted against
the assigned INR values according to the guidelines on
preparation, certification, and use of certified plasma for
ISI calibration and INR determination.23 The derived
orthogonal regression line was used to determine local ISI
of the 5 commercial thromboplastins.23 INR“LD” was
calculated as follows: INR“LD” ⫽ (patient PT/mean nor-
mal prothrombin time)ISI “LD”.
MELD Score. The MELD score was calculated for
the 34 patients tested in the standardization study using
the following formula: 9.57 ⫻ loge (creatinine mg/dL) ⫹
3.78 ⫻ loge (bilirubin mg/dL) ⫹11.2 ⫻ loge (INR) ⫹
6.43.14 For each patient, MELD scores were calculated
according to the 5 different INR values obtained with the
5 commercial thromboplastins.
HEPATOLOGY, August 2007
Statistical Analysis. Data were expressed as means,
standard deviations, and ranges.
For each mode of PT reporting, statistical differences
between mean values of PT results across the different
thromboplastins used were determined by a 1-way analy-
sis of variance (ANOVA) for repeated measures followed
by the post-hoc Bonferroni’s multiple comparison test.
The same statistical analysis was used to determine statis-
tical difference between mean values of MELD score cal-
culated with the INR obtained with the 5 different
thromboplastins.
Coefficients of variation (CV%) were calculated to
represent within-subject variation of the PT results ob-
tained with the 5 different thromboplastins.
Bland and Altman plots24 of differences between INR
and mean INR and differences between INR“LD” versus
mean INR“LD” obtained with 2 different thromboplas-
tins were used to identify agreement between the meth-
ods. The 2 thromboplastins used in each graph were the
most and the least sensitive to the coagulation defect in-
duced by liver failure as assessed by the mean INR and
INR“LD” obtained with the 34 patients with liver dis-
ease. The same plot analysis was used to test the agree-
ment between the MELD scores calculated with the INR
obtained with the most and least sensitive thromboplastin
to the coagulation defect induced by liver failure as as-
sessed by the mean INR obtained with the 34 patients
with liver disease.
Graphic and statistical data were analyzed using Anal-
yse-it for Microsoft Excel, Leeds, UK (http://www.anal-
yse-it.com) and GraphPad Prism version 4.02 for
Windows (GraphPad Software, San Diego, CA; http://
www.graphpad.com).
A P value of less than 0.05 was considered to indicate
statistical significance.
Results
Characteristics of the Patients. There was no dif-
ference between the patient group selected for the calibra-
tion procedure and that for the standardization study,
regarding demographic characteristics and liver disease
causes, with alcohol being the most frequent cause of liver
damage (Table 2).
Sensitivities of the Thromboplastins to Defects In-
duced by Vitamin K Antagonists and by Liver Disease.
When the “local” ISI (Table 1), determined to take into
account the thromboplastin/coagulometer combination
in our laboratory, were compared with the ISI provided
by the manufacturers (Table 1), the values of both were
similar except for a difference of 0.15 for thrombo-
plastin 2.
HEPATOLOGY, Vol. 46, No. 2, 2007 BELLEST ET AL. 531

Table 2. Characteristics of the Patients with Liver Failure Table 4. Within-Patients (n ⴝ 34) Variation of Prothrombin
Selected for the Calibration Procedure and for the Study of Time (PT) Results Obtained with the 5 Different
Prothrombin Time Standardization Thromboplastins According to the Mode of PT Reporting
Patients Selected for Mode of PT Reporting

Calibration Standardization PTr INR INR“LD”

Procedure
Characteristics (n ⴝ 60)
Males n, (%) 41 (68)
Age (y), mean (SD) 54 (16)
Cause of liver disease
Alcohol n, (%) 31 (52)
Viral hepatitis(B and/or C) n, (%) 11 (18)
Alcohol and viral hepatitis n, (%) 9 (15)
Other, n (%) 9 (15)
The ISI“LD” calculated by the calibration procedure
were equal or below 0.94 (which is the ISI of the reference
preparation rTF/95) for 4 of 5 thromboplastins. This
means that these 4 reagents have the same or a greater
sensitivity to coagulation defects induced by liver failure
than the reference thromboplastin. The variability in
thromboplastin responsiveness to these defects, repre-
sented by the range of ISI“LD” from 0.98 to 0.70, was
smaller than that observed for defects induced by vitamin
K antagonist for which the “local” ISI of the most sensi-
tive thromboplastin was 2 times greater than that of the
less sensitive thromboplastin (Table 1). Finally, among
the 5 reagents, the most sensitive thromboplastin to de-
fects induced by liver failure was a rabbit brain thrombo-
plastin (no. 3), whereas the 2 human thromboplastins
(nos. 4 and 5) were the most sensitive to defects induced
by vitamin K antagonist.
Agreement Among PT Results Obtained With 5
Thromboplastins in Patients With Liver Failure Ac-
cording to the Methods of Reporting. The mean PT
values obtained with the 5 different thromboplastins were
Study
(n ⴝ 34) Mean CV (%) 9 16 3
Range 3-16 4-29 1-7
23 (68)
49 (12)
19 (56)
8 (23) significantly different (P ⬍ 0.0001) for 3 modes of report-
3 (9)
ing: PTs, PTr, and INR (Table 3). The multiple compar-
4 (12)
ison test showed significant differences between most
pairs of thromboplastins except the following: thrombo-
plastins 1 versus 4 and 1 versus 5 in the PTs group; throm-
boplastins 1 versus 2 and 4 versus 5 in the PTr group;
thromboplastins 1 versus 2 in INR group. Only the
INR“LD” mode of PT reporting led to nonsignificant
differences (P ⫽ 0.09) between mean PT values obtained
with the 5 different thromboplastins (Table 3).
The INR“LD” mode of reporting led to the smallest
mean within-patients CV observed for PT results per-
formed with the 5 thromboplastins, whereas the highest
CV were observed for INR modes of expression as indi-
cated in Table 4.
The Bland-Altman difference plots illustrate the great
discordances for PT results reported as INR (Fig. 1). The
scatter of the differences between results increased accord-
ing to the prolongation of the INR, and the discrepancy
for INR values ⬎3 was as large as 75% of the mean INR.
In contrast, the narrow scatter of difference data points
around the value zero observed when PT results were
reported as INR“LD” (Fig. 1) confirmed the excellent
agreement between the results when using this mode of
reporting.

Table 3. Prothrombin Time (PT) Results Obtained for Patients with Liver Failure (n ⴝ 34) Using 5 Different Thromboplastins
and Expressed as PTs, PTr, INR, and INR“LD”
Thromboplastin Number

1 2 3 4 5

PTs
Mean (SD) 22.5 (5.4) 20.3 (5.0) 31.2 (9.5) 23.9 (6.1) 22.1 (6.5)
Range 16.3-34.9 14.4-31.5 19.7-55.2 16.6-37.7 15.2-37.1
PTr
Mean (SD) 1.8 (0.4) 1.8 (0.4) 2.2 (0.7) 1.9 (0.5) 1.9 (0.6)
Range 1.3-2.7 1.3-2.8 1.4-3.8 1.3-3.0 1.3-3.2
INR
Mean (SD) 2.7 (1.1) 2.5 (1.0) 2.3 (0.7) 2.0 (0.5) 1.7 (0.4)
Range 1.5-5.4 1.4-4.8 1.4-4.1 1.3-3.1 1.3-2.6
INR“LD”
Mean (SD) 1.8 (0.4) 1.7 (0.4) 1.7 (0.4) 1.7 (0.4) 1.7 (0.4)
Range 1.3-2.7 1.2-2.6 1.2-2.6 1.3-2.5 1.3-2.7

PTs, PT results reported in seconds; PTr, PT results reported in the ratio of the patient’s PT to MNPT.
532 BELLEST ET AL.
Agreement Among MELD Scores Calculated With
the Different INR Values Obtained With the 5 Com-
mercial Thromboplastins. The mean MELD scores
values calculated with the INR obtained with 5 different
thromboplastins were significantly different (P ⬍
0.0001), and post hoc analysis showed significant differ-
ences between all pairs of thromboplastins. The Bland-
Altman difference plots (Fig. 2) show the great
discordances between the MELD scores calculated with
the INR values obtained with the 2 most different throm-
boplastins in terms of INR values (thromboplatins 1 and
5). The discrepancy between MELD scores was more
than 4 points in 52% of the patients and more than 7
points in 17% of the patients (Fig. 2).
Discussion
This study shows that thromboplastin reagents have
different sensitivities to coagulation defects induced by
vitamin K antagonists and to those induced by liver fail-
ure. As a consequence, in this latter situation, a standard-
ization of PT reporting based on the ISI/INR system can
only be achieved by a modification of the existing system,
the ISI“LD”/INR“LD,” making it specific for the defects
induced by liver disease.
We demonstrate, in keeping with previous studies of
our group10 and others17-19 that, in patients with liver
disease, poor agreement is observed among PT results
reported as PTs, PTr, and INR. This disagreement wors-
ens markedly according to the prolongation of PT as
shown by the Bland-Altman plots. Moreover, the within-
patients variation observed for INR results being twice
greater than that observed for PTr results clearly shows
that the correction of the PTr by the ISI value of the
correspondent thromboplastin worsens the discrepancy
of the PT results obtained with different reagents for pa-
tients with liver disease. In other words, the rough “stan-
Fig. 1. Agreement between the INR (A) or the INR“LD” (B) obtained
with 2 different thromboplastins in patients with liver failure (n ⫽ 34).
For each plasma sample, the differences between the INR (A) or INR“LD”
(B) obtained with the most and the least sensitive thromboplastin to the
coagulation defect induced by liver failure were plotted against the mean
of the INR (A) and INR“LD” (B) generated by the 2 reagents. The
thromboplastins were as follows: (A) reagent numbers 1 and 5 and (B)
reagents 1 and 3.
HEPATOLOGY, August 2007
Fig. 2. Agreement between the MELD scores calculated with the INR
values obtained with 2 different thromboplastins in patients with liver
failure (n ⫽ 34). For each plasma sample, the differences between the
scores calculated with the INR obtained with the most (reagent no. 1)
and the least sensitive thromboplastin (5) to the coagulation defect
induced by liver failure were plotted against the mean of the scores
generated by the 2 reagents.
dardization” brought out by the use of the PTr mode of
reporting was abolished by the use of INR expression.
These results can be explained by the inappropriate use of
an ISI value, which reflects the thromboplastin sensitivity
to the effects of oral anticoagulation and not its sensitivity
to the effects of liver disease, to correct, in the INR for-
mula, the PTr obtained in patients with liver disease. Oral
anticoagulation antagonizes the vitamin K– dependent
carboxylation of coagulation factors II, VII, and X. This
results in the synthesis of non-carboxylated or partially
carboxylated forms of these factors, named proteins in-
duced by vitamin K absence or antagonist, which are bi-
ologically inactive or even inhibitory.25,26 In most liver
diseases, the level of proteins induced by vitamin K ab-
sence or antagonist is low and the prolonged PT is rather
due to reduced synthesis of coagulation factors II, VII, X,
as well as factor V and fibrinogen.27 The different sensi-
tivities of the thromboplastins to the defects induced by
vitamin K antagonists and liver failure are illustrated in
the current study by the differences observed between ISI
and ISI“LD” values and could be explained, at least in
part, by the differences in the origin and the nature of the
different commercial and reference thromboplastins. In-
deed, human thromboplastins are known to have a greater
sensitivity to proteins induced by vitamin K absence or
antagonist inhibitor effect than rabbit brain thromboplas-
tins.18,28
A main result of our study is the achieved PT standard-
ization in liver disease provided by the use of the
HEPATOLOGY, Vol. 46, No. 2, 2007
INR“LD” mode of reporting. This standardization has
been obtained by one main and several minor modifica-
tions of the WHO calibration model for thromboplastins
in the ISI/INR system.22 The main modification was the
use of plasmas of patients with liver disease instead of
plasmas from patients receiving oral anticoagulation for
the calibration procedure. Three other points deserving
comments. First, deep-frozen instead of fresh plasmas
were used because of the difficulty of obtaining, on the
same day, the 6 fresh plasmas samples from patients with
liver failure needed for a working session of calibration.22
However, studies have shown that INR for patients on
anticoagulation therapy or PT in other clinical situations
can be reliable even if determined on frozen plasmas.29,30
Because both our calibration and standardization studies
were performed on frozen plasmas, we do not believe that
sample freezing could have influenced our data. Second,
the WHO calibration model uses international reference
thromboplastin preparation with a great responsiveness to
the defect induced by the vitamin K antagonist with an
ISI value close to 1. The results of our calibration study
showed that the human recombinant reference thrombo-
plastin rTF/95 had a similar or lower responsiveness to
coagulation defects induced by liver failure than the
thromboplastins tested because the ISI“LD” of these 5
reagents was equal to or below the ISI of the reference
thromboplastin. Therefore, a thromboplastin with a
greater sensitivity to the defects induced by liver failure
would have been, perhaps, a better choice as a reference
material. With the use of a rabbit brain thromboplastin as
a reference material, the ISI“LD” of the commercial
thromboplastins tested would have been similar to or
greater than the ISI of the reference material. However,
considering the close agreement among the INR“LD,”
the choice of a rabbit brain reference material would be
unlikely to improve the PT standardization in patients
with liver failure. Third, the WHO guidelines recom-
mend for the calibration a selection of patients who have
been on oral anticoagulants for at least 6 weeks with an
INR value in the range 1.5 to 4.5.22 These criteria could
not be applied to the patients with liver failure selected to
calibrate the ISI“LD”/INR“LD” system. Lastly, we chose
to select patients with a large range of PT/INR results to
ensure a PT standardization whatever the liver disease
severity.
The harmonization of PT results in liver failure, ob-
tained in our laboratory, by the use of the INR“LD” re-
mains to be confirmed in a multicenter study. For this
purpose, a “local” ISI“LD” calibration taking into ac-
count thromboplastin/coagulometer combination ap-
pears necessary for each laboratory.31 However, the
manual determination of PT, the requirement for WHO
BELLEST ET AL. 533
thromboplastin preparation, and the need for 60 plasmas
from patients with liver failure for the ISI“LD” calibra-
tion according to the WHO recommended procedure22 is
not possible in routine hospital laboratories. To avoid
these constraints, laboratories could calibrate their own
local system with supplied frozen plasmas from patients
with liver failure to which certified values of INR“LD”
would have been assigned by following, with some mod-
ifications, the guidelines on preparation, certification, and
use of certified plasmas for ISI calibration and INR deter-
mination elaborated by the Subcommittee on Control of
Anticoagulation of the Scientific and Standardization
Committee of the International Society on Thrombosis
and Haemostasis.23
Our study provides evidence that the adoption of the
INR“LD” expression as a common scale of PT reporting
in hepatology is an important goal, especially in view of
the striking discrepancies that we and others20 found be-
tween MELD scores calculated with INR values obtained
with different thromboplastins. Moreover, our results, il-
lustrated in the Bland-Altman plot, show that the higher
the MELD scores the more discrepant. This effect likely
results from the deterioration of the INR agreement ob-
served with prolongation of PT. Therefore, PT standard-
ization with INR“LD” appears particularly important in
view of the policy prioritizing patients with a MELD
score of 15 or greater.32 However, even if INR “LD” is
accepted as a better standardized prognostic parameter
than INR in liver diseases, its appropriate weight as a
variable in indexes such as MELD score remains to be
determined. Although the MELD score variability is a key
issue, the need for PT standardization by the use of
INR“LD” instead of INR does not have to be overlooked
in screening, diagnosis, and monitoring acute and chronic
liver injury.2
Besides liver diseases, the INR/ISI system has been also
extended to standardize PT from patients whose PT is
prolonged because of reasons other than oral anticoagu-
lation, such as sepsis or disseminated intravascular coag-
ulation.33,34 We can hypothesize that, as for liver diseases,
INR-based criteria are proposed inadvertently for those
patients and that INR“LD” expression could represent a
common international scale of PT reporting.
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