Le Bonniec Bernard

Biography

In France 15% of the population aged 65 years and older is treated with and anti-thrombotic (either anti-platelet or anti-coagulant reagent). Direct oral anticoagulant drugs (DOAC), targeting thrombin (dabigatran etexilate) or factor Xa (rivaroxaban, apixaban, edoxaban), have been approved for clinical use in the prophylaxis and/or the treatment of thromboembolic disease. The number of patients receiving DOAC is rising steadily and it is expected that hundreds of thousands of patients will soon be treated with these drugs.

Anti-thrombotic drugs, thus including DOAC, instigate a potentially life-threatening bleeding risk. Not all DOAC have yet an available antidote and management of bleeding remains empirical in several instances. Therefore, there is a clear need to get further data regarding the reversal options and their in vitro management including the development of predictive laboratory haemostasis tests. In addition, the extent of the inter-individual variability of the response to DOAC is not well known in the “real life” for a number of clinical situations (e.g. elderly patients), as well as the potential contribution of pharmacogenetic and non-genetic factors to this inter-individual variability.

Our aims are:

1. Optimizing the management of antithrombotic agents and their reversal
   Our group develops two potential antidotes for the DOAC targeting factor Xa. Beside, several pro-haemostatic agents are currently used in specific bleeding disorders (e.g. haemophilic patients with inhibitors, coagulation factor deficiency…). These are candidates for DOAC reversal (prothrombin complex concentrates either partially activated or unactivated, and other bypassing reagents such as recombinant factor VIIa. Other options are fibrinogen concentrates, factor XIII concentrates, and anti-fibrinolytic agents such as tranexamic acid.
2. Inter-individual variability in the response to antithrombotic agents
   Better understanding the causes of inter-individual variability could optimize the use of anticoagulant drugs and minimize their iatrogenic effects. Substantial inter-individual variability has been shown to occur in healthy volunteers and patients receiving DOAC. Rivaroxaban and apixaban are metabolized into inactive molecules by the P450 cytochromes (CYP) CYP3A4 and CYP3A5, with apixaban metabolized in addition by CYP2J2. Moreover, the xenobiotic efflux transporter P-glycoprotein (P-gp) is involved in the transport of DOAC. Genetic variations (SNPs) affecting CYP genes or ABCB1 encoding P-gp could contribute to variability. Several non-genetic factors such as body mass index, renal and hepatic functions as well as co-medications also contribute to the variability of the pharmacokinetic/pharmacodynamic response.
3. Developing in vitro tests to manage patients in emergency haemorrhagic situations
   Most haemostatic tests are carried out using platelet poor plasma (PPP), and thus only investigate plasmatic haemostasis without taking into account the crucial contribution of platelets and blood cells. Indeed, we and others have shown that tests using PPP are inadequate for investigating pro-haemostatic agents acting through a mechanism involving directly or indirectly platelets. For instance, our group has demonstrated that the effect of supra-physiologic amounts of rFVIIa on haemostasis is hardly detectable in PPP because factor X activation predominantly involves platelets in this situation. Therefore, there is a need for haemostatic tests performed in platelet rich plasma or even better in whole blood to evaluate the potential antagonization of new antithrombotic drugs. For that purpose, we are developing innovative tests.