Study of extracellular vesicles roles in the pathophysiology of thrombosis in paroxysmal nocturnal hemoglobinuria patients during eculizumab treatment: A pilot prospective longitudinal clinical study

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Résumé

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a disease characterized by complement-mediated hemolysis (Brodsky et al. Hematology, 2008). Complement can induce the production of extracellular vesicles (EV) (Burnouf et al. Transfus Apher Sci, 2015). These EV are cell-derived vesicles whose the size-range is around 50 and 1000nm. They can expose phosphatidylserine (PSanionic phospholipid) and tissue factor (TF), which explains their involvement in the coagulation cascade (Owens et al. Circ Res, 2011). The EV could have a role in the thrombus formation, the leading cause of death in PNH patients (Brodsky et al. Hematology, 2008; Simak et al. Br J Haematol, 2004; Hugel et al. Blood, 1999). Eculizumab, a human anti-C5 monoclonal antibody, used in the treatment of PNH seems to decrease the thrombosis frequency (relative reduction of 85%of thromboembolism event rate with the introduction of the treatment in the patients) (Hillmen et al. Blood, 2007; Kelly et al. Ther Clin Risk Manag, 2009; Weitz et al. Thromb Res, 2012; Al-Jafar et al. Hemato Rep, 2015). Aims: The general purpose of this project is a better understanding about the role of EVs in thrombosis in the context of PNH patients under eculizumab. We assessed the impact of eculizumab on the EV quantification and on their procoagulant activity, in order to check, if the antithrombotic activity of the eculizumab could be in part explained by its interaction with the EVs. Methods:We conducted a pilot prospective open label longitudinal clinical study with six PNH patients treated with eculizumab. The study was led according to the declaration of Helsinki and approved by the local Ethic Committee. Informed consent was obtained for each patient. The aim was to measure, by flow cytometry, the production of EVs in patient's platelet-free plasma (PFP) before the start of eculizumab, after 4 weeks and after 11 weeks of treatment. We also assessed the procoagulant activity in PFP by STAR-Procoag-PPL assay and by thrombin generation assay (TGA). A more sensitive version of TGA was also performed to study the procoagulant profile induced by the EVs (use of EVs pelleted from PFP). We used mixed-effects linear regression (R 3.1.2 with nlme package) with logarithmic transformation for flow cytometry results. We compared the results after 4 weeks or 11 weeks of treatment against the inclusion value. Results:We observed a decrease in platelet EVs with the eculizumab treatment (p
langue originaleAnglais
Pages (de - à)62
journalActa haematologica
Volume102
Etat de la publicationPublié - 2017

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