Questions and Answers on Prothrombin Time Standardisation in Oral Anticoagulant Control

1985 ◽  
Vol 54 (02) ◽  
pp. 515-517 ◽  
Author(s):  
E A Loeliger ◽  
L Poller ◽  
M Samama ◽  
J M Thomson ◽  
A M H P Van den Besselaar ◽  
...  
Keyword(s):  
Plasma Sample ◽  
Oral Anticoagulants ◽  
Sensitivity Index ◽  
International Normalised Ratio ◽  
Questions And Answers ◽  
Reference Preparation ◽  
Tissue Thromboplastin ◽  
The Individual ◽  
International Sensitivity Index ◽  
New System

SummaryOne of the reasons why oral anticoagulants fell into disrepute is the absence of internationally accepted standardised procedures for controlling the level of anticoagulatiori. This deplorable situation resulted in over- and under-coagulation and uncertainty in the therapeutic range. International conformity can now be obtained by using an International Normalised Ratio (INR) which is derived from the individual result obtained in a given plasma sample and the International Sensitivity Index (ISI) of the tissue thromboplastin reagent used. Any thromboplastin reagent can be calibrated against an international primary or secondary W.H.O. reference preparation, so as to obtain its International Sensitivity Index. The new system of reporting the level of anticoagulation was designed and can only safely be applied in patients taking oral anticoagulants.

Effect of Concentration of Trisodium Citrate Anticoagulant on Calculation of the International Normalised Ratio and the International Sensitivity Index of Thromboplastin

1994 ◽  
Vol 72 (01) ◽  
pp. 084-088 ◽  
Author(s):  
E M Duncan ◽  
C R Casey ◽  
B M Duncan ◽  
J V Lloyd
Keyword(s):  
Reference Material ◽  
Oral Anticoagulants ◽  
Reference Method ◽  
Trisodium Citrate ◽  
Sensitivity Index ◽  
Blood Samples ◽  
Orthogonal Regression ◽  
Significant Difference ◽  
International Normalised Ratio ◽  
International Sensitivity Index

SummaryThe aim of this study was to determine whether the concentration of trisodium citrate used to anticoagulate blood has an effect on the INR of the sample and the ISI of the thromboplastin. Five thromboplastins including and Australian reference material were used to measure the prothrombin time of normal and patient samples collected into two concentrations of trisodium citrate - 109 mM and 129 mM. There was no effect of citrate concentration on the INRs determined with the reference material. However for the other four thromboplastins there was a significant difference between INRs for the two citrate groups. The prothrombin times of the samples collected into 129 mM were longer than those collected into 109 mM. This difference was only slight in normal plasma but more marked in patients receiving oral anticoagulants, causing the INRs for patient plasmas collected into 129 mM citrate to be higher then the corresponding samples collected into 109 mM citrate.From orthogonal regression of log prothrombin times by the reference method against each thromboplastin, we found that the ISI for each thromboplastin was approximately 10% lower when determined with samples collected into 129 mM citrate than with samples collected into 109 mM. These results suggest that the concentration of trisodium citrate used for collection of blood samples can affect the calculation of the INR and the calibration of the ISI of thromboplastin. This was found both for commercial thromboplastins prepared by tissue extraction and for a recombinant tissue factor.

The Effect of Some Instruments for Prothrombin Time Testing on the International Sensitivity Index (ISI) of Two Rabbit Tissue Thromboplastin Reagents

1989 ◽  
Vol 62 (03) ◽  
pp. 868-874 ◽  
Author(s):  
Marina Poggio ◽  
Antonius M H P van den Besselaar ◽  
Edo A van der Velde ◽  
Rogier M Bertina
Keyword(s):  
Prothrombin Time ◽  
Oral Anticoagulants ◽  
International Normalized Ratio ◽  
World Health ◽  
Sensitivity Index ◽  
Optical Instruments ◽  
Rabbit Tissue ◽  
Reference Preparation ◽  
Health Organization ◽  
International Sensitivity Index

SummaryTwo commercial rabbit tissue thromboplastins were calibrated against the International Reference Preparation for rabbit thromboplastin (coded RBT/79) by one laboratory using the manual technique, a semi-automatic electro-mechanical coagulometer and three different automatic photo-optical instruments. The calibration of the two reagents was performed in three and two different exercises, respectively, and showed good reproducibility of the procedure. The purpose of calibration is providing a formula for the assessment of the International Normalized Ratio (INR) for patients receiving oral anticoagulants. The World Health Organization (WHO) model for thromboplastin calibration leads to the equation INR = RISI, in which R is the prothrombin time ratio and ISI the International Sensitivity Index of the calibrated thromboplastin/instrument system. This equation was adequate for one reagent, but not for the other when it was used in combination with the four instruments. At therapeutic intensities of anticoagulation, the deviation from the WHO-model observed for the second reagent was clinically insignificant. The WHO model was fully adequate when the second reagent was used with the manual technique. For both thromboplastins, there were statistically significant differences in ISI between the four instruments. The largest difference-amounting to approximately 10%-was observed between two photo-optical instruments. The order of instruments with increasing ISI was the same for the two reagents. It is recommended that thromboplastin manufacturers specify the instruments used for calibration of their reagent.

Multi-Center Study of Thromboplastin Calibration Precision – Influence of Reagent Species, Composition, and International Sensitivity Index (ISI)

1993 ◽  
Vol 69 (01) ◽  
pp. 035-040 ◽  
Author(s):  
A M H P van den Besselaar ◽  
R M Bertina
Keyword(s):  
Oral Anticoagulants ◽  
International Normalized Ratio ◽  
The Other ◽  
World Health ◽  
Rabbit Brain ◽  
Sensitivity Index ◽  
Bovine Plasma ◽  
Significant Difference ◽  
The Mean ◽  
International Sensitivity Index

SummaryFour thromboplastin reagents were tested by 18 laboratories in Europe, North-America, and Australasia, according to a detailed protocol. One thromboplastin was the International Reference Preparation for ox brain thromboplastin combined with adsorbed bovine plasma (coded OBT/79), and the second was a certified reference material for rabbit brain thromboplastin, plain (coded CRM 149R). The other two thromboplastin reagents were another rabbit plain brain thromboplastin (RP) with a lower ISI than CRM 149R and a rabbit brain thromboplastin combined with adsorbed bovine plasma (RC). Calibration of the latter two reagents was performed according to methods recommended by the World Health Organization (W. H. O.).The purpose of this study was to answer the following questions: 1) Is the calibration of the RC reagent more precise against the bovine/combined (OBT/79) than against the rabbit/plain reagent (CRM 149R)? 2) Is the precision of calibration influenced by the magnitude of the International Sensitivity Index (ISI)?The lowest inter-laboratory variation of ISI was observed in the calibration of the rabbit/plain reagent (RP) against the other rabbit/plain reagent (CRM 149R) (CV 1.6%). The highest interlaboratory variation was obtained in the calibration of rabbit/plain (RP) against bovine/combined (OBT/79) (CV 5.1%). In the calibration of the rabbit/combined (RC) reagent, there was no difference in precision between OBT/79 (CV 4.3%) and CRM 149R (CV 4.2%). Furthermore, there was no significant difference in the precision of the ISI of RC obtained with CRM 149R (ISI = 1.343) and the rabbit/plain (RP) reagent with ISI = 1.14. In conclusion, the calibration of RC could be performed with similar precision with either OBT/79 or CRM 149R, or RP.The mean ISI values calculated with OBT/79 and CRM 149R were practically identical, indicating that there is no bias in the ISI of these reference preparations and that these reference preparations have been stable since their original calibration studies in 1979 and 1987, respectively.International Normalized Ratio (INR) equivalents were calculated for a lyophilized control plasma derived from patients treated with oral anticoagulants. There were small but significant differences in the mean INR equivalents between the bovine and rabbit thromboplastins. There were no differences in the interlaboratory variation of the INR equivalents, when the four thromboplastins were compared.

In-house Calibration of the International Sensitivity Index or Calibration Curve for Determination of the International Normalized Ratio

2004 ◽  
Vol 128 (3) ◽  
pp. 308-312
Author(s):  
William F. Brien ◽  
Linda Crawford ◽  
Anne Raby ◽  
Harold Richardson
Keyword(s):  
Calibration Curve ◽  
Oral Anticoagulants ◽  
International Normalized Ratio ◽  
Sensitivity Index ◽  
Improve Performance ◽  
Accuracy And Precision ◽  
The Stability ◽  
Method Of Assessment ◽  
International Sensitivity Index

Abstract Context.—The international normalized ratio (INR) has been used since 1983 to standardize prothrombin time results for patients on oral anticoagulants. However, significant interlaboratory variations have been noted. Attempts have been made to address these differences with the use of instrument-specific International Sensitivity Index (ISI) values and in-house calibration of ISI values. Objective.—To assess the performance of laboratories using a calibration curve for INR testing. Design.—Attempts to improve performance of the INR include the use of instrument-specific ISI values, model-specific ISI values, in-house calibration of ISI values, and more recently, the preparation of a calibration curve. Several studies have shown an improvement in performance using these procedures. In this study of licensed laboratories performing routine coagulation testing in the Province of Ontario, Canada, the determination of the INR by a calibration curve was compared with the laboratories' usual method of assessment. These methods were subsequently analyzed by comparing the results to instrument-specific ISI, model-specific ISI, and in-house calibrators. International normalized ratios derived by both methods were analyzed for accuracy and precision. The stability of a calibration curve was also investigated. Results.—Performance of INR testing has improved with use of a calibration curve or in-house calibrators. Conclusion.—The results confirm that either in-house calibrators or the calibration curve improve performance of INR testing. The calibration curve may be easier to use and appears stable up to 4 months.

Assessment of the Influence of Citrate Concentration on the International Normalized Ratio (INR) Determined with Twelve Reagent-instrument Combinations

1998 ◽  
Vol 80 (08) ◽  
pp. 258-262 ◽  
Author(s):  
Veena Chantarangkul ◽  
Marigrazia Clerici ◽  
Barbara Negri ◽  
Pier Mannuccio Mannucci ◽  
Armando Tripodi
Keyword(s):  
External Quality Assessment ◽  
International Normalized Ratio ◽  
Local System ◽  
Sensitivity Index ◽  
External Quality ◽  
Citrate Concentration ◽  
Coagulation Tests ◽  
Reference Preparation ◽  
Anticoagulated Patients ◽  
International Sensitivity Index

SummaryCitrate concentration is one of the variables that can affect coagulation tests. However, few studies have so far been performed to assess the magnitude of this effect on coagulation tests in general and PT in particular. The aim of this study was to assess the extent of influence of citrate concentration on the PT test with results expressed as INR. Twelve reagent-instrument combinations (systems) were calibrated vs. the Reference Preparation BCT/441 using plasmas collected in either 105 mM or 129 mM citrate from normals and anticoagulated patients (OAT). PTs for plasmas collected in 129 mM citrate were longer than those collected in 105 mM both for normals and patients on OAT, but the ratios (patient-to-normal clotting times) for the two citrate concentrations were significantly different in many instances, implying that the International Sensitivity Index (ISI) is also different. ISIs for calibrations with plasmas collected in 105 mM were greater (up to 10%) than those with plasmas collected in 129 mM citrate. When PT ratios were transformed into INR using crossover ISIs (i.e., plasmas collected in 105 mM and ISI determined with plasmas collected in 129 mM citrate, or vice versa) we found that an INR of 4.5 could be up to 20% apart from the value that would have been obtained if the appropriate ISI was used. Moreover, if the ISI determined with the manual technique was used to convert PTs obtained with a particular instrument into INR, the effect of citrate concentration was even greater (INR difference up to 64%). Should these observations be valid for other systems, they might provide additional explanations for the frequent reports which document discrepancies in the INR determined with different systems to which incorrect ISI might have been applied. World-wide consensus on a single citrate concentration to collect patients’ as well as lyophilized plasmas to be used in External Quality Assessment Schemes and for local system calibration is therefore urgently needed.

The Dependence of the International Sensitivity Index on the Coagulometer Used to Perform the Prothrombin Time

1990 ◽  
Vol 63 (03) ◽  
pp. 424-429 ◽  
Author(s):  
M J Ray ◽  
I R Smith
Keyword(s):  
Prothrombin Time ◽  
Reference Method ◽  
Calibration Procedure ◽  
World Health ◽  
Sensitivity Index ◽  
Optical Instruments ◽  
Different Types ◽  
Reference Preparation ◽  
Health Organization ◽  
International Sensitivity Index

SummaryThis study was designed to detect any effect that different types of coagulation instrument may have on the International Sensitivity Index (ISI) of a thromboplastin.Manufacturers of commercial thromboplastins now calibrate their reagents against the World Health Organization international reference preparation to assign them an IST. This enables the prothrombin time (PT) estimated with that reagent to be expressed as an International Normalised Ratio (INR).One batch of Thromborel S was calibrated against the Australasian Reference Thromboplastin (ART). The Thromborel S was used on three photo-optical instruments, the Automated Coagulation Laboratory (ACL) (Instrumentation Laboratory), the Cobas Fibro (Roche), and the Coag-a-Pet (General Diagnostics). PTs using ART were performed manually using the reference method.The ISIs calibrated in our laboratory when the ACL and Cobas Fibro were used were not significantly different at the 95% level, being 1.102 ± 0.018 and 1.134 ± 0.022 respectively. The ISI with the Coag-a-Pet of 1.223 ± 0.023 was significantly different to that of the ACL and the Cobas Fibro at the 95% level.The flowcharts for a computer program to perform the necessary calculations are provided. The program allows for the entry and editing of data from the calibration procedure, and provides a mean normal PT and normal range, the ISI and 95% confidence limits of the calibration, and a chart for the conversion of the test PTs to INRs.The authors have made available an IBM compatible program for the calibration of thromboplastins.

A Simplified Procedure for Thromboplastin Calibration -The Usefulness of Lyophilized Plasmas Assessed in a Collaborative Study

1996 ◽  
Vol 75 (02) ◽  
pp. 309-312 ◽  
Author(s):  
A Tripodi ◽  
V Chantarangkul ◽  
C Manotti ◽  
M Poggi ◽  
M Braga ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Oral Anticoagulants ◽  
Collaborative Study ◽  
Repeated Measurements ◽  
Easy Access ◽  
Sensitivity Index ◽  
Orthogonal Regression ◽  
Simplified Procedure ◽  
International Sensitivity Index

SummaryThe International Sensitivity Index (ISI) of thromboplastins is determined by calibration using fresh plasmas from 60 patients stabilized on oral anticoagulants and 20 healthy subjects. This procedure is demanding, particularly for those who have no easy access to patients. The alternative use of a smaller number of lyophilized plasmas has already been considered, but one important issue, the number of repeated measurements to be carried out, has never been addressed. Two commercial rabbit thromboplastins, A and B, were calibrated in 3 laboratories against CRM 149R. On each of 10 working days, prothrombin times were measured for a different set of 8 fresh plasmas and for the same set of 8 lyophilized plasmas. The ISI values for both thromboplastins were estimated by orthogonal regression on fresh and lyophilized plasmas. The between- and within-laboratory CV values of the estimated ISI were taken as measures of precision of the calibration. In addition, ISI and CV were calculated daily on cumulative results obtained with lyophilized plasmas from day 1 to day 10. The ISI values for both thromboplastins calculated with lyophilized plasmas were not significantly different from those with fresh plasmas (mean of 3 laboratories: 1.42 vs 1.48 for A and 1.22 vs 1.20 for B). The between-laboratory precision of the calibration with lyophilized plasmas was not considerably different from that with fresh plasmas (CV for 3 labs: 5.2% vs 6.8% for A and 0.9% vs 2.2% for B). The ISI estimated with lyophilized plasmas on results of day 1 were not different from those of days 2 through 10. Good within-laboratory precision of the calibration (CV around 2%) was already achieved on day 3. In conclusion, this study shows that lyophilized plasmas pooled from normals and patients on oral anticoagulants can be used as substitutes for individual fresh plasmas to simplify the existing procedure for thromboplastin calibration.

The Calibration of the Second Primary International Reference Preparation for Thromboplastin (Thromboplastin, Human, Plain, Coded BCT/253)

1984 ◽  
Vol 52 (03) ◽  
pp. 336-342 ◽  
Author(s):  
Jean M Thomson ◽  
J A Tomenson ◽  
L Poller
Keyword(s):  
Statistical Analysis ◽  
Prothrombin Time ◽  
International System ◽  
Second Primary ◽  
Sensitivity Index ◽  
Calibration Model ◽  
International Reference ◽  
Reference Preparation ◽  
Time Test ◽  
International Sensitivity Index

SummaryAn international collaborative exercise has been undertaken to calibrate a replacement for the first WHO primary international reference preparation (IRP) for thromboplastin. The replacement preparation is a lyophilised batch of British Comparative Thromboplastin (BCT/253, human plain) for use in the Quick prothrombin time test. Seventeen centres participated. The experimental design, calibration model and statistical analysis were based on the recommended WHO procedure. As a result of this calibration exercise an International Sensitivity Index (ISI) of 1.1 has been assigned to the preparation by WHO and it has been officially recognised as the second primary IRP for thromboplastin.The calibration of BCT/253 is an essential link in a new hierarchical structure for the standardisation of the prothrombin time. The aim is to provide a uniform international system of reporting prothrombin time results using International Normalised Ratios (INR) derived from the ISI of individual thromboplastins.

scholarly journals Influence of Three Types of Automated Coagulometers on the International Sensitivity Index (ISI) of Rabbit, Human, and Recombinant Human Tissue Factor Preparations

1999 ◽  
Vol 81 (01) ◽  
pp. 66-70 ◽  
Author(s):  
L. L. Houbouyan ◽  
M. F. Aillaud ◽  
K. W. E. Denson ◽  
M. Johnston ◽  
S. Kitchen ◽  
...  
Keyword(s):  
Tissue Factor ◽  
International Normalized Ratio ◽  
Sensitivity Index ◽  
International Reference ◽  
Rabbit Tissue ◽  
Reference Preparation ◽  
The Mean ◽  
Automated Instruments ◽  
International Multicenter ◽  
International Sensitivity Index

SummaryFive tissue factor reagents and three types of automated instruments for prothrombin time (PT) determination were studied in an international multicenter collaborative exercise. The purpose of this work was to determine the international sensitivity index (ISI) for each combination of reagent and instrument against the international reference preparation RBT/90. Each type of instrument was used by 3 or 4 centers to assess the interlaboratory variation of the ISI. The interlaboratory variation of the ISI for each combination of reagent and instrument ranged between 0.4% and 7.8% coefficient of variation. For three reagents, the mean ISI values for ACL (nephelometric) and STA (mechanical) were practically identical, but the mean ISI values for MLA (photo-optical) were at least 10% higher. For two other reagents prepared from rabbit tissue, the mean ISI values increased in the order ACL, STA, MLA. The widest range of mean ISI values was noted with one rabbit tissue factor reagent: 1.68 for ACL and 2.00 for MLA. Exclusion of patient specimens with INR <1.5 and INR >4.5 determined by the international reference preparation resulted in a slight decrease of the mean ISI.The interlaboratory variation of the International Normalized Ratio (INR) was assessed from the results obtained with common lyophilized and deep-frozen plasmas. The use of instrument-specific ISI values resulted in reduced interlaboratory variation of the INR. It is recommended that thromboplastin manufacturers provide instrument-specific ISI values.

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