C Negrier

Hospices Civils de Lyon, Lyons, Rhône-Alpes, France

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Publications (177)734.11 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: This study aims to determine the way to predict the haemophilia A (HA) carrier status and the potential severity in six females with low FVIII:C levels (<0.50 IU mL(-1) ), F8 gene variations and without family history of HA. Except p.Ser577Tyr, F8 gene variations that we reported have never been described (p.Leu107His, p.Pro521Leu, p.Val682Leu, p.Leu2032Pro, p.Ala315dup). Prediction of their potential causal impact was studied by two strategies: bioinformatics approaches and site-directed mutagenesis followed by FVIII cellular expression into COS-1 cell. FVIII clotting assay (FVIII:C) and antigen (FVIII:Ag) were assayed in vitro. In silico analysis showed the probably damaging effect of all substitutions and the full conservation of the residues across mammalian species, except for p.Leu2032Pro. The in vitro variant expression model showed abnormal intra and/or extracellular FVIII:C and FVIII:Ag levels for five mutations, which suggest their causality in HA and provide informations about the involved mechanism. We suspect a defect in synthesis and secretion for p.Leu107His, p.Ala315dup and p.Pro521Leu. The mutation p.Val682Leu only affects the FVIII function while p.Ser577Tyr alters function and synthesis. The variant p.Leu2032Pro is probably a polymorphism because no alteration of the FVIII protein expression was observed in vitro. In vitro results suggest that mutations p.Ser577Tyr and p.Ala315dup could led to a severe HA in men. This study demonstrates the ability of this in vitro cellular expression model to contribute to the diagnosis strategy for female suspected of being HA carrier, without HA family history and with a novel F8 gene variation and to provide new criteria for the genetic counselling. © 2015 John Wiley & Sons Ltd.
    Haemophilia 02/2015; DOI:10.1111/hae.12651 · 2.47 Impact Factor
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    ABSTRACT: We describe a family with an autosomal dominant disorder characterized by severe trauma- and surgery-related bleeding. The proband, who experienced life-threatening bleeding during a routine operation, had normal clotting times, but markedly reduced prothrombin consumption. Plasma levels of all coagulation factors and of the main coagulation inhibitors were normal. Thrombin generation at low triggers was severely impaired and mixing experiments suggested the presence of a coagulation inhibitor. Using whole exome sequencing, the underlying genetic defect was identified as the THBD c.1611C>A mutation (p.Cys537Stop), predicting a truncated form of thrombomodulin that is shed from the vascular endothelium. The patient had decreased expression of endothelium-bound thrombomodulin, but extremely elevated levels of soluble thrombomodulin in plasma, impairing the propagation phase of coagulation via rapid activation of protein C and consequent inactivation of FVa and FVIIIa. The same thrombomodulin mutation has been recently described in an unrelated British family with strikingly similar features. Copyright © 2015 American Society of Hematology.
    Blood 01/2015; DOI:10.1182/blood-2014-10-604553 · 9.78 Impact Factor
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    ABSTRACT: Inhibitor development is the most serious and challenging complication in the treatment of severe haemophilia A. Up to 38% of such patients develop inhibitors with current recombinant factor VIII (rFVIII) products produced in hamster cell lines. Human-cl rhFVIII is a new generation fully sulfated B-domain-deleted FVIII coagulant glycoprotein, which is generated from a human cell line. Thus, there are no non-human epitopes which would be potentially immunogenic. This molecule has significantly higher VWF-binding affinity compared with existing full-length rFVIII produced in hamster cell lines. The development aim of Human-cl rhFVIII is to address the challenges of FVIII inhibitors and frequent infusions during prophylaxis. Human-cl rhFVIII's mean half-life is very comparable to some of the newer products which involve modification of the FVIII molecule to extend the circulating half-life. There are promising data concerning the use of a personalized prophylaxis regimen with Human-cl rhFVIII. Preliminary data indicate a median dosing interval of 3.5 days with 66.7% of the patients on a twice per week or fewer infusions schedule combined with a low bleeding rate and no increased FVIII consumption when compared to standard prophylaxis. No product-specific laboratory assay is required to monitor the coagulation activity for Human-cl rhFVIII. The results of registration clinical trials with Human-cl rhFVIII as well as the ongoing studies in previously untreated patients (NuProtect) and personalized prophylaxis study in previously treated patients (NuPreviq), will be discussed. The manufacturer has received marketing authorization for Human-cl rhFVIII in Europe and Canada under the name Nuwiq(®) and plans to launch it in the USA and globally in 2015. © 2014 John Wiley & Sons Ltd.
    Haemophilia 01/2015; 21 Suppl 1:1-12. DOI:10.1111/hae.12582 · 2.47 Impact Factor
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    ABSTRACT: Melanoma differentiation associated gene-9 (MDA-9), also known as syntenin, is a novel gene that positively regulates cancer cell motility, invasion and metastasis through distinct biochemical and signaling pathways, but how MDA-9/syntenin is regulated in response to signals with the extracellular environment and promotes tumor progression is unclear. We now demonstrate that MDA-9/syntenin is dramatically up-regulated by the combination of rFVIIa and factor F(X) in malignant melanoma. Induction of MDA-9/syntenin in melanoma was found to occur in a thrombin-independent signaling pathway and involves the PAR-1/c-Src/Rho GTPases Rac1 and Cdc42/c-Jun N-terminal kinase axis resulting in the activation of paxillin, NF-κB and matrix metalloproteinase-2 (MMP-2). MDA-9/syntenin physically interacts with c-Src through its PDZ binding motif following stimulation of melanoma cells with rFVIIa and FX. We also document that induction of this signaling pathway is required for TF/FVIIa/Xa-induced cell migration, invasion and metastasis by melanoma cells. The present finding uncover a novel role of MDA-9/syntenin as an important TF/FVIIa/Xa/PAR-1-regulated gene that initiates a signaling circuit essential for cell motility and invasion of metastatic melanoma. In these contexts, targeting TF-FVIIa-Xa and its relevant downstream targets such as MDA-9/syntenin, may represent a novel therapeutic strategy to control the evolution of neoplastic cells. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 12/2014; DOI:10.1074/jbc.M114.606913 · 4.60 Impact Factor
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    ABSTRACT: This multinational, randomized, single-blind trial (NCT01333111 [www.clinicaltrials.gov]) investigated safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in 74 previously treated hemophilia B patients (FIX activity ≤2 IU/dL). Patients received prophylaxis for 52 weeks, randomized to 10 IU/kg or 40 IU/kg once weekly, or on-demand treatment for 28 weeks. No patients developed inhibitors and no safety concerns were identified. Three-hundred and forty-five bleeding episodes were treated with an estimated success rate of 92.2%. The median annualized bleeding rates (ABRs) were 1.04 in the 40 IU/kg prophylaxis arm, 2.93 in the 10 IU/kg prophylaxis arm, and 15.58 in the on-demand treatment arm. In the 40 IU/kg arm, 10 of 15 patients (66.7%) experienced no bleeding episodes into target joints, compared with 1 of 13 patients (7.7%) in the 10 IU/kg arm. Health-related quality of life (HR-QoL) assessed with the EQ-5D VAS score improved from median 75 to 90 in the 40 IU/kg prophylaxis arm. Nonacog beta pegol was well tolerated and efficacious for treatment of bleeding episodes, and associated with low ABRs in patients on prophylaxis. Once-weekly prophylaxis with 40 IU/kg resolved target joint bleeds in 66.7% of the affected patients and improved HR-QoL.
    Blood 09/2014; 124(26). DOI:10.1182/blood-2014-05-573055 · 9.78 Impact Factor
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    ABSTRACT: In the phase 3 B-LONG [Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Subjects with Haemophilia B] study, rFIXFc dosed every 1–2 weeks was safe and efficacious in previously treated subjects with haemophilia B. To date, there are no evaluations of transitioning from conventional to long-acting factor IX (FIX) prophylaxis. This post-hoc analysis of B-LONG subjects compared prophylaxis with other FIX products and rFIXFc. Pre- and on-study data were analysed to assess dosing regimen, weekly FIX consumption and annualized bleeding rates (ABRs). Population pharmacokinetics models were used to generate FIX activity profiles with rFIXFc and recombinant FIX prophylaxis. Thirty-nine subjects, previously treated prophylactically, were evaluated. Prior to study, most subjects (69·2%) received twice-weekly FIX infusions; on study, subjects infused rFIXFc once every 1–2 weeks with c. 30–50% reductions in weekly consumption. On-study estimated mean ABRs were lower than pre-study estimated mean ABRs. Models predicted that rFIXFc administered 50 iu/kg weekly and 100 iu/kg every 10 d would maintain steady-state FIX trough levels ≥1 iu/dl in 95·4% and 89·2% of subjects, respectively. These results indicate that patients receiving rFIXFc prophylaxis can markedly reduce infusion frequency and FIX consumption, have a greater likelihood of maintaining FIX activity >1 iu/dl and experience fewer bleeding episodes compared with prior FIX prophylaxis.
    British Journal of Haematology 09/2014; DOI:10.1111/bjh.13109 · 4.94 Impact Factor
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    ABSTRACT: IntroductionRecently, rapid immunoassays have been developed to allow the detection of antibodies anti-PF4/heparin. In this prospective study, we evaluated the performances of a automatized immunoassay (HemosIL HIT-Ab) in comparison with an ELISA (Zymutest HIA IgG) used for the diagnosis of heparin-induced thrombocytopenia (HIT) in association with the 4T's score.Methods According to the 4T's score, samples with score ≤3 had no further analysis. Two immunological assays Zymutest HIA IgG and HemosIL HIT-Ab were performed in samples with score ≥4. In patients with at least one positive immunological assay or two negative immunological assays but with high-pretest probability (4T's score ≥6), HIT was screened by one functional assay using washed platelets.ResultsThe sensitivities of both assays were excellent and comparable (100%). The specificity was 92.3% for ELISA and 91.2% for HemosIL HIT-Ab. The analysis of the operating characteristics showed that both assays have almost identical ROCs (AUROC, 0.9951 and 0.9853, respectively, for ELISA and HemosIL HIT-Ab) and the calculating of the κ coefficient revealed a good agreement (0.67).Conclusion Performance characteristics of the HemosIL HIT-Ab are comparable to the Zymutest HIA IgG. The HemosIL HIT-Ab can be used in association with the 4T's score to rule out HIT.
    International journal of laboratory hematology 07/2014; 37(2). DOI:10.1111/ijlh.12275 · 1.30 Impact Factor
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    ABSTRACT: An ideal medical biology internal quality control (IQC) plan should both monitor the laboratory methods efficiently and implement the relevant clinical-biological specifications. However, many laboratories continue to use the 12s quality control rule without considering the high risk of false rejection and without considering the relationship of analytical performance to quality requirements. Alternatively, one can move to the Bayesian arena, enabling probabilistic quantification of the information coming in, on a daily basis from the laboratory's IQC tests, and taking into account the laboratory's medical and economic contexts. Using the example of one-stage clotting factor VIII assay, the present study compares frequentist (12s quality control rule) and Bayesian IQC management with respect to prescriber requirements, process start-up phase issues, and abnormal scenarios in IQC results. To achieve comparable confidence, the traditional 12s quality control rule requires more data than the Bayesian approach in order to detect an increase in the random or systematic error of the method. Moreover, the Bayesian IQC management approach explicitly implements respect of prescriber requirements in terms of calculating the probability that the variable in question lies in a given predefined interval: for example, the factor VIII concentration required after knee surgery in a hemophilia patient.
    Blood coagulation & fibrinolysis: an international journal in haemostasis and thrombosis 03/2014; 25(6). DOI:10.1097/MBC.0000000000000105 · 1.25 Impact Factor
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    ABSTRACT: Thirty per cent of patients with mild haemophilia A (MHA) present markedly different FVIII: C level when assayed by one-stage clotting and two-stage chromogenic assays. It is, therefore, a real clinical challenge to predict the individual bleeding risk of these patients. The aim of the present work was to study the relationship between the bleeding tendency of these patients with the results of a panel of phenotypic and genotypic tools. Thirty-six patients with MHA were included in this multicentre prospective clinical study. The severity of bleeding symptoms was evaluated using the ISTH/SSC score. FVIII:C levels were measured using an activated partial thromboplastin time-based one-stage FVIII assay (FVIII: C1) and three commercial chromogenic kits (FVIII:CR). FVIII antigen levels, thrombin generation measurement and FVIII gene mutation analysis were also performed. Our results showed that a one-stage FVIII: C assay cannot rule out the diagnosis of MHA, a combined use of FVIII:C1 with a FVIII:CR is suitable for detecting MHA. We observed that FVIII:CR results better reflected the clinical bleeding tendency of patients compared to FVIII:C1. We also observed a relationship between thrombin generation (TG) capacity and FVIII:CR of these patients. FVIII gene mutation analysis showed mutations previously reported in MHA patients with discrepant FVIII:C measurements, but with no predictive value of the individual bleeding phenotype of patients. Overall, we observed a relationship between chromogenic FVIII:C results, TG assay and bleeding tendency of patients with discrepant FVIII:C measurements, while FVIII:C1 was not well correlated with clinical bleeding phenotype in this particular population.
    Haemophilia 02/2014; DOI:10.1111/hae.12381 · 2.47 Impact Factor
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    ABSTRACT: The development of inhibitors and the need for frequent venous access for FVIII injection are major challenges in current haemophilia treatment. Presently available recombinant FVIII (rFVIII) products produced in hamster cell lines are associated with inhibitor formation in up to 32% of previously untreated patients. The new human cell line-derived recombinant human FVIII (Human-cl rhFVIII) protein is the first native, unmodified truly human rFVIII product produced in a human cell line without additive animal proteins. The aim of using a human cell line for the production of rFVIII is the avoidance of non-human epitopes on rFVIII, thereby potentially reducing the rate of inhibitor development, avoiding allergic reactions and allowing personalized prophylaxis with the chance of fewer infusions. Studies to date show that prophylaxis with Human-cl rhFVIII prevents 96% of bleeding events in adults with severe haemophilia A when compared to on-demand treatment. Available pharmacokinetic data with a mean half-life of 17.1 h allow personalized prophylaxis with the chance of fewer infusions. Studies in previously treated children and adults indicate that Human-cl rhFVIII is efficacious and safe in the prevention and treatment of bleeding episodes and that none of the treated patients developed inhibitors or allergic reactions thus far.
    Haemophilia 01/2014; 20 Suppl 1:1-9. DOI:10.1111/hae.12322 · 2.47 Impact Factor
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    ABSTRACT: Haemophilia A (HA) is an X-linked recessive bleeding disorder, caused by a wide variety of mutations in the factor VIII (F8) gene, leading to deficiency in the activity of coagulation FVIII. These mutations can affect all the F8 exons from the initiation codon to the termination codon, however, only few molecular changes in the promoter region of the F8 gene were reported so far. Here, we describe six nucleotide variations (c.-51G>A, c.-218T>C, c.-219C>T, c.-219delC, c.-221T>A and c.-664G>A) detected in the F8 promoter and their correlation with clinical phenotype of the patients. Potential role of these mutations in HA was also assessed. Causality was demonstrated with transient transfection experiments using luciferase reporter gene plasmids and computational analysis. Two molecular changes (c.-51G>A and c.-664G>A) did not seem to affect the promoter function of the F8 gene whereas c.-218T>C, c.-219C>T, c.-219delC, c.-221T>A mutations had an impact on the F8 promoter function and were responsible for HA. Furthermore, these mutations were associated with resistance to 1-deamino-8-d-argininevasopressin (desmopressin) therapy when they were causative. When molecular variation was detected in F8 promoter, we propose to use prediction software and to verify predictions by reporter gene analysis. If the mutation is causative, it will be probably associated with a lack of therapeutic response to desmopressin and this clinical implication should be considered by clinicians.
    Haemophilia 12/2013; DOI:10.1111/hae.12346 · 2.47 Impact Factor
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    ABSTRACT: Standardization of pre-analytical conditions is the obligatory step for all potential diagnostic tests. Spatial clot growth (Thrombodynamics) is a new global hemostasis assay that considers spatial organization of coagulation. The principal parameter is rate of fibrin clot growth from the tissue-factor coated surface. In this work we studied the pre-analytical variables of Thrombodynamics assay that include conditions of blood collection, sample preparation and storage. Blood of apparently healthy volunteers was used. Eight types of citrate blood collection tubes were tested, centrifugation conditions for plasma preparation were evaluated and impact of plasma freezing/thawing was tested. Among the blood collection tubes tested, BD Vacutainer glass tubes showed a significantly higher clot growth rate compared to plastic tubes. There was no difference between 3.2% and 3.8% of sodium citrate. For plasma preparation, a single 15min centrifugation at 1 600g shows significantly increased clot growth rate compared to plasma obtained by two sequential centrifugations (15min 1 600g, 5min 10 000g). There was no significant difference between 1 600g and 2 100g if the second centrifugation was performed. For the second centrifugation there was no difference between 20min at 1 600g and 5min at 10 000g. Frozen-thawed plasma showed increased clot growth rate compared to fresh plasma. The data represent the necessary steps for the standardization of Thrombodynamics assay and for the formulation of the operating guide.
    Thrombosis Research 12/2013; DOI:10.1016/j.thromres.2013.12.014 · 2.43 Impact Factor
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    ABSTRACT: This study investigated the underlying mechanism of 4-hydroxy-3-methoxycinnamic acid (ACCA), on the growth of breast cancer cells and normal immortal epithelial cells, and compared their cytotoxic effects responses. Treatment of breast cancer cells (MCF-7, T47D, and MDA-231) with ACCA resulted in dose- and time-dependent decrease of cell proliferation, viability in colony formation assay, and programmed cell death (apoptosis) with minimal effects on non-tumoral cells. The ability of ACCA to suppress growth in cancer cells not expressing or containing defects in p53 gene indicates a lack of involvement of this critical tumor suppressor element in mediating ACCA-induced growth inhibition. Induction of apoptosis correlated with an increase in Bax protein, an established inducer of programmed cell death, and the ratio of Bax to Bcl-2, an established inhibitor of apoptosis. We also documented the ability of ACCA to inhibit the migration and invasion of MDA-231 cells with ACCA in vitro. Additionally, tumor growth of MDA-231 breast cancer cells in vivo was dramatically affected with ACCA. On the basis of its selective anticancer inhibitory activity on tumor cells, ACCA may represent a promising therapeutic drug that should be further evaluated as a chemotherapeutic agent for human breast cancer.
    PLoS ONE 09/2013; 8(9):e72953. DOI:10.1371/journal.pone.0072953 · 3.53 Impact Factor
  • Lutfi Suleiman, Claude Négrier, Habib Boukerche
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    ABSTRACT: Since its discovery in 1970, protein S (PS) has emerged as a key vitamin K-dependent natural anticoagulant protein at the crossroads of multiple biological processes, including coagulation, apoptosis, atherosclerosis, angiogenesis/vasculogenesis, and cancer progression. Following the binding to a unique family of protein tyrosine kinase receptors referred to as Tyro-3, Axl and Mer (TAM) receptors, PS can lead to regulation of coagulation, phagocytosis of apoptotic cells, cell survival, activation of innate immunity, vessel integrity and angiogenesis, and local invasion and metastasis. Because of these dynamics and multiple functions of PS, which are largely lost following invalidation of the mouse PROS1 gene, this molecule is currently intensively studied in biomedical research. The purpose of this review is to provide a brief chronicle of the discovery and current understanding of the mechanisms of PS signaling, and how PS and their signaling partners regulate various cellular functions, with a particular focus on TAM receptors.
    Critical reviews in oncology/hematology 08/2013; DOI:10.1016/j.critrevonc.2013.07.004 · 5.27 Impact Factor
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    ABSTRACT: Patients with haemophilia A and inhibitors are at high risk for severe bleeding, progression of joint disease and deterioration of health-related quality of life (HRQoL). To determine the impact of prophylaxis with an activated prothrombin complex concentrate (aPCC) on HRQoL, HRQoL was assessed using the Short-Form (SF)-36 Health Survey and the EQ-5D questionnaire in subjects ≥14 years participating in a prospective, randomized, crossover study comparing 6 months of aPCC prophylaxis with 6 months of on-demand therapy. Eighteen of 19 patients completed the survey or questionnaire before and after the on-demand therapy and prophylaxis periods. A general trend towards improved HRQoL after prophylaxis was observed for the 18 evaluable patients in all SF-36 dimensions except for vitality/energy and physical functioning. After prophylaxis, 'good responders,' defined as patients experiencing ≥50% reduction in bleeding, exhibited statistically and clinically significant differences in the physical component score (P = 0.021), role - physical (P = 0.042), bodily pain (P = 0.015), and social functioning (P = 0.036). Similarly, the EQ-5D health profile showed a trend towards improvement after prophylaxis in all evaluable patients. Among the good responders, improvements did not differ from those observed after on-demand treatment. EQ visual analogue scale values were slightly improved following prophylaxis for all evaluable patients and the EQ-5D utility index improved in the good responders only. During prophylaxis, patients missed significantly fewer days from school or work because of bleeding than during on-demand treatment (P = 0.01). In conclusion, by significantly reducing bleeding frequency in good responders, aPCC prophylaxis improved HRQoL compared with on-demand treatment.
    Haemophilia 06/2013; 19(5). DOI:10.1111/hae.12178 · 2.47 Impact Factor
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    ABSTRACT: OBJECTIVE: Bleeding is the main complication of warfarin therapy, even patients with an INR in the target range can suffer bleeding, suggesting that INR does not perfectly reflect the therapeutic effect of warfarin. We hypothesized the INR might underestimate the level of anticoagulation in a subject with a lower factor IX (FIX) level than average. METHODS & RESULTS: We modeled warfarin anticoagulation in our in vitro thrombin generation (TG) model by adjusting the levels of vitamin K-dependent factors to those of patients with an INR of 2-3. Variation in FIX had a marked effect on TG but had no effect on the PT-INR. A prospective observational, cross-sectional clinical study including 341 consecutive patients admitted to the emergency department with an INR between 2 and 3, showed a statistically lower FIX activity in bleeders (p=0.004) compared to others. No correlation was found between TG capacity and PT-INR results (p=0.36).However, in patients, presenting with warfarin-related hemorrhage, TG was significantly lower (p<0.001) than others. And a correlation on the boundary of significance was observed between TG capacity and FIX levels (p=0.09). CONCLUSION: These data demonstrates that patients who bleed when their PT-INR is in the target range 2-3 might have defective TG related to a lower level of FIX than expected. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 04/2013; 11(6). DOI:10.1111/jth.12244 · 6.08 Impact Factor
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    Expert Review of Hematology 04/2013; 6(2):111-3. DOI:10.1586/ehm.13.12 · 2.38 Impact Factor
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    ABSTRACT: Most health care professionals involved in the management of people with haemophilia (PWH) believe that exercise is beneficial and its practice is widely encouraged. This article aims to demonstrate that appropriate exercise (adapted to the special needs of the individual PWH) may be beneficial for all PWH through improved physical, psychosocial and medical status. Based on evidence gathered from the literature, many PWH, particularly those using long-term prophylaxis or exhibiting a mild/moderate bleeding phenotype, are as active as their healthy peers. PWH experience the same benefits of exercise as the general population, being physically healthier than if sedentary and enjoying a higher quality of life (QoL) through social inclusion and higher self-esteem. PWH can also gain physically from increased muscle strength, joint health, balance and flexibility achieved through physiotherapy, physical activity, exercise and sport. Conversely, very little data exist on activity levels of PWH in countries with limited resources. However, regarding specific exercise recommendations in PWH, there is a lack of randomized clinical trials, and consequently formal, evidence-based guidelines have not been produced. Based on published evidence from this review of the literature, together with the clinical experience of the authors, a series of recommendations for the safe participation of PWH in regular physical activities, exercises and sport are now proposed. In summary, we believe that appropriately modified programmes can potentially allow all PWH to experience the physical and psychosocial benefits of being physically active which may ultimately lead to an improved QoL.
    Haemophilia 03/2013; 19(4). DOI:10.1111/hae.12118 · 2.47 Impact Factor
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    ABSTRACT: Hemophilia is a bleeding disorder afflicting about 1 in 5000 males. Treatment relies upon replacement of the deficient factor and response to treatment both in clinical research and practice is based upon subjective parameters such as pain and joint mobility. Existing laboratory assays quantify the amount of factor in plasma, which is useful diagnostically and prognostically, however, these assays are limited in their ability to fully evaluate the clot-forming capability of patients. Newer assays, known as global assays, provide a far more detailed view of thrombin generation and clot formation, and have been studied in hemophilia for about 10 years. They have the potential to offer a more objective measure of both the hemophilic phenotype as well as the response to treatment. In particular, in patients who develop inhibitors to deficient clotting factors in whom bypassing agents are required for hemostasis, these assays offer the opportunity to determine the laboratory response to these interventions where traditional coagulation assays cannot. This review will discuss the physiology of hemostasis as it relates to global assays, review the existing literature, and discuss several controversial issues surrounding the assays. Lastly, a vision of the future clinical uses of these assays will be briefly described.
    Blood 01/2013; DOI:10.1182/blood-2012-08-378935 · 9.78 Impact Factor
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    ABSTRACT: INTRODUCTION: Prothrombin complex concentrates (PCC) are haemostatic blood preparations indicated for urgent anticoagulation reversal, though the optimal dose for effective reversal is still under debate. The latest generation of PCCs include four coagulation factors, the so-called 4-factor PCC. The aim of this study was to compare the efficacy and safety of two doses, 25 and 40 IU/kg, of 4-factor PCC in vitamin K antagonist (VKA) associated intracranial haemorrhage. METHODS: We performed a phase III, prospective, randomised, open-label study including patients with objectively diagnosed VKA-associated intracranial haemorrhage between November 2008 and April 2011 in 22 centres in France. Patients were randomised to receive 25 or 40 IU/kg of 4-factor PCC. The primary endpoint was the International Normalised Ratio (INR) 10 minutes after the end of 4-factor PCC infusion. Secondary endpoints were changes in coagulation factors, global clinical outcomes and incidence of adverse events (AEs). RESULTS: A total of 59 patients were randomised: 29 in the 25 IU/kg and 30 in the 40 IU/kg group. Baseline demographics and clinical characteristics were comparable between the groups. The mean INR was significantly reduced to 1.2 - and [lessthan or equal to] 1.5 in all patients of both groups - 10 min after 4-factor PCC infusion. The INR in the 40 IU/kg group was significantly lower than in the 25 IU/kg group 10 min (p=0.001), 1 hour (p=0.001) and 3 hours (p=0.02) after infusion. The 40 IU/kg dose was also effective in replacing coagulation factors such as PT (p=0.038), FII (p=0.001), FX (p<0.001), protein C (p=0.002) and protein S (0.043), 10 min after infusion. However, no differences were found in hematoma volume or global clinical outcomes between the groups. Incidence of death and thrombotic events was similar between the groups. CONCLUSIONS: Rapid infusion of both doses of 4-factor PCC achieved an INR of 1.5 or less in all patients with a lower INR observed in the 40 IU/kg group. No safety concerns were raised by the 40 IU/kg dose. Further trials are needed to evaluate the impact of the high dose of 4-factor PCC on functional outcomes and mortality. Trial registration: Eudra CT number 2007-000602-73.
    Critical care (London, England) 01/2013; 17(1):R4. DOI:10.1186/cc11923 · 5.04 Impact Factor

Publication Stats

3k Citations
734.11 Total Impact Points

Institutions

  • 1998–2015
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
    • Aarhus University Hospital
      • Department of Clinical Immunology
      Århus, Central Jutland, Denmark
  • 2004–2014
    • University of Lyon
      Lyons, Rhône-Alpes, France
  • 1998–2014
    • Claude Bernard University Lyon 1
      Villeurbanne, Rhône-Alpes, France
  • 1993–2014
    • CHU de Lyon - Groupement Hospitalier Edouard Herriot
      Lyons, Rhône-Alpes, France
  • 2013
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • CHU de Lyon - Hôpital de la Croix-Rousse
      Lyons, Rhône-Alpes, France
  • 2007
    • French National Centre for Scientific Research
      • Laboratoire d'aérologie (LA)
      Lutetia Parisorum, Île-de-France, France
  • 2002
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 2000
    • The University of Manchester
      Manchester, England, United Kingdom
    • Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud)
      Lutetia Parisorum, Île-de-France, France
  • 1996
    • Centre Hospitalier Universitaire de Grenoble
      Grenoble, Rhône-Alpes, France
  • 1991–1993
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France