DR2, Inserm, Pharmacist, PhD
Phone: 01 53 73 94 26
The research program of Sophie Gandrille (DR2 Inserm, Pharmacien, PhD) is to design and prepare a “universal” antidote able to antagonize any molecule belonging to the family of direct anti-FXa anticoagulants, a family of new anticoagulants.
The direct oral anticoagulants (DOAC) are new anticoagulant molecules with promising properties, which the use is increasing year after year. They target a specific factor of coagulation, either thrombin (in the case of dabigatran) or Factor Xa (in the case of rivaroxaban, apixaban, betrixaban and edoxaban, grouped under the name of anti-FXa or DOAC). They are as effective as the conventional anticoagulants (heparins and derivatives, VKA), without having some of their disadvantages.
However, unlike conventional anticoagulants and dabigatran, there is currently no commercialy available drug (except in the USA) able to efficiently antagonize DOACs, while they are increasingly used and expose patients to a hemorrhagic risk, like heparines and AVK do.
This lack of available antidote can be a critical issue with dramatic consequences for a patient treated with one of these molecules in case of an accident or of an emergency procedure requiring an initially unplanned invasive action.
In addition, none of the hemostasis tests used in medical biology analysis laboratories is able to reliably detect or measure anti-FXa DOACs.
The aim of our research program is to address the two critical points of the new anticoagulants:
- by designing reliable, fast and simple tests to detect the presence and to measure DOACs
- by designing a “universal” antidote, thus able to antagonize any anti-FXa DOACs, and having imperatively two other properties: it should not induce a hemorrhagic risk in the patient receiving it, and should not disrupt the tests used to assess the patient’s hemostatic status.
The proof of concept that such an antidote is feasible has been obtained at our research Unit U1140. The product has been patented, but this product is too complex to obtain to be used as an in vivo antidote.
Sophie Gandrille (DR2 Inserm, Pharmacien, PhD) is more particularly involved in designing a simpler antidote, but nonetheless meeting the three conditions defined above. Bernard Le Bonniec (DR2 Inserm, PhD), Johan Abdoul (Pharmacien, Doctorant) and Georges El Jourdi (Pharmacien, Post-doctoral fellow) are also involved in this program.
This program uses techniques such as in silico modelisation, site-directed mutagenesis, protein expression and production by eukaryotic cells, protein purification methods, biochemical methods protein function analyses, in vivo studies.
Major publications 2020 / 2010
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. Epub 2018 Aug 2.
Low-Molecular-Weight Fucoidan Induces Endothelial Cell Migration via the PI3K/AKT Pathway and Modulates the Transcription of Genes Involved in Angiogenesis. Bouvard C, Galy-Fauroux I, Grelac F, Carpentier W, Lokajczyk A, Gandrille S, Colliec-Jouault S, Fischer AM, Helley D. Mar Drugs. 2015 Dec 18;13(12):7446-62. doi: 10.3390/md13127075.
Three-Dimensional Environment Sustains Hematopoietic Stem Cell Differentiation into Platelet-Producing Megakaryocytes. Pietrzyk-Nivau A, Poirault-Chassac S, Gandrille S, Derkaoui SM, Kauskot A, Letourneur D, Le Visage C, Baruch D. ,PLoS One. 2015 Aug 27;10(8):e0136652. doi: 10.1371/journal.pone.0136652.
[Clinical and biological features of patients with essential thrombocythaemia according to their mutational status JAK2 or CALR: Single-center study of 40 patients and review of the literature]. Ben Said M, Gandrille S, Fischer AM, Darnige L. Pathol Biol (Paris). 2015 Jun;63(3):117-21. doi: 10.1016/j.patbio.2015.01.001. Epub 2015 Apr 1. Review. French.
Assessment of the interplay between blood and skin vascular abnormalities in adult purpura fulminans. Lerolle N, Carlotti A, Melican K, Aubey F, Pierrot M, Diehl JL, Caille V, Hékimian G, Gandrille S, Mandet C, Bruneval P, Dumenil G, Borgel D. Am J Respir Crit Care Med. 2013 Sep 15;188(6):684-92. doi: 10.1164/rccm.201302-0228OC.
Endothelial colony-forming cells from patients with paroxysmal nocturnal haemoglobinuria are not PIGA mutated. Gandrille S, Peffault de Latour R, Levionnois E, Rodriguez-Otero P, Galy-Fauroux I, Zemori L, Abbes S, Petropoulou AD, Socié G, Fischer AM, Helley D. Br J Haematol. 2013 Apr;161(1):144-7. doi: 10.1111/bjh.12193.
Platelet dysfunction associated with the novel Trp29Cys thromboxane A₂ receptor variant. Mumford AD, Nisar S, Darnige L, Jones ML, Bachelot-Loza C, Gandrille S, Zinzindohoue F, Fischer AM, Mundell SJ, Gaussem P; UK GAPP Study Group. J Thromb Haemost. 2013 Mar;11(3):547-54. doi: 10.1111/jth.12117.
Elevated soluble endothelial cell protein C receptor (sEPCR) levels in women with preeclampsia: a marker of endothelial activation/damage? Saposnik B, Peynaud-Debayle E, Stepanian A, Baron G, Simansour M, Mandelbrot L, de Prost D, Gandrille S. Thromb Res. 2012 Feb;129(2):152-7. doi: 10.1016/j.thromres.2011.07.023.
Comparison of endothelial biomarkers according to reversibility of pulmonary hypertension secondary to congenital heart disease. Smadja DM, Gaussem P, Mauge L, Lacroix R, Gandrille S, Remones V, Peyrard S, Sabatier F, Bonnet D, Lévy M. Pediatr Cardiol. 2010 Jul;31(5):657-62. doi: 10.1007/s00246-010-9674-0.
Novel human pathological mutations. Gene symbol: PROS1. Disease: Protein S deficiency. Pintao M, Garcia AA, Borgel D, Alhenc-Gelas M, Spek CA, de Visser MC, Gandrille S, Reitsma PH. Hum Genet. 2010 Jan;127(1):121.
Membrane binding and anticoagulant properties of protein S natural variants. Baroni M, Pavani G, Marescotti D, Kaabache T, Borgel D, Gandrille S, Marchetti G, Legnani C, D’Angelo A, Pinotti M, Bernardi F. Thromb Res. 2010 Feb;125(2):e33-9. doi: 10.1016/j.thromres.2009.09.015.
Gross deletions/duplications in PROS1 are relatively common in point mutation-negative hereditary protein S deficiency. Pintao MC, Garcia AA, Borgel D, Alhenc-Gelas M, Spek CA, de Visser MC, Gandrille S, Reitsma PH. Hum Genet. 2009 Sep;126(3):449-56. doi: 10.1007/s00439-009-0687-9.
No influence of the VAMP8 rs1010 single nucleotide polymorphism on platelet functions in vitro. Gaussem P, Ishida BY, Fontana P, Pullinger CR, Khane JP, Aiach M, Bachelot-Loza C, Gandrille S. J Cell Mol Med. 2009 Mar;13(3):601-3. doi: 10.1111/j.1582-4934.2009.00500_2.x.