The effect of instruments for prothrombin time testing on the international normalized ratio

Prothrombin time (PT) testing is used for monitoring oral anticoagulant therapy, its result being usually expressed as international normalized ratio (INR). This is done using the international sensitivity index (ISI) specific of thromboplastin employed to carry out the test. In this way a good PT standardization may be achieved although the instruments used to calibrate the thromboplastins might influence the ISI value. Presented at the ‘2nd International Symposium on Standardization and Quality Control of Coagulation Tests: Implications for the Clinical Laboratory’, Rome, September 28–29, 1989.     

Poor agreement among prothrombin time international normalized ratio methods: comparison of seven commercial reagents

BACKGROUND: Prothrombin time (PT) has long been the most popular test for monitoring oral anticoagulation therapy. The International Normalized Ratio (INR) was introduced to overcome the problem of marked variation in PT results among laboratories and the various recommendations for patient care. According to this principle, all reagents should be calibrated to give identical results and the same patient care globally. This is necessary for monitoring of single patients and for application of the results of anticoagulation trials and guidelines to clinical practice. METHODS: We took blood samples from 150 patients for whom oral anticoagulation had been prescribed. Plasmas were separated and PTs determined by use of seven commercial reagents and four calibrator sets. The differences in results were assessed by plotting, for each possible pair of methods, the differences in INR values for each sample against the mean INR value (Bland-Altman difference plots). RESULTS: Mean results differed significantly (P <0.001) for 17 of 21 possible paired comparisons of methods. Only two pairs of methods produced very similar results when assessed for problems of substantial differences in INR values; a significant, systematic increase in the difference with INR; and a significant systematic increase in the variation in difference with increasing INR values. CONCLUSIONS: The agreement among several (and perhaps most) commercial INR methods is poor. The failure of current calibration strategies may severely compromise both the monitoring of individual patients and the application of oral anticoagulation guidelines and trial results to clinical practice.     

凝血酶原时间ISI/INR系统测定中的一些问题及改进意见

目的对凝血酶原时间(PT)测定ISI/INR系统出现的一些问题提出相应的改进建议。方法对上海市12家医院在用的仪器和匹配的PT试剂,对日常使用的正常血浆平均凝血酶原时间(MNPT)作调研实测,将结果进行分析;调查试剂的仪器特定(spec ific)国际敏感度指数(ISI)值与世界卫生组织(WHO)的手工法ISI定标值之间的差异;用2种已知国际标准化比值(INR)的异常参比血浆代替WHO的ISI系统作质控并行比较。结果12家中有4家日常使用的平均正常凝血酶原时间(MNPT)明显偏离实测值,分别为0.8、0.9、1.0和1.8 s。用WHO CRM149R参比,用手工法标定的凝血活酶和109 mmol枸橼酸钠抗凝的不同PT值血标本,在Sysm ex1500型、C.2000型仪器上测定试剂的仪器特定ISI,其结果比手工法分别减少4.1%和4.7%,但采用HEPES-枸橼酸钠抗凝剂标本时,2种型号仪器的特定ISI比手工法分别减少16.7%及7.7%。用已知INR异常参比血浆,国产品与进口品对照的结果良好。结论受调研12家中,有4家血凝分析仪器调研时实测的MNPT明显偏离日常使用值。有几家医院试剂的仪器特定ISI值也存在问题,建议纠正。用已知INR异常参比血浆代替WHO手工法标定凝血活酶ISI法作质控,使用简便,又不需MNPT参数,值得推广。     

凝血酶原时间ISI/INR系统测定中的一些问题及改进意见

目的 对凝血酶原时间（PT）测定ISI／INR系统出现的一些问题提出相应的改进建议。方法 对上海市12家医院在用的仪器和匹配的胛试剂，对日常使用的正常血浆平均凝血酶原时间（MNPT）作调研实测，将结果进行分析；调查试剂的仪器特定（specific）国际敏感度指数（ISI）值与世界卫生组织（WHO）的手工法ISI定标值之间的差异；用2种已知国际标准化比值（INR）的异常参比血浆代替WHO的ISI系统作质控并行比较。结果 12家中有4家日常使用的平均正常凝血酶原时间（MNPT）明显偏离实测值，分别为0．8、0．9、1．0和1．8S。用WHO CRM149R参比，用手工法标定的凝血活酶和109mmol枸橼酸钠抗凝的不同胛值血标本，在Sysmex1500型、C．2000型仪器上测定试剂的仪器特定ISI，其结果比手工法分别减少4．1％和4．7％，但采用HEPES-枸橼酸钠抗凝剂标本时，2种型号仪器的特定ISI比手工法分别减少16．7％及7．7％。用已知INR异常参比血浆，国产品与进口品对照的结果良好。结论 受调研12家中，有4家血凝分析仪器调研时实测的MNPT明显偏离日常使用值。有几家医院试剂的仪器特定ISI值也存在问题，建议纠正。用已知INR异常参比血浆代替WHO手工法标定凝血活酶ISI法作质控，使用简便，又不需MNPT参数，值得推广。     

An analysis of discrepancy between point-of-care and central laboratory international normalized ratio testing in ED patients with cerebrovascular disease

Objective

Our objective was to identify demographic, clinical, and operational variables associated with discrepancy between point-of-care (POC) and central laboratory international normalized ratio (INR) results in emergency department (ED) patients with acute cerebrovascular disease.

Methods

We conducted a retrospective, observational cohort study of a series of 637 patients with acute cerebrovascular disease over 30 months who underwent simultaneous POC, using the i-STAT POC analyzer (Abbott, Princeton, NJ), and central laboratory INR testing at ED presentation. Point-of-care INR results greater than ± 0.25 INR units from the central laboratory INR value were considered discrepant. We analyzed potential predictors of POC INR discrepancy from demographic, clinical, and operational variables using multivariable logistic regression. We evaluated the change in POC INR discrepancy incidence over the study interval using analysis of variance methodology.

Results

The final diagnoses of the 637 subjects were acute ischemic stroke (n = 427), transient ischemic attack (n = 105), and intracranial hemorrhage (n = 105). Discrepant POC INR results occurred in 21.5% (137/637) of subjects. The mean bias between POC and central laboratory INR was 0.24 ± 0.69 (range, 0-11.3). Significant covariates of POC INR discrepancy were oral anticoagulant use (odds ratio, 3.03; confidence interval, 1.37-6.68) and increasing activated partial thromboplastin time (aPTT) (odds ratio, 1.07; confidence interval, 1.02-1.12). We observed a significant reduction trend in the incidence of POC-central laboratory discrepancy over the study period, decreasing on average at 0.42% per month (F = 5.59, P = .025).

Conclusion

In this retrospective study, oral anticoagulant use and increasing aPTT were significantly associated with POC INR discrepancy in ED patients with acute cerebrovascular disease. Point-of-care INR discrepancy incidence decreased over the study interval.     

Accuracy and precision of point-of-care testing for glucose and prothrombin time at the critical care units

The use of point-of-care testing (POCT) in critical care patient units has continued to increase since the 1980s. This increase is due to the need for prompt therapeutic interventions that may impact mortality and morbidity, and reduce the overall cost of healthcare for critically ill patients. The diagnostic manufacturing industry has risen to this challenge by introducing portable and/or handheld analyzers for use at the point-of-care. In order to ensure the public safety in the USA, the Food and Drug Administration (FDA) must approve the use of each POCT analyzer. The FDA approval is based on established performance criteria that includes relative accuracy and precision documentation. This study evaluated the precision and accuracy of the POCT prothrombin time and glucose analyzers relative to the manufacturers' specifications, to the internal QC in the main laboratory, and to the results of the external proficiency-testing program. The QC for the prothrombin time had a precision that ranged from 2.84% to 3.45% (POCT) and from 1.27-1.66% (main laboratory). The precision for the glucose QC ranged from 5% to 5.2% (POCT) and 0.9-2.7% (main laboratory). Using the results of the external proficiency testing, the inter-laboratory CV% for the POCT prothrombin time ranged from 3.5% to 5.0% and the main laboratory had a range of 2.5-2.9%. The inter-laboratory CV% ranges for glucose POCT and the main laboratory were 4.9-10.6% and 1.8-3.5%, respectively. The main laboratory analyzers proved to be more accurate than the POCT analyzers as indicated by comparison to the mean prothrombin time and glucose results of all participating laboratories in the proficiency testing program.     

Effect of lepirudin on the international normalized ratio

BACKGROUND: Many patients receiving direct thrombin inhibitor (DTI) therapy require transition to warfarin. This transition may be complicated by DTI-induced elevations in the international normalized ratio (INR). While the effect of argatroban on the INR has been characterized, data assessing the effect of lepirudin on the INR are limited. OBJECTIVE: To evaluate the effect of lepirudin on the INR. METHODS: Patients receiving lepirudin therapy between January 2000 and May 2001 were identified using the pharmacy database, and a retrospective chart review was conducted. Patients were included for analysis if they had paired activated partial thromboplastin time (aPTT) and INR data while receiving lepirudin monotherapy. RESULTS: Fifty-three paired aPTT and INR data points from 8 patients receiving lepirudin monotherapy were collected. The Organon MDA 180 instrument was used for aPTT and prothrombin time (PT) determination. Organon MDA Platelin L reagent was used for the aPTT and Organon Simplastin L reagent was used for the PT. The international sensitivity index (ISI) of the Simplastin L thromboplastin was 2.0. The mean +/- SD lepirudin dose was 0.05 +/- 0.04 mg/kg/h. Linear regression was used to identify the INRs that correspond to a therapeutic aPTT value of 45-75 seconds (1.5-2.5 times mean laboratory normal of 30 sec). The correlation between aPTT and INR was 0.77. An aPTT of 45-75 seconds with lepirudin correlated to an INR of 1.6-3.2. CONCLUSIONS: Based on laboratory results, when using a thromboplastin with an ISI of 2, lepirudin appears to elevate the INR in the absence of warfarin.     

Preanalytical variables and off-site blood collection: influences on the results of the prothrombin time/international normalized ratio test and implications for monitoring of oral anticoagulant therapy

BACKGROUND: The quality of oral anticoagulant therapy management with coumarin derivatives requires reliable results for the prothrombin time/International Normalized Ratio (PT/INR). We assessed the effect on PT/INR of preanalytical variables, including ones related to off-site blood collection and transportation to a laboratory. METHODS: Four laboratories with different combinations of blood collection systems, thromboplastin reagents, and coagulation meters participated. The simulated preanalytical variables included time between blood collection and PT/INR determinations on samples stored at room temperature, at 4-6 degrees C, and at 37 degrees C; mechanical agitation at room temperature, at 4-6 degrees C, and at 37 degrees C; time between centrifugation and PT/INR determination; and times and temperatures of centrifugation. For variables that affected results, the effect of the variable was classified as moderate when <25% of samples showed a change >10% or as large if >25% of samples showed such a change. RESULTS: During the first 6 h after blood collection, INR changed by >10% in <25% of samples (moderate effect) when blood samples were stored at room temperature, 4-6 degrees C, or 37 degrees C with or without mechanical agitation and independent of the time of centrifugation after blood collection. With one combination of materials and preanalytical conditions, a 24-h delay at room temperature or 4-6 degrees C had a large effect, i.e., changes >10% in >25% of samples. In all laboratories, a 24-h delay at 37 degrees C or with mechanical agitation had a large effect. We observed no clinically or statistically relevant INR differences among studied centrifugation conditions (centrifugation temperature, 20 degrees C or no temperature control; centrifugation time, 5 or 10 min). CONCLUSIONS: We recommend a maximum of 6 h between blood collection and PT/INR determination. The impact of a 24-h delay should be investigated for each combination of materials and conditions.     

Coagulometer international sensitivity index (ISI) derivation,a rapid method using the prothrombin time/international normalized ratio (PT/INR) Line: a multicenter study

Summary. Background: The original WHO procedure for prothrombin time (PT) standardization has been almost entirely abandoned because of the universal use of PT coagulometers. These often give different international normalized ratio (INR) results from the manual method, between individual makes of instruments and with instruments from the same manufacture. Method A simple procedure is required to derive local INR with coagulometers. The PT/INR Line method has recently been developed using five European Concerted Action on Anticoagulation (ECAA) certified plasmas to derive local INR. This procedure has been modified to derive a coagulometer PT/INR Line providing International Sensitivity Index (ISI) and mean normal PT (MNPT) for coagulometers and give local INR. Results have been compared with conventional ISI calibrations at the same laboratories. Results: With human thromboplastins, mean ISI by local calibration was 0.93 (range: 0.77–1.16). With the PT/INR Line, mean coagulometer ISI was higher, for example 0.99 (0.84–1.23) but using the PT/INR Line derived MNPT there was no difference in local INR. Between‐centre INR variation of a certified validation plasma was reduced with human and bovine reagents after correction with local ISI calibrations and the PT/INR Line. Conclusion: The PT/INR Line–ISI with its derived MNPT is shown to provide reliable local INR with the 13 different reagent/coagulometer combinations at the 28 centres in this international study.     

Clinical evaluation of the first medical whole blood, point-of-care testing device for detection of myocardial infarction

BACKGROUND: Validation of whole blood, point-of-care testing devices for monitoring cardiac markers to aid clinicians in ruling in and ruling out myocardial infarction (MI) is necessary for both laboratory and clinical acceptance. METHODS: This study evaluated the clinical diagnostic sensitivity and specificity of the First Medical Cardiac Test device operated by nursing and laboratory personnel that simultaneously measures cardiac troponin I (cTnI), creatine kinase (CK) MB, myoglobin, and total CK on the Alpha Dx analyzer in whole blood for detection of MI. Over a 6-month period, 369 patients initially presenting to the emergency department with chest pain were evaluated for MI using modified WHO criteria. Eighty-nine patients (24%) were diagnosed with MI. RESULTS: In whole blood samples collected at admission and at 3- to 6-h intervals over 24 h, ROC curve-determined MI decision limits were as follows: cTnI, 0.4 microgram/L; CKMB, 7.0 microgram/L; myoglobin, 180 microgram/L; total CK, 190 microgram/L. Based on peak concentrations within 24 h after presentation, the following sensitivities (+/- 95% confidence intervals) were found: cTnI, 93% +/- 5.5%; myoglobin, 81% +/- 9.7%; CKMB, 90% +/- 6.3%; total CK, 86% +/- 7.5%. Sensitivities were maximal at >90% for both cTnI and CKMB at >12 h in MI patients, without differences between ST-segment elevation and non-ST-segment elevation MI patients. CONCLUSIONS: The First Medical point-of-care device provides cardiac marker assays that can be used by laboratories and clinicians in a variety of hospital settings for ruling in and ruling out MI.     

International normalized ratio in the prothrombin test: clinical significance and use

The safety and efficiency of therapy by peroral anticoagulants (PA) depend on a laboratory monitoring based on the prothrombin test (PT). The test is distinguished through its variability conditioned by different means of results' presentation as well as through the sensitivity of thromboplastin and a type of a device used in coagulation detection. WHO recommended, 1983, to standardize the thromboplastin preparations through adjusting their sensitivity (the so-called International Sensitivity Index--ISI) to blood coagulation defects induced by PA versus the primary international reference thromboplastin. Thromboplastin ISI as well as the mean normal prothrombin time (MNPT) of blood plasma are used to calculate the international normalized ratio (INR). The presentation of PT results as INR is justified exclusively for the PA-therapy stabilized patients. The INR system makes it possible to optimize the PA therapy only if the laboratory expert and clinician can clearly understand the PT standardization essence and observe the key WHO recommendations, i.e. definition of a coagulometer-specific ISI by manufacturing companies, estimation of MNPT by laboratories and use of the correct anticoagulant concentration.