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The introduction of international reference preparations (IRP) of thromboplastins was an important step forward in the standardisation of laboratory monitoring of coumarin therapy for the treatment and prevention of thrombosis. In more recent years, the standard manual technique for prothrombin time (PT), which was used to monitor coumarin therapy, has been replaced gradually by a variety of different automated techniques in the laboratory. The international sensitivity index (ISI), assigned to a working thromboplastin by comparison to the IRP, is invalidated by the use of automated techniques, and is not necessarily consistent among analysers of the same type. Consequently, current recommendations are that individual laboratories should standardise their own thromboplastin with their routine method, using calibrated lyophilised plasmas which have international normalised ratios (INR) assigned to them.

The international normalized ratio (INR) was established as a means of standardizing the prothrombin time regardless of the thromboplastin used in the individual laboratories. The INR is the prothrombin time ratio of the sample raised to the power of the International Sensitivity Index (ISI). Traditionally, the ISI is determined by using a manual clotting technique by comparing the test thromboplastin with a World Health Organization international reference thromboplastin with results from 60 patient samples standardized on warfarin, and 20 samples from normal volunteers. Most laboratories no longer perform prothrombin time testing by a manual technique but instead automate the procedure by using a variety of coagulation instruments. Thromboplastin ISI values have the potential to be modified considerably by instrumentation, and as a consequence, they, may result in INRs that are unreliable when compared to those obtained by the traditional manual method. It has been proposed that the use of calibrant plasmas tested with the laboratory's thromboplastin and instrument may overcome this problem and a local ISI value could be established. Our study objective was to determine whether a local ISI calibration with the plasma calibrants could reduce the variation of the INR over a wide range of thromboplastin/ instrument combinations. A total of 58 laboratories from across Canada, including community hospitals, private laboratories, and large tertiary care units, participated. The findings indicate that the use of calibrant plasmas to calculate the local ISI does improve the accuracy of INR reporting in the majority of thromboplastin/instrument combinations.

Objective: To determine whether a 24-hour delay in testing affects international normalized ratio (INR) reproducibility as much as using alternative thromboplastin reagents., Methods: Specimens from warfarin-treated patients were tested at 0 hours and again at 24 hours to determine the INR, each time using RecombiPlasTin, Innovin, and C-Plus thromboplastin reagents., Results: There was no clinically significant difference in INRs when a specimen was tested with the same reagent at 0 and 24 hours. However, at 0 hours, the INRs were significantly higher when a specimen was tested using C-Plus and RecombiPlasTin as compared with the result with Innovin (both P < .0001)., Conclusions: A specimen can be maintained at room temperature for 24 hours without a significant change in the INR. Changing the reagent, however, can result in statistically and clinically significant differences in the INR.

Local calibration studies have been performed with lyophilized plasmas at 155 European laboratories to assess coagulometer effects on manual ISI of ECAA thromboplastins (low ISI human recombinant and high ISI rabbit brain). Common sets of 7 normal and 20 artificially depleted lyophilized plasmas were tested with the thromboplastins in the routine local coagulometers. With the human reagent, marked lowering of the manual ISI resulted with most coagulometers, which was associated with disproportionate shortening of the normals. Where this shortening did not occur, there was little coagulometer effect on the ISI. With the rabbit reagent, proportionate shortening with both normal and abnormal plasmas occurred in most instruments with little effect on ISI. INR correction by local ISI assignment appeared successful with the ECAA human reagent. There was negligible INR correction from local calibration of the ECAA rabbit reagent in coagulometers where thromboplastin ISI were unchanged from the ECAA established manual values.

Objective: To review the state of the art of laboratory monitoring of oral anticoagulant therapy, as reflected by the medical literature and the consensus opinion of recognized experts in the field, and to make recommendations for improvement in laboratory monitoring of oral anticoagulant therapy., Data Sources: Review of the medical literature, primarily from the last 10 years, and current laboratory practices by a panel of 8 international experts in the field of oral anticoagulant monitoring., Data Extraction and Synthesis: After an initial assessment of the literature, key points were identified. Experts were assigned to do an in-depth review of the literature and current practices relevant to each of the key points and to prepare a summary of their findings and recommendations. A draft manuscript was prepared and circulated to every participant in the College of American Pathologists Conference XXXI on Laboratory Monitoring of Anticoagulant Therapy prior to the conference. Each of the key points and associated recommendations was then presented for discussion at the Conference. Recommendations were accepted if a consensus of the 26 experts attending the Conference was reached. The results of the discussion were used to revise the manuscript into its final form., Conclusions: Consensus was reached on 12 recommendations concerning the laboratory monitoring of oral anticoagulant therapy. Detailed discussion of the rationale for each of these recommendations is found in the text of this article. Discussion of points on which consensus was not reached is also included in the text. It is hoped that widespread adoption of these recommendations will further improve the laboratory monitoring of oral anticoagulant therapy.

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.

Stocks of the International Reference Preparation (IRP) for thromboplastin, human, plain, coded BCT/253 and held by the World Health Organization (WHO) are nearly exhausted and must be replaced. For practical reasons the choice of the replacement candidate was restricted to two available human recombinant preparations which were coded as X/95 and Y/95 and calibrated in an international collaborative study involving 19 laboratories from Europe, Australia, Canada and Argentina. To minimize the differences between routes of calibration, the two candidates were calibrated against the existing WHO-IRP from human, rabbit and bovine origin and the final ISI was the resultant average value. On the basis of predefined criteria (i.e., within- and between-laboratory precision of the calibration and the conformity to the calibration model), X/95 was the preferred candidate. The assigned ISI (SE of the mean) value is 0.940 (0.0060) and the interlaboratory coefficient of variation 4.7%.

Purpose: The Programme for Quality Assessment in Anticoagulant Therapy, which was started in the Basque Country in 1984, included the manufacturing of a standard human thromboplastin reagent plus periodical quality controls of the prothrombin time. A rabbit thromboplastin reagent was available in 1994; it was called Thromboplastin Bilbao, or TBi, and had to be used as a pattern reagent. Its stability, sensitivity and composition were plotted against the Manchester Reagent, of similar nature and composition. A new phase of quality quality controls was simultaneously started with this new reagent, a group of hospitals of the Autonomous Community taking part in the programme. The aim was to compare this reagent with the others used by the hospitals and to evaluate the variations with regard to the stages previous to the introduction of the human reagent., Material and Methods: Nine centres joined the study. Controls were performed every fourth month including plasma from patients under anticoagulant treatment, plus the reference reagents. The partaking centres used their usual reagents and routine procedures, as well as the reference reagents and manual technique., Results: The coefficient of variation (CV) of the INR of anticoagulated plasmas used for these studies when following the centres' own methods and thromboplastins was 9.5 +/- 6.40%, versus 9.94 +/- 1.57% when TBi was used. These results are in accordance with those attained with the previously manufactured human reagent, whose CV was 8.75 +/- 2.19% in the quality assurance methods performed in the period 1984-88. Concurrently with the programme, the reagent was sent as a part of the Spanish Programme for Quality Assessment in Anticoagulant Treatment to the 51 centres taking part in the study. The CV of the INR of the two lyophilized plasmas sent was, respectively, 14.97% and 16.5%. The average value for the healthy subjects was 14.77 seconds, with 8% inter-centres variation when using manual methods., Conclusions: These results suggest that a thromboplastin is now available whose sensitivity and reproducibility make it suitable as the national standard for usage in the quality assessment of prothrombin time.

Objective: To assess the extent of incorporation of international normalized ratio (INR) reporting in US academic hospitals., Design: Survey of academic hospital clinical laboratories in January 1995., Setting/participants: Fifty-eight academic hospital clinical laboratories at institutions that are members of the University Health System Consortium., Main Outcome Measures: The methods for monitoring oral anticoagulant therapy at the surveyed laboratories were determined. The extent of reporting of prothrombin time (PT), PT ratio, INR, and INR therapeutic range was determined., Results: All 58 of the responding hospital clinical laboratories reported INR in patients receiving oral anticoagulation. The median length of time that hospitals had been reporting INR was 24 months (range 3-108). A majority of hospitals continued to report PT values (95%) and PT reference ranges (93%) in addition to INR. Therapeutic INR ranges were reported by only 25 of the laboratories (43%). Of those that report INR ranges, many follow the published recommendations by the American College of Chest Physicians and the Food and Drug Administration. A majority of the hospitals (79%) do not confirm the accuracy of the international sensitivity index (ISI) for their own analyzers., Conclusions: Contrary to previous reports, academic hospital clinical laboratories have now adopted the more accurate system of reporting INR values in addition to PT values in patients receiving oral anticoagulation. However, better reporting of INR ranges, use of more sensitive thromboplastins, and confirmation of the accuracy of the ISI for local analyses would further improve the monitoring of oral anticoagulation.

Precision is defined as the agreement between replicate analyses of the same material. Within-laboratory precision of the prothrombin time (PT) and INR can be optimized by choosing an appropriate combination of thromboplastin and instrument. Accuracy (true value) of the International Sensitivity Index (ISI), required for the calculation of INR, depends on the choice of international reference preparation for the thromboplastin, and on the instrument used by the local laboratory. Interaction between thromboplastin and each patient's individual coagulation factors influences the accuracy of the INR. The contributions of imprecision, inaccuracy, and interaction effects can be combined to calculate the total uncertainty of the INR using Tomenson's equation. Confidence intervals for the INR were calculated in typical examples. The 95% confidence intervals of the INR around 3 are approximately as wide as currently recommended therapeutic target ranges.

Recent advances in recombinant technology have led to the development of prothrombin time (PT) reagents containing recombinant tissue factor which has been lipidated to allow expression of procoagulant activity. In this study we have compared International Normalised Ratios (INRs) determined using two such reagents and conventional thromboplastins in widespread use in the UK. Lyophilised plasma samples from eight different warfarinised patients were distributed to 33 laboratories in the UK. Each participant determined prothrombin times on 20 local fresh normal plasmas (used to derive mean normal PT and calculate INR) and the eight lyophilised samples, using manual technique and the following thromboplastins; Recombiplastin (Ortho Diagnostics Ltd); Innovin (Baxter Diagnostics Ltd); the conventional thromboplastin in local use. For eight plasmas the mean INRs determined with different reagents were as follows: Innovin (33 laboratories) - 3.4; Manchester Reagent (MR = 8 laboratories) - 3.4; Recombiplastin (33 laboratories) - 3.7; Instrumentation Laboratory (IL = 13 laboratories) - 4.4. Mean INR results with Recombiplastin were on average 7% greater than those obtained with Innovin, 8% greater than results with MR and 18% less than INRs with IL thromboplastin. There was no significant difference between results obtained with Innovin and MR. In contrast INRs obtained with IL were markedly (mean 28%) greater than results obtained with Innovin. This study employed lyophilised plasma and it is possible that some of the relationships described are influenced by this. However, the lyophilisation process employed did not influence the relationship between INRs of warfarinised plasmas obtained by the four main reagents described, indicating that the results are relevant to routine clinical practice. In conclusion, our data show some important differences are present between INRs determined using Recombiplastin, Innovin and two conventional thromboplastins.

Purpose: Management of anticoagulated patients has changed significantly over the past 10 years. The change occurred after the introduction of the international normalized ratio (INR) in 1983. This method of reporting prothrombin time for anticoagulated patients has resulted in a decrease in the level at which hematologists and cardiologists keep their patients anticoagulated. Currently, patients are anticoagulated less for the successful prevention of thromboemboli. Recent recommendations are to keep patients anticoagulated to an INR no greater than 3.5. It has been proposed that the extraction of teeth can be performed with INRs of 4 or less. Therefore, the current trend is to maintain patients on their anticoagulation regimens without altering their warfarin dosages., Conclusion: With proper local measures, teeth can be extracted safely and the development of thromboemboli in high-risk patients can still be prevented. However, with procedures having a high risk of bleeding, warfarin dosage may need to be modified.

The World Health Organization (WHO), the International Committee for Thrombosis and Hemostasis, and the International Committee for Standardization in Hematology, have strongly suggested that INR (International Normalized Ratio) values should be used to report a patient's level of coagulation. This paper discusses the use of the INR to monitor a patient's coagulation level, and reviews the recommendations on the INR levels at which dental extractions and similar oral surgical procedures may be performed safely. Studies are needed to determine whether new local hemostatic agents are sufficient for the safe management of patients at higher INR levels, thereby avoiding the need for hospitalization and heparin therapy.

The 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.

In a collaborative study by eleven laboratories performed within the framework of the European Community Bureau of Reference (BCR), a third reference material for thromboplastin, rabbit, plain, has been calibrated against RBT/90, the current WHO international reference preparation for thromboplastin, rabbit, plain. This third reference material (coded CRM 149S) has a mean International Sensitivity Index (ISI) of 1.257 with a standard error of the mean of 0.013. The previous BCR reference material for thromboplastin, rabbit, plain (coded CRM 149R) and the reference material for thromboplastin, bovine, combined (coded OBT/79) were also included in the trial for assessment of the long-term stability of the ISI values. The relationship between ISI values determined in the present study was nearly identical to that of the historical values. These results offer reassurance with regard to the long-term stability of these reference materials.

Anticoagulant therapy with coumarin drugs requires tests on the patient's blood to determine the dose rate for the drug. The tests involve measuring the effect of a preparation of a certain reagent, thromboplastin, in accelerating the clotting of the patient's blood. Features of the World Health Organization's recommendation on the appropriate laboratory procedure for a calibration assay and evaluation of results call for comment. The standard method involves estimation of a linear structural relation, a statistical technique long known but seldom finding practical application. This paper reviews its history, as a prelude to discussing strange mistakes in earlier publications; it also examines assessment of the precision of estimation and other aspects of the statistical method.

Oral anticoagulant therapy may be inappropriately managed and thus potentially place the warfarin-treated patient at an increased and unnecessary risk of bleeding or thromboembolic complications. This management issue is largely due to variations in measuring the pro-thrombin time. These variations may lead to an inaccurate and inconsistent assessment of the patient's true level of anticoagulation. The adoption of the International Normalized Ratio (INR) is recommended because it provides a mathematical correction for one of these variations--specifically, the thromboplastin reagents currently used. This article focuses on the appropriate use of the INR to monitor patients' responses to warfarin sodium therapy. It is vitally important for health care providers to be aware of the INR, to use it in clinical practice, and to interpret it correctly.

Dental professionals frequently treat patients who are receiving anticoagulation therapy. Proper treatment may require adjustment of the anticoagulant dose usually on the basis of the patient's current prothrombin time. This test has been shown to be less accurate than previously thought. The international normalized ratio is another method that attempts to standardize the degree of anticoagulation and to improve reproducibility of results. This system is slowly being implemented in laboratories in the United States. Practitioners who treat patients taking anticoagulants need to be aware of this system in order to make appropriate management decisions.

The introduction of the INR system for the monitoring of oral anticoagulant control represents a major advance, not only in terms of therapeutic efficacy but also in respect of patient safety. It is important to recognize that the system is only viable if careful attention is paid to the many important variables which contribute to its overall value. These include the choice of thromboplastin, assignation of ISI, determination of the mean normal prothrombin time and the method of end-point detection. Participation in independent external quality assessment schemes permits a unique opportunity for individual laboratories to identify, through laboratory performance analysis, problems relating to their own laboratory practice. Another major advantage, particularly of the larger schemes, is the identification of poor reagents and coagulometers and inconsistencies in their performance. One example of this is the recent identification of problems in respect of ISI assignment for thromboplastins used with coagulometers. This, in turn, provided the necessary stimulus to the potentially important development of calibrants for local ISI determination (21).

To assess the organization and the quality of care of an anticoagulation clinic, the structure, the process of laboratory control and the clinical outcome in our Center are described. 1068 patients under control in 1994 (M/F 572/496; median age 63 range 6-91 ys., 74% in long-term prophylaxis) were evaluated. The clinic was run twice weekly by a physician, two nurses and a technician; management for emergencies was always warranted. Prothrombin time was carried out with a sensitive thromboplastin (ISI < 1.1) and a computer program provided calculation and graphical representation of INR, comparison with therapeutic range, automatic dosage prescription and print out. Laboratory quality of therapy was assessed by three different techniques: 'cumulative INR', 'last check in file' and 'linear change', yielding respectively 69% of laboratory controls, 71% of patients and 80% of days within the therapeutic range. The rate of thrombosis, major and total bleeding were respectively 0.2%, 0.2% and 12.5%. An anticoagulation clinic represents an effective organizational model for the management of patients taking oral anticoagulants.

The comparative value of lyophilized artificially depleted plasmas and plasmas from warfarin-treated patients in local (thromboplastin/coagulometer) system International Sensitivity Indices (ISI) determination has been studied at 39 centers in an international collaborative study. At each center, both types of plasmas were tested with two common thromboplastins (low ISI RecombiPlasTin and high ISI OBT), and in-house reagents using three brands of coagulometers. In 95 local systems, they was agreement. With both thromboplastins, coagulometers lowered the ISI from the manual or stated ISI with all systems. Differences between the two types of lyophilized plasmas with the two common thromboplastins were not of clinical importance. Artificially depleted plasmas are easier to obtain in sufficient volumes than plasma from warfarin-treated patients, and more easily provide the wide range of INR values required for reliable local ISI calibration. The agreement between the two types of lyophilized calibrant is reassuring.

A study of lyophilized plasma calibrants in correcting for coagulometer effects on International Normalized Ratios (INR) has been conducted in an international survey. Prothrombin times were performed with the calibrants on 2 "common" thromboplastins and in-house thromboplastins in 3 brands of coagulometer at 37 centers. The International Sensitivity Indices (ISI) of 95 local systems with the calibrants were derived. The "true" INR of 10 test plasmas from warfarin-treated patients were established centrally using thromboplastin International Reference Preparations (IRP). International Normalized Ratios of these plasmas for each center were calculated using both the manufacturers' stated and the local ISI. The mean deviation of the 95 systems from the "true" INR of the warfarin plasmas was +14.4% with the manufacturers' ISI, but reduced to +1.04% with the local ISI. Local ISI determination with the calibrants avoids many of the difficulties of conventional thromboplastin calibrations. Plasmas from patients on warfarin and parallel manual PT with thromboplastin IRP are not required.

Aims: To examine the magnitude of thromboplastin and coagulometer interactions on the precision of International Normalised Ratio (INR) values when the manufacturers' recommended instrument specific International Sensitivity Index (ISI) values are adopted for the INR calculation., Methods: The variability of INR values obtained from four automated phototopical coagulometers frequently used in North American laboratories was studied. When used with five commercial thromboplastins of moderate to high sensitivity (ISI values 0.92-1.97), 20 prothrombin time results were generated for each of a population of 98 patients on established warfarin treatment., Results: The mean INR values of the patients ranged from 2.05 to 2.81, depending on which reagent/coagulometer combination was used. Within patient variation increased as the median INR value increased. The mean coefficient of variation of within patient INR values was 10%; the mean coefficient of variation of the prothrombin time results in seconds and prothrombin time ratio were 21 and 18%, respectively., Conclusions: There was considerable bias in the estimated ISI values of the thromboplastins compared with the manufacturers' instrument specific ISI value. Despite this apparent imperfection, our study clearly showed that the INR is preferable to other prothrombin time reporting formats for assessing the degree of anticoagulation for patients on warfarin treatment.

The recent introduction of thromboplastin reagents with low international sensitivity index (ISI) values into the US market for the purpose of generating a more precise international normalized ratio than high ISI thromboplastins could has necessitated an evaluation of the impact of the low ISI reagents on prothrombin time (PT) testing in general. In this study, PT testing with three thromboplastin reagents, one of which (presently used in our laboratory) has an ISI of 2.10 and the other two ISI values of 0.92 and 1.06, respectively, was performed on normal individuals, on quality control reference plasma specimens and single-factor-deficient plasma specimens, and on patients with liver disease, intravascular coagulation, and receiving oral anticoagulant therapy. We found that PTs of normal individuals determined by all three thromboplastins were virtually identical. The thromboplastins with a low ISI generated much longer PTs on abnormal reference plasma specimens than did the high ISI product. Low ISI reagents also produced longer PTs in all three groups of patients. However, the degree of prolongation was far greater for patients receiving warfarin than for the other two groups of patients. Conversion of the PT to an international normalized ratio minimized the discrepancy seen in the PT ratio in patients receiving oral anticoagulants. The two low ISI thromboplastins did not produce near-identical values of PT, PT ratio, or international normalized ratio on plasma specimens obtained from patients who received warfarin therapy. The critical value set for PT with a high ISI thromboplastin would not be adequate if the reagent is to be replaced with a low ISI product.

When the International Normalised Ratio (INR) is used for control of oral anticoagulant therapy the same result should be obtained irrespective of the laboratory reagent used. However, in the UK National External Quality Assessment Scheme (NEQAS) for Blood Coagulation INRs determined using different reagents have been significantly different. For 18 NEQAS samples Manchester Reagent (MR) was associated with significantly lower INRs than those obtained using Diagen Activated (DA, p = 0.0004) or Instrumentation Laboratory PT-Fib HS (IL, p = 0.0001). Mean INRs for this group were 3.15, 3.61, and 3.65 for MR, DA, and IL respectively. For 61 fresh samples from warfarinised patients with INRs of greater than 3.0 the relationship between thromboplastins in respect of INR was similar to that observed for NEQAS data. Thus INRs obtained with MR were significantly lower than with DA or IL (p < 0.0001). Mean INRs for this group were 4.01, 4.40, and 4.59 for MR, DA, and IL respectively. We conclude that the differences between INRs measured with the thromboplastins studied here are sufficiently great to influence patient management through warfarin dosage schedules, particularly in the upper therapeutic range of INR. There is clearly a need to address the issues responsible for the observed discrepancies.

Various methods have been described to evaluate efficacy of anticoagulant therapy using the international normalized ratio (INR). We compared the following approaches: (1) total INR's or the most recent measurement; (2) percent time within therapeutic range, with INR changing directly or halfway between visits; and (3) total observation time assuming INR changing linearly. The study population comprised 1700 post myocardial infarction patients. Treatment comprised 3725 patient-years. There were 61,471 INR assessments with target therapeutic level of 2.8-4.8. Acenocoumarol as well as phenprocoumon were employed. Therapeutic achievement in the first months of treatment was low: less than 60% of INR's were in range. Treatment stabilized after 6 months. Patients on acenocoumarol were within range 70% of the time compared to 80% for phenprocoumon. Method 3 is preferred because it incorporates time and is capable of calculating incidence rates at different INR levels. Our findings call for an urgent improvement of standard of anticoagulant control in the first months following commencement of treatment.

Purpose: To check out the reproducibility and costs of prothrombin time (PT) determination as a control of oral anticoagulant therapy (OAT) in plasma and capillary blood., Patients and Methods: The study was carried out in two phases: along two years, 1,700 patients with OAT were controlled, 700 of them in the hospital outpatient clinic. In 149 patients INR was simultaneously determined in both capillary and venous blood. The 700 patients receiving acenocoumarin who had been controlled in 1991 according to the conventional plasma-sample fashion, were controlled in the second year (i.e., 1992) by means of capillary blood testing, a comparison of the costs of each method and the need for anticoagulant drugs being undertaken. Venous blood PT was assessed with reagent thromboplastin (Tromborel S) in an Electra-1000 (MLA) system. An automated Trombotrack system was used for the capillary blood tests using Thrombotest as current procedure. The results were expressed as INR in both methods. The statistical evaluation of the results was carried out by means of Student's t, variance analysis, and correlation study., Results: No significant differences were found in the anticoagulation intervals attained from venous or capillary blood samples. No significant differences were seen in 87 patients on whom the test was repeated in two samples drawn from a single capillary puncture. The weekly OAT doses of 30 patients along six months were analysed. The need for anticoagulant drugs was similar (17.4 vs 17.2 mg/patient/week). The mean INR in 1991 was 2.82 and the mean drug-need was 15.24 mg/week, whereas in 1992 the mean INR was 2.86 and the need for anticoagulant was 15.49 mg/week. The costs of the conventional method were 103.6 Pta, this being 70 Pta for capillary blood, which means a 32% savings., Conclusions: OAT control by means of PT performed on capillary blood must be considered a substitutive method for the venous blood assay due to its efficacy, simplicity and lower costs.

An international collaborative study involving 20 laboratories was undertaken to evaluate the status of standardization of a commercial recombinant thromboplastin. The results show that the reagent fulfills the WHO requirements for thromboplastin calibration against two International Reference Preparations (IRP) from different species, because there was a linear relationship of log-transformed prothrombin times as measured by the recombinant reagent and the two IRPs in normal individuals and patients stabilized on oral anticoagulants. The regression lines drawn through the patient data points passed through the normal data points in the majority of instances. The average ISI values for three different batches were close to unity. On the average, the ISI value calculated against BCT/253 (human, plain) was slightly smaller than that against RBT/79 (rabbit, plain). The between laboratory precision of calibration (CV = 5-6%) did not change whether BCT/253 or RBT/79 was used, whereas it was substantially improved when the calibrations of batches 2 and 3 were performed against batch 1, arbitrarily taken as standard (CV < or = 1.7%). Statistical analysis to test for differences between slopes revealed no significant between-batch differences in 16 of 20 laboratories. However slight differences for the third batch (2.8% less than the average ISI value of batches 1 and 2) leave room for further improvement in the standardization of the reagent.

The 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.

Plasma from healthy individuals, pregnant women and patients on warfarin were distributed to 3 laboratories supporting major cardiovascular surveys (Northwick Park, Muenster and Houston) for assay of factor VII coagulant activity (VIIc) with their own bio-assays. The mean VIIc in 147 samples agreed to within 1% of standard in Northwick Park and Houston, but was 14% of standard lower in Muenster owing to its more potent standard. In samples with an increased VIIc the Northwick Park assay gave a higher result than the other assays owing to its increased responsiveness to activated factor VII (VIIa). Thus when VIIa concentrations were determined directly with a clotting assay which utilises a soluble recombinant tissue factor, the increase in VIIc with increase in VIIa was considerably greater with the Northwick Park assay than the Muenster assay. This feature of the Northwick Park assay was traced to the virtual absence of protein C in its substrate plasma. Factor Va appears rate-limiting for the coagulant expression of VIIa in test plasma. If the thrombotic response to release of tissue factor is determined by the circulating concentration of VIIa, then the Northwick Park factor VII bio-assay may be preferable to other bio-assays currently employed to estimate risk of acute coronary events.

A multi-center study of the three W.H.O. international reference preparations (IRP) for thromboplastin has been performed. The main purpose of the study was the determination of the mean international sensitivity index (ISI) of a proposed replacement IRP for thromboplastin, rabbit, plain. Twenty laboratories in Europe, North America, and Australasia participated in the study. All clotting times were determined with the manual technique. The inter-laboratory variation of the ISI was considered as the relevant parameter for assessment of ISI precision. Low interlaboratory variation was observed in the calibration of rabbit thromboplastin against rabbit thromboplastin (2.9-3.0% coefficient of variation of calibration line slope). Relatively high interlaboratory variation was observed in the calibration of rabbit against human thromboplastin (3.7-7.2 CV). Intermediary interlaboratory variation was obtained in the comparison of rabbit or human plain thromboplastin with bovine combined thromboplastin (3.5-4.0% CV). These findings confirm the principle of like-to-like calibration in biological standardization. The mean ISI values based on the IRP for rabbit thromboplastin (RBT/79) are in excellent agreement with those obtained with the IRP for bovine thromboplastin (OBT/79). In contrast, the mean ISI values determined with the IRP for human thromboplastin (BCT/253) were 6% lower than those with RBT/79. This bias may be caused by a difference in design of the two historical calibration studies. The mean ISI of the proposed replacement IRP for thromboplastin, rabbit, plain obtained by calibration against RBT/79 was 1.035 (standard error: 0.027). It is recommended to round the mean ISI off to 1.0. Opportunity was also taken to compare a lyophilized normal pooled plasma with fresh individual normal plasmas.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Patients receiving long-term anticoagulant therapy may be subject to unnecessary risks of bleeding or thromboembolism because of variability in the commercial thromboplastins used to determine prothrombin time and consequent uncertainty about the actual intensity of anticoagulation., Methods: We explored the effect of this uncertainty on the benefits and risks of anticoagulation in patients with prosthetic heart valves, using models of thromboembolic and hemorrhagic complications as a function of the intensity of anticoagulation, with quality-adjusted life expectancy and average variable costs used to describe outcomes., Results: Anticoagulation provides a striking benefit for patients whose treatment is conducted within the recommended range of the international normalized ratio (INR)--i.e., 2.5 to 3.5--but if uncertainty about the laboratory results causes the intensity of anticoagulation to fall outside this range, the gain becomes smaller. Uncertainty about the true intensity of anticoagulation may reduce the potential gain in life expectancy, adjusted for quality of life, by more than half and may increase the ratio of costs to effectiveness to almost five times the optimal value. Variability in the intensity of anticoagulation is even greater if older recommendations advocating a higher level of anticoagulation are followed., Conclusions: Uncertainty about the sensitivities of the commercially available thromboplastins used in the United States can have important clinical and economic effects. This problem could be eliminated if clinical laboratories uniformly reported the intensity of anticoagulation as the INR, by adjusting prothrombin-time ratios for variability in thromboplastins.

Oral anticoagulants are employed very frequently in the prophylaxis and treatment of several diseases. For their optimal effectiveness, many vigilance schedules have been proposed but none has proved to be 100% effective. The international normalization ratio (INR) can be a safer way to monitor oral anticoagulation, and our objective was to determine its clinical usefulness. A prothrombin time test (PT) was carried out by means of either a chromogenic or a coagulometric method, and an INR was obtained using the ratio of the PT patient/PT control elevated to an exponential given by the international sensitivity index (ISI) of our thromboplastin. Our objective was to maintain our patients in a therapeutical INR range between two and three. We present our experience with 77 patients and 810 results during an 18 months period. We observed 26 cases of hemorrhage and three of thrombosis. In all these cases, the INR was out of the desired therapeutical range. No deaths occurred in our patients. Our analysis showed a significative disagreement between the INR and the prothrombin time ratio (PTR) but a better correlation with hemorrhage and thrombosis was seen with the INR than with the PTR. Our experience supports the use of INR in the clinical vigilance of oral anticoagulation as a useful method.

Background: The intensity of warfarin anticoagulation in the United States may be inappropriate if the international normalized ratio (INR) is not used, or if the international sensitivity index (ISI) of the thromboplastin is outside the range of 2.2 to 2.6., Methods: Fifty-three hospital laboratories provided data on the sensitivity of their thromboplastin and whether they reported INR values. Additional data on thromboplastin sensitivity were obtained from 140 laboratories involved in the Stroke Prevention in Atrial Fibrillation study. The three major manufacturers of thromboplastin confirmed the range of thromboplastin sensitivity reported by the laboratories., Results: Of 53 laboratories surveyed, 16 (30%) could not provide ISI data and only 11 (21%) reported INR results. Unlabeled thromboplastin was being used by 20% to 24% of laboratories, and only 8% to 20% were using thromboplastins with an ISI of 2.2 to 2.6. At the time the three manufacturers were contacted, they reported marketing thromboplastins with ISI values from 1.2 to 2.8, but none of the thromboplastins at that time had ISI values between 2.2 and 2.6., Conclusion: Warfarin therapy in the United States is managed inappropriately because most laboratories do not report INRs and the variability in thromboplastin sensitivity produces misleading prothrombin time ratio results. Additionally, recent research may require reexamination if INR or ISI data were not provided.