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    • Although drug monitoring is not usually requested there

    2022-06-29

    Although drug monitoring is not usually requested, there are some cases where measurement of DOACs in Regorafenib is useful, and of special help for managing patients at risk. These cases include the control of adherence to a therapeutic protocol, surveillance of drug accumulation risk in long term treated patients (measurement of concentration, just before the next drug intake), overdose, occurrence of thrombotic or bleeding events in treated patients, especially when urgent surgery is needed and the risk of bleeding, which could be induced by a high residual DOAC concentration, must be excluded. Until recently, no specific antidote was available for DOACs [19]. In this context, the presence of a residual high DOAC concentration, scientific societies recommend, when possible, to delay surgery and to undertake it only when this concentration is ≤30 ng/ml especially when the needed surgery is at a high bleeding risk [19], [20], [21], [22]. If delay is not possible, a reversal strategy is then necessary [23], [24], [25], [26]. Many articles and recommendations have now been published for safely undertaking surgery in DOAC treated patients [27], [28], [29], [30]. Measurement of DOACs is also useful for management of patients with mild or more severe impaired renal (especially for Dabigatran and Edoxaban) or hepatic function (all DOACs and more especially for Rivaroxaban and Apixaban), as drug clearance can be reduced and high DOAC concentrations can be present in the circulation [20]. In addition, measurement of the DOAC plasma concentration is also needed in the laboratory setting, in the presence of an unexplained prolonged coagulation time, or for patients admitted in emergency or in intensive care units and for whom use of an anticoagulant therapy is unknown [31]. Global coagulation tests can produce values in the normal range, even in the presence of a significant DOAC concentration which is capable of inducing bleeding episodes. This is of special relevance for Apixaban [32]. The reference method used for measurement of a DOAC concentration in plasma is Liquid Chromatography: Mass Spectrometry (LC:MS). This method was extensively used for validation studies and clinical trials but it cannot be used in emergency conditions or in the usual laboratory setting as it is complex and time consuming [33]. Fast, quantitative, accurate, sensitive, specific and friendly use laboratory assays are then highly expected by clinical laboratories for easy measurement of anticoagulant activity associated with plasma DOAC concentrations when needed [21], [23], [34]. The general principles of laboratory measurement of Dabigatran concentrations in plasma were recently reported by us in a previous article [35]. In this new report we focus on measurements of DiXaIs in plasma using anti-Xa assays. Expected concentrations can span a dynamic range from <30 ng/ml to >500 ng/ml, and a special focus is required for accurately measuring concentrations at the 30 ng/ml threshold value in patients needing surgery [27], [30]. Currently, Anti-Factor Xa kinetic methods are already available for unfractionated or low molecular weight heparins (UFH, LMWH), and they can be adapted for the measurement of DiXaIs, when drug dedicated calibrators and controls are available [35], [36], [37]. Specific two-stage assays can also be designed for that application, and they can be made insensitive, in part, to heparins [38], [39]. Our objective is to review these assays, their performances and usefulness in clinical laboratory practice. This article is also a tribute to Professor Michel Meyer Samama (Fig. 1) who dedicated his scientific and professional lives (among many other scopes of interest in hemostasis, thrombosis and fibrinolysis) to develop, to teach and to promote methods and strategies for laboratory monitoring of anticoagulants [4], [36], [37], first for Vitamin K Antagonists (VKA such as Coumadin or Warfarin), when he was with Leon Poller the pioneer for standardization of Prothrombin Time (PT) measurements with the introduction of the International Normalized Ratio (INR) [4], then with the Anti-Factor Xa methods for measurement of UFH and LMWH [36], [37], and, more recently, he had a strong involvement in introducing and extending measurement of DOACs in plasma when needed [19], [37], [38], [39], [40], [41]. We, JS and JA, had the privilege to collaborate with him on some of his projects, and this was a great opportunity to learn more in our scientific field, on objectives, laboratory applications and research approaches. No doubt that he will miss all of us, and all the scientific community will miss him for a long time, and that his work and scientific commitment will lead and inspire new generations of researchers and laboratory scientists and technologists. We would like to express our thanks and acknowledge his invaluable contribution, as well as our respectful thoughts in his memory.