P de Moerloose

SRH Kurpfalzkrankenhaus Heidelberg, Heidelburg, Baden-Württemberg, Germany

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Publications (336)1466.11 Total impact

  • Haemophilia 12/2014; · 3.17 Impact Factor
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    ABSTRACT: Background The HemosIL AcuStar Antiphospholipid assay (Instrumentation Laboratory, Bedford, USA) is a fully automated assay using chemiluminescent technology for the detection of anticardiolipin and anti-β2GPI antibodies. This assay showed excellent agreement between results of different laboratories. The cut-off values to define positivity were calculated in 250 healthy blood bank donors but were associated with large confidence intervals (CI).Objective The objective of this study was to more precisely determine the cut-off values of the HemosIL AcuStar Antiphospholipid assay by increasing the number of healthy blood bank donors through a multicenter study and by applying a normalization procedure of the distribution of each antibody.Methods Five laboratories participated to this study allowing the inclusion of 626 samples. We used a Box-Cox power transformation method to normalize the distribution and calculate the 99th percentile and the corresponding 95%CI for each antibody.ResultsThe revised cut-off values were overall lower than those initially calculated with more stringent CI and yielded a 4.2%-increase of sensitivity with a 2.7% decrease of specificity regarding thrombotic events or obstetrical complications.Conclusions We provide refined cut-off values for the detection of anticardiolipin and anti-β2GPI antibodies with the HemosIL AcuStar Antiphospholipid assay that should be preferred for routine use.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 09/2014; · 6.08 Impact Factor
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    M. Shima, C. Hermans, P. Moerloose
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    ABSTRACT: The primary major issue in haemophilia treatment remains the development of inhibitors. Recently two novel bypassing products have been developed. First, a humanized bispecific antibody against FIXa and FX, termed hBS23, was produced utilizing these two molecules placed into a spatially appropriate position to mimic FVIIIa, and recently this mimetic activity and the pharmacokinetics of the original antibody were improved by engineering the charge properties of the variable region within the immunoglobulin. Using the new antibody, termed ACE910, a phase 1 study in 64 Japanese and Caucasian healthy adults was performed and data from this trial suggested that the product had medically acceptable safety and tolerability profiles. The other new bypassing agent is named MC710, and consists of a mixture of plasma-derived FVIIa and FX. Preclinical studies using in vitro and in vivo haemophilia B inhibitor monkey models indicated that the haemostatic effects of FVIIa and FX were enhanced by simultaneous administration. Results from phase I and II clinical studies suggested that MC710 had equal or greater pharmacokinetic (PK), pharmacodynamic (PD), efficacy and safety profiles than conventional bypassing agents in the treatment of joint bleeding in haemophilia patients with inhibitors. Another significant current issue in this context is the increased medical cost of conventional treatment due to the higher consumption of concentrates. Biosimilar products may offer advantages in these circumstances and may offer a less expensive alternative. Regulatory issues, however, together with acceptability of biosimilar materials and reimbursement policies as well as supply and demand incentives remain to be considered. Rare bleeding disorders (RBDs) have attracted less attention from the pharmaceutical industry than haemophilia or von Willebrand disease due to the limited number of patients involved. Many cases of this type have been treated, therefore, using fresh frozen plasma (FFP) or prothrombin complex concentrates (PCCs) which carry serious risks of infections, allergic reactions and fluid overload. Several specific plasma-derived or recombinant products including fibrinogen, FVIIa, FXI and FXIII have now become available, however, and a phase III clinical study of recombinant FXIIIa has recently been completed demonstrating safety and efficacy of substances of this nature.
    Haemophilia 05/2014; 20(s4). · 3.17 Impact Factor
  • Haemophilia 05/2014; · 3.17 Impact Factor
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    ABSTRACT: Background Obstetrical antiphospholipid syndrome (APS) is defined by pregnancy complications associated with antiphospholipid antibodies (aPL). The mechanisms of the pathogenic effects of aPL in pregnancy are poorly understood. Toll-like receptors (TLR) have been implicated previously in APS.Objectives The aims of our study were: 1) to determine aPL effects on trophoblastic cell fusion and differentiation, 2) to identify which TLR is involved in this process and 3) to evaluate the efficacy of hydroxychloroquine (HCQ) to counteract the effects of aPL.Methods BeWo cells are a model for trophoblast fusion and differentiation. Fusion index (FI) was assessed by immunocytochemistry; and biochemical differentiation by ELISA measuring β-human choronic gonadotropin (β-hCG) hormone secretion. We used three types of aPL to study their effect on cell fusion and differentiation: aPL derived from obstetrical APS patients, affinity purified and polyclonal rabbit anti-β2-glycoprotein-1 (anti-β2GP1) antibodies. Experiments on fusion were confirmed on primary cytotrophoblastic cells.ResultsAll types of aPL used decreased fusion index in BeWo and primary trophoblastic cells (respectively 64%, 52%, 41% for BeWo cells and 67%, 62% for primary cells) and anti-β2GP1 antibodies decreased hCG secretion in BeWo cells (41%). To block TLR4 antibodies or to abolish TLR4 cell surface expression restored fusion index in both cell types and hCG excretion in BeWo cells. HCQ treatment induced the same effect and decreased TLR4 mRNA (resp. 40%; 35%) and protein expressions (resp. 62%; 42%) in BeWo cells.Conclusion Anti-β2GP1 antibodies decrease trophoblastic differentiation via TLR4. This effect is restored by HCQ suggesting its therapeutic interest in APS pregnancies.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 03/2014; · 6.08 Impact Factor
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    ABSTRACT: The antiphospholipid antibody syndrome (APS) is an auto-immune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). We recently demonstrated that Toll-like receptor 2 (TLR2) and CD14 contribute to monocyte activation aPLA. To study the mechanisms of cell activation by aPLA leading to pro-coagulant and pro-inflammatory responses. For this study, we used purified antibodies from plasmas of ten different patients with APS and from healthy donors. We demonstrate that aPLA but not control IgG, colocalizes with TLR2 and TLR1 or TLR6 on human monocytes. Blocking antibodies to TLR2, TLR1 or TLR6, but not to TLR4 decreased TNF and Tissue Factor (TF) responses to aPLA. Pharmacological and siRNA approaches revealed the importance of the clathrin/dynamin-dependent endocytic pathway in cell activation by aPLA. In addition, soluble aPLA induced NF-kB activation, while bead-immobilized aPLA-beads, which cannot be internalized, were unable to activate NF-kB. Internalization of aPLA in monocytes and NF-kB activation was dependent on the presence of CD14. We show that TLR2 and its co-receptors, TLR1 and TLR6, contribute to the pathogenicity of aPLA, that aPLA are internalized via clathrin- and CD14-dependent endocytosis and that endocytosis is required for NF-kB activation. Our results contribute to a better understanding of the APS and provide a possible therapeutic approach. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 02/2014; · 6.08 Impact Factor
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    ABSTRACT: Introduction Causative mutations leading to congenital quantitative fibrinogen are frequently clustered in FGA encoding the fibrinogen Aα-chain. Mutations of FGB encoding the Bβ-chain are less common and of interest since the Bβ chain is considered the rate-limiting factor in the hepatic production of the fibrinogen hexamer. Method Four novel FGB mutations were identified in two afibrinogenemic (one new-born and one 30 years old male) and hypofibrinogenemic (a 49 years old female) patient, with heterogeneous thrombotic and bleeding phenotype. The human fibrinogen beta chain precursor protein sequence (P02675) was obtained from the UniProt database. The resulting models were analysed in SwissPdbViewer 4.1 and POV-Ray 3.7. Results The FGB c.895 T > C p.Y299H (numbering from the initiator Met) and the FGB c.1415G > T p.G472V were predicted to be deleterious by SIFT analysis. The first replaces an uncharged aromatic amino acid side chain by a positively charged side chain modifying the balance in the distribution of hydrophobic and hydrophilic of the 10 Å neighbourhood residues. The second replaces one non-charged aliphatic side chain by another without any changes for the 10 Å surrounding region. The FGB c.352C > T p.Q118X leads to a severe premature termination codon and the FGB intron 4: IVS4-1G > C (c719-1G > C) leads to skipping of exon 5 or usage of a cryptic acceptor site located upstream or downstream of the normal site. Conclusions The continuous characterization of novel molecular defects responsible for fibrinogen deficiency combined with modelling of mutant proteins will continue to provide a better comprehension of the complexity of fibrinogen synthesis and physiology.
    Thrombosis Research 01/2014; · 3.13 Impact Factor
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    ABSTRACT: Introduction Point of care devices (POCT) are used for coagulation evaluation in adults. Reduced blood volumes and the direct use of whole blood allow studies when venous puncture is difficult, such as in newborns. Elimination of sample transport is attractive for use in emergencies and intensive care. Objective To prospectively compare neonatal coagulation parameters measured by the GEM®PCL POCT versus a central laboratory. Materials and Methods Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT) were performed on whole cord blood (POCT) and plasma (central laboratory) collected from consecutive newborns at Geneva University Hospital. Agreement was assessed with a Bland & Altman plot and intra-class correlation coefficient (ICC) in 213 newborns cord blood; intra-assay variability (repeatability) was assessed using ICC and coefficient of variation (CV). Results 189 samples were available for the agreement analysis, 24 were excluded for technical problems. The 95% limits of agreements in the Bland & Altman plot ranged from -5.6 to 11.6 and from -39.6 to 11.6 seconds for the PT and aPTT, respectively. The ICC between the two methods was 0.28 (CI 95% 0.06 to 0.47) for PT and 0.20 (CI 95% -0.06 to 0.42) for aPTT. Repeatability (ICC) on the 43 eligible samples was 0.46 (CI 95% 0.19 to 0.67) for PT and 0.52 (CI 95% 0.26 to 0.71) for aPTT. The CV was 10.6% and 12% for PT and aPTT, respectively. Conclusions In newborn cord blood, PT and aPTT measurements with the GEM®PCL POCT had poor agreement with the central laboratory and poor repeatability.
    Thrombosis Research 01/2014; · 3.13 Impact Factor
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    ABSTRACT: Congenital dysfibrinogenemias are characterized by biosynthesis of a structurally abnormal fibrinogen molecule that exhibits reduced functional levels compared with the level of fibrinogen antigen. To date a large number of mutations have been identified in patients with dysfibrinogenemia. Mutations occurring at the thrombin cleavage site (Arg16-Gly17 in the mature alpha-chain) at the amino-terminal end of the fibrinogen alpha chain are a common cause of the disease. These mutations causing abnormal fibrin polymerization are associated with different phenotypes. Here, we report the identification of a novel heterozygous missense mutation of Glycine 17 (Gly17Asp) in a female patient with mild bleeding manifestations, and compare it with other previously reported mutations also resulting in abnormal knob A.
    Blood coagulation & fibrinolysis: an international journal in haemostasis and thrombosis 12/2013; · 1.25 Impact Factor
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    Karim J Brandt, Egbert K O Kruithof, Philippe de Moerloose
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    ABSTRACT: The antiphospholipid syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). The plasma protein β2-glycoprotein 1 (β2GP1) has been identified as a major target of aPLA associated with APS. Cell activation by aPLA appears to be a major pathogenic cause in the pathogenesis of APS. Receptors, co-receptors and accessory molecules are known to assist the pathogenic effects of aPLA. Members of the TLR family and the platelet receptor apolipoprotein E receptor 2' (apoER2'), a receptor belonging to the low-density lipoprotein receptor (LDL-R) family, as well as GPIbα, were identified as putative candidates for aPLA recognition. CD14, a co-receptor for TLR2 and TLR4, and annexin A2, a ubiquitous Ca2(+)-binding protein that is essential for actin-dependent vesicle transport, could serve as important accessory molecules in mediating the pathogenic effects of aPLA. Finally, complement activation has been reported in association with the pathogenicity of APS. The relative contribution of these different mechanisms in the pathogenesis of APS is controversial. Here, we review the various in vivo and in vitro models that have been used to investigate the pathogenic mechanisms of aPLA in APS.
    Thrombosis Research 08/2013; · 3.13 Impact Factor
  • C Hermans, P de Moerloose, G Dolan
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    ABSTRACT: Life expectancy for people with haemophilia (PWH) has improved and is now approaching that of the general population. The growing population of elderly PWH will therefore increasingly face the age-related morbidities such as cardiovascular diseases, malignant disease, liver disease, and bone and joint related diseases, as well as the lifestyle and psychosocial factors that accompany many of these conditions. For many PWH, frequent contact with haemophilia specialists within the comprehensive care centres supplants the relationship that individuals in the general population have with their general practitioners. As a result, there is a risk that elderly PWH may miss the chronic disease screening opportunities offered to the general population. This review focuses on the screening tests and examinations recommended for age-related comorbidities in the general population that may be applicable to the growing population of older people with haemophilia.
    Critical reviews in oncology/hematology 08/2013; · 5.27 Impact Factor
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    ABSTRACT: Lymphomas or hepatocarcinomas related to blood-borne transmitted diseases are well-known malignancies in persons with haemophilia (PWH). However, rising life expectancy has increased the number of PWH suffering from other malignancies. This study aimed to collect cancer occurrence data in PWH followed in five European haemophilia treatment centres (Brussels, Geneva, Marseille, Montpellier and Paris-Bicêtre) over the last 10 years and to analyse some particular features of cancer occurring in PWH. In total, 45 malignancies were diagnosed in 1067 PWH. The most common malignancies were hepatocellular carcinoma (12/45) and urogenital tract tumours (9/45). Bleeding at presentation or changes in bleeding pattern was indicative of cancer in four patients. Three patients with mild haemophilia developed anti-factor VIII inhibitors after intensive substitution therapy prior to surgery or invasive procedures. There was no bleeding associated with chemotherapy or radiotherapy. A few bleeding complications occurred following invasive (3/39) or surgical procedures (2/27) as a result of insufficient hemostatic coverage or in spite of adequate substitution. No bleeding was noted after liver or prostate biopsies. Following cancer diagnosis, five patients were switched from on-demand to prolonged prophylaxis substitution. In the majority of cases, the standard cancer treatment protocol was not modified on account of concomitant haemophilia. Thus, oncological treatments are not contraindicated and should not be withheld in PWH assuming that adequate haemostasis correction is undertaken. As shown by our study results, a change in bleeding pattern in adult PWH should raise suspicion of a malignancy. Intensive substitution must be considered a risk factor for inhibitor development.
    Haemophilia 08/2013; · 3.17 Impact Factor
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    ABSTRACT: Hereditary fibrinogen abnormalities comprise two classes of plasma fibrinogen defects: Type I, afibrinogenemia or hypofibrinogenemia, which has absent or low plasma fibrinogen antigen levels (quantitative fibrinogen deficiencies), and Type II, dysfibrinogenemia or hypodysfibrinogenemia, which shows normal or reduced antigen levels associated with disproportionately low functional activity (qualitative fibrinogen deficiencies). In afibrinogenemia and hypofibrinogenemia, most mutations of the FGA, FGB, or FGG fibrinogen encoding genes are null mutations. In some cases, missense or late truncating nonsense mutations allow synthesis of the corresponding fibrinogen chain but intracellular fibrinogen assembly and/or secretion are impaired. Afibrinogenemia is associated with mild-to-severe bleeding, whereas hypofibrinogenemia is most often asymptomatic. Thromboembolism may occur either spontaneously or in association with fibrinogen substitution therapy. Women with afibrinogenemia suffer from recurrent pregnancy loss but this can also occur in women with hypofibrinogenemia. Dysfibrinogenemia, caused mainly by missense mutations, is commonly associated with bleeding, thrombophilia, or both; however, most individuals are asymptomatic. Hypodysfibrinogenemia is a subcategory of this disorder. Even in specialized laboratories, the precise diagnosis of some fibrinogen disorders may be difficult. Determination of the molecular defects is important because it gives the possibility to confirm the diagnosis, to elaborate a diagnostic strategy, to distinguish in some cases that the patient is at risk of thrombosis rather than bleeding, and to enable prenatal diagnosis. However, genotype-phenotype correlations are not easy to establish. Replacement therapy is effective in treating bleeding episodes, but because the pharmacokinetics of fibrinogen after replacement therapy is highly variable among patients, it is important to adjust the treatment individually.
    Seminars in Thrombosis and Hemostasis 07/2013; · 4.22 Impact Factor
  • P Staritz, P de Moerloose, R Schutgens, G Dolan
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    ABSTRACT: There are no evidence-based guidelines for antithrombotic management in people with haemophilia (PWH) presenting with acute coronary syndrome (ACS). The aim of the study was to review the current European Society of Cardiology guidelines, and to consider how best they should be adapted for PWH. Structured communication techniques based on a Delphi-like methodology were used to achieve expert consensus on key aspects of clinical management. The main final statements are as follows: (i) ACS and myocardial revascularization should be managed promptly by a multidisciplinary team that includes a haemophilia expert, (ii) each comprehensive care centre for adult PWH should have a formal clinical referral pathway with a cardiology centre with an emergency unit and 24 h availability of percutaneous coronary intervention (PCI), (iii) PCI should be performed as soon as possible under adequate clotting factor protection, (iv) bare metal stents are preferred to drug-eluting stents, (v) anticoagulants should only be used in PWH after replacement therapy, (vi) minimum trough levels should not fall below 5-15% in PWH on dual antiplatelet therapy, (vii) the duration of dual antiplatelet therapy after ACS and PCI should be limited to a minimum, (viii) the use of GPIIb-IIIa inhibitors is not recommended in PWH other than in exceptional circumstances, (ix) the use of fibrinolysis may be justified in PWH when primary PCI (within 90 min) is not available ideally under adequate clotting factor management. It is hoped that the results of this initiative will help to guide optimal management of ACS in PWH.
    Haemophilia 05/2013; · 3.17 Impact Factor
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    ABSTRACT: Rare inherited bleeding disorders include fibrinogen disorders, and deficiencies of factors II (prothrombin), V, VII, X, XI, XIII, and combined V + VIII, and combined vitamin K-dependent factors, with general population prevalence rates between 1/500,000 and 1/2,000,000. These inherited disorders, transmitted as autosomal recessive traits, are characterized by a heterogeneous clinical presentation (asymptomatic, mild, moderate or severe bleeding tendency); this variability is more important for deficiencies with factor levels ranging from 5 to 50%. Individual bleeding risk assessment before an invasive procedure or during peri-partum period remains difficult, although an essential step to decide whether a substitution with clotting factor is necessary or not. Because there is a poor correlation between factor activity levels and the severity of bleeding symptoms, factor correction before an invasive procedure should not be based on factor level only, but physicians must also take into account the patient phenotype as well as the haemorrhagic risk of the procedure.
    Annales francaises d'anesthesie et de reanimation 03/2013; 32(3):198–205. · 0.77 Impact Factor
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    ABSTRACT: Rare inherited bleeding disorders include fibrinogen disorders, and deficiencies of factors II (prothrombin), V, VII, X, XI, XIII, and combined V+VIII, and combined vitamin K-dependent factors, with general population prevalence rates between 1/500,000 and 1/2,000,000. These inherited disorders, transmitted as autosomal recessive traits, are characterized by a heterogeneous clinical presentation (asymptomatic, mild, moderate or severe bleeding tendency); this variability is more important for deficiencies with factor levels ranging from 5 to 50%. Individual bleeding risk assessment before an invasive procedure or during peri-partum period remains difficult, although an essential step to decide whether a substitution with clotting factor is necessary or not. Because there is a poor correlation between factor activity levels and the severity of bleeding symptoms, factor correction before an invasive procedure should not be based on factor level only, but physicians must also take into account the patient phenotype as well as the haemorrhagic risk of the procedure.
    Annales francaises d'anesthesie et de reanimation 02/2013; · 0.77 Impact Factor
  • A Casini, F Boehlen, T Lecompte, P de Moerloose
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    ABSTRACT: Polycythaemia vera, essential thrombocythemia and primary myelofibrosis are stem cell-derived clonal haemopathies classified in the group of myeloproliferative neoplasms. Their clinical course may be complicated by both arterial and venous (sometimes in unusual sites) thrombotic events. Although general risk factors contribute to the prevalence of thrombotic events in this population, some other risk factors are specifically associated with the myeloproliferative neoplasms. The treatment options are aspirin, anticoagulation, cytoreduction and phlebotomies.
    Revue médicale suisse 02/2013; 9(372):315-8, 320.
  • M Righini, L Mazzolai, P de Moerloose
    Revue médicale suisse 02/2013; 9(372):299-300.
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    P de Moerloose, A Casini, F Boehlen, P Fontana
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    ABSTRACT: Physicians are confronted with many new antithrombotic drugs, either antiplatelet agents or new oral anticoagulants (NOAC). Targets of NOAC are specific (either anti-IIa or antiXa) and clinical studies have shown that NOAC are as efficacious and as safe as "old" anticoagulants (heparin, low molecular weight heparin, vitamin K antagonists); moreover they present some advantages. Indeed, NOAC have a wide therapeutic window and do not require laboratory monitoring. Therefore, it is very tempting to prescribe them on a large scale basis in patients at risk or having thromboembolic diseases. However, things are not so simple in the day-to-day practice and this review aims at answering in a brief and simplified manner to some questions.
    Revue médicale suisse 01/2013; 9(369):104-7.
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    ABSTRACT: Less than 60 cases of acquired factor (F)XIII deficiencies have been reported, most having distinct clinical features. To illustrate the therapeutic challenges of acquired FXIII inhibitors, we report a case of a 65-year-old patient with no previous bleeding history who suddenly developed massive haemorrhages associated to a strong and isolated FXIII inhibitor. No underlying disorder has been detected till now after three years of follow-up. Despite aggressive treatment with prednisone, rituximab, cyclophosphamide, immunoglobulin, immunoadsorption and immune tolerance his inhibitor is still present, although at low titre and with a clinical benefit since the patient has no more bleed since more than one year. Moreover the patient had a venous thromboembolic complication. After a review of the management of acquired FXIII deficiency patients and based on the management of acquired haemophilia we discuss a possible strategy for such difficult cases.
    Thrombosis and Haemostasis 01/2013; 109(3). · 5.76 Impact Factor

Publication Stats

5k Citations
1,466.11 Total Impact Points

Institutions

  • 2013
    • SRH Kurpfalzkrankenhaus Heidelberg
      Heidelburg, Baden-Württemberg, Germany
  • 2009–2013
    • Cliniques Universitaires Saint-Luc
      • Division of Hematology
      Bruxelles, Brussels Capital Region, Belgium
    • Jagiellonian University
      • Department of Hematology
      Kraków, Lesser Poland Voivodeship, Poland
  • 2006–2013
    • Hôpitaux Universitaires de Genève
      • • Service d'anesthésiologie
      • • Service d'angiologie et d'hémostase
      • • Service de cardiologie
      Genève, GE, Switzerland
    • University Medical Center – Rizk Hospital
      Beyrouth, Beyrouth, Lebanon
  • 1989–2013
    • University of Geneva
      • • Division of Angiology and Hemostasis
      • • Division of Haematology
      • • Department of Genetic Medicine and Development (GEDEV)
      • • Department of Internal Medicine
      • • School of Clinical Medicine
      Versoix, GE, Switzerland
  • 2008–2009
    • Centre Hospitalier de Beziers
      Béziers, Languedoc-Roussillon, France
    • Universität Basel
      Bâle, Basel-City, Switzerland
  • 2005
    • Swiss Institute of Bioinformatics
      Lausanne, Vaud, Switzerland
    • The Ottawa Hospital
      Ottawa, Ontario, Canada
  • 2002–2004
    • Centre Hospitalier Universitaire de Montpellier
      Montpelhièr, Languedoc-Roussillon, France
  • 2001
    • Hôpital Européen Georges-Pompidou (Hôpitaux Universitaires Paris-Ouest)
      Lutetia Parisorum, Île-de-France, France
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
  • 1994
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 1993
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland