Clin Chem Lab Med 2002; 40(4):399403 2002 by Walter de Gruyter Berlin New York

Comparison of Quick and Owren Prothrombin Time with Regard to the

Harmonisation of the International Normalised Ratio (INR) System

Juha Horsti*
Laboratory, District Hospital of Valkeakoski, University
Hospital of Tampere, 37600 Valkeakoski Finland

Prothrombin time (PT) is tested mostly to monitor patients on oral anticoagulant treatment. The International Normalised Ratio (INR) was introduced to improve and harmonise PT results and therapeutic range
globally for patient care and the scientific literature.
We studied the Quick PT in 179 patients and the
Owren PT in 137 patients on oral anticoagulant therapy using two different reagents for the two methods
of measuring PT. We assessed the clinical significance
of the INR results obtained by each method using the
two reagents and compared the Quick and Owren
methods.
We conclude that with the Quick method individual
INR results differed from each other too much clinically, while using the Owren method individual INR results were clinically acceptable. Our opinion is that we
should develop the INR system using the Owren PT
method rather than the Quick to improve patient care.
Clin Chem Lab Med 2002; (40):399403
Key words: Prothrombin time (PT); International Normalised Ratio (INR); Oral anticoagulant therapy; Coagulation.
Abbreviations: EDTA, ethylenediaminetetraacetic acid;
INR, International Normalised Ratio; ISI, International
Sensitivity Index; MNPT, mean normal PT; PT, Prothrombin time.

Introduction
The prothrombin time (PT) is a primary coagulation
test used in laboratories to detect preoperative bleeding tendency and to monitor oral anticoagulant therapy
at regular intervals in view of its narrow therapeutic
range.
Two major methods are used globally to measure PT.
Quick and co-workers (1, 2) developed the first method
for PT, and Owren (3) subsequently the Quick
method to overcome its drawbacks. The Owren
reagent (the combined thromboplastin reagent) is the
one used almost exclusively in the Nordic countries,
Benelux and Japan. Because of its different reagent
composition, the Quick technique is sensitive to fibrinogen and coagulation factors II, V, VII and X, while
*E-mail of the corresponding author: :juha.horsti@tays.fi

the Owren technique is affected by deficiencies in factors II, VII and X. Dicoumarol drug is a vitamin K antagonist and antithrombotic treatment reduces the synthesis of coagulation factors in the liver and lengthens
coagulation time in PT.
The aim of using the International Normalised Ratio
(INR) is the worldwide harmonisation of the PT results
and therapeutic ranges both in clinical practice and in
research. The units formerly used were inadequate for
international communication (46).
PT estimation carries its own analytical difficulties
depending, for example, on sampling (79) and on
sample and reagent stability (1012), reagent composition (13, 14), instrumentation (15, 16) and measuring
principles (17), the source of thromboplastins (13) and
the calibration (6, 1820). Thus, there is a need for continuous research to improve the uniformity of INR results.
In the Owren method of PT assessment the sample is
diluted before estimation and the sample volume in the
reaction mixture is 5%. In the Quick method there is no
sample dilution and the sample volume in the reaction
mixture is many times greater (33%), which means
sensitivity to preanalytical factors such as sample citrate concentration (1517, 21, 22).
The Owren method has the advantage of the small
sample volume and the fact that EDTA plasma can also
be used for PT measurement (2325).
The literature contains few publications comparing
the Quick and Owren methods and only few individual
patient results on INR obtained using different
reagents. Most of the studies have used only the mean
values of results, which is not a good method for PT
studies because individual changes may be marked
while the mean is acceptable. The aim of the present
work was to measure PT using two different sensitive
Quick and Owren reagents (International Sensitivity Index (ISI) near 1.0), using the same calibration, and to
compare the influence of different reagents on patient
INR results within the two methods. We sought to establish which of the methods is better for INR result
harmonisation.

Patients, Materials and Methods

Patients and blood sampling
All procedures were approved by our institutions responsible
committee in accordance with the Helsinki Declaration of
1975. We studied the Quick PT in 179 patients and the Owren
PT in 137 patients receiving oral anticoagulant therapy, chosen without conscious bias from among hospital and health
centre patients. PT was measured and reported in seconds

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Horsti J: Comparison of Quick and Owren PT methods to improve INR system

and as INR using the same calibration. Measurement commenced within 4 hours of blood collection.
The citrate coagulation tube (Greiner Labortechnik GmbH,
Kremsmnster, Austria, Vacuette, cat. no. 454322, 9NC) contained 0.2 ml 0.109 mol/ (3.2%) citrate solution and a blood
volume of 1.8 ml. The sample needle (Becton Dickinson,
Plymouth, UK, Precision Glide, cat. no.360213) was 0.8 38
mm. Sample tubes were centrifuged at 1560 g for 10 min at
20 C to separate plasma.
Instruments and reagents
We measured Quick PT with the ACL 7000 (Instrumentation
Laboratory, IL, Milano, Italy), a fully automatic microcentrifugal analyser. The coagulation reagents were PT-Fibrinogen
Recombinant, rabbit tissue thromboplastin from Instrumentation Laboratory, Lexington, USA and Dade Innovin, human tissue thromboplastin from Dade Behring Marburg GmbH, Marburg, Germany. We used 50 l sample and 100 l of the
reagent.
We measured Owren PT with an ACL analyser with the following coagulation reagents: Nycotest PT, rabbit brain thromboplastin from Axis-Shield as, Oslo, Norway and SPA 20, tissue thromboplastin from Diagnostica Stago, Asnieres,
France, and with a diluent (Nycotest PT, dilution liquid, AxisShield as, Oslo, Norway and SPA buffer, Diagnostica Stago,
Asnieres, France). We used 10 l sample, 50 l diluent and
140 l of the reagent. We used the ACL 7000 internal standard
(IL Test Reference, cat. no. 9756900).
For Quick and Owren reagents ISI calibration was carried on
with ISI calibrators (Etaloquick cat. no. 00496, Diagnostica
Stago, France). The ACL was calibrated with the calibration
plasma (IL cat. no. 08467300): PT-Fibrinogen Recombinant,
n=4 at every point: 100%, 9.38 s, CV=0.48; 50%, 15.7 s,
CV=0.53; 25% 27.7 s, CV=0.44, R2=1.000; Dade Innovin, n=4 at
every point: 100%, 8.18 s, CV=0.55; 50%, 12.9 s, CV=1.29; 25%
22.7 s, CV=1.46, R2=1.000; Nycotest PT, n=4 at every point:
100%, 21.0 s, CV=0.00; 50%, 30.53 s, CV=0.38; 25% 45.8 s,
CV=0.44, R2=0.997; SPA 20, n=4 at every point: 100%, 20.4 s,
CV=0.00; 50%, 28.53 s, CV=0.40; 25%, 40.8 s, CV=0.49,
R2=0.995.
The day-to-day CVs (NKP 160, cat. no. GHI 160, normal
plasma, and OKP 165, cat. no. GHI 165, abnormal plasma from
the Global Hemostasis Institute, Linkping, Sweden) (n=8)
were as follows:

Figure 1

PT-Fibrinogen Recombinant, NKP, mean SD, 1.1 0.021

INR, CV 1.88%; OKP, mean SD, 2.90.048 INR, CV 1.64%;
Dade Innovin, NKP, mean SD, 1.00.010 INR, CV 1.02%; OKP,
mean SD, 2.70.028 INR, CV 1.04%; Nycotest PT, NKP, mean
SD, 0.910.01 INR, CV 1.39%; OKP, mean SD, 2.40.05 INR,
CV 1.98%; SPA 20, NKP, mean SD, 0.920.01 INR, CV 0.59%;
OKP, mean SD, 2.40.02 INR, CV 0.87%.
Methods and statistics
PT was measured on 179 patient samples using PT-Fibrinogen
Recombinant and Dade Innovin reagents for Quick PT and on
137 patient samples using Nycotest PT and SPA 20 reagents
for Owren PT. INR results were calculated in seconds using the
formula: INR=( sample s/normal s )ISI.
The Microsoft Excel 5.0 software was used to compute the
correlation functions and INR results and the Bland and Altman method to compare differences between results (26).

Results
Quick PT results were between 0.9 INR (7.05 s) and 8.1
INR (59.0 s), Owren PT results between 0.9 INR (18.2 s)
and 4.8 INR (97.2 s). The mean of patient results using
PT-Fibrinogen Recombinant reagent was 2.55 INR, using Dade Innovin reagent 2.49 INR and using Nycotest
PT 2.32 INR, SPA 20 2.31 INR.
The regression equations for Quick PT using PT-Fibrinogen Recombinant (x) and Dade Innovin reagent (y)
were:
y = 1.23x 0.63 INR, R2 = 0.98 (Figure 1)
y = 0.92x 3.00 s, R2 = 0.98
The regression equations for Owren PT using Nycotest
PT (x) and SPA 20 reagent (y) were:
y = 0.98x + 0.04 INR, R2 = 1.00 (Figure 2)
y = 0.86x + 3.05 s, R2=1.00
According to the Bland and Altman plot (26) seven
Quick PT INR results were out of range out of the 179
patient results (mean difference 0.05 INR, 2SD limits

Correlation study of Quick PT results. y=1.23x0.63, R2=0.98.

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Horsti J: Comparison of Quick and Owren PT methods to improve INR system

Figure 2

Correlation study of Owren PT results. y=0.98x+0.04, R2=1.00.

Figure 3

Differences between PT-Fibrinogen Recombinant and Innovin INR results.

Figure 4

Differences between Nycotest PT-SPA 20 INR results.

0.53 to +0.63 INR). Differences in INR results between the two Quick PT reagents are shown in Figure 3. INR results did not differ with respect to clinical

401

significance and the t-test gave an acceptable result

(p=0.64).
Owren PT INR results are presented in Figure 4; eight

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Horsti J: Comparison of Quick and Owren PT methods to improve INR system

results were out of range out of the 137 patient results

(mean difference 0.01 INR, 2SD limits 0.11 to +0.11
INR). With a probability of 94% the results were within
the 2 SD range (p=0.89).

Discussion
The objective of harmonising PT results and therapeutic
ranges using the INR units is commendable and worth
pursuing. For most indications the recommended INR
therapeutic range is 2.0 to 3.0 (6). Since the range is narrow there is a need for high quality of PT results. The
overall coefficient of variation of INR is 1113% under
favourable conditions if ISI is around 1 (27).
A variety of factors affect the final PT result in INR
units, and we should minimise the sources of error of
every factor in order to optimise results. The INR formula is a key factor in analysing the sources of error:
INR = (samples/normals )ISI. For evaluating variation in
INR results we took the logarithm from the formula:
Log10 INR = ISI Log10 (samples/normals). Low ISI
means low CV for INR according to the formula, but the
PT ratio is nevertheless not independent of ISI (6).
Using sensitive reagents improves the quality of INR
results and ISI as the power function plays a minimal
role. The role of ISI is enhanced with higher INR results
because the ratio differs from 1 and the power function
(ISI) has more meaning in calculating INR. The mean
normal PT (MNPT = normals) plays an important role in
the formula and markedly affects variation in INR results. The MNPT can be determined from the fresh
plasma of healthy persons or from lyophilised plasma
obtained commercially (13). As they are biological
materials from different sources, differences arise
between preparations, and this affects the INR results.
Sensitive reagents were selected for this study to
eliminate sources of error and compare Quick and
Owren methods. The calibrators for ISI and MNPT calculation were the same for Quick and Owren estimations.
Recombinant Quick PT reagents were chosen for the
study because they ensure excellent lot-to-lot uniformity and better performance than thromboplastins derived from natural sources. The correlation between
Quick PT reagents is good (R2=0.98), but the correlation
equation (y=1.23x0.63 INR) reveals considerable divergence from the ideal correlation line (Figure 1). Although the mean difference was only 0.05 INR, the
Bland and Altman plot (Figure 3) showed increasing
differences towards higher INR results, and this is
caused by ISI. The magnitude of the 2SD (0.53 to +0.63
INR) and deviations of INR results are in our opinion
too wide clinically, considering that the therapeutic
range is only 23 INR. These results show that although the means of INR results may be acceptable,
the individual results may be clinically unacceptable
with the Quick method.
Figure 2 shows good correlation (R2=1.00) for patient
INR results between the two Owren reagents, and the
equation (y=0.98x +0.04) is very close to the ideal line.

The mean difference is only 0.01 INR, and the 2SD

range (0.11 to +0.11 INR) is narrow with the Owren
method; differences between INR results are clinically
acceptable over the whole range (Figure 4).
We found the Owren method to be more suitable
than the Quick method for INR system uniformity using
different thromboplastins and reagents, and we conclude that this is due to technical and theoretical differences between the two methods. The variability of individual INR results using Quick method and different
thromboplastins and other reagents is too wide. We
used the same calibrators for both used reagents. The
acceptability of the means, but not of individual results,
is not satisfactory (13). The situation is more demanding in inter-laboratory comparisons because of different calibrators, reagents, instruments, etc. (28). The
Owren method is not sensitive to preanalytical factors
(17).We found the Owren method being more suitable
with regard to harmonisation of INR results using different reagents. Since the Owren PT methodology
proved to be more reliable using different reagents we
should develop the INR system using the Owren rather
than the Quick PT method in the future to improve the
quality of INR results and patient care.

Acknowledgements
I thank the staff of the Laboratory at Valkeakoski District Hospital for their co-operation.

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Received 8 October 2001, revised 11 February 2002,
accepted 20 February 2002
Corresponding author: Juha Horsti, District Hospital of
Valkeakoski, University Hospital of Tampere, Laboratory,
37600 Valkeakoski, Finland
Phone: +358 3 586 7251, Fax: +358 3 586 7435
E-mail:juha.horsti@tays.fi

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