Low International Sensitivity Index Research Articles

Impact of an Institutional Change in Prothrombin Time Methodology on INR and MELD Scores in Liver Transplant Evaluations.

Allocation of liver grafts based on the model for end-stage liver disease (MELD) has been questioned because the prothrombin time (PT) measurement in cirrhosis patients changes with different commercially available thromboplastin reagents due to variations in the international sensitivity index (ISI). Our hospital laboratory electively changed the thromboplastin used in the PT/INR from PT-HS (ISI of 1.464) to Recombiplastin (ISI of 0.870). Theoretically, this change may yield lower INR and MELD scores in cirrhosis patients at our institution and thus impact access to organs. 27 patients listed for liver transplant prior to change in thromboplastin (Cohort A) were compared to 36 patients listed after the change (Cohort B). Patients in Cohort A had a mean INR of 1.41 and mean MELD of 13.9 compared to Cohort B with a mean INR of 1.39 and mean MELD of 13.8. Student's t-tests showed no statistically significant difference in INR (p = 0.799) or MELD (p = 0.955) between cohorts. We expected overall INR and MELD scores to decrease following the change to a thromboplastin with a lower ISI. On the contrary, we found no evidence of a major trend in these values supporting the relative robustness of the MELD.

Mathematical Derivative Applied to International Normalised Ratio and Analytical Variations in Oral Anticoagulant Therapy Control

A reliable prothrombin time (PT) testing and a careful drug dosage can prevent thrombotic or bleeding complications of the oral anticoagulant therapy. The international normalised ratio (INR) as PT standardisation introduced an analytical variation that increases with higher PT measures and higher international sensitivity index (ISI) values. Our study was conducted to investigate the INR accuracy through the mathematical derivative application to reduce the analytical component of the INR uncertainty. The evaluation of accuracy among four different systems (prothrombin activity percent, PT seconds, PT ratio and INR) was determined by the simulation of a systematic error. Plasma samples were diluted 1:2; then they were compared observed with the expected values. We analysed the calculation system of the INR through the mathematical derivative in 87 PT ratio measurements. The analytical incidence of thromboplastin ISI was performed through an elaboration of INR mathematical derivative considering 10 different ISI values ranging from 1.1 to 2. The data expressed as PT ratios revealed a lower systematic error propagation suggesting that a linear system is more accurate. According to the calculation formula of INR, analytical variability increases with the PT measurements, then with the intensity of anticoagulation. Mathematical derivative suggests that the INR uncertainty due to the ISI can be reduced using a thromboplastin reagent with a low ISI or with ISI close to 1.

The effects of freeze drying and freeze drying additives on the prothrombin time and the international sensitivity index.

AIM: To determine whether freezing, freeze drying protective additives, or freeze drying of plasma samples from patients on coumarin treatment and from normal individuals affects prothrombin times or the international...

Clinically significant differences in the International Normalized Ratio measured with reagents of different sensitivities. SPAF Investigators. Stroke Prevention in Atrial Fibrillation.

The International Normalized Ratio (INR) system was introduced a decade ago as a way of standardizing the results of prothrombin time testing for patients taking oral anticoagulants. A strong emphasis has been placed upon using thromboplastin reagents that are very sensitive to the effects of oral anticoagulants upon the prothrombin time [i.e. reagents with low International Sensitivity Index (ISI)]. In order to assess how well the INR system functions as currently used in clinical laboratories, we compared the INRs determined using thromboplastins of differing ISIs in samples collected during a large clinical trial of oral anticoagulation for atrial fibrillation (Stroke Prevention in Atrial Fibrillation III trial). Frozen plasma was subjected to prothrombin time testing using thromboplastins with ISIs ranging from 0.97 to 2.49. INRs were calculated using machine-specific ISIs and Westgard's rules were followed to maintain quality control. An unanticipated coagulometer failure allowed a determination of the effect of machine recalibration upon the INR of control plasmas. The correlation between each pair of INRs obtained from 1181 plasmas was high (> 0.9), but the differences between reagents were statistically different from zero (P<0.001 for pairwise comparisons). Plasmas had INRs within the therapeutic range (2.0-3.0) with one reagent but not with another in an average of 20% of instances. Among the 20% discordant pairings, 43% (8.5% of the total tested) showed a difference in INR of more than 0.2 INR units above or below the target range. Low ISI thromboplastins did not perform better in this pairwise comparison than other reagents or the locally determined INR. Recalibration of a coagulometer resulted in a significant change in the INRs obtained from control plasmas (P<0.0001), which confirms and extends the observations of other authors concerning the sensitivity of the INR to coagulometer-related variables. There was a clinically significant difference in the INRs obtained with different thromboplastins, and low ISI reagents did not perform better than others. Since the risk of thrombosis rises sharply below the lower limit of the currently recommended target ranges, consideration should be given to narrowing the recommended range, or advising clinicians to aim for its mid-point. These findings illustrate the difficulties in imposing standardization upon coagulation testing after a test is in widespread use.

INR reporting in Canadian medical laboratories: an update. Thrombosis Interest Group of Canada.

A written survey of all licensed medical laboratories performing coagulation testing in Canada was undertaken in 1996 as a follow-up to a study performed in 1992. The an overall response rate was 77.4% of the laboratories surveyed. During the 4-year period between surveys, the percentage of responding laboratories using some format for international normalized ratio (INR) reporting increased from 57% to 98%. The mean International Sensitivity Index (ISI) of the various thromboplastins used had decreased from 2.07 to 1.63. However, only 35% of responding laboratories used a thromboplastin with an ISI of 1.2 or less as recommended by the American College of Chest Physicians. In 92% of cases, the ISI was said to be specified for the type of instrument, ie, optical density vs mechanical. However, in only 52% of cases was the ISI known to be specific for the particular reagent-analyzer combination used in the individual laboratory. Nine percent of the laboratories were still using an inappropriate denominator for the INR calculation. While 87% of laboratories quoted a therapeutic INR range of 2.0 to 3.0 for venous thromboembolism, there was much greater variation in the range reported for patients undergoing heart valve replacement. The situation in Canada has improved in using the INR system for prothrombin time reporting. However, additional education is required, as is greater use of thromboplastins with a lower ISI.

The importance of "like to like" ISI calibrations with freeze dried plasmas. European Concerted Action on Anticoagulation.

AIM: To assess reliability of like to like and cross species calibrations using two types of certified freeze dried plasma calibrants--artificially depleted of vitamin K clotting factors, and from coumarin...

Minimum lyophilized plasma requirement for ISI calibration. European Concerted Action on Anticoagulation.

The minimum requirement of lyophilized plasma samples for a reliable International Sensitivity Index (ISI) was assessed by calibrations based on reducing numbers from a maximum of 60 depleted and 20 plasma samples from patients receiving coumarin using a manual technique and low ISI thromboplastin. The probability of achieving an international normalized ratio (INR) result within a clinically important range of 20% deviation has been assessed at European Concerted Action on Anticoagulation (ECAA) national laboratories in calibrations of ECAA reference thromboplastin against the certified prothrombin time (PT) with a reference thromboplastin. With conventional orthogonal regression using a certified PT and linear regression using certified INR, deviations and the coefficient of variation of the calibration slope increased with reduced numbers. The INR deviations became marked when the number of abnormal plasma samples was reduced to fewer than 20. Calibrations of 3 abnormal plasma samples and 1 lyophilized normal plasma sample gave a high incidence of deviations greater than 10% with an INR of 3.0. The study demonstrates that with both methods of analysis, an optimum minimum number of lyophilized plasma samples is needed for a reliable local ISI.

Influence of plasma volumetric errors on the prothrombin time ratio and International Sensitivity Index.

The International Sensitivity Index (ISI) for prothrombin time systems depends on the thromboplastin manufacturer's recommended method for use. The purpose of the present study was to investigate the influence of small deviations from the recommended sample volume on the prothrombin time ratio and ISI. Four commercial reagents were studied; three with low ISI and one with high ISI. The effects of volumetric errors on the ISI were used to assess the associated effects on the International Normalized Ratio (INR). The effect of 10% volume error on the INR was not greater than 5%. The effects with the three low-ISI reagents were slightly greater than those with the high-ISI reagent. It is recommended that each laboratory should check the volumes of sample and reagent used for the prothrombin time test.

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

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.

The use and limitations of the INR system

This study was undertaken to answer some practical questions physicians and medical directors of clinical laboratories face when they contemplate replacing their high international sensitivity index (ISI) thromboplastins with low ISI ones and using international normalized ratio (INR) in place of prothrombin time ratio (PTR) for monitoring warfarin therapy. To the question of whether low-ISI thromboplastins would produce a prolonged PT on normal patients, the answer is probably no. To the question of the extent of normalization of disparate PTs, determined by high and low ISI thromboplastins, of patients on oral anticoagulants upon the conversion of PTR to INR, the answer is a mixed one. For those whose PTs were 14-20 sec, conversion of PTR to INR would markedly, but not completely, normalize the PTR values. In other words, there would be a lessening of disparity of the PTR after the conversion. For patients whose PTs were > 20 sec, conversion of PTR to INR could even widen the disparity seen with the PTR. Finally, when PTs were assayed on different coagulation devices with the same reagent, highly congenial results were obtained.

Comparison of a Standard and a Sensitive Thromboplastin in Monitoring Low Intensity Oral Anticoagulant Therapy

The greater precision in prothrombin time monitoring obtained using thromboplastins with low international sensitivity index (ISI) values are believed to result in improved patient care. The authors conducted a blinded prospective study of 84 random patients on low-intensity warfarin therapy who were monitored with either a sensitive (ISI, 1.3) or standard (ISI, 1.9) thromboplastin. For the patients monitored with standard and sensitive thromboplastins, respectively, no difference was found in the degree of anticoagulation (standard thromboplastin mean INR, 2.4 vs. 2.5, P = .37; sensitive thromboplastin mean INR, 2.6 vs. 2.6, P = .74; mean daily warfarin dose, 5.1 vs. 4.7 mg, P = .28) or efficacy (warfarin dosage adjustments, 117 vs. 116; clinic visits, 362 vs. 378; percentage of therapeutic INR determinations, 47% vs. 48%). In addition, no difference was found in bleeding prevalence or severity (.22 vs. .27 events per person-year observation). The authors concluded that monitoring anticoagulant therapy in the INR range of 2-3 with a standard thromboplastin may be comparable to monitoring with a more sensitive thromboplastin with respect to efficacy, safety, and degree of anticoagulation achieved.

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

Four 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 inter-laboratory 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Quality control of the prothrombin time and international normalized ratios. National and international schemes

The international normalized ratios (INR) system allows valid comparisons in results and quality of performance to be made between users of different thromboplastin reagents. In the international quality control surveys currently over 80% of the 53 countries participating report INR. Stated local international sensitivity index (ISI) values show fair agreement with values calculated from quality control returns obtained with local and reference reagents. The coefficient of variations (CV) of the INR in these surveys are between 11-22% depending upon INR values. In comparison, CV of the UK national scheme are currently 7-13%. However, analysis of UK results has shown high CV with high ISI reagents. This is due to the ISI effect as CV of INR is CV of prothrombin ratio (PR) multiplied by the ISI. Ideal thromboplastins should show good precision of PR and a low ISI to prevent this apparent deterioration when PR results are transformed into the INR scale. Instrumentation has a further effect on the INR result. Unfortunately, the effect is not uniform even within instrument type and model or even between normal and therapeutic results. Local instrument adjustment or local calibration is therefore necessary. Thus, quality control surveys continue to highlight problems in prothrombin time standardization.

Effect of international sensitivity index (ISI) of thromboplastins on precision of international normalised ratios (INR)

The contribution of the thromboplastin international sensitivity index (ISI) to the interlaboratory coefficient of variation (CV) of the international normalised ratio (INR) with individual reagents was assessed. In theory the precision of the INR should increase with lower ISI values. An empirical relation has been established between the ISI, the INR, and its CV for two rabbit thromboplastins used in sufficient numbers for analysis in the United Kingdom. This was based on the cumulative data from the United Kingdom National External Quality Assessment Scheme (NEQAS) surveys over two years beginning in 1986. The actual precision achieved in NEQAS for the two reagents depends on the ISI value of the thromboplastin and it agreed closely with the figure predicted by the empirical model. The findings show that the ISI value of a thromboplastin strongly influences the interlaboratory variability of the INR obtained with it. The CV of the INR approximates to the CV of the prothrombin ratio multiplied by the ISI. Manufacturers of thromboplastin should therefore be encouraged to produce reagents showing good precision of results reported as simple prothrombin ratios and a low ISI value to avoid impairment in precision when ratio results are transformed to INR.