Validity of International Normalized Ratio in Expressing Prothrombin Times in Anticoagulated and Nonanticoagulated Patients

1996 ◽  
Vol 2 (1) ◽  
pp. 25-29 ◽  
Author(s):  
Rasheed Alshameeri ◽  
Eberhard F. Mammen ◽  
Christa Paisley ◽  
Christine Perry
Keyword(s):  
Human Placenta ◽  
Oral Anticoagulant ◽  
High Sensitivity ◽  
International Normalized Ratio ◽  
Rabbit Brain ◽  
Sensitivity Index ◽  
Normal Range ◽  
Normal Ranges ◽  
Highly Sensitive ◽  
International Sensitivity Index

We investigated the effect of four thrombo plastins with different International Sensitivity Index (ISI) values on prothrombin times (PTs), expressed as International Normalized Ratios (INRs), of 30 normal plasmas, 30 patients on stable oral anticoagulant (OA) therapy, and 30 patients with prolonged PTs for reasons other than OA therapy. Normal ranges became signifi cantly longer when three thromboplastins of rabbit brain origin were used—the lower the ISI, the wider the normal range. The human placenta-derived thromboplastin had a range similar to the values obtained with the most insen sitive rabbit reagent. Significantly different INR values were noted when normal plasmas and plasmas of patients with prolonged PTs not due to OA therapy were tested. This was not the case when specimens from patients on OAs were tested. When PT values from 212 consecutive ly selected patients were tested with the least sensitive rabbit reagent (ISI 2.477) and the most sensitive human placenta reagent (ISI 1.06), significantly more "abnor mal" PTs were identified with the high-sensitivity throm boplastin. The data indicate that special attention has to be paid to "normal" ranges when thromboplastins with low ISI replace less sensitive reagents, that INR should not be used to express PT in patients not on stable OA therapy, and that with the routine use of highly sensitive reagents (low ISI) more abnormal patients are identified.

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.

Are Capillary Whole Blood Coagulation Monitors Suitable for the Control of Oral Anticoagulant Treatment by the International Normalized Ratio?

1993 ◽  
Vol 70 (06) ◽  
pp. 0921-0924 ◽  
Author(s):  
Armando Tripodi ◽  
Arnaldo A Arbini ◽  
Veena Chantarangkul ◽  
Donato Bettega ◽  
Pier Mannuccio Mannucci
Keyword(s):  
Whole Blood ◽  
Oral Anticoagulant ◽  
Oral Anticoagulant Therapy ◽  
Oral Anticoagulants ◽  
Regression Line ◽  
International Normalized Ratio ◽  
Rabbit Brain ◽  
Sensitivity Index ◽  
Calibration Model ◽  
Oral Anticoagulant Treatment

SummaryThe 512 Coagulation Monitor is a portable coagulation photometer that uses disposable cartridges containing a lyophilized rabbit brain thromboplastin to measure the PT for capillary whole blood. It has been proposed as a suitable system for patient self monitoring at home, but its performance has never been thoroughly assessed for results expressed as International Normalized Ratio (INR). In particular, there is no available information about the adequacy of the WHO calibration model with the Monitor. The aims of the study were to determine the International Sensitivity Index (ISI) against the secondary International Reference Preparation for rabbit thromboplastin and to assess the precision of the INR. The study demonstrates that the Monitor can be calibrated with the WHO model, because log-transformed PTs for patients stabilized on oral anticoagulants and normal individuals are linearly related and because the same orthogonal regression line describes patient and normal data points adequately. However, the ISI calculated in this study (2.715) is higher than that adopted by the manufacturer (2.036). The between-assay reproducibility of the Monitor is acceptable (CV = 9.7%) with results expressed in seconds, but become unacceptably poor when the results are converted into INR (CV = 18.8%) because of the high ISI value of the thromboplastin used. We think that the Monitor might be suitable for monitoring oral anticoagulant therapy if the manufacturer would provide a more sensitive thromboplastin in the cartridges.

scholarly journals Monitoring "mini-intensity" anticoagulation with warfarin: comparison of the prothrombin time using a sensitive thromboplastin with prothrombin fragment F1+2 levels

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 2034-2038 ◽  
Author(s):  
MM Millenson ◽  
KA Bauer ◽  
JP Kistler ◽  
S Barzegar ◽  
L Tulin ◽  
...  
Keyword(s):  
Prothrombin Time ◽  
Factor Xa ◽  
High Sensitivity ◽  
International Normalized Ratio ◽  
Target Range ◽  
Lower Sensitivity ◽  
Sensitivity Index ◽  
Plasma Samples ◽  
Prothrombin Activation

Treatment with warfarin using a target International Normalized Ratio (INR) range of 1.7 to 2.5 is efficacious for many clinical indications, but the minimal intensity of anticoagulation required for antithrombotic protection has yet to be determined. To evaluate whether patients could be reliably monitored with a less intense regimen, we anticoagulated patients with warfarin for several months using a target INR range of 1.3 to 1.6 as determined by prothrombin time (PT) using a sensitive thromboplastin (Dade IS, International Sensitivity Index [ISI] = 1.3). Plasma measurements of F1+2, a marker of factor Xa action on prothrombin in vivo, were also obtained to determine the suppressive effect of warfarin on hemostatic system activity. Overall, 20 of 21 patients with a history of cerebrovascular events (mean age, 61 years) could be reliably regulated with warfarin in the target INR range. F1+2 levels were significantly suppressed from baseline in all patients, with a mean reduction of 49% (range, 28% to 78%). We found a significant relationship between the extent of suppression of prothrombin activation levels and the baseline measurements. A mean reduction of 65% was observed for those patients with baseline F1+2 greater than or equal to 1.5 nmol/L, but only 38% for baseline F1+2 less than or equal to 0.5 nmol/L. Overall, 68% of plasma samples obtained during stable anticoagulation were within the target INR range. PTs were also determined on all plasma samples with two thromboplastins of lower sensitivity (C+, ISI = 2.09; and automated simplastin, ISI = 2.10). Only 47% and 35% of PT determinations, respectively, were within the target range with these reagents. We conclude that prothrombin activation can be significantly suppressed in vivo with use of warfarin in an INR range of 1.3 to 1.6. This level of anticoagulation can be reliably achieved by monitoring PTs with a thromboplastin of high sensitivity.

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.

scholarly journals Monitoring "mini-intensity" anticoagulation with warfarin: comparison of the prothrombin time using a sensitive thromboplastin with prothrombin fragment F1+2 levels

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 2034-2038 ◽  
Author(s):  
MM Millenson ◽  
KA Bauer ◽  
JP Kistler ◽  
S Barzegar ◽  
L Tulin ◽  
...  
Keyword(s):  
Prothrombin Time ◽  
Factor Xa ◽  
High Sensitivity ◽  
International Normalized Ratio ◽  
Target Range ◽  
Lower Sensitivity ◽  
Sensitivity Index ◽  
Plasma Samples ◽  
Prothrombin Activation

Abstract Treatment with warfarin using a target International Normalized Ratio (INR) range of 1.7 to 2.5 is efficacious for many clinical indications, but the minimal intensity of anticoagulation required for antithrombotic protection has yet to be determined. To evaluate whether patients could be reliably monitored with a less intense regimen, we anticoagulated patients with warfarin for several months using a target INR range of 1.3 to 1.6 as determined by prothrombin time (PT) using a sensitive thromboplastin (Dade IS, International Sensitivity Index [ISI] = 1.3). Plasma measurements of F1+2, a marker of factor Xa action on prothrombin in vivo, were also obtained to determine the suppressive effect of warfarin on hemostatic system activity. Overall, 20 of 21 patients with a history of cerebrovascular events (mean age, 61 years) could be reliably regulated with warfarin in the target INR range. F1+2 levels were significantly suppressed from baseline in all patients, with a mean reduction of 49% (range, 28% to 78%). We found a significant relationship between the extent of suppression of prothrombin activation levels and the baseline measurements. A mean reduction of 65% was observed for those patients with baseline F1+2 greater than or equal to 1.5 nmol/L, but only 38% for baseline F1+2 less than or equal to 0.5 nmol/L. Overall, 68% of plasma samples obtained during stable anticoagulation were within the target INR range. PTs were also determined on all plasma samples with two thromboplastins of lower sensitivity (C+, ISI = 2.09; and automated simplastin, ISI = 2.10). Only 47% and 35% of PT determinations, respectively, were within the target range with these reagents. We conclude that prothrombin activation can be significantly suppressed in vivo with use of warfarin in an INR range of 1.3 to 1.6. This level of anticoagulation can be reliably achieved by monitoring PTs with a thromboplastin of high sensitivity.

Multicenter Evaluation of Lyophilized and Deep-frozen Plasmas for Assignment of the International Normalized Ratio

1999 ◽  
Vol 82 (11) ◽  
pp. 1451-1455 ◽  
Author(s):  
L. L. Houbouyan-Reveillard ◽  
M. F. Aillaud ◽  
K. W. E. Denson ◽  
C. Droullé ◽  
M. Johnston ◽  
...  
Keyword(s):  
Prothrombin Time ◽  
External Quality Assessment ◽  
Calibration Procedure ◽  
International Normalized Ratio ◽  
Sensitivity Index ◽  
Local Calibration ◽  
External Quality ◽  
Different Types ◽  
Time Systems ◽  
International Sensitivity Index

SummaryThe interlaboratory variation of the International Normalized Ratio (INR) in various external quality assessment schemes is still relatively high. This is partly caused by inaccuracy of manufacturers’ stated International Sensitivity Index (ISI) and/or local instrumentation effects. The interlaboratory variation and accuracy of INR determinations may be improved by a local calibration procedure based on lyophilized plasmas with assigned INRs. The purpose of the present study was to determine INR values for different types of lyophilized plasmas to be used for local calibration. A total of 13 lyophilized plasmas (one normal, six from coumarin-treated patients, six artificially depleted) were analyzed by 10 laboratories, each using five calibrated prothrombin time (PT) systems. INRs were calculated for each plasma using each laboratory’s specific ISI and mean normal prothrombin time values. In the same way, five deep-frozen pooled plasmas from coumarin-treated patients were analyzed. There were significant INR differences for the lyophilized plasmas between the prothrombin time systems. The differences were relatively small for the deep-frozen coumarin plasmas (CV 2.6-3.3%) and three lyophilized coumarin plasmas from one manufacturer (CV 3.7-4.8%). Important INR differences were observed for three lyophilized coumarin plasmas from another manufacturer (CV 9.5-14.1%) and several artificially depleted plasmas (CV 5.3-12.8%). The citrate concentrations in the artificially depleted plasmas were lower than those in the normal and coumarin plasmas. These differences should be considered in the selection and certification of plasmas as calibrants for local calibration of PT systems. The lyophilized plasmas’ INR values obtained in the present study will be used for a field study of local PT calibration to assess their efficacy.

scholarly journals Effects of a Synthetic Factor Xa Inhibitor (JTV-803) on Various Laboratory Tests

2002 ◽  
Vol 8 (4) ◽  
pp. 325-336 ◽  
Author(s):  
Mahmut Tobu ◽  
Omer Iqbal ◽  
Debra A. Hoppensteadt ◽  
Christopher Shultz ◽  
Walter Jeske ◽  
...  
Keyword(s):  
Oral Anticoagulant ◽  
Laboratory Tests ◽  
Factor Xa ◽  
International Normalized Ratio ◽  
Factor Xa Inhibitors ◽  
Rabbit Brain ◽  
Factor Xa Inhibitor ◽  
Thrombin Time ◽  
Clotting Time ◽  
Direct Inhibitors

Synthetic direct inhibitors of factor Xa are capable of prolonging the global anticoagulant assay times in a concentration-dependent fashion. The relative degree of thrombin generation inhibition at an equivalent prolongation is not similar to the results observed with heparins and oral anticoagulant drugs. In addition, the direct factor Xa inhibitors prolong the Russell' viper venom test (RVVT) and Heptest clotting times. Ecarin clotting time (ECT) and thrombin time (TT) remain unaffected. The kinetics of factor Xa inhibition are markedly different than those observed with pentasac-charide and heparins. Therefore, the methods developed for heparins and pentasaccharides may not be applicable for the monitoring of factor Xa inhibitors. To test the feasibility of using the prothrombin time (PT), International Normalized Ratio (INR), activated partial thromboplastin time (aPTT), Heptest, thrombin time, RVVT, ECT, and a modified anti-Xa amidolytic assay, to monitor a synthetic factor Xa inhibitor, normal human pool plasma samples were spiked with a synthetic factor Xa inhibitor in the concentration range of 0 to 1 μg/mL and 0 to 25 μg/mL. Different laboratory tests were performed and INR and other ratios were calculated. The anticoagulant effects on whole blood were measured using the activated clotting time (ACT). Further studies on the effect of factor Xa inhibitor on platelet aggregation; factor II, VII, and X functional levels; and fibrinopeptide A (FPA) generation were carried out at equivalent INR levels in comparison to oral anticoagulant and antithrombin agents. FPA generation at equivalent anticoagulant level in comparison to heparin (twice the baseline) was also carried out. Factor Xa inhibitor produced a concentration-dependent prolongation of the ACT. ACT was doubled at a concentration of 4 to 5 μg/mL. There was a marked difference in the prolongation of the PT by a synthetic factor Xa inhibitor dependent on the ISI of the PT reagent used. When the results were calculated to determine INR, marked variations were noted between the recombinant thromboplastin and rabbit brain thromboplastin. The rabbit brain thromboplastin reagent gave markedly high INR values. Similar results were observed when different aPTT reagents were studied. In the anti-Xa assay, modification of the incubation time was employed to extend the proper sensitivity range. These studies warrant further investigation to understand the mechanism of action of factor Xa inhibitors.

Intrahospital Correlation of the International Normalized Ratio

2008 ◽  
Vol 15 (2) ◽  
pp. 220-224 ◽  
Author(s):  
Alejandro Lazo-Langner ◽  
Rosario Villa-Márquez ◽  
Darinel Hernández-Hernández ◽  
Sonia Rojas-Maya ◽  
Josefa Piedras
Keyword(s):  
Oral Anticoagulant Therapy ◽  
Warfarin Dose ◽  
Correlation Coefficients ◽  
Coagulation Factors ◽  
International Normalized Ratio ◽  
Rabbit Brain ◽  
Clinical Use ◽  
Altman Analysis ◽  
Bland Altman Analysis ◽  
Highly Sensitive

Background. Monitoring of oral anticoagulant therapy (OAT) is usually accomplished by measuring prothrombin time and the international normalized ratio (INR). However, thromboplastins have different responsiveness and sensitivity to vitamin K—dependent coagulation factors depletion. Several studies have shown INR variation when low sensitive thromboplastins are used. This study compared INR variability between two laboratories using highly sensitive thromboplastins. Methods. A total of 237 plasmas were tested, half of them from patients under OAT. Samples were tested simultaneously in two laboratories: in laboratory A, a Behring Coagulation Timer instrument and a human recombinant thromboplastin (Innovin, Dade Behring) (ISI 1.01) were used. In laboratory B, a Thrombolyzer Compact (Behnk Elektronik) and a rabbit brain thromboplastin (Simplastin Excel S, Organon Teknika) with an ISI of 1.30 were used. Statistical analysis was carried out according to the method of Bland and Altman. Results. Even though high correlation coefficients were obtained when comparing both laboratories, Bland—Altman analysis showed a variation of INR between laboratories ranging from −0.77 to +1.07. After logarithmic transformation of data, these values yielded a variation of the INR either 25% below or 44% above. Conclusions. These results are clearly inadequate for clinical use because such a variation would most probably induce the clinician to make a change in warfarin dose. Standardization of instruments, reagents, and controls is warranted to decrease this variation.

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