br Anti Factor Xa methods

Anti-Factor Xa methods for DiXaIs measurement in plasma Concerning Anti-Factor Xa methods, there is an excellent correlation between the 1-stage and 2-stage Anti-assays as shown in Fig. 6, and the concentrations measured are very similar with all methods. These methods and the DiXaI concentrations obtained are in an excellent correlation with the LC:MS technique, also for low concentrations [44], [46]. One of the major applications for DiXaI drug measurement in PKC412 concerns emergency situations when a treated patient needs surgery. Safe surgery can be undertaken when DiXaIs/DOACs concentrations are below a usually accepted threshold level, which is <30 ng/ml [27]. When the DOAC concentration is below this, it eliminates any risk of bleeding due to treatment. This objective is not always obvious to reach, as treated patients are frequently aged, under life-long anticoagulant therapy, and they have associated pathologies, including decreased kidney or liver function. Clearance of DiXaIs/DOACs does not always match the standard kinetics documented during drug clinical validation studies (in healthy volunteers), and higher concentrations than expected can last for longer times in disease states. Measuring the drug concentration in plasma allows safer management of patients undergoing surgery by adjusting the protocol to the DiXaI/DOAC residual concentration: i.e. delaying the surgery when possible, until the concentration is in the safe range; or anticipating a reversal therapy in the case of bleeding. From now, and in the near future, the newly upcoming drug antidotes, when available, are facilitating and will improve the management of patients in the peri-operative period. At this time the single antidote available (Praxbind®) is only for Dabigatran [47]. Other antidotes are in an advanced development stage for the other DiXaI drugs [48], [49], [50], [51], [52].
Reversal therapy in bleeding context and new antidotes When they were introduced, a major inconvenience of the DOACs was the absence of an antidote. In the presence of bleeding risks context, or in case of overdose, treated patients can be exposed to the occurrence of hemorrhagic episodes, which can be difficult to manage. Reversal therapies are considered with the possible use of procoagulant fractions. Treating bleeding in patients with DOAC therapy is a case by case intervention, and various strategies have been proposed or used such as infusion of activated Factor VII (Novoseven®), activated prothrombin complex concentrate (FEIBA), prothrombin complex concentrate, and even hemodialysis (for Dabigatran, in order to reduce drug concentration in blood) [23], [24], [25], [26], [52]. Recently, many studies have been undertaken in order to develop specific or polyvalent antidotes for DOACs [18], [47], [50], [51]. Three different strategies have been followed: a) development of a high affinity humanized monoclonal antibody fragment, specific for dabigatran and neutralizing its activity [47]; b) inactive, GLA-domainless human Factor Xa, which neutralizes DiXaI activity [50]; c) a polyvalent antidote, PER 977, which is an cationic peptide binding and inhibiting all DOACs activity, and which can also be used as an antidote for Fondaparinux or LMWH [49]. Today, only the specific dabigatran antidote (Idarucizumab/Praxbind®) has been released in many countries, and is approved by the EMA (EU) and FDA (USA). It allows an efficient reversal of the DTI anticoagulant activity with a 5 g single dose injection. For DiXaI, Andexanet (modified recombinant inactive Factor Xa), a competitive inhibitor for direct (DiXaLs) and indirect Factor Xa inhibitors, is in a final development/validation stage and is expected to be rapidly available. The polyspecific antidote, PER977 (Perosphere, a small synthetic, water-soluble cationic peptide) will offer great utility through its broad range for applications as Crossing-over can reverse the anticoagulant effect of all anticoagulants without antidote, including DTI, DiXaIs, Fondaparinux, and LMWH [48]. Anti-Factor Xa assays, used for measuring the drug concentration in plasma, will also be very useful for checking the efficacy of specific/polyvalent reversal agents [31], [38], [39].