Agnès Veyradier

Paris Diderot University, Lutetia Parisorum, Île-de-France, France

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Publications (134)485.67 Total impact

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    ABSTRACT: Von Willebrand disease-type 2A (VWD-2A) and acquired von Willebrand syndrome (AVWS) due to aortic stenosis (AS) or left ventricular assist device (LVAD) are associated with an increased proteolysis of von Willebrand factor (VWF). Analysis of VWF multimeric profile is the most sensitive way to assess such increased VWF-proteolysis. However, several technical aspects hamper a large diffusion among routine diagnosis laboratories. This makes early diagnosis and early appropriate care of increased proteolysis challenging. In this context of unmet medical need, we developed a new ELISA aiming a quick, easy and reliable assessment of VWF-proteolysis. This ELISA was assessed successively in a LVAD-model, healthy subjects (n=39), acquired TTP-patients (n=4), VWD-patients (including VWD-2A(IIA), n=22; VWD-2B, n=26; VWD-2A(IIE), n=21; and VWD-1C, n=8) and in AVWS-patients (AS, n=9; LVAD, n=9; and MGUS, n=8). A standard of VWF-proteolysis was specifically developed. Extent of VWF-proteolysis was expressed as relative percentage and as VWF proteolysis/VWF:Ag ratio. A speed-dependent increase in VWF-proteolysis was assessed in the LVAD model whereas no proteolysis was observed in TTP-patients. In VWD-patients, VWF-proteolysis was significantly increased in VWD-2A(IIA) and VWD-2B and significantly decreased in VWD-2A(IIE) versus controls (p< 0.0001). In AVWS-patients, VWF-proteolysis was significantly increased in AS- and LVAD-patients compared to controls (p< 0.0001) and not detectable in MGUS-patients. A significant increase in VWF-proteolysis was detected as soon as three hours after LVAD implantation (p< 0.01). In conclusion, we describe a new ELISA allowing a rapid and accurate diagnosis of VWF-proteolysis validated in three different clinical situations. This assay represents a helpful alternative to electrophoresis-based assay in the diagnosis and management of AVWS with increased VWF-proteolysis.
    No preview · Article · Jan 2016 · Thrombosis and Haemostasis

  • No preview · Article · Dec 2015
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    ABSTRACT: L’activité de télémédecine d’un centre de référence maladies rares (CNR) est un des indicateurs de son expertise et de sa capacité de recours. Les microangiopathies thrombotiques (MAT) sont des maladies dont la faible incidence et le niveau d’expertise requis pour leur prise en charge a justifié la mise en place d’un centre de référence, le CNR-MAT. En effet, la gravité des MAT met en jeu le pronostic vital des malades à court terme ; cependant, prises en charge de manière optimale, ces maladies peuvent être de pronostic excellent. Il est donc nécessaire de savoir les reconnaître afin d’en établir le diagnostic rapidement et d’instituer un traitement adapté en urgence. Dans ce travail, nous décrivons l’activité de télémédecine du CNR-MAT depuis sa création. Sa particularité est que le niveau d’urgence requis par les maladies relevant de son expertise implique souvent une réponse en temps réel, ce qui a eu pour conséquence la nécessité de mettre en place une organisation spécifique fonctionnelle 24/7. Cette activité, amenée à se développer dans les années à venir, nécessite d’être évaluée, quantifiée avec précision et valorisée.
    No preview · Article · Dec 2015
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    ABSTRACT: Background: Daily therapeutic plasma exchange (TPE) and rituximab improved thrombotic thrombocytopenic (TTP) prognosis. In the more severe cases, salvage therapies including twice-daily TPE and/or cyclophosphamide may be proposed and require evaluation. Methods: TTP was defined as a thrombotic microangiopathy (TMA) with severe (< 10%) acquired ADAMTS13 deficiency. Among patients included in the French Reference Center for TMA registry, we considered those with a severe disease (i.e., unresponsive to daily TPE and rituximab) who received twice-daily TPE. Results: 19/289 (6.6%) patients with TTP were treated by twice-daily TPE between 2008 and 2014. Twice-daily TPE were associated with rituximab in 16 cases. The median duration of twice-daily TPE treatment was 3 days (2-22 days). In 6 patients (31.6%), additional treatments (mainly pulses of cyclophosphamide) were performed because of a persistently refractory disease (4 cases) or an exacerbation (2 cases), despite twice-daily TPE. Only one patient (5.3%) died. The other 18 achieved a durable complete remission 25.5 days (13-68 days) after the first TPE. The median follow-up was 14.4 months (7 days-45 months). Conclusions: Twice-daily TPE may be an efficient strategy in the more severe TTP patients with a short term life-threatening disease that could overcome their poor prognosis. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2015 · European Journal Of Haematology
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    ABSTRACT: Background: Patients with cancer are at high risk for venous thromboembolism (VTE). ADAMTS-13 regulates von Willebrand factor (VWF) activity, which plays a role in the development of cancer and in VTE. Objectives The aim of this study was to search for an association between the levels of VWF and ADAMTS-13 and VTE in patients with cancer and to compare current scoring systems for VTE prediction before and after addition of these parameters. Patients/methods: In a case-control study of 6 months follow-up of patients with recently diagnosed cancer, we compared 20 patients who developed VTE (cases) and 140 patients with cancer without VTE (controls), matched for sex, age, type and stage of cancer. We measured VWF, ADAMTS-13 (activity and antigen), P-selectin, D-Dimer and F1+2 levels at baseline, and calculated both the Khorana score and the Khorana score expanded after addition of P-selectin and D-Dimer levels. Results: VWF levels were significantly higher in cases when compared to controls (326 ± 185% versus 242 ± 158%) and correlated with advanced stage of cancer: localized 185 [142; 222], locally advanced 240 [146; 257], metastatic 267 [153; 324] (mean [interquartile range]). The addition of 2 biomarkers ADAMTS-13 activity and F1+2 levels to the Khorana score improved receiver operating curves CONCLUSIONS: von Willebrand factor and ADAMTS-13 are associated associated with the occurrence of VTE in patients with cancer. Moreover, addition of ADAMTS-13 and F1+2 levels to the Khorana score considerably increases the predictive value for VTE. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2015 · Journal of Thrombosis and Haemostasis
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    ABSTRACT: Autoimmune thrombotic thrombocytopenic purpura (TTP) can be associated with other autoimmune disorders, but their prevalence following autoimmune TTP remains unknown. To assess the prevalence of autoimmune disorders associated with TTP and to determine risk factors for and the time course of the development of an autoimmune disorder after a TTP episode, we performed a cross sectional study. Two-hundred sixty-one cases of autoimmune TTP were included in the French Reference Center registry between October, 2000 and May, 2009. Clinical and laboratory data available at time of TTP diagnosis were recovered. Each center was contacted to collect the more recent data and diagnosis criteria for autoimmunity. Fifty-six patients presented an autoimmune disorder in association with TTP, 9 years before TTP (median; min: 2 yr, max: 32 yr) (26 cases), at the time of TTP diagnosis (17 cases) or during follow-up (17 cases), up to 12 years after TTP diagnosis (mean, 22 mo). The most frequent autoimmune disorder reported was systemic lupus erythematosus (SLE) (26 cases) and Sjögren syndrome (8 cases). The presence of additional autoimmune disorders had no impact on outcomes of an acute TTP or the occurrence of relapse. Two factors evaluated at TTP diagnosis were significantly associated with the development of an autoimmune disorder during follow-up: the presence of antidouble stranded (ds)DNA antibodies (hazard ratio (HR): 4.98; 95% confidence interval (CI) [1.64-15.14]) and anti-SSA antibodies (HR: 9.98; 95% CI [3.59-27.76]). A follow-up across many years is necessary after an acute TTP, especially when anti-SSA or anti-dsDNA antibodies are present on TTP diagnosis, to detect autoimmune disorders early before immunologic events spread to prevent disabling complications.
    Preview · Article · Oct 2015 · Medicine
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    ABSTRACT: Reactive hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition related to a cytokine storm leading to multiorgan dysfunction. A better understanding of coagulation disorders, frequently reported in HLH patients, may improve outcomes. Critically ill HLH patients managed in a multidisciplinary national reference center were retrospectively included. Relationships between coagulation disorders, severe bleedings, and outcomes were assessed. One hundred and seventeen patients fulfilled the HLH 2004 criteria. The most common HLH etiology was hematologic conditions (73%), followed by infectious diseases (20%), systemic rheumatic diseases (5%), and undetermined HLH etiology (3%). All patients exerted thrombocytopenia. Coagulation disorders were diagnosed in 79 (68%) patients (61 had hypofibrinogenemia < 1.5 g/L, 51 had prothrombin time [PT] < 50%). The worst median value throughout ICU stay was 52% (38–65) for PT with a factor V level of 35% (27–43), 1.59 (1.30–2.09) for the activated partial thromboplastin time (APTT) ratio, and 2.33 g/L (1.13–3.86) for the fibrinogen level. Disseminated intravascular coagulation (DIC) was found in 50% of patients. Coagulation disorders were more frequent in immunocompromised patients, those with histological/cytological feature of hemophagocytosis, those with the highest ferritin concentrations, and in patients with HLH not related to infection. These patients were more prone to receive mechanical ventilation, vasopressors, or renal replacement therapy. Twenty-six (22%) patients presented severe bleeding complications, including 5 patients dying from hemorrhagic shock. Strikingly, the only coagulation parameter significantly associated with severe bleeding was low fibrinogen with a cutoff value of 2 g/L (P = 0.03). Overall, 33 (28%) patients died in the ICU and hospital mortality was 44%. Coagulation disorders were associated with higher mortality, especially fibrinogen < 2 g/L (P = 0.04) and PT value (P = 0.03). The occurrence of bleeding complications was not associated with higher risk of hospital death. Risk factors associated with mortality by multivariate analysis were fibrinogen level < 2 g/L (OR 2.42 [1.08–5.41]), SOFA score > 6 (OR 3.04 [1.32–6.98]), and age > 46 years (OR 2.26 [1.02–5.04]). Up to two-third of critically ill HLH patients present with coagulation disorders. Hypofibrinogenemia or DIC was found in half of the patients and low PT in 40%. These patients require more life support and have a higher mortality rate. Fibrinogen <2 g/L is associated with the occurrence of severe bleeding and mortality.
    Full-text · Article · Oct 2015 · Medicine
  • Eric Mariotte · Agnès Veyradier
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    ABSTRACT: Purpose of review: Thrombotic thrombocytopenic purpura (TTP) is a rare but challenging disease for intensive care specialists. Patients with acute TTP frequently require admission to the intensive care unit because of organ dysfunctions due to the disease or because of the risk of sudden aggravation at the onset of the disease. This review aims at describing recent evolutions in the diagnosis and for the management of TTP for the use of intensive care specialists. Recent findings: The use of A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS13) activity along with clinico-biological features to define TTP by most researchers' teams has led to easier interpretation of the literature. The main issues in TTP treatment in 2015 remain the indication and timing of introduction of anti-CD20 antibody rituximab for the treatment of inaugural TTP and the preemptive use of rituximab in asymptomatic patients with decreasing ADAMTS13 activity. Summary: The classification of thrombotic microangiopathies has evolved from a clinical to a pathophysiological definition. TTP is characterized by a severe ADAMTS13 deficiency that can be documented in vitro, along with anti-ADAMTS13 antibodies in most adult cases. Plasmapheresis and immunosuppressive therapy with steroids remain the standard of care for acute inaugural TTP. Anti-CD20 monoclonal antibody rituximab is safe and indicated in relapsing and/or refractory TTP. Its indication in inaugural TTP remains to be evaluated but is nevertheless recommended by experts. Novel therapies for TTP are still in preclinical phases.
    No preview · Article · Sep 2015 · Current opinion in critical care
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    ABSTRACT: Henoch-Schönlein purpura is a common form of immunological vasculitis in children. Hemophilia A is a genetic disorder, inherited in a X-linked recessive pattern, and characterized by spontaneous hemorrhage or prolonged bleeding due to factor VIII deficiency. The clinical signs depend on the severity of factor VIII deficiency. We herein report the case of a 4-year-old boy admitted to the emergency room for typical rheumatoid purpura, associated with a lengthening of aPTT, whose exploration had uncovered mild hemophilia A. Laboratory assays should explore lengthening of aPTT: firstly the presence of lupus anticoagulant without bleeding risk, in an inflammatory context; secondly a deficiency of VWF and one of the factors involved in the extrinsic coagulation pathway associated with bleeding risk.
    No preview · Article · Sep 2015 · Archives de Pédiatrie
  • Antoine Froissart · Agnès Veyradier · Miguel Hié · Ygal Benhamou · Paul Coppo
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    ABSTRACT: Despite a significant improvement of thrombotic thrombocytopenic purpura (TTP) prognosis since the use of plasma exchange, morbidity and mortality remained significant because of poor response to standard treatment or exacerbations and relapses. Rituximab, a chimeric monoclonal antibody directed against the B-lymphocyte CD20 antigen, has shown a particular interest in this indication. Recent studies also reported strong evidence for its efficiency in the prevention of relapses. This review addresses these recent progresses and still opened questions in this topic: should rituximab be proposed in all patients at the acute phase? Should all patients benefit from a preemptive treatment? Is the infectious risk acceptable in this context? Copyright © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
    No preview · Article · Aug 2015 · European Journal of Internal Medicine
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    ABSTRACT: Background Thrombotic thrombocytopenic Purpura (TTP) defined as ADAMTS-13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 domain 13) activity <10 % is a rare aetiology of thrombocytopenia during pregnancy, although the precise incidence is unknown. During pregnancy, the diagnosis of TTP is crucial as it has high feto-maternal morbidity-mortality and requires urgent plasma exchange. The purpose of this study was to assess the incidence of TTP retrospectively and to describe case presentations and follow-up. Methods A monocentric retrospective study (2008–2009) was conducted among pregnant women followed in a tertiary care obstetrical unit who experienced at least one episode of severe thrombocytopenia (platelets ≤75 G/L) during 2008 and 2009. In cases of uncertain aetiology of thrombocytopenia, ADAMTS-13 activity was assessed by the full length technique. Results Among 8,908 deliveries over the 2 year period, 79 women had a platelet count nadir ≤75 G/L. Eighteen had a known aetiology of thrombocytopenia and 11 were lost to follow-up. Among 50 remaining patients, ADAMTS-13 activity was undetectable (<5 %) in 4, consistent with the diagnosis of TTP. Platelet count spontaneously normalized in 3 patients after delivery. None presented focal cerebral involvement. Three of the four, who were primipara patients, had a sustained severe deficiency in the absence of anti-ADAMTS-13 antibodies, and ADAMTS-13 gene sequencing indicated a constitutive deficiency. The fourth, a multipara patient, had an acquired, auto-immune TTP. Placental pathology in the three primipara patients showed severe and non-specific ischemic lesions. Two patients lost their babies shortly after birth. In subsequent pregnancies in these two patients, prophylactic plasma infusion initiated early with increasing volume throughout pregnancy prevented TTP relapse, improved placental pathology, and led to normal delivery. Conclusions The prevalence of TTP among thrombocytopenic pregnant women is high, up to 5 % in a tertiary unit. Platelet count normalization after delivery does not eliminate TTP. Clinicians should be aware of TTP during pregnancy, and, even if assessed retrospectively, ADAMTS-13 assessment is of particular importance for identifying patients with congenital TTP. In these patients, preventive plasma infusion and/or exchange can dramatically improve foetal prognosis, resulting in successful childbirth.
    Full-text · Article · Jun 2015 · BMC Pregnancy and Childbirth

  • No preview · Article · Mar 2015 · American Journal of Hematology
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    ABSTRACT: Thrombotic microangiopathy (TMA) occurring after allogeneic hematopoietic stem cell transplantation (HSCT) has a devastating prognosis. Response rates to current therapies (mainly plasma exchange) are unsatisfactory. Thrombotic microangiopathy after allogeneic HSCT shares similarities with atypical hemolytic uremic syndrome (aHUS) in the underlying pathomechanisms. Eculizumab has been associated with impressive results in aHUS. We retrospectively analyzed 12 patients who received Eculizumab in France between 2010 and 2013 for severe post-HSCT TMA. All 12 patients had severe TMA with neurological and/or renal involvement. Fifty-eight percent were refractory to first-line plasma exchange. At the time of TMA diagnosis, infections were present in 50% of the patients and acute graft-versus-host disease in 33%. Patients were treated with Eculizumab according to the aHUS therapeutic scheme. With a median follow-up of 14 months, hematological response and overall survival were 50% and 33%, respectively. Active acute graft-versus-host disease at TMA diagnosis was the only factor associated with worse overall survival (P = 0.009). Response rate and overall survival after Eculizumab in our cohort compare favorably with previously published data in TMA after allogeneic HSCT. Prospective trials are warranted to confirm these results. Early initiation of Eculizumab may have a favorable effect on long-term renal function and further contribute to the prolongation of survival.
    No preview · Article · Feb 2015 · Transplantation
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    ABSTRACT: Drug-mediated thrombotic microangiopathy may cause life-threatening medical emergencies. Novel targeted therapies have dramatically changed the prognosis of a number of oncological diseases. Tyrosine kinase inhibitors of the Breakpoint Cluster Region-Abelson (BCR-ABL) oncoprotein are used in patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Imatinib mesylate, which was the first anti-BCR-ABL tyrosine kinase inhibitor, has demonstrated a high tolerance profile and efficacy in these patients for many years. Good results have also been observed in patients with gastrointestinal stromal tumors. In this study, we describe two patients with Philadelphia chromosome-positive hematological malignancies who presented with secondary thrombotic microangiopathy that was most likely linked to the use of imatinib. Other potential causes of thrombotic microangiopathy were discarded, and the predisposing role of some comorbidities and potential short or long-term drug-drug interactions was assessed. The clinical and biological data were more indicative of atypical secondary hemolytic uremic syndrome in one of the cases and of secondary thrombotic microangiopathy with renal and cardiac impairment in the other, which is also categorized as secondary hemolytic uremic syndrome. The outcome was favorable after imatinib discontinuation and the treatment of severe cardiac and renal failures. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
    No preview · Article · Jan 2015 · Journal of Oncology Pharmacy Practice
  • P. Coppo · J. Gay · A. Veyradier

    No preview · Article · Jan 2015 · Sang Thrombose Vaisseaux
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    ABSTRACT: Background Among patients with thrombotic microangiopathies, acute kidney injury (AKI) is the hallmark of hemolytic uremic syndrome (HUS) and is largely underestimated in patients with thrombotic thrombocytopenic purpura (TTP).Objective We sought to report AKI features and outcomes in patients with TTP.Methods We conducted a retrospective study of 92 patients with TTP assessed by low ADAMTS13 activity (< 10%) between 2001 and 2013. A logistic regression identified variables independently associated with AKI.ResultsAmong the 92 patients, 54 (58.7%) presented with AKI, including 25 (46.3%) with stage 3 AKI. Fourteen (27.4%) patients had a nephrotic-range proteinuria and 21 (45.6%) had hemoglobinuria. Hematuria and leucocyturia were detected in 19 (41.3%) and 16 patients (36.4%), respectively. Renal replacement therapy (RRT) was required in 14 patients (25.9%). Six months after TTP remission, RRT-free patients had median (IQR) MDRD of 93 ml/min/1.73m2 [68.8-110] and 3 patients required long-term dialysis. Mild or moderate chronic renal disease occurred in 23/54 (42.6%) AKI patients. By multivariate analysis, serum level of complement component 3 at admission was the only factor independantly associated with AKI (OR per 0.25 unit decrease of C3: 0.85, CI [1.82-8.33]; p=0.001)Conclusions In patients with TTP, AKI is present in more than half the patients, of whom half will have renal lasting effects. Further studies to better understand the pathophysiology of renal involvement in patients with TTP and to identify a subset of patients with TTP syndrome overlapping HUS are warranted.This article is protected by copyright. All rights reserved.
    Full-text · Article · Dec 2014 · Journal of Thrombosis and Haemostasis

  • No preview · Article · Dec 2014

  • No preview · Article · Dec 2014
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    ABSTRACT: Background Cardiac involvement is a major cause of mortality in patients with thrombotic thrombocytopenic purpura (TTP). However, diagnosis remains underestimated and delayed, owing to subclinical injuries. Cardiac troponin-I measurement (cTnI) on admission could improve the early diagnosis of cardiac involvement and have prognostic value.Objectives To assess the predictive value of cTnI in patients with TTP for death or refractoriness.Patients/Methods The study involved a prospective cohort of adult TTP patients with acquired severe ADAMTS-13 deficiency (< 10%) and included in the registry of the French Reference Center for Thrombotic Microangiopathies. Centralized cTnI measurements were performed on frozen serum on admission.ResultsBetween January 2003 and December 2011, 133 patients with TTP (mean age, 48 ± 17 years) had available cTnI measurements on admission. Thirty-two patients (24%) had clinical and/or electrocardiogram features. Nineteen (14.3%) had cardiac symptoms, mainly congestive heart failure and myocardial infarction. Electrocardiogram changes, mainly repolarization disorders, were present in 13 cases. An increased cTnI level (> 0.1 μg L−1) was present in 78 patients (59%), of whom 46 (59%) had no clinical cardiac involvement. The main outcomes were death (25%) and refractoriness (17%). Age (P = 0.02) and cTnI level (P = 0.002) showed the greatest impact on survival. A cTnI level of > 0.25 μg L−1 was the only independent factor in predicting death (odds ratio [OR] 2.87; 95% confidence interval [CI] 1.13-7.22; P = 0.024) and/or refractoriness (OR 3.03; 95% CI 1.27-7.3; P = 0.01).ConclusionsA CTnI level of > 0.25 μg L−1 at presentation in patients with TTP appears to be an independent factor associated with a three-fold increase in the risk of death or refractoriness. Therefore, cTnI level should be considered as a prognostic indicator in patients diagnosed with TTP.
    No preview · Article · Nov 2014 · Journal of Thrombosis and Haemostasis
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    G Sauvètre · S Grange · A Froissart · A Veyradier · P Coppo · Y Benhamou
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    ABSTRACT: Thrombotic microangiopathies (TMA) define a syndrome characterized by the association of microangiopathic haemolytic anaemia with schistocytes, peripheral thrombocytopenia, and organ injury of variable severity. Thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uremic syndrome (HUS) are the main forms of TMA. Recent advances in the pathophysiology of those two diseases, which include in HUS the identification of a deregulation of the alternative complement pathway, and in TTP a severe deficiency in ADAMTS-13, allowed to develop specific, pathophysiology-based therapies. Therefore, rituximab and eculizumab tends to be increasingly used, and there is an urgent need to define consensual modes of administration at the international level, as well as common definitions of response evaluation and follow-up explorations. Copyright © 2014 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.
    Full-text · Article · Oct 2014 · La Revue de Médecine Interne

Publication Stats

3k Citations
485.67 Total Impact Points

Institutions

  • 2015
    • Paris Diderot University
      Lutetia Parisorum, Île-de-France, France
  • 2008-2015
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2007-2015
    • Université Paris-Sud 11
      Orsay, Île-de-France, France
  • 2006-2015
    • Hôpital Antoine-Béclère – Hôpitaux universitaires Paris-Sud
      Clamart, Île-de-France, France
  • 2011
    • CHU de Lyon - Groupement Hospitalier Edouard Herriot
      Lyons, Rhône-Alpes, France
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2001
    • Unité Inserm U1077
      Caen, Lower Normandy, France