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PubMedDate not supplied

Delayed elevation of international normalized ratio with concurrent clarithromycin and warfarin therapy.

Clarithromycin is rarely reported to cause disturbances in anticoagulation. Theoretically, clarithromycin administered concurrently with warfarin could result in enhanced anticoagulation, since many properties of clarithromycin are similar to those of erythromycin, which interacts with warfarin. A search of the National Library of Medicine produced no published reports of an interaction between the drugs. Erythromycin competitively inhibits hepatic metabolism of warfarin, specifically the R-warfarin enantiomer, by the cytochrome P450 3A3 and 3A4 pathways, resulting in increased prothrombin time and international normalized ratio (INR). Two men, age 61 and 70 years, who received stable warfarin regimens, experienced supratherapeutic elevations in prothrombin time (98.4 and 26.8 sec) and INR (90.3 and 5.6), respectively. While taking warfarin, both patients experienced dramatically increased anticoagulation effects 5 days after starting clarithromycin for atypical pneumonia. They were similarly managed for overanticoagulation by discontinuing clarithromycin, holding warfarin, and receiving intravenous phytonadione. Neither man suffered from medical complications related to anticoagulation. Until clear documentation of the exact mechanism and temporal relationship of this interaction is known, patients receiving warfarin who require the concurrent clarithromycin should have prothrombin time and INR closely monitored.

Aged↗
PubMed1995

A simple method for the derivation of the international normalized ratio for the reporting of prothrombin time results.

In order to harmonize the prothrombin time (PT) reporting systems, the World Health Organization, in collaboration with the International Committee on Thrombosis and Hemostasis, and the International Council on the Standardization in Hematology proposed a reporting system, the so-called international normalized ratio (INR). As the calculation of the INR depends on mathematical formula requiring a special calculator or mathematic tables, its derivation is associated with some difficulties and errors. In this article a nomogram is presented, by which derivation of the INR from different PT reporting methods can be easily done within a few seconds.

Anticoagulants↗
PubMedDate not supplied

Mechanical valve replacement in congenital heart defects in the era of international normalized ratio self-management.

As the number of patients with congenital heart defects requiring heart valve replacement increases, the need for durable valve substitutes with good hemodynamic performance and a low incidence of complications becomes more apparent. The use of porcine xenografts is burdened with early fibrocalcific degeneration, whereas the use of mechanical heart valves led to an increased number of thromboembolic events, especially when implanted in the right side of the heart. We report on our experiences implanting bileaflet heart valves in congenital heart defects since the introduction of international normalized ratio (INR) self-management. The data of 68 long-term survivors (33 males, 35 females) who underwent mechanical heart valve replacement in congenital heart defect were reviewed. Patient age at the time of valve replacement ranged from 5 months to 61 years (mean 21 years). Underlying diagnoses were tetralogy of Fallot (n=33), morbus Ebstein (n=4), atrioventricular canal (n=13), truncus arteriosus communis (n=5), transposition of the great arteries (n=10), and congenitally corrected transposition of the great arteries (n=3). In all patients, bileaflet valves were implanted (St. Jude Medical n=40, Carbomedics n=28). Anticoagulation was performed using dicumarol (Marcumar) and INR self-management in all cases. The mean follow-up was 72 months (range 6-132 months; 409 patient-years). Valve thrombosis developed in 3 of 68 patients (4.4%, all three had tetralogy of Fallot, mean age 9.8 years) after a mean follow-up of 3.5 years. In two of these three patients, re-pulmonary valve replacement was necessary, whereas the third patient was treated by thrombolysis. From our experience, we conclude that mechanical heart valve replacement is a good therapy option with a low complication rate for patients with congenital heart defects requiring valve replacement, especially when INR self-management is performed.

Adolescent↗
PubMedDate not supplied

[The international normalization ratio in the monitoring of oral anticoagulant therapy].

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.

Administration, Oral↗
PubMed2001

The clinical relevance of the citrate effect on International Normalized Ratio determinations depends on the reagent and instrument combination used.

Multiple studies have shown that the two different citrate concentrations in common use as the anticoagulant in blood collection for haemostasis assays can affect the results obtained with the prothrombin time assay. It is clear from the literature that there is considerable variability in the results obtained using different instrument-reagents combinations, but the clinical relevance of these differences is unclear. Most of the studies have used an optical system for end-point detection. This study reports on the citrate sensitivity using mechanical end-point detection. Using two different reagents, one previously shown to be citrate sensitive on optical systems (Neoplastin CI plus) and a citrate-insensitive reagent (Neoplastin CI), we demonstrate that the effect of using different citrate concentrations (0.105 or 0.129 mol/l) has statistically significant but clinically irrelevant effects on the International Normalized Ratio using a mechanical instrument (STA)-reagent combination (mean percentage difference in results, 1.9 and 3.8% respectively). This demonstrates that the citrate effect is both instrument type and reagent dependent. Every reagent and instrument combination needs to be tested to see whether any citrate effect exists. In a secondary study, it was shown that the international reference rabbit thromboplastin (CRM 149(s)) was not citrate-concentration sensitive.

Animals↗
PubMed2006

[Modified capillary blood prothrombin-time test for the calculation of an international normalized ratio].

Prothrombin time (PT) is usually measured in citrated venous blood. This test is undesirable in pediatric practice and in patients taking anticoagulants due to frequent venepunctures. Capillary blood PT test has no adverse impact. The authors have developed a standardized modified method for PT measurement in capillary blood. The adequacy of the test is due to the fact that analyzed test packed cell volumes are kept in mind. The modified test has shown that the values of normal plasma PT may be used to calculate an international normalized ratio (INR). It makes it possible to determine capillary blood PT in the range of packed cell volumes from 0.15 to 0.7 in the examinees and to monitor anticoagulant therapy. The results of the modified test closely correlated with those when determining PT and INR in venous plasma (r = 0.99) and applying the CoaguChek test (r = 0.97).

Anticoagulants↗
PubMed2006

Study on warfarin plasma concentration and its correlation with international normalized ratio.

A sensitive high-performance liquid chromatographic (HPLC) method was developed for warfarin determination in plasma of patients who undertook cardiac valve replacement and were on anticoagulation with warfarin. The method described proved to be accurate, sensitive, easy to perform, reproducible and specific for plasma warfarin measurement with relative standard deviation (R.S.D.) of <5.27% for inter-day and <6.89% for intra-day. The assay was linear in warfarin concentration ranges of 0.12-3 microg/ml (r=0.9995) with mean recovery of 94.6%. The mean warfarin plasma concentration of 58 patients with heart valve replacement within 1 month of post operation was 567.6+/-122.3 ng/ml. The anticoagulant effect of the drug was monitored by international normalized ratio (INR). The correlation of warfarin dosage and concentration with INR was analysed, and the coefficients were 0.21, 0.1<p<0.2 and 0.30, 0.02<p<0.1, respectively. The correlation of warfarin dosage or concentration with INR is very poor, and hence in order to adjust the dosage more objectively and accurately, concentration monitoring is necessary and helpful for the patient management. It is needed especially when the ideal INR is difficult to target.

Anticoagulants↗
PubMed2005

Use of the chromogenic factor X assay to predict the international normalized ratio in patients transitioning from argatroban to warfarin.

STUDY OBJECTIVE: To determine the clinical utility of the chromogenic factor X level for conversion from argatroban to warfarin in hospitalized patients. DESIGN: Prospective observational study. PATIENTS: Sixty-two hospitalized patients with indications for anticoagulation in whom the chromogenic factor X assay was used for conversion from argatroban to warfarin. SETTING: University-affiliated hospital. INTERVENTION: From December 2003-May 2004, data for all patients in whom the chromogenic factor X assay was used for conversion from argatroban to warfarin were screened for inclusion. When the chromogenic factor X level was satisfactory, the clinician discontinued the argatroban and a confirmatory international normalized ratio (INR) was obtained. MEASUREMENTS AND MAIN RESULTS: To determine the ability of the chromogenic factor X level to predict the INR free of argatroban influence, we calculated the sensitivity and specificity by using a cutoff chromogenic factor X level of 45% or less, or greater than 45%, which corresponded to an INR of 2 or greater, or less than 2, respectively. We constructed a receiver operating characteristic curve to illustrate various cutoff levels of chromogenic factor X. Of 146 patients screened, 62 had data that met criteria for analysis. An average of 6 +/- 3 doses of warfarin were administered before the confirmatory coagulation studies were obtained. The average time from the chromogenic factor X measurement to obtainment of confirmatory coagulation studies was 9 +/- 4 hours. Use of a chromogenic factor X level of 45% or less to predict an INR of 2 or greater absent of argatroban influence had a sensitivity of 93%, a specificity of 78%, and an accuracy of 89%. The area under the receiver operating characteristic curve was 0.91 (95% confidence interval 0.81-0.99, p<0.0001). CONCLUSION: The chromogenic factor X level is an accurate alternative when converting hospitalized patients from argatroban to warfarin. A chromogenic factor X level of 45% or less is a reliable predictor that the INR will be therapeutic when argatroban therapy is discontinued.

Aged↗
PubMed2000

Clinical utilization of the international normalized ratio (INR).

The prothrombin time (PT) is one of the most important laboratory tests to determine the functionality of the blood coagulation system. It is used in patient care to diagnose diseases of coagulation, assess the risk of bleeding in patients undergoing operative procedures, monitor patients being treated with oral anticoagulant (coumadin) therapy, and evaluate liver function. The PT is performed by measuring the clotting time of platelet-poor plasma after the addition of calcium and thromboplastin, a combination of tissue factor and phospholipid. Intra- and interlaboratory variation in the PT was a significant problem for clinical laboratories in the past, when crude extracts of rabbit brain or human placenta were the only source of thromboplastin. The international normalized ratio (INR), developed by the World Health Organization in the early 1980s, is designed to eliminate problems in oral anticoagulant therapy caused by variability in the sensitivity of different commercial sources and different lots of thromboplastin to blood coagulation factor VII. The INR is used worldwide by most laboratories performing oral anticoagulation monitoring, and is routinely incorporated into dosage planning for patients receiving warfarin. Although the recent availability of sensitive PT reagents prepared from recombinant human tissue factor (rHTF) and synthetic phospholipids eliminated many of the earlier problems associated with the use of crude thromboplastin preparations, local instrument variability in the INR still remains a problem. Presently, the use of plasma calibrants seems the best solution to this problem. Standardizing the point-of-care instruments for INR monitoring is another dilemma faced by the industry. Ultimately, new generations of anticoagulant drugs may eliminate the need for laboratory monitoring of anticoagulant therapy.

Hematology↗
PubMed2002

Need of more frequent International Normalized Ratio monitoring in elderly patients on long-term anticoagulant therapy after influenza vaccination.

Previous findings suggest the safety of influenza vaccination for patients on oral anticoagulant therapy (OAT). However, some studies reported a moderate reduction or increase of the anticoagulation. We assessed the effect of influenza vaccination on anticoagulation levels. Seventy-three patients on stable long-term OAT were recruited. Patients were compared with a control group of 72 patients observed during the same period. No differences in the anticoagulation levels were found in patients and in controls during the 3 months before and after the vaccination. However, in patients older than 70 years we observed a reduction of anticoagulation intensity achieved in the month after the vaccination, with a prolonged time spent below the therapeutic range (10% before and 27% after, P = 0.001), and this behaviour was still observed 3 months after vaccination. Influenza vaccination is safe in patients on OAT, but it is associated with a slight reduction in warfarin effect in the elderly, suggesting the need of more frequent International Normalized Ratio monitoring after vaccination in these subjects.

Aged↗
PubMed2006

Reversal of elevated international normalized ratios and bleeding with low-dose recombinant activated factor VII in patients receiving warfarin.

STUDY OBJECTIVE: To assess the effectiveness of using low-dose recombinant activated factor VII (rFVIIa) to reverse the effects of warfarin in critically ill patients with major bleeding events. DESIGN: Prospective observational study. SETTING: Intensive care unit of a 500-bed university-affiliated hospital. PATIENTS: Sixteen nonhemophiliac patients who had been receiving warfarin and had an acute major bleeding event. INTERVENTION: Patients received rFVIIa 1.2 mg for reversal of anticoagulation. MEASUREMENTS AND MAIN RESULTS: Patients were identified from clinical pharmacology consult service electronic tracking records, and their data were cross-checked with the pharmacy information system. Information collected for each patient included extent of bleeding and magnitude of elevation in international normalized ratio (INR). A mean +/- SD dose of rFVIIa 16.3 +/- 4.1 microg/kg (range 11-25 microg/kg) reduced the mean INR from 2.8 +/- 1.6 (range 1.44-6.34) to 1.07 +/- 0.27 (range 0.86-1.92, p<0.001). A rapid onset of response for achieving a desirable hemostatic effect was observed in 14 of the 16 patients. CONCLUSION: Low-dose rFVIIa appears to be an effective, rapid reversal modality for major bleeding events in the presence of warfarin and an elevated INR. The agent's response is quicker than that expected with fresh frozen plasma combined with vitamin K. In emergency situations, rFVIIa 1.2 mg can be used to reverse the anticoagulant effect of warfarin and other vitamin K antagonists without inducing a hypercoagulable state; the product, however, is expensive.

Adolescent↗
PubMed2003

Multivariate relationships between international normalized ratio and vitamin K-dependent coagulation-derived parameters in normal healthy donors and oral anticoagulant therapy patients.

BACKGROUND AND OBJECTIVES: International Normalized Ratio (INR) is a world-wide routinely used factor in the monitoring of oral anticoagulation treatment (OAT). However, it was reported that other factors, e. g. factor II, may even better reflect therapeutic efficacy of OAT and, therefore, may be potentialy useful for OAT monitoring. The primary purpose of this study was to characterize the associations of INR with other vitamin K-dependent plasma proteins in a heterogenous group of individuals, including healthy donors, patients on OAT and patients not receiving OAT. The study aimed also at establishing the influence of co-morbid conditions (incl. accompanying diseases) and co-medications (incl. different intensity of OAT) on INR. DESIGN AND METHODS: Two hundred and three subjects were involved in the study. Of these, 35 were normal healthy donors (group I), 73 were patients on medication different than OAT (group II) and 95 were patients on stable oral anticoagulant (acenocoumarol) therapy lasting for at least half a year prior to the study. The values of INR and activated partial thromboplastin time (APTT) ratio, as well as activities of FII, FVII, FX, protein C, and concentration of prothrombin F1+2 fragments and fibrinogen were obtained for all subjects. In statistical evaluation, the uni- and multivariate analyses were employed and the regression equations describing the obtained associations were estimated. RESULTS: Of the studied parameters, three (factors II, VII and X) appeared as very strong modulators of INR, protein C and prothrombin fragments F1+2 had moderate influence, whereas both APTT ratio and fibrinogen had no significant impact on INR variability. Due to collinearity and low tolerance of independent variables included in the multiple regression models, we routinely employed a ridge multiple regression model which compromises the minimal number of independent variables with the maximal overall determination coefficient. The best-fitted two-component model included FII and FVII activities and explained 90% of INR variability (compared to 93% in the 5-component model including all vitamin K-dependent proteins). Neither the presence of accompanying diseases nor the use of OAT nor any other medication (acetylsalicylic acid, statins, steroids, thyroxin) biased significantly these associations. CONCLUSION: Among various vitamin K-dependent plasma proteins, the coagulation factors II, VII and X showed the most significant associations with INR. Of these variables, the two-component model, including factors II and VII, deserves special attention, as it largely explains the overall variability observed in INR estimates. The statistical power of this model is validated on virtue of the estimation that the revealed associations are rather universal and remain essentially unbiased by other compounding variables, including clinical status and medical treatment. Further, much broader population studies are needed to verify clinical usefulness of methods alternate or compounding to INR monitoring of OAT.

Journal Article↗
PubMed1993

Are capillary whole blood coagulation monitors suitable for the control of oral anticoagulant treatment by the international normalized ratio?

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

Administration, Oral↗
PubMed1994

Use of lyophilized calibration plasmas and control blood for international normalized ratio calculation in external quality assessment of the prothrombin time.

In the Netherlands, most anticoagulant clinics (thrombosis centers) use the reagent Thrombotest with citrated venous blood for laboratory control of oral anticoagulant therapy. In a national external quality assessment scheme, artificial control blood samples were mailed to 160 participants. Each participant returned prothrombin times and international normalized ratio (INR) values for these blood samples. The author investigated whether local calibration with lyophilized plasmas could reduce the interlaboratory variation of the INR. Five lyophilized plasmas were mailed along with the control blood samples. Using a local calibration line determined with the lyophilized plasmas, the interlaboratory variation of INRs determined routinely could be reduced slightly from 5.8% to 7% coefficient of variation (CV) to 5.3% to 6.5% CV. In contrast, when a local calibration line was determined with four similar control blood samples, the interlaboratory variation of the INR was reduced substantially to 2.5% CV.

Calibration↗
PubMed1991

Warfarin and the international normalized ratio: reducing interlaboratory effects.

In North America, the dose of warfarin has been unintentionally increased during the past two decades because of failure to recognize the effect on the anticoagulation test of less sensitive tissue thromboplastins. Although there still is some controversy, the suggested dose of warfarin has now been adjusted downward to reduce the risk of bleeding. These revised dosing recommendations incorporate the international normalized ratio (INR), which takes into account the source of thromboplastin. However, there is considerable variability in the sensitivities of thromboplastin from manufacturer to manufacturer and lot to lot. Therefore, prothrombin times (PTs) are not comparable from laboratory to laboratory without knowing the sensitivity of the thromboplastin. Unless laboratories adopt a standardized tissue thromboplastin, the PT should be reported as an INR.

Humans↗
PubMed1997

Biological variation of International Normalized Ratio for prothrombin times, and consequences in monitoring oral anticoagulant therapy: computer simulation of serial measurements with goal-setting for analytical quality.

Oral anticoagulant therapy (OAT) has a well-established efficacy in prophylaxis and treatment of thromboembolic disorders. Because complications are related to intensity of OAT, optimal control of treatment is mandatory. In studies of OAT, as many as 30% of International Normalized Ratio (INR) measurements for prothrombin times fall outside the therapeutic interval. Preanalytical, analytical, and biological variation all contribute to this. Computer simulations of serial INR measurements were performed for various assumed in-treatment setpoints within the therapeutic interval INR 2.0-3.0 and for an "in-treatment within-subject variation" (CV) of 10.1%. Results are presented in difference plots with therapeutic intervals and critical differences. If the in-treatment setpoint is mid-interval (INR = 2.5), only 5% of simulated INR values fall outside the therapeutic interval. Setpoints deviating from the mid-interval and increases in the in-treatment within-subject variation considerably increase the number of observations outside the therapeutic interval and the critical differences. In conclusion, random variation, biological or analytical, and setpoints (targets) deviating from mid-interval explain a substantial number of the INR values outside therapeutic intervals observed in clinical studies. Analytical imprecision should be kept < 5% and analytical bias < +/- 0.2 INR.

Administration, Oral↗