Le Bonniec Bernard
Phone: 01 53 73 98 28
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:
- 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.
- 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.
- 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.
Major publications 2020 / 2010
The Immunomodulatory Effect of IrSPI, a Tick Salivary Gland Serine Protease Inhibitor Involved in Ixodes ricinus Tick Feeding. Adrien A Blisnick, Ladislav Šimo, Catherine Grillon, Fabienne Fasani, Sébastien Brûlé, Bernard Le Bonniec, Eric Prina, Maud Marsot, Anthony Relmy, Sandra Blaise-Boisseau, Jennifer Richardson, Sarah I Bonnet – 2019 Oct 12 – PMID: 31614804 PMCID: PMC6963187 DOI: 10.3390/vaccines7040148
Epinephrine restores platelet functions inhibited by ticagrelor: A mechanistic approach. Anne-Céline Martin, Diane Zlotnik, Guillaume Porta Bonete, Elodie Baron, Benoît Decouture, Tiphaine Belleville-Rolland, Bernard Le Bonniec, Sonia Poirault-Chassac, Marie-Christine Alessi, Pascale Gaussem, Anne Godier, Christilla Bachelot-Loza – 2020 Jan 5 – PMID: 31738933 DOI: 10.1016/j.ejphar.2019.172798
Strategies of neutralization of the direct oral anticoagulants effect: review of the literature. Jourdi G, Le Bonniec B, Gouin-Thibault I. Ann Biol Clin (Paris). 2019 Feb 1;77(1):67-78. doi: 10.1684/abc.2018.1400. Review.
Treprostinil treatment decreases circulating platelet microvesicles and their procoagulant activity in pediatric pulmonary hypertension. Bacha NC, Levy M, Guerin CL, Le Bonniec B, Harroche A, Szezepanski I, Renard JM, Gaussem P, Israel-Biet D, Boulanger CM, Smadja DM. Pediatr Pulmonol. 2019 Jan;54(1):66-72. doi: 10.1002/ppul.24190. Epub 2018 Nov 28.
Modified ROTEM for the detection of rivaroxaban and apixaban anticoagulant activity in whole blood: A diagnostic test study. Pailleret C, Jourdi G, Siguret V, Gouin-Thibault I, Gandrille S, Stepanian A, Curis E, Golmard JL, Gaussem P, Le Bonniec B, Samama CM. Eur J Anaesthesiol. 2019 Jun;36(6):449-456. doi: 10.1097/EJA.0000000000000903.
FXa-α2-Macroglobulin Complex Neutralizes Direct Oral Anticoagulants Targeting FXa In Vitro and In Vivo. Jourdi G, Gouin-Thibault I, Siguret V, Gandrille S, Gaussem P, Le Bonniec B. Thromb Haemost. 2018 Sep;118(9):1535-1544. doi: 10.1055/s-0038-1667014.
Erratum to “Thrombin generation test: A reliable tool to evaluate the pharmacodynamics of vitamin K antagonist rodenticides in rats” [Pestic. Biochem. Physiol. 146 (2018) 19-24]. Jourdi G, Lefèbvre S, Le Bonniec B, Curis E, Gaussem P, Lattard V, Siguret V. Pestic Biochem Physiol. 2018 Jul;149:149. doi: 10.1016/j.pestbp.2018.05.003.
Thrombin generation test: A reliable tool to evaluate the pharmacodynamics of vitamin K antagonist rodenticides in rats. Jourdi G, Lefèbvre S, Le Bonniec B, Curis E, Gaussem P, Lattard V, Siguret V. Pestic Biochem Physiol. 2018 Apr;146:19-24. doi: 10.1016/j.pestbp.2018.02.004. Epub 2018 Feb 15. Erratum in: Pestic Biochem Physiol. 2018 Jul;149:149. Georges, Jourdi [corrected to Jourdi, Georges]; Sebastien, Lefèbvre [corrected to Lefèbvre, Sebastien]; Bernard, Le Bonniec [corrected to Le Bonniec, Bernard]; Emmanuel, Curis [corrected to Curis, Emmanuel]; Pascale, Gaussem [corrected to Gaussem, Pascale].
Pulsed cavitational therapy using high-frequency ultrasound for the treatment of deep vein thrombosis in an in vitro model of human blood clot. Goudot G, Mirault T, Arnal B, Boisson-Vidal C, Le Bonniec B, Gaussem P, Galloula A, Tanter M, Messas E, Pernot M. Phys Med Biol. 2017 Nov 21;62(24):9282-9294. doi: 10.1088/1361-6560/aa9506.
Gestational age-related patterns of AMOT methylation are revealed in preterm infant endothelial progenitors. Vinci G, Buffat C, Simoncini S, Boubred F, Ligi I, Dumont F, Le Bonniec B, Fournier T, Vaiman D, Dignat-George F, Simeoni U. PLoS One. 2017 Oct 16;12(10):e0186321. doi: 10.1371/journal.pone.0186321.
Ticagrelor reversal: in vitro assessment of four haemostatic agents. Calmette L, Martin AC, Le Bonniec B, Zlotnik D, Gouin-Thibault I, Bachelot-Loza C, Gaussem P, Godier A. J Clin Pathol. 2017 Sep;70(9):733-739. doi: 10.1136/jclinpath-2016-204117.
Association rate constants rationalise the pharmacodynamics of apixaban and rivaroxaban. Jourdi G, Siguret V, Martin AC, Golmard JL, Godier A, Samama CM, Gaussem P, Gouin-Thibault I, Le Bonniec B. Thromb Haemost. 2015 Jul;114(1):78-86. doi: 10.1160/TH14-10-0877.
Multimodal assessment of non-specific hemostatic agents for apixaban reversal. Martin AC, Gouin-Thibault I, Siguret V, Mordohay A, Samama CM, Gaussem P, Le Bonniec B, Godier A. J Thromb Haemost. 2015 Mar;13(3):426-36. doi: 10.1111/jth.12830.
Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Martin AC, Le Bonniec B, Fischer AM, Marchand-Leroux C, Gaussem P, Samama CM, Godier A. Int J Cardiol. 2013 Oct 9;168(4):4228-33. doi: 10.1016/j.ijcard.2013.07.152.
Large-scale chromatin immunoprecipitation with promoter sequence microarray analysis of the interaction of the NSs protein of Rift Valley fever virus with regulatory DNA regions of the host genome. Benferhat R, Josse T, Albaud B, Gentien D, Mansuroglu Z, Marcato V, Souès S, Le Bonniec B, Bouloy M, Bonnefoy E. J Virol. 2012 Oct;86(20):11333-44.
A motif within the N-terminal domain of TSP-1 specifically promotes the proangiogenic activity of endothelial colony-forming cells. Dias JV, Benslimane-Ahmim Z, Egot M, Lokajczyk A, Grelac F, Galy-Fauroux I, Juliano L, Le-Bonniec B, Takiya CM, Fischer AM, Blanc-Brude O, Morandi V, Boisson-Vidal C. Biochem Pharmacol. 2012 Oct 15;84(8):1014-23. doi: 10.1016/j.bcp.2012.07.006.
Recombinant activated factor VII and prothrombin complex concentrates have different effects on bleeding and arterial thrombosis in the haemodiluted rabbit. Le Saché F, Le Bonniec B, Gaussem P, Dizier B, Tagzirt M, Godier A, Emmerich J, Samama CM. Br J Anaesth. 2012 Apr;108(4):586-93. doi: 10.1093/bja/aer450
Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Godier A, Miclot A, Le Bonniec B, Durand M, Fischer AM, Emmerich J, Marchand-Leroux C, Lecompte T, Samama CM. Anesthesiology. 2012 Jan;116(1):94-102. doi: 10.1097/ALN.0b013e318238c036.
Recombinant activated factor VII does not reduce bleeding in rabbits treated with aspirin and clopidogrel. Hindy-François C, Bachelot-Loza C, Le Bonniec B, Grelac F, Dizier B, Godier A, Emmerich J, Gaussem P, Samama CM. Thromb Haemost. 2010 Oct;104(4):823-30. doi: 10.1160/TH10-01-0039.