This article reviews the commonly used anticoagulants (warfarin and heparin) and associated recommended laboratory testing. Emphasis is on the various modes of International Normalized Ratio testing and associated variability (clinical laboratory, point of care, patient self-testing). Unfractionated heparin and well-recognized coagulation testing issues are reviewed. The newer anticoagulants (heparin analogs, direct factor Xa inhibitors, and direct thrombin inhibitors) and various applied coagulation laboratory testing and related issues are also discussed.
[Show abstract][Hide abstract] ABSTRACT: Clinicians should be aware of new developments to familiarize themselves with pharmacokinetic and pharmacodynamic characteristics of new anticoagulant agents to appropriately and safely use them. For the moment, cardiologists and other clinicians also require to master currently available drugs, realizing the mechanism of action, side effects, and laboratory monitoring to measure their anticoagulant effects. Warfarin and heparin have narrow therapeutic window with high inter- and intra-patient variability, thereby the use of either drug needs careful laboratory monitoring and dose adjustment to ensure proper antithrombotic protection while minimizing the bleeding risk. The prothrombin time (PT) and the activated partial thromboplastin time (aPTT) are laboratory tests commonly used to monitor warfarin and heparin, respectively. These two tests depend highly on the combination of reagent and instrument utilized. Results for a single specimen tested in different laboratories are variable; this is mostly attributable to the specific reagents and to a much lesser degree to the instrument used. The PT stands alone as the single coagulation test that has undergone the most extensive attempt at assay standardization. The international normalized ratio (INR) was introduced to “normalize” all PT reagents to a World Health Organization (WHO) reference thromboplastin preparation standard, such that a PT measured anywhere in the world would result in an INR value similar to that which would have been achieved had the WHO reference thromboplastin been utilized. However, INRs are reproducible between laboratories for only those patients who are stably anticoagulated with vitamin K antagonists (VKAs) (i.e., at least 6 weeks of VKA therapy), and are not reliable or reproducible between laboratories for patients for whom VKA therapy has recently been started or any other clinical conditions associated with a prolonged PT such as liver disease, disseminated intravascular coagulation, and congenital factor deficiencies. In contrast to marked progress in the standardization of PT reagents for INR reporting, no standardization system has been globally adopted for standardization of PTT reagents. Recently College of American Pathologists recommend that individual laboratories establish their own therapeutic range by using aPTT values calibrated against accepted therapeutic unfractionated heparin (UFH) levels calibrated against accepted therapeutic UFH levels performing anti-Xa test (which is the most accurate assay for monitoring UFH therapy).
Herein, we review recent data on the monitoring of conventional anticoagulant agents. Marked interlaboratory variability still exists for PT, INR, and PTT tests. Further research should be focused on improving the standardization and calibration of these assays.
[Show abstract][Hide abstract] ABSTRACT: Oral anticoagulation therapy (OAT) with coumarins (vitamin K-antagonists) is prescribed for both prophylactic and therapeutic use to patients at increased risk of thromboembolism. OAT has a narrow therapeutic index, and monitoring is based on the International Normalized Ratio (INR) conventionally determined on citrated plasma obtained by venepuncture. Based on the INR measurements, health care providers determine the appropriate dose of coumarins (e.g. warfarin (Marevan). Optimised management of OAT improves the quality of treatment. Patient self-management (PSM) is a new concept where the patient takes an active part in his or her own treatment. PSM in OAT implies that the patient analyses a drop of blood using a portable coagulometer (INR-monitor). The coagulometer displays the INR, which the patient uses for coumarins dosage. It is still not clarified which subset of patients (in terms of indication for OAT, age, co-morbidity etc.) that potentially will benefit from PSM, and how large this potential effect is. A precondition for a correct dosage of coumarins is a correct estimation of the INR, and the method and apparatus used for providing the INR measurements is in this context essential. The coagulometers used for PSM have not been investigated adequately in terms of precision and agreement, so this is warranted. INR has proven adequate for adjusting dosages. It is doubtful that the level of INR reflects the overall haemostatic capacity or thrombotic potential of individual patients. Measurement of continuous calibrated automated thrombin generation (CAT) and coagulation factors activities may serve as a more sensitive and global haemostatic parameter and potentially with better performance in predicting risk of complications in patients on OAT. We found that the clotting activity of coagulation factors II, VII, IX, and X and CAT exhibited no variability over a 6-week period. The activity of the coagulation factors and CAT was significantly associated with the INR, so these two tests can be used concomitantly and/or interchangeably with the INR. Approximately 50% of the total variability of the coagulation factor activities and CAT was reflected by the INR, whereas the remaining variability was within the subject (patient). Coagulation factor activities and CAT can therefore potentially be used to provide further information to the risk of bleeding and thromboembolism, since almost 50% of the variability within the subject is not displayed in the INR value. Yet it remains uncertain if this method can predict complications in individual patients on OAT. Larger clinical trials with a longer follow-up period, preferably using clinical endpoints, are needed in order to draw any firm conclusions regarding the clinical consequences. However, measurement of coagulation factor activities and CAT may improve measurement of coagulation activity in patients prescribed OAT beyond the parameters currently clinically available. The CoaguChek S and XS coagulometers used for PSM were found to have an adequate precision. Regarding the accuracy, the INR measurements tended to be lower on the coagulometers, compared with the laboratory. A large proportion of the measurements on the coagulometers deviated more than 15% from the laboratory measurements. However, only one laboratory was used for comparison and the original WHO method (gold standard) for estimating INR was not used. Furthermore, the inherent limitations of the INR have to be taken into consideration, and the results have to be viewed in this context. The accuracy of the coagulometers seems in this respect acceptable and they can be used in a clinical setting. However, external quality control is essential. In the observational studies, it was found that PSM was feasible and provides satisfactory treatment quality for various indications and in a wide range of patient age. In a randomised controlled trial, using a documented blinded composite endpoint, PSM was found to provide a treatment quality that was at least as good as that provided by conventional management. Additionally it was found, that training and implementation of PSM lead to a smaller variance in INR measurements, a higher median INR and a higher dose of coumarins compared to that obtained for conventionally managed patients. Further evidence was provided in a systematic review and meta-analysis, where it was documented, that PSM appears at least as good as and possibly better than conventional management in highly selected patients.
Danish medical bulletin 05/2011; 58(5):B4284. · 1.01 Impact Factor
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