Clinical interpretation of the one-stage prothrombin time.
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Effect of aspirin and sodium salicylate on thrombosis, fibrinolysis, prothrombin time, and platelet survival In rabbits with indwelling aortic catheters.
We have studied the effect of different doses of aspirin on platelet function, PGI2 formation, platelet survival, thrombosis, fibrinolysis, and prothrombin time in rabbits with indwelling aortic catheters. The thrombi formed around indwelling aortic catheters were found to have a large fibrin component, and their formation was inhibited by heparin administration. Thus, in these experiments we examined the effect of aspirin (a weak inhibitor of thrombin-mediated platelet aggregation) under conditions in which thrombin was a major factor in the initiation and growth of the thrombi. Only very high doses of aspirin tended to inhibit thrombus formation over the 5-day period of observation, and a statistically significant inhibition of thrombus formation was produced by equivalent concentrations of sodium salicylate. The failure of high doses of aspirin to achieve a significant inhibition of thrombosis under the conditions of these experiments (whereas an equivalent dose of sodium salicylate was inhibitory) could be due to aspirin inhibition of PGI2 formation. Shortened platelet survival was not affected by aspirin treatment or the dose sodium salicylate that inhibited thrombus formation. The tendency to inhibit thrombus formation appeared to be unrelated to an effect on platelets but was associated with prolongation of the one-stage prothrombin time and increased whole blood fibrinolytic activity; doses of aspirin that inhibited platelet aggregation in response to sodium arachidonate or collagen, and PGI2 formation by the vessel wall, did not have a significant effect on the amount of thrombus present at 5 days. However, the high doses of aspirin that inhibited PGI2 formation were associated with a tendency to increased thrombus formation during the first 3 hr after insertion of the catheter. The results of these experiments show that when thrombin is an important factor in the formation of thrombi, aspirin is a weak inhibitor of thrombosis unless doses are used that provide sufficient salicylate to interfere with blood coagulation and promote whole blood fibrinolytic activity. These results also show that thrombus formation can be inhibited without an apparent change in platelet survival.
Animals↗
Prothrombin time standardization by correction of the Pivka inhibitor.
The standardization of prothrombin time (PT) assays needs two steps: (1) calibration of PT assays towards a reference assay or reference thromboplastin, (2) correction of PT assays according to the calibration. The present recommended calibration by clotting times is favored for the linearity between assays; the clotting times of abnormal plasma are partly prolonged due to the protein induced by vitamin K absence (Pivka) inhibitor. Calibration by coagulation activities also demonstrated linearity between PT assays; the regression line for abnormal plasma deviated from the line of identity due to differences in sensitivity of assays for the Pivka inhibitor. The corrected PT assays demonstrated similar results using calibration by clotting time or coagulation activities, but the correction was simpler for coagulation activities. Patient plasma was the preferable material in calibration by clotting times as well as by coagulation activities. The corrections between the reference assay and other PT assays were equal to the differences in sensitivities for the Pivka inhibitor. The corrected PT assays did not differ from the reference assay by statistical analysis; any of the six PT assays tested might be used as reference assay.
Biomarkers↗
Effect of magnesium contamination in evacuated blood collection tubes on the prothrombin time test and ISI calibration using recombinant human thromboplastin and different types of coagulometer.
UNLABELLED: The purpose of the present study was to assess the effect of two types of evacuated blood collection tube on the prothrombin time and international sensitivity index (ISI) of Recombiplastin, a recombinant human thromboplastin. Vacutainer tubes were compared with Venoject II tubes. Magnesium contamination was detected in the sodium citrate solutions contained in the Vacutainer tubes with concentrations ranging from 1.1 to 1.5 mmol/l. In contrast, magnesium ions could not be detected in the Venoject II tubes. The prothrombin ratio was decreased by contamination with magnesium ions and, hence, the ISI was increased. The magnitude of the effect of magnesium contamination on the ISI was influenced by the type of coagulometer and increased in the order: ACL Advance (3%), ACL-300 (4%), Electra-1000 (6%). The ISI bias is transmitted to the international normalized ratio (INR). In the case of the Electra-1000, the INR bias would be approximately 6% at INR 3.0 if the two types of blood collection tubes would be used without distinction. In a secondary study, the effect of magnesium contamination on the prothrombin time was assessed with the current World Health Organization international reference preparation for recombinant human thromboplastin (rTF/95). Magnesium chloride added to patients' blood (0.2 mmol/l) induced 2.3% reduction of the INR determined with rTF/95 and the manual technique. CONCLUSION: The magnitude of the influence of blood collection tubes contaminated with magnesium on ISI and INR determined with recombinant human thromboplastin depends on the coagulometer.
Anticoagulants↗
Effect of laboratory variation in the prothrombin-time ratio on the results of oral anticoagulant therapy.
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.
Cost-Benefit Analysis↗
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.
Administration, Oral↗
The prothrombin time test: effect of varying citrate concentration.
Blood samples from 12 normal subjects and 46 patients on oral anticoagulants were divided so that each was anticoagulated with four concentrations of trisodium citrate solution in the range 0.09-0.15 M, 9 vol blood being added to 1 vol citrate solution in each case. Citrated blood haematocrit and plasma prothrombin time was measured on each subsample; 0.025 M CaCl2-solution was used for recalcification throughout. Three laboratories participated, each using a different prothrombin-time technique.
Anticoagulants↗
[Evaluation of the quality of prothrombin time technique in the Basque Country].
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.
Animals↗
Prothrombin time. Determination by a whole blood micro-method for control of anticoagulant therapy.
A micro technique that is here described for "prothrombin time" determinations, employing capillary whole blood, provides a range of values which is closely correlated with the Quick one-stage plasma method, thus providing inter-changeability of results both in normal persons and in patients who have been treated with anticoagulant drugs. Avoidance of the use of a water bath and centrifuge permit this technique to yield immediate results at the bedside, in the office or in the patient's home. The use of a whole blood instead of a plasma technique lends additional safety to control of anticoagulant medication, since it may reflect depression of clotting factors not apparent by the usual plasma methods.
Anticoagulants↗
European Concerted Action on Anticoagulation (ECAA): multicentre international sensitivity index calibration of two types of point-of-care prothrombin time monitor systems.
A multicentre modified World Health Organization (WHO)-type international sensitivity index (ISI) calibration has been performed at 10 European Concerted Action on Anticoagulation (ECAA) national laboratories using non-citrated whole-blood on two point-of-care test (POCT) prothrombin time (PT) monitor systems, CoaguChek Mini and TAS PT-NC, using single lots of test cards/strips. The relevant species (human and rabbit) WHO international reference preparations (IRPs) were tested with the manual PT technique on citrated plasma from the same blood donations. The ISI was calculated from the slope of the orthogonal regression line relating log PT (POCT) to log PT (IRP). The mean ISI of the CoaguChek Mini system was 1.75 and 1.13 with the prothrombin time non-citrated Thrombolytic Assessment System (TAS PT-NC). With the CoaguChek Mini system, seven out of 10 calibrations exceeded the current 3% WHO recommended limit for the coefficient of variation (CV) of the slope with conventional PT testing, whereas with the TAS PT-NC system, it was eight out of 10. All the POCT calibrations had a CV of the slope <5%. It is suggested that this level of precision be adopted as the limit of acceptability of calibration of these monitor systems. In these circumstances, the modified WHO-type ISI calibration appeared to be satisfactory for the POCT whole-blood monitors.
Animals↗
The interval between prothrombin time tests and the quality of oral anticoagulants treatment in patients with chronic atrial fibrillation.
BACKGROUND: The incidence of stroke in patients with atrial fibrillation (AF) can be significantly reduced with warfarin therapy especially if optimally controlled. OBJECTIVES: To evaluate the effect of the interval between consecutive prothrombin time measurements on the time in therapeutic range (INR 2-3) in a cohort of patients with AF on chronic warfarin treatment in the community. METHODS: All INR measurements available from a relatively large cohort of patients with chronic AF were reviewed and the mean interval between consecutive INR tests of each patient was correlated with the time in therapeutic range (TTR). RESULTS: Altogether 251,916 INR measurements performed in 4408 patients over a period of seven years were reviewed. Sixty percent of patients had their INR measured on average every 2 to 3 weeks and most others were followed at intervals of 4 weeks or longer. A small proportion (3.6%) had their INR measured on average every week. A significant decline in the time in therapeutic range was observed as the intervals between tests increased. At one to three weeks interval the TTR was 48%, at 4 weeks interval 45% and at 5 weeks 41% (P<0.0005). A five percent increment in TTR was observed if more tests were performed at multiplications of exactly 7 days (43% vs 48% P<0.0001). CONCLUSIONS: A better control with an increase in the TTR was observed in patients with atrial fibrillation if prothrombin time tests are performed at regular intervals of no longer than 3 weeks.
Administration, Oral↗
Pulmonary embolism in total hip and knee arthroplasty. Risk factors in patients on warfarin prophylaxis and analysis of the prothrombin time as an indicator of warfarin's prophylactic effect.
This study was designed to identify those total arthroplasty patients at high risk for embolism even while on a proven warfarin prophylactic regimen and to identify the measure of anticoagulation that would be most efficacious in the prevention of pulmonary embolism (PE). A series of 2348 total arthroplasty patients had a preoperative perfusion scan and a postoperative ventilation/perfusion scan. All patients were placed on a low-dose warfarin protocol. Eighty-one patients were identified as having a PE by pulmonary arteriography (incidence of 3.4%). Of these, 89% were asymptomatic and no case was fatal. A control group of 159 patients without PE was used for comparison. Patients older than 65 years of age with a history of genitourinary infection were identified as being at higher risk of PE while on a proven warfarin prophylactic program. These patients may need additional prophylactic measures to reduce the risk of PE. In contrast, patients with a history of phlebitis, PE, obesity, or varicosities were not at excess risk for PE while on warfarin prophylaxis; therefore, no additional prophylactic measures are required. All prothrombin time profiles were within the prophylactic range. Therefore, the actual prothrombin time may not be the critical determinant of the level of anticoagulation or prophylaxis achieved.
Analysis of Variance↗
Automation of prothrombin time on the Cobas Fara II centrifugal analyser.
The automation of the prothrombin time using Low Turbidity Australian Reference Thromboplastin on the Cobas Fara II centrifugal analyser is described. Initially this test was programmed as a 2-step technique to mimic the reference manual method. However, the wide variation of Cobas Fara normal control values obtained with several different batches of the reagent was unacceptable. Investigation of 1-step techniques resulted in dramatic changes in the normal control values. These changes would consequently alter reference values and affect International Sensitivity Index (ISI) and International Normalized Ratio (INR) determinations. This paper stresses the necessity to fully assess all methodology variables when evaluating new reagents.
Blood Coagulation Tests↗
Screening INR deviation of local prothrombin time systems.
AIM: To assess the reliability of local international normalised ratios (INR) using a set of three international reference preparation (IRP) certified freeze dried plasmas. METHODS: 55 centres in the United Kingdom and the Republic of Ireland participated; 36 centres employed coagulometers and 19 a manual prothrombin time technique, all with the same batch of routine commercial thromboplastin. The plasmas had certified INR with the manual technique using a thromboplastin IRP, and results were provided graphically to participants for self assessment. An INR deviation of more than +/- 10% from the certified INR with any of the screening plasmas was regarded as unsatisfactory and clinically significant. Sets of 20 freeze dried plasmas were provided for local ISI calibrations and sets of seven freeze dried normals were provided for supplementary exercises where screening results were unsatisfactory. RESULTS: 15 of 38 coagulometers, but only three of the 19 manual prothrombin time test techniques, gave unsatisfactory results. With 10 of the 15 unsatisfactory coagulometer results the problem was resolved by local ISI calibrations with plasma calibrant sets provided. Unsatisfactory results with manual technique in all four instances were corrected by substitution of the mean result with freeze dried normal plasmas provided. CONCLUSIONS: The freeze dried plasma screening set was useful in detecting incorrect INR in a high proportion of coagulometer users and a smaller number of participants using the manual technique.
Calibration↗
International sensitivity index calibration of the near-patient testing prothrombin time monitor, ProTime.
Near-patient testing devices (monitors) capable of measuring prothrombin time on an unmeasured drop of blood would be suitable alternatives to centralized laboratory monitoring of patients receiving oral anticoagulants. The essential prerequisite for the use of these monitors is their conformity to the international sensitivity index (ISI) calibration model recommended by the World Health Organization. We report on the ISI calibration of the ProTime monitor (International Technidyne, Edison, NJ) designed and approved for patient self-testing. According to our results, this monitor can be calibrated by adopting the model already used for other monitors. The apparent ISI was close to unity. Overall, the international normalized ratio values displayed by the monitor agreed with those measured with the international reference preparation for thromboplastin. Confirmation of these results in a large multicenter study is warranted.
Administration, Oral↗
Has the Quick or the Owren prothrombin time method the advantage in harmonization for the International Normalized Ratio system?
Prothrombin time (PT) is the most commonly used coagulation test in health care. We sought here to compare two major PT methods (Quick and Owren) for harmonization of International Normalized Ratio (INR) results. We measured PT with an ACL 7000 analyser. We used three Owren and three Quick reagents for PT, and estimated the International Sensitivity Index (ISI) for each reagent using two local and two manufactured ISI calibrator sets. The coagulation time was measured using five different normal plasmas to assess variation for every reagent and both methods. We studied the analytical bias for every reagent and both methods at INR = 1.0 and INR = 2.5. The mean percentage coefficient of variation of the Owren reagent ISI was 2.40% and that of the Quick reagent ISI was 12.85%. The mean percentage coefficient of variation of normal plasma seconds for the Owren method was 2.54% and that for Quick was 4.02%. The absolute error at INR = 1.0 and INR = 2.5 was 0.00 and 0.04 INR for Owren, and 0.01 and 0.16 INR for Quick. The Owren PT method has the advantage over the Quick PT method in ISI calibration, normal plasma variation, within-run analytical variation and absolute error at INR = 2.5. The INR system is more demanding on analytical quality than earlier units (Ratio,%). The data would indicate that the Owren PT method has advantages over the Quick PT method in harmonization of the INR system.
Calibration↗
The influence of heparin on the prothrombin time.
We studied the effect of known concentrations of heparin on the prothrombin time (PT) in patients receiving warfarin and in controls who were not anticoagulated. Plasma from the subjects and controls was serially diluted with known concentrations of heparin, and PT was measured. Linear regression of heparin concentration versus percentage change in PT resulted in r = 0.86 in the warfarin group and r = 0.72 in the control group. The warfarin group was more sensitive to the effects of heparin than the control group, as manifested by a steeper slope of the regression line (p less than 0.001). Over the therapeutic range of heparin concentration (0.2-0.4 units/ml), the 95% prediction interval of the percentage change in PT was -6-12% at 0.2 units/ml, and 2-20% at 0.4 units/ml in the warfarin group. These results demonstrate a strong relationship between the heparin concentration in plasma and the percentage change in the PT. This effect should be considered when adding warfarin to the regime of patients receiving heparin therapy.
Adolescent↗
Effect of using warfarin plasma concentrations in Bayesian forecasting of prothrombin-time response.
The predictive performance of a Bayesian computer program using prothrombin-time (PT) response data with and without warfarin plasma concentrations to forecast patients' PTs at the time of hospital discharge was evaluated. A log-linear pharmacokinetic-pharmacodynamic model was used to describe and predict warfarin dose response in patients recently started on warfarin sodium. Individual patients' pharmacodynamic variables relating warfarin concentration to clotting-factor synthesis were obtained by Bayesian nonlinear regression analysis. Pharmacokinetic values for warfarin clearance and volume of distribution were either calculated using nonlinear regression from measured plasma warfarin concentrations or estimated based on literature-derived population regression equations. Percent mean absolute prediction error (precision) and prediction error (bias) for PT predictions were compared among and between analysis methods that used only literature data to estimate PT response and methods that used zero to five PTs with or without warfarin plasma concentrations. Eleven women and eight men completed the study. Predictions after four days of warfarin therapy using PT measurements beginning after either the first or third warfarin dose were clinically useful regardless of whether warfarin concentrations were used in the predictions. Predictions using fewer than four PT measurements were imprecise and biased. The Bayesian method in this study provided good predictions of PTs immediately before hospital discharge based on warfarin dosing and PT response after either four or five days of therapy. The use of warfarin plasma concentrations in the pharmacokinetic-pharmacodynamic model used here appears unwarranted.
Adolescent↗