Publications by authors named "Philippe Nguyen"

65 Publications

Heparin-induced thrombocytopenia: construction of a pre-test diagnostic score derived from the analysis of a prospective multinational database, with internal validation.

J Thromb Haemost 2021 Apr 19. Epub 2021 Apr 19.

F-Crin INNOVTE, Université de Lyon, CIC 1408, Inserm U1059 SAINBIOSE, Saint-Etienne, France.

Background: Diagnosis of heparin-induced thrombocytopenia (HIT) requires pre-test probability assessment and dedicated laboratory assays.

Objective: To develop a pre-test score for HIT.

Design: Observational; analysis of prospectively collected data of hospitalized patients suspected with HIT (ClinicalTrials.gov NCT00748839).

Setting: Thirty-one tertiary hospitals in France, Switzerland, and Belgium.

Patients: Patients tested for HIT antibodies (2,280 evaluable), randomly allocated to derivation and validation cohorts.

Measurements: Independent adjudicators diagnosed HIT based on the prospectively collected data and Serotonin Release Assay results.

Results: HIT was diagnosed in 234 (14.7%) and 99 (14.5%) patients in the two cohorts. Eight features were associated with HIT (in brackets, points assigned for score calculation of the score): unfractionated heparin (1); therapeutic-dose heparin (1); cardiopulmonary bypass (cardiac surgery) (2); major trauma (3); 5- to 21-day interval from anticoagulation initiation to suspicion of HIT (4); ≥ 40% decrease in platelet count over ≤ six days (3); thrombotic event, arterial (3) or venous (3). The C-statistic was 0.79 [95% CI, 0.76-0.82]. In the validation cohort, the area under the receiver operating characteristic curve was 0.77 [95% CI, 0.74-0.80]. Three groups of scores were defined; HIT prevalence reached almost 30% in the high-probability group.

Limitation: The performance of the score may depend on settings and practices.

Conclusion: The objective, easy-to-collect, clinical features of HIT we evidenced were incorporated into a pre-test score, which may guide clinical decisions regarding diagnostic testing and anticoagulation.
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http://dx.doi.org/10.1111/jth.15344DOI Listing
April 2021

Functional Flow Cytometric Assay for Reliable and Convenient Heparin-Induced Thrombocytopenia Diagnosis in Daily Practice.

Biomedicines 2021 Mar 25;9(4). Epub 2021 Mar 25.

Inserm U1059 Sainbiose, Université de Lyon, 42055 Saint-Etienne, France.

Reliable laboratory diagnosis of heparin-induced thrombocytopenia (HIT) remains a major clinical concern. Immunoassays are highly sensitive, while confirmatory functional tests (based on heparin-dependent platelet activation) lack standardization. We evaluated the diagnostic performance of a functional flow cytometric assay (FCA) based on the detection of heparin-dependent platelet activation with an anti-p-selectin. A total of 288 patients were included (131 HIT-positive and 157 HIT-negative) with a HIT diagnosis established by expert opinion adjudication (EOA) considering clinical data and local laboratory results. The FCA was centrally performed in a single laboratory on platelet-rich plasma, using a very simple four-color fluorometer. The results were standardized according to the Heparin Platelet Activation (HEPLA) index. The serotonin release assay (SRA) was performed in the four French reference laboratories. Based on the final HIT diagnosis established by EOA, the sensitivity and specificity of the FCA were 88 and 95%, respectively, values very similar to those of the SRA (88 and 97%, respectively). This study showed that the FCA, based on easily implementable technology, may be routinely used as a reliable confirmatory test for HIT diagnosis.
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http://dx.doi.org/10.3390/biomedicines9040332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064483PMC
March 2021

A pilot study of procoagulant platelet extracellular vesicles and P-selectin increase during induction treatment in acute lymphoblastic leukaemia paediatric patients: two new biomarkers of thrombogenic risk?

J Thromb Thrombolysis 2021 Apr 28;51(3):711-719. Epub 2020 Nov 28.

EA3801-HERVI, Université de Reims Champagne-Ardenne, Reims, France.

In paediatric acute lymphoblastic leukaemia (ALL), focus has shifted towards preventing treatment-related complications, including venous thromboembolism, the cause of significant mortality and morbidity. To better understand thrombogenic mechanisms during induction treatment, we studied the number, origin and procoagulant activity of extracellular vesicles (EVs) and P-selectin level throughout the induction course in 24 paediatric patients. EVs were mainly of platelet origin. We observed a significant increase in EV number, in platelet EV number and P-selectin level throughout the induction course. There was a correlation between higher EV and platelet EV number, P-selectin level, higher platelet count and leucocyte count. We also observed a correlation between higher EV procoagulant activity and higher platelet count and leucocyte count and higher P-selectin level. Older age and T phenotype were associated with a higher EV procoagulant activity. Platelet EV generation may play a role in thrombogenic complications in ALL patients and could serve as a biomarker to identify patients with a high risk of thrombosis. As a marker of platelet activation, P-selectin may be another relevant marker with the advantage of being easier to analyse in clinical practice.
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http://dx.doi.org/10.1007/s11239-020-02346-7DOI Listing
April 2021

AgeR deletion decreases soluble fms-like tyrosine kinase 1 production and improves post-ischemic angiogenesis in uremic mice.

Angiogenesis 2021 02 23;24(1):47-55. Epub 2020 Sep 23.

Department of Nephrology, University Hospital of Limoges, Limoges, France.

Peripheral arterial disease occurs more frequently and has a worse prognosis in patients with chronic kidney disease (CKD). The receptor for advanced glycation end products (RAGE) is involved in multiple aspects of uremia-associated vasculopathy. Previous data suggest that the RAGE pathway may promote soluble fms-like tyrosine kinase 1 (sFlt1) production, an anti-angiogenic molecule. Thus, we tested the hypothesis that the deletion of AgeR would decrease sFlt1 production and improve post-ischemic revascularization in uremic condition. We used a well-established CKD model (5/6 nephrectomy) in WT and AgeR C57/Bl6 mice. Hindlimb ischemia was induced by femoral artery ligation. Revascularization was evaluated by complementary approaches: ischemic limb retraction, LASCA imagery, and capillary density. The production of sFlt1 was assessed at both RNA and protein levels. After hindlimb ischemia, uremic mice showed slower functional recovery (p < 0.01), decreased reperfusion (p < 0.01), lower capillary density (p = 0.02), and increased circulating sFlt1 levels (p = 0.03). AgeR deletion restored post-ischemic angiogenesis and was protective from sFlt1 increase in uremic mice. These findings show the main role of RAGE in post-ischemic angiogenesis impairment associated with CKD. RAGE may represent a key target for building new therapeutic approaches to improve the outcome of CKD patients with PAD.
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http://dx.doi.org/10.1007/s10456-020-09747-5DOI Listing
February 2021

Protein S100B as a reliable tool for early prognostication after cardiac arrest.

Resuscitation 2020 11 25;156:251-259. Epub 2020 Aug 25.

Inserm UMR-S 942, Lariboisiere Hospital, Paris, France; Surgical ICU, Lariboisiere University Hospital, Paris, France.

Purpose: Early and reliable prognostication after cardiac arrest (CA) remains crucial. We hypothesized that protein-S100B (PS100B) could predict more accurately outcome in the early phase of CA compared with other current biomarkers.

Methods: This prospective single-center study included 330 adult comatose non-traumatic successfully resuscitated CA patients, treated with targeted temperature management but not extra-corporeal life support. Lactate, pH, creatinine, NSE, and PS100B were sampled in ICU early after return of spontaneous circulation (ROSC) corresponding to admission (Adm). Serial measurements were also performed at H24 and H48. PS100B was the sole biomarker blinded to physicians.

Measurements And Main Results: The median delay between ROSC and first PS100B sampling was 220 min. At admission, all biomarkers were significantly associated with good outcome (CPC1-2; 109 patients) at 3-month follow-up (P ≤ 0.001, except for NSE: P = 0.03). PS100B-Adm showed the best AUC of ROC curves for outcome prediction at 3-month (AUC 0.83 [95%-CI: 0.78-0.88]), compared with other biomarkers (P < 0.0001), while AUC for lactate-Adm was higher than for NSE-Adm. AUC for PS100B-H24 was significantly higher than for other biomarkers except NSE-H24 (P ≤ 0.0001), while AUC for NSE-H24 was higher than for lactate-H24 and pH-H24. AUCs for PS100-H48 and NSE-H48 were significantly higher than for all other biomarkers (P < 0.001). Compared to patients with decreased PS100B values over time, an increasing PS100B value between admission and H24 was significantly associated with poor outcome at 3 months (P = 0.001). No-flow, initial non-shockable rhythm, PS100B-Adm, lactate-Adm, pH-Adm, clinical seizures, and absence of therapeutic hypothermia were independent predictors associated with poor outcome at 3-month in multivariate analysis. Net-Reclassification-Index was 70%, 64%, and 81% when PS100B-Adm was added to the clinical model, to clinical model with NSE-Adm, and to clinical model with standard biological parameters, respectively.

Conclusions: Early PS100B compared with other biomarkers was independently correlated with outcome after CA, with an interesting added value.
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http://dx.doi.org/10.1016/j.resuscitation.2020.08.010DOI Listing
November 2020

Receptor for Advanced Glycation End Products is Involved in Platelet Hyperactivation and Arterial Thrombosis during Chronic Kidney Disease.

Thromb Haemost 2020 Sep 29;120(9):1300-1312. Epub 2020 Jul 29.

UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2 "Matrix Aging and Vascular Remodelling," Université de Reims Champagne Ardenne, Reims, France.

Background:  Chronic kidney disease (CKD) is associated with a high cardiovascular mortality due to increased rates of vascular lesions and thrombotic events, as well as serum accumulation of uremic toxins. A subgroup of these toxins (advanced glycation end products [AGEs] and S100 proteins) can interact with the receptor for AGEs (RAGE). In this study, we analyzed the impact of CKD on platelet function and arterial thrombosis, and the potential role of RAGE in this process.

Methods:  Twelve weeks after induction of CKD in mice, platelet function and time to complete carotid artery occlusion were analyzed in four groups of animals (sham-operated, CKD, apolipoprotein E [Apoe], and Apoe/Ager mice).

Results:  Analysis of platelet function from whole blood and platelet-rich plasma showed hyperactivation of platelets only in CKD Apoe mice. There was no difference when experiments were done on washed platelets. However, preincubation of such platelets with AGEs or S100 proteins induced RAGE-mediated platelet hyperactivation. In vivo, CKD significantly reduced carotid occlusion times of Apoe mice (9.2 ± 1.1 vs. 11.1 ± 0.6 minutes for sham,  < 0.01). In contrast, CKD had no effect on occlusion times in Apoe/Ager mice. Moreover, carotid occlusion in Apoe CKD mice occurred significantly faster than in Apoe/Ager CKD mice ( < 0.0001).

Conclusion:  Our results show that CKD induces platelet hyperactivation, accelerates thrombus formation in a murine model of arterial thrombosis, and that RAGE deletion has a protective role. We propose that RAGE ligands binding to RAGE is involved in CKD-induced arterial thrombosis.
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http://dx.doi.org/10.1055/s-0040-1714101DOI Listing
September 2020

Excess soluble fms-like tyrosine kinase 1 correlates with endothelial dysfunction and organ failure in critically ill COVID-19 patients.

Clin Infect Dis 2020 Jul 16. Epub 2020 Jul 16.

University of Reims Champagne Ardenne, France.

Excess soluble fms-like tyrosine kinase 1 (sFlt-1), a soluble inhibitor of the vascular endothelial growth factor pathway, has been demonstrated to promote endothelial dysfunction. Here we demonstrate that sFlt-1 plasma levels correlate with respiratory symptoms severity, expression of endothelial dysfunction biomarker and incidence of organ failure in COVID-19 patients.
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http://dx.doi.org/10.1093/cid/ciaa1007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454379PMC
July 2020

Prevention of thrombotic risk in hospitalized patients with COVID-19 and hemostasis monitoring.

Crit Care 2020 06 19;24(1):364. Epub 2020 Jun 19.

Department of Hematology-Hemostasis, Tours University Hospital, CHRU Tours, Tours, France.

COVID-19 is an infection induced by the SARS-CoV-2 coronavirus, and severe forms can lead to acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) management. Severe forms are associated with coagulation changes, mainly characterized by an increase in D-dimer and fibrinogen levels, with a higher risk of thrombosis, particularly pulmonary embolism. The impact of obesity in severe COVID-19 has also been highlighted.In this context, standard doses of low molecular weight heparin (LMWH) may be inadequate in ICU patients, with obesity, major inflammation, and hypercoagulability. We therefore urgently developed proposals on the prevention of thromboembolism and monitoring of hemostasis in hospitalized patients with COVID-19.Four levels of thromboembolic risk were defined according to the severity of COVID-19 reflected by oxygen requirement and treatment, the body mass index, and other risk factors. Monitoring of hemostasis (including fibrinogen and D-dimer levels) every 48 h is proposed. Standard doses of LMWH (e.g., enoxaparin 4000 IU/24 h SC) are proposed in case of intermediate thrombotic risk (BMI < 30 kg/m, no other risk factors and no ARDS). In all obese patients (high thrombotic risk), adjusted prophylaxis with intermediate doses of LMWH (e.g., enoxaparin 4000 IU/12 h SC or 6000 IU/12 h SC if weight > 120 kg), or unfractionated heparin (UFH) if renal insufficiency (200 IU/kg/24 h, IV), is proposed. The thrombotic risk was defined as very high in obese patients with ARDS and added risk factors for thromboembolism, and also in case of extracorporeal membrane oxygenation (ECMO), unexplained catheter thrombosis, dialysis filter thrombosis, or marked inflammatory syndrome and/or hypercoagulability (e.g., fibrinogen > 8 g/l and/or D-dimers > 3 μg/ml). In ICU patients, it is sometimes difficult to confirm a diagnosis of thrombosis, and curative anticoagulant treatment may also be discussed on a probabilistic basis. In all these situations, therapeutic doses of LMWH, or UFH in case of renal insufficiency with monitoring of anti-Xa activity, are proposed.In conclusion, intensification of heparin treatment should be considered in the context of COVID-19 on the basis of clinical and biological criteria of severity, especially in severely ill ventilated patients, for whom the diagnosis of pulmonary embolism cannot be easily confirmed.
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http://dx.doi.org/10.1186/s13054-020-03000-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303590PMC
June 2020

Ticagrelor Prevents Endothelial Cell Apoptosis through the Adenosine Signalling Pathway in the Early Stages of Hypoxia.

Biomolecules 2020 05 9;10(5). Epub 2020 May 9.

Department of Pharmacology, Hémostase et Remodelage Vasculaire post-Ischémie (HERVI) E.A.3801, SFR CAP-santé, Reims University Hospital, 51, rue Cognacq-Jay, 51095 Reims CEDEX, France.

Background: Several studies have reported the beneficial effects of anti-platelet drugs in cardioprotection against ischaemia-reperfusion injuries. To date, no studies have focused on the indirect cytoprotective effects of ticagrelor via adenosine receptor on the endothelium.

Method: By evaluating cell viability and cleaved caspase 3 expression, we validated a model of endothelial cell apoptosis induced by hypoxia. In hypoxic endothelial cells treated with ticagrelor, we quantified the extracellular concentration of adenosine, and then we studied the involvement of adenosine pathways in the cytoprotective effect of ticagrelor.

Results: Our results showed that 10 µM ticagrelor induced an anti-apoptotic effect in our model associated with an increase of extracellular adenosine concentration. Similar experiments were conducted with cangrelor but did not demonstrate an anti-apoptotic effect. We also found that A2B and A3 adenosine receptors were involved in the anti-apoptotic effect of ticagrelor in endothelial cells exposed to 2 h of hypoxia stress.

Conclusion: we described an endothelial cytoprotective mechanism of ticagrelor against hypoxia stress, independent of blood elements. We highlighted a mechanism triggered mainly by the increased extracellular bioavailability of adenosine, which activates A2B and A3 receptors on the endothelium.
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http://dx.doi.org/10.3390/biom10050740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277469PMC
May 2020

Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

Pharmaceutics 2020 Apr 21;12(4). Epub 2020 Apr 21.

Department of Medical Pharmacology, University Hospital of Reims, EA3801, SFR Cap-Santé, University of Reims, 51100 Reims, France.

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.
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http://dx.doi.org/10.3390/pharmaceutics12040380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238177PMC
April 2020

In vivo efficacy of endothelial growth medium stimulated mesenchymal stem cells derived from patients with critical limb ischemia.

J Transl Med 2019 08 9;17(1):261. Epub 2019 Aug 9.

EA-3801, SFR CAP-santé, Université de Reims Champagne-Ardenne, 51092, Reims Cedex, France.

Background: Cell therapy has been proposed for patients with critical limb ischemia (CLI). Autologous bone marrow derived cells (BMCs) have been mostly used, mesenchymal stem cells (MSCs) being an alternative. The aim of this study was to characterize two types of MSCs and evaluate their efficacy.

Methods: MSCs were obtained from CLI-patients BMCs. Stimulated- (S-) MSCs were cultured in endothelial growth medium. Cells were characterized by the expression of cell surface markers, the relative expression of 6 genes, the secretion of 10 cytokines and the ability to form vessel-like structures. The cell proangiogenic properties was analysed in vivo, in a hindlimb ischemia model. Perfusion of lower limbs and functional tests were assessed for 28 days after cell infusion. Muscle histological analysis (neoangiogenesis, arteriogenesis and muscle repair) was performed.

Results: S-MSCs can be obtained from CLI-patients BMCs. They do not express endothelial specific markers but can be distinguished from MSCs by their secretome. S-MSCs have the ability to form tube-like structures and, in vivo, to induce blood flow recovery. No amputation was observed in S-MSCs treated mice. Functional tests showed improvement in treated groups with a superiority of MSCs and S-MSCs. In muscles, CD31+ and αSMA+ labelling were the highest in S-MSCs treated mice. S-MSCs induced the highest muscle repair.

Conclusions: S-MSCs exert angiogenic potential probably mediated by a paracrine mechanism. Their administration is associated with flow recovery, limb salvage and muscle repair. The secretome from S-MSCs or secretome-derived products may have a strong potential in vessel regeneration and muscle repair. Trial registration NCT00533104.
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http://dx.doi.org/10.1186/s12967-019-2003-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688282PMC
August 2019

Subcutaneous and transcutaneous monitoring of murine hindlimb ischemia by in vivo Raman spectroscopy.

Analyst 2019 Jul;144(15):4677-4686

BioSpectroscopie Translationnelle BioSpecT, EA 7506, Université de Reims Champagne-Ardenne, France.

We have investigated the development of murine hindlimb ischemia from day 1 to day 55 after femoral artery ligation (FAL) using blood flow analysis, functional tests, histopathological staining, and in vivo Raman spectroscopy. FAL resulted in hindlimb blood deprivation and the loss of functionality as attested by the blood flow analysis and functional tests, respectively. The limbs recovered a normal circulation progressively without recovering complete functionality. Histological analysis showed changes in the morphology of muscle fibers with intense inflammation. From day 22 to day 55 post-ischemia, regeneration of the myofibers was observed. Raman spectroscopic results related to subcutaneous analysis made the identification of modification in the biochemical constituents of hindlimb muscles possible during disease progression. Ischemia was characterized by a quantitative increase in the lipid content and a decrease in the protein content. The lipid to protein ratio can be used as a spectroscopic marker to score the severity of ischemia. Multivariate statistical analysis PC-LDA (Principal Component-Linear Discriminant Analysis) was used to classify all the data measured for the normal and ischemic tissues. This classification illustrated an excellent separation between the control and ischemic tissues at any time during the course of ischemic development. In vivo Raman spectroscopy was then applied to assess the potential of this technique as a screening tool to explore an ischemic disease non-invasively (transcutaneously). For this purpose, the influence of skin on the diagnostic accuracy was evaluated; transcutaneous analysis revealed the accuracy of this technique, indicating its potential in the in situ monitoring of muscle structural changes during ischemia.
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http://dx.doi.org/10.1039/c8an02449aDOI Listing
July 2019

Vincristine induces procoagulant activity of the human lymphoblastic leukemia cell line Jurkat through the release of extracellular vesicles.

J Thromb Thrombolysis 2019 Aug;48(2):195-202

EA3801-HERVI, Université de Reims Champagne-Ardenne, Reims, France.

Thromboembolic events are frequent and serious complications of acute lymphoblastic leukaemia treatment. The importance of chemotherapy in the pathogenesis of this increased risk is enhanced by the fact that thrombosis rarely occurs at diagnosis. Our study aims at investigating the effect of chemotherapy on pro-coagulant activity (PCA), phosphatidylserine (PS) exposure, tissue factor (TF) activity and derived extracellular vesicles (EV) of Jurkat cells. Jurkat cells were treated with two commonly used chemotherapeutics: Vincristine (VCR) or Daunorubicin (DNR), at relevant concentrations. PCA of cells and derived EV were evaluated using Thrombin generation Assay (TGA). Cells or EV were incubated with annexin V or anti TF antibodies to assess the respective contribution of TF and PS. PS exposure on cells was analysed by flow cytometry. Derived EV were evaluated in fluorescence microscopy and flow cytometry. Untreated Jurkat cells and EV support thrombin generation. Thrombin generation was abolished when PS activity was inhibited by annexin V. VCR treatment resulted in a time dependent increase of thrombin generation. After VCR exposure, TF activity increased as well as PS exposure increased on the cell surface. The increase in TF activity was abolished by annexin V indicating that PS was required. A spontaneous release of EV from Jurkat cells was observed and VCR treatment increased the number of generated EV. Our results indicate that VCR increased the PCA of Jurkat cells predominantly through PS exposure and increased EV generation. Lymphoid blasts derived EV could be biomarkers to determine high thrombotic risk ALL patients.
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http://dx.doi.org/10.1007/s11239-019-01894-xDOI Listing
August 2019

Complementary Role of P2 and Adenosine Receptors in ATP Induced-Anti-Apoptotic Effects Against Hypoxic Injury of HUVECs.

Int J Mol Sci 2019 Mar 22;20(6). Epub 2019 Mar 22.

Department of Pharmacology, E.A.3801, SFR CAP-santé, Reims University Hospital, 51, rue Cognacq-Jay, 51095 Reims CEDEX, France.

Background: Vascular endothelial injury during ischemia generates apoptotic cell death and precedes apoptosis of underlying tissues. We aimed at studying the role of extracellular adenosine triphosphate (ATP) on endothelial cells protection against hypoxia injury.

Methods: In a hypoxic model on endothelial cells, we quantified the extracellular concentration of ATP and adenosine. The expression of mRNA (ectonucleotidases, adenosine, and P2 receptors) was measured. Apoptosis was evaluated by the expression of cleaved caspase 3. The involvement of P2 and adenosine receptors and signaling pathways was investigated using selective inhibitors.

Results: Hypoxic stress induced a significant increase in extracellular ATP and adenosine. After a 2-h hypoxic injury, an increase of cleaved caspase 3 was observed. ATP anti-apoptotic effect was prevented by suramin, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), and CGS15943, as well as by selective A2A, A2B, and A3 receptor antagonists. P2 receptor-mediated anti-apoptotic effect of ATP involved phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinases (ERK1/2), mitoK, and nitric oxide synthase (NOS) pathways whereas adenosine receptor-mediated anti-apoptotic effect involved ERK1/2, protein kinase A (PKA), and NOS.

Conclusions: These results suggest a complementary role of P2 and adenosine receptors in ATP-induced protective effects against hypoxia injury of endothelial. This could be considered therapeutic targets to limit the development of ischemic injury of organs such as heart, brain, and kidney.
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http://dx.doi.org/10.3390/ijms20061446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470483PMC
March 2019

Effects of Aircraft Noise Exposure on Heart Rate during Sleep in the Population Living Near Airports.

Int J Environ Res Public Health 2019 01 18;16(2). Epub 2019 Jan 18.

Université Lyon, Université Claude Bernard Lyon1, IFSTTAR, UMRESTTE, UMR T_9405, F-69675 Bron, France.

Noise in the vicinity of airports is a public health problem. Many laboratory studies have shown that heart rate is altered during sleep after exposure to road or railway noise. Fewer studies have looked at the effects of exposure to aircraft noise on heart rate during sleep in populations living near airports. The aim of this study was to investigate the relationship between the sound pressure level (SPL) of aircraft noise and heart rate during sleep in populations living near airports in France. In total, 92 people living near the Paris-Charles de Gaulle and Toulouse-Blagnac airports participated in this study. Heart rate was recorded every 15 s during one night, using an Actiheart monitor, with simultaneous measurements of SPL of aircraft noise inside the participants' bedrooms. Energy and event-related indicators were then estimated. Mixed linear regression models were applied, taking into account potential confounding factors, to investigate the relationship between energy indicators and heart rate during sleep measured every 15 s. Event-related analyses were also carried out in order to study the effects of an acoustic event associated with aircraft noise on heart rate during sleep. The more the SPL from all sources (L) and the SPL exceeded for 90% of the measurement period (L) increased, the more heart rate also increased. No significant associations were observed between the maximum 1-s equivalent SPL associated with aircraft overflight (L) and differences between the heart rate recorded during or 15 or 30 s after an aircraft noise event and that recorded before the event. On the other hand, a positive and significant association was found between L and the heart rate amplitude calculated during an aircraft noise event. Results were unchanged when analyses were limited to participants who had lived more than five years in their present dwelling. Our study shows that exposure to the maximum SPL linked to aircraft overflight affect the heart rate during sleep of residents near airports. However, further studies on a larger number of participants over several nights are needed to confirm these results.
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http://dx.doi.org/10.3390/ijerph16020269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352139PMC
January 2019

Management of antiplatelet therapy for non-elective invasive procedures or bleeding complications: Proposals from the French Working Group on Perioperative Haemostasis (GIHP) and the French Study Group on Thrombosis and Haemostasis (GFHT), in collaboration with the French Society for Anaesthesia and Intensive Care (SFAR).

Arch Cardiovasc Dis 2019 Mar 6;112(3):199-216. Epub 2019 Jan 6.

Service d'angiologie et d'hémostase, département de spécialités de médecine, hôpitaux universitaires de Genève, 1205 Genève, Switzerland; Geneva Platelet Group, faculté de médecine, université de Genève, 1205 Genève, Switzerland.

The French Working Group on Perioperative Haemostasis (GIHP) and the French Study Group on Haemostasis and Thrombosis (GFHT), in collaboration with the French Society for Anaesthesia and Intensive Care (SFAR), drafted up-to-date proposals on the management of antiplatelet therapy for non-elective invasive procedures or bleeding complications. The proposals were discussed and validated by a vote; all proposals could be assigned with a high strength. Management of oral antiplatelet agents in emergency settings requires knowledge of their pharmacokinetic and pharmacodynamic parameters, evaluation of the degree of alteration of haemostatic competence and the associated bleeding risk. Platelet function testing may be considered. When antiplatelet agent-induced bleeding risk may worsen the prognosis, measures should be taken to neutralize antiplatelet therapy, by considering not only the efficacy of available means (which can be limited for prasugrel and even more for ticagrelor), but also the risks that these means expose the patient to. The measures include platelet transfusion at the appropriate dose and haemostatic agents (tranexamic acid; recombinant activated factor VII for ticagrelor). When possible, postponing non-elective invasive procedures at least for a few hours until the elimination of the active compound (which could compromise the effect of transfused platelets) or, if possible, for a few days (reduction of the effect of antiplatelet agents) should be considered.
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http://dx.doi.org/10.1016/j.acvd.2018.10.004DOI Listing
March 2019

The impact of aircraft noise exposure on objective parameters of sleep quality: results of the DEBATS study in France.

Sleep Med 2019 02 28;54:70-77. Epub 2018 Oct 28.

Univ Lyon, Université Claude Bernard Lyon 1, IFSTTAR, UMRESTTE, UMR T_9405, Bron, France. Electronic address:

Background: Noise in the vicinity of airports is a public health issue. Exposure to aircraft noise has been shown to have adverse effects on health and particularly on sleep. Many studies support the hypothesis that noise at night can affect subjective sleep quality. Fewer studies, however, have performed objective measurements of sleep.

Objectives: This study aimed to investigate by actigraphy the relationship between aircraft noise exposure and objective parameters of sleep quality in the population living near two French airports.

Methods: This study includes 112 participants living in the vicinity of Paris-Charles de Gaulle and Toulouse-Blagnac airports. Wrist actigraphy measurements were performed during eight nights to evaluate objective parameters of sleep quality such as sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), time in bed (TB) and sleep efficiency (SE). Acoustic measurements were made simultaneously both inside the participants' bedrooms and outside (at the exterior frontage) to estimate aircraft noise levels. Energy indicators related to the sound energetic average for a given period of time, as well as indicators related to noise events (eg, the number of events that exceed a given threshold), were estimated. Logistic and linear regression models were used, taking into account potential confounders: age; gender; marital status; education; and body mass index (BMI).

Results: Energy indicators, in particular, indicators related to noise events were significantly associated with objective parameters of sleep quality. Increased levels of aircraft noise and increased numbers of aircraft noise events increased the time required for sleep onset (SOL) and the total wake time after sleep onset (WASO) and decreased sleep efficiency (SE). An association was also observed between aircraft noise exposure and an increase in total sleep time (TST) and time in bed (TB).

Conclusion: The findings of the present study contribute to the overall evidence suggesting that nocturnal aircraft noise exposure may decrease the objective quality of sleep. Aircraft noise exposure affects objective parameters of sleep quality, not only regarding noise levels but also regarding the number of events. Mechanisms for adapting to sleep deprivation could be observed.
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http://dx.doi.org/10.1016/j.sleep.2018.10.013DOI Listing
February 2019

Feasibility of Implementing an Exercise Program in a Geriatric Assessment Unit: the SPRINT Program.

Can Geriatr J 2018 Sep 30;21(3):284-289. Epub 2018 Sep 30.

Centre de recherche, Institut universitaire de gériatrie de Montréal, Montréal, QC, Canada.

Background: An exercise program involving patients, caregivers, and professionals, entitled SPecific Retraining in INTerdisciplinarity (SPRINT), has been developed to prevent functional decline during hospitalization of older patients.

Goal: Assess the feasibility of implementing SPRINT in the context of a Geriatric Assessment Unit (GAU).

Methods: GAU's health-care professionals were instructed with the SPRINT. All new patients were evaluated by a physiotherapist shortly after admission to validate the eligibility criteria and allocation category of exercises. Questionnaires on physical activities were filled out by professionals, patients, and caregivers at baseline and after intervention. Quantitative and qualitative information was collected on adherence to the program.

Results: SPRINT was applied to 19 of the 50 patients admitted during the three-month pilot study. A daily average of one exercise session per patient was performed, most frequently with a nurse (37%), physician (20%), care attendant (13%) or by the patient alone (22%). The caregivers participated only 4% of the time. Barriers and facilitators in applying SPRINT have been identified.

Conclusions: SPRINT appears relevant and applicable within GAUs. Future studies should be conducted to assess its safety and effectiveness in preventing hospital-related functional decline.
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http://dx.doi.org/10.5770/cgj.21.311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136909PMC
September 2018

Determinants of adherence and consequences of the transition from adolescence to adulthood among young people with severe haemophilia (TRANSHEMO): study protocol for a multicentric French national observational cross-sectional study.

BMJ Open 2018 07 25;8(7):e022409. Epub 2018 Jul 25.

Haemophilia Treatment Centre, Hospital Edouard Herriot, University Hospital of Lyon, Lyon, France.

Introduction: Severe haemophilia is a rare disease characterised by spontaneous bleeding from early childhood, which may lead to various complications, especially in joints. It is nowadays possible to avoid these complications thanks to substitutive therapies for which the issue of adherence is major. The transition from adolescence to adulthood in young people with severe haemophilia is a critical period as it is associated with a high risk of lack of adherence to healthcare, which might have serious consequences on daily activities and on quality of life.

Methods And Analysis: We present the protocol for a cross-sectional, observational, multicentric study to assess the differences between adolescents and young adults with severe haemophilia in France through the transition process, especially on adherence to healthcare. This study is based on a mixed methods design, with two complementary and consecutive phases, comparing data from a group of adolescents (aged 14-17 years) with those from a group of young adults (aged 20-29 years). The quantitative phase focuses on the determinants (medical, organisational, sociodemographic and social and psychosocial and behavioural factors) of adherence to healthcare (considered as a marker of the success of transition). The qualitative phase explores participants' views in more depth to explain and refine the results from the quantitative phase. Eligible patients are contacted by the various Haemophilia Treatment Centres participating in the French national registry FranceCoag.

Ethics And Dissemination: The study was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2016-A01034-47). Study findings will be disseminated to the scientific and medical community in peer-reviewed journals and presented at scientific meetings. Results will be popularised to be communicated via the French association for people with haemophilia to participants and to the general public.

Trial Registration Number: NCT02866526; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-022409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067371PMC
July 2018

Management of bleeding and emergency invasive procedures in patients on dabigatran: Updated guidelines from the French Working Group on Perioperative Haemostasis (GIHP) - September 2016.

Anaesth Crit Care Pain Med 2018 Aug 2;37(4):391-399. Epub 2018 May 2.

Department of Haematology, Toulouse University Hospital, 31300 Toulouse, France. Electronic address:

In 2013, the GIHP published guidelines for the management of severe haemorrhages and emergency surgery. This update applies to patients treated with dabigatran, with a bleeding complication or undergoing an urgent invasive procedure. It includes how to handle the available specific antidote (idarucizumab), when to measure dabigatran plasmatic concentration and when to use non-specific measures in these situations. It also includes guidelines on how to perform regional anaesthesia and analgesia procedures.
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http://dx.doi.org/10.1016/j.accpm.2018.04.009DOI Listing
August 2018

Autologous Bone Marrow Mononuclear Cell Implantation and Its Impact on the Outcome of Patients With Critical Limb Ischemia - Results of a Randomized, Double-Blind, Placebo-Controlled Trial.

Circ J 2017 Oct 10;81(11):1713-1720. Epub 2017 Jun 10.

Research Unit HERVI EA, Medical School, Champagne-Ardenne University.

Background: Cell therapy is a therapeutic option for patients presenting with nonrevascularizable critical limb ischemia (CLI). However there is a lack of firm evidence on its efficacy because of the paucity of randomized controlled trials.Methods and Results:The BALI trial was a multicenter, randomized, controlled, double-blind clinical trial that included 38 patients. For all of them, 500 mL of bone marrow were collected for preparation of a BM-MNC product that was implanted in patients assigned to active treatment. For the placebo group, a placebo cell-free product was implanted. Within 6 months after inclusion, major amputations had to be performed in 5 of the 19 placebo-treated patients and in 3 of the 17 BM-MNC-treated patients. According to a classical logistic regression analysis there was no significant difference. However, when using the jackknife analysis, 6 months after inclusion BM-MNC implantation was associated with a lower risk of major amputation (odds ratio (OR): 0.55; 95% confidence interval (CI): 0.52-0.58; P<0.0001) and of occurrence of any event (major or minor amputation, or revascularization) (OR: 0.30; 95% CI: 0.29-0.31; P<0.0001). The secondary endpoints (i.e., pain, ulcers, TcPO, and ankle-brachial index value) were not statistically different between groups.

Conclusions: Our results suggested that cell therapy reduced the risk of major amputation in patients presenting with nonrevascularizable CLI.
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http://dx.doi.org/10.1253/circj.CJ-17-0045DOI Listing
October 2017

The Association between Generalized Anxiety Disorder, Subthreshold Anxiety Symptoms and Fear of Falling among Older Adults: Preliminary Results from a Pilot Study.

Clin Gerontol 2017 May-Jun;40(3):197-206. Epub 2017 Feb 26.

b Centre de recherche de l'Institut universitaire de gériatrie de Montréal , Quebec , Canada.

Objective: A relationship between generalized anxiety disorder (GAD) and fear of falling (FOF) has long been proposed but never specifically studied. This study aimed at analyzing the relationship between FOF and GAD or anxiety symptoms, while controlling for major depressive episodes (MDE), depressive symptoms, fall risk, and sociodemographic variables.

Methods: Twenty-five older adults participated in this pilot study. Assessments included the following: Anxiety Disorder Interview Schedule, Geriatric Anxiety Inventory, Geriatric Depression Scale, Falls-Efficacy Scale-International. A multidisciplinary team evaluated fall risk.

Results: FOF was significantly correlated with GAD, MDE, anxiety and depressive symptoms, and fall risk, but not with sociodemographic variables. Multiple regression analyses indicated that GAD and anxiety symptoms were significantly and independently associated with FOF.

Conclusion: Although the results of this pilot study should be replicated with larger samples, they suggest that FOF is associated with GAD and anxiety symptoms even when considering physical factors that increase the risk of falling.

Clinical Implications: Treatment of FOF in patients with GAD may present a particular challenge because of the central role of intolerance of uncertainty, which may prevent patients from regaining confidence despite the reduction of fall risk. Clinicians should screen for GAD and anxiety symptoms in patients with FOF to improve detection and treatment.
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http://dx.doi.org/10.1080/07317115.2017.1296523DOI Listing
June 2018

Cell therapy in critical limb ischemia: A comprehensive analysis of two cell therapy products.

Cytotherapy 2017 02 30;19(2):299-310. Epub 2016 Nov 30.

Laboratoire d'Hématologie, Centre Hospitalier Universitaire Robert Debré, Reims, France; Equipe d'accueil de recherche, Structure Fédératrice de Recherche Champagne Ardenne Picardie-Santé, Université de Reims Champagne-Ardenne, Reims, France. Electronic address:

Background: Cell therapy has been proposed as a salvage limb procedure in critical limb ischemia (CLI). In spite of the fact that clinical trials found some efficacy, the mechanism of action remains elusive. The objective of this study was to characterize two autologous cell therapy products (CTPs) obtained from patients with advanced peripheral arterial disease.

Methods: Bone marrow (BM-CTPs) (n = 20) and CTPs obtained by non-mobilized cytapheresis (peripheral blood [PB]-CTPs) (n = 20) were compared. CTPs were characterized by their cell composition, by the quantification of endothelial progenitor cells (EPCs) and mesenchymal stromal cells (MSCs) and by transcriptomic profiling. The angiogenic profile and the 6-month outcome of CLI patients are described.

Results: Patients presented inflammation syndrome and high levels of CXCL12, soluble stem cell factor and granulocyte colony-stimulating factor, whereas granulocyte macrophage colony-stimulating factor was low. Circulating CD34+ cells represented rare events. BM and PB-CTPs were heterogeneous. Mature cells and colony-forming unit-endothelial cells were in higher concentration in PB-CTPs, whereas CD34+ stem cells and EPCs were more abundant in BM-CTPs. MSCs were identified in both CTPs. Transcriptomic profiling revealed the strong angiogenic potential of BM-CTPs. Transcutaneous partial pressure of oxygen, C-reative protein and neutrophil content in CTPs are predictive of the clinical outcome at 6 months.

Discussion: Transcriptomic allows an accurate characterization of CTPs. BM-CTPs have the richest content in terms of stem cells and transcriptome. The high content of mature cells in PB-CTPs means that they work via a paracrine mechanism. The clinical outcome indicates the deleterious influence the patients' status and the limits of an autologous approach. In this respect, MSCs may allow an allogenic strategy.
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http://dx.doi.org/10.1016/j.jcyt.2016.10.013DOI Listing
February 2017

Critical limb ischaemia and the response to bone marrow-derived cell therapy according to tcPO measurement.

Vasa 2017 01 21;46(1):23-28. Epub 2016 Nov 21.

1 Department of Vascular Medicine, University Hospital Grenoble-Alpes, France.

Background: Cell therapy is an emerging potential biotherapy for critical limb ischaemia (CLI) patients who are not eligible for revascularization. However, the findings on this technique's efficacy are inconsistent. Trials investigating this topic focused on the more severe CLI patients who were often beyond any therapy. Therefore, identifying those who may truly benefit from cell transplantation is now warranted. To this end, we studied the prognostic value of tcPO for major amputation after 1 year in patients treated with bone marrow-derived cells.

Patients And Methods: CLI patients ineligible for revascularization were included in a cell-therapy pilot study. On inclusion, patients underwent tcPO measurement in supine and sitting positions. For a tcPO < 10 mmHg in the supine position, the vascular reserve was defined by tcPO > 30 mmHg in the sitting position. Patients were administered intramuscular injections of mononuclear cells derived from aspirated bone marrow.

Results: In total, 25 patients (a lower limbs) were included for analysis. At inclusion, 11 lower limbs had tcPO at rest > 10 mmHg, and 16 lower limbs had a tcPO < 10 mmHg. The success probability for cell therapy was 0.79 (95 % CI 0.38-0.94) and 0.44 (95 % CI 0.18-0.67), respectively (p = 0.1). Of the 16 limbs with tcPO2 < 10 mmHg, the success rate was considerably higher in patients demonstrating a tcPO increase in a sitting position of over 30 mmHg (6/8, success probability 0.71, 95 % CI 0.26-0.92) compared to those without (2/8, success probability 0.15, 95 % CI 0.01-0.48, p = 0.03).

Conclusions: For patients with chronic CLI for whom cellular therapy is a therapeutic option, a tcPO < 10 mmHg at rest, without vascular reserve (i. e. < 30 mmHg when sitting), is a prognostic indicator for poor outcome.
.
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http://dx.doi.org/10.1024/0301-1526/a000590DOI Listing
January 2017

Tissue factor expressed by adherent cells contributes to hemodialysis-membrane thrombogenicity.

Thromb Res 2016 Aug 27;144:218-23. Epub 2016 May 27.

Equipe d'accueil 3801 Hémostase et Remodelage Vasculaire Post-Ischémie, Université de Reims, France. Electronic address:

End-stage renal patients present a high risk of thrombosis and bleeding. Consequently, it is challenging to prevent clotting during hemodialysis. If a contact system induces thrombin generation in the extra corporeal circuit, recent data suggest a role of tissue factor (TF) in hemodialysis-associated thrombosis. Using a method of elution, we collected adhering cells to an acrylonitrile membrane layered by polythyleneimine (AN69-ST). Using optic microscopy and flow cytometry, we observed that adherent cells were mainly constituted by activated polymorphonuclear neutrophils (PMNs). Using a sensitive fluorogenic method of thrombin generation, we found that adhering cells triggered thrombin generation in a TF-dependent manner. We next identified the presence of TF mRNA (Q-PCR) in adhering cells. Using immunofluorescence, we observed the presence of TF in PMNs and of TF-decorated neutrophil extracellular traps (NETs). As TF triggers thrombin generation after binding to serine protease FVIIa, we evaluated the effect of an inactivated human recombinant factor VIIa (hrFVIIai) in a sheep model of hemodialysis (HD). One single bolus of hrFVIIai maintained the full patency of the hemodialysis circuit without any measurable systemic anticoagulant effect. TF is a promising target for preventing thrombosis during HD.
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http://dx.doi.org/10.1016/j.thromres.2016.05.017DOI Listing
August 2016

Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial.

Crit Care 2015 Nov 11;19:396. Epub 2015 Nov 11.

Laboratory of Hematology, University Hospital of Dijon, Dijon, France.

Introduction: The aim of this study was to collect data in France in patients with heparin-induced thrombocytopenia who required parenteral anticoagulation and for whom other non-heparin anticoagulant therapies were contraindicated including patients with renal failure, cross-reactivity to danaparoid or at high hemorrhagic risk.

Methods: A total of 20 patients, of mean age 72 ± 10 years, were enrolled in this open-label, multicenter clinical study. Exploratory statistical data analysis was performed with descriptive interpretation of intra-individual comparisons using simple univariate statistics.

Results: The diagnosis of HIT was confirmed in 16 subjects by an independent scientific committee. Fourteen patients (70 %) were in an intensive care unit during the course of the study. Patients were treated with argatroban for a mean duration of 8.5 ± 6.1 days. The mean starting dose of argatroban was 0.77 ± 0.45 μg/kg/min. Platelet recovery was rapid. aPTT and anti-IIa activity assays were used to monitor the dose of argatroban. The mean baseline aPTT value was 45.0 ± 9.8 sec and increased to 78.2 ± 35.8 sec two hours after initiating argatroban. At this time mean argatroban concentration was 0.34 ± 0.16 and 0.61 ± 0.28 μg/ml using ECT and TT measurements, respectively. New and/or extended thromboses were reported in 25 % of patients and major bleedings were documented in 15 %. Six patients died due to their underlying medical condition.

Conclusion: Considering its hepatic elimination and its short half-life, argatroban can be considered as a safe therapeutic option in HIT patients at high hemorrhagic risk and with renal failure, particularly in an ICU setting.
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http://dx.doi.org/10.1186/s13054-015-1109-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641392PMC
November 2015

Critical limb ischemia: thrombogenic evaluation of two autologous cell therapy products and biologic profile in treated patients.

Transfusion 2015 Nov 29;55(11):2692-701. Epub 2015 Jul 29.

Laboratoire d'Hématologie, CHU Robert Debré, Reims.

Background: Cell therapy has been proposed as a salvage limb procedure in critical limb ischemia (CLI). Autologous cell therapy products (CTP) are obtained from patients with advanced peripheral arterial disease to be injected at the site of ischemia. Thrombogenicity of CTPs has not yet been assessed. The objectives were: 1) to assess thrombotic risk in candidates for cell therapy, 2) to evaluate two different CTPs in terms of thrombogenic potential, and 3) to evaluate clinical thrombotic events.

Study Design And Methods: In this ancillary study of a Phase I and II clinical trial, bone marrow (BM)-CTPs (n = 20) and CTPs obtained by cytapheresis (peripheral blood [PB]-CTPs; n = 20) were compared. Inflammatory and coagulation markers were measured at baseline and 24 hours after CTP implantation. CTP cell content and tissue factor (TF) expression (mRNA and protein) were analyzed. Thrombin generation assessed CTP-related thrombogenicity.

Results: All patients presented cardiovascular risk factors. At baseline, the patients' biologic profile was characterized by high levels of fibrinogen, C-reactive protein (CRP), D-dimer, interleukin (IL)-6, and plasmatic TF, whereas IL-10 was low. Although different in terms of cell composition, both BM- and PB-CTPs support low thrombin generation. Twenty-four hours after implantation, biologic markers remained stable in the PB-CTP group, except for IL-6. In the BM-CTP group, a significant increase of IL-6 but also of CRP and D-dimer was observed. Clinically, one single patient developed deep vein thrombosis 24 hours after the implantation of autologous PB-CTP.

Conclusion: CTPs supported low thrombin generation and were well tolerated after calf implantation.
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http://dx.doi.org/10.1111/trf.13203DOI Listing
November 2015

Anticoagulation in Chronic Hemodialysis: Progress Toward an Optimal Approach.

Semin Dial 2015 Sep-Oct;28(5):474-89. Epub 2015 Apr 25.

Department of Hematology, University Hospital, Reims, France.

Appropriate anticoagulation for hemodialysis (HD) requires a subtle balance between under- and over-heparinization to prevent extracorporeal circuit (ECC) clotting and bleeding, respectively. We discuss five key issues relating to anticoagulation therapy for chronic HD in adults following a review of relevant literature published since 2002: (i) options for standardization of anticoagulation in HD settings. The major nephrology societies have issued low evidence level recommendations on this subject. Interventional studies have generally investigated novel low-molecular weight heparins and provided data on safety of dosing regimens that cannot readily be extrapolated to clinical practice; (ii) identification of clinical and biological parameters to aid individualization of anticoagulation treatment. We find that use of clinical and biological monitoring of anticoagulation during HD sessions is currently not clearly defined in routine clinical practice; (iii) role of ECC elements (dialysis membrane and blood lines), dialysis modalities, and blood flow in clotting development; (iv) options to reduce or suppress systemic heparinization during HD sessions. Alternative strategies have been investigated, especially when the routine mode of anticoagulation was not suitable in patients at high risk of bleeding or was contraindicated; (v) optimization of anticoagulation therapy for the individual patient. We conclude by proposing a standardized approach to deliver anticoagulation treatment for HD based on an individualized prescription prepared according to the patient's profile and needs.
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http://dx.doi.org/10.1111/sdi.12380DOI Listing
June 2016

Venous thromboembolism: What pharmacists know? What do they need?

J Oncol Pharm Pract 2016 Feb 25;22(1):135-41. Epub 2014 Nov 25.

Leo Pharma, Medical Affairs, Voisins le Bretonneux, France.

Introduction: Venous thromboembolism is common in cancer. Low-molecular weight heparins are recommended for prolonged treatment (3-6 months or more if the cancer is active) and prevention of recurrence of venous thromboembolism in cancer. Community pharmacists are often faced with questions from patients. The main objective of this study was to describe the organization, practices and knowledge of pharmacists in care of venous thromboembolism in cancer patients.

Methods: A descriptive survey was conducted electronically in October and November 2013 with pharmacists in the Champagne-Ardenne region. The questionnaire collected data on the general organization of the pharmacy, management of outpatients with cancer and thrombosis, and the level of knowledge regarding recommendations on the management of thrombosis in patients with cancer.

Results: The participation rate was 31.6%. In 93% of cases, pharmacists had no particular expertise in oncology and/or supportive care. In addition, 96% did not know the existence of recommendations for "thrombosis in cancer." Finally, 49% gave the correct answer to the case report (low-molecular weight heparins).

Conclusion: Training sessions on the management of venous thromboembolism in cancer are currently available to pharmacists in the region. A new assessment of knowledge will be performed at the end of the year 2014. This regional experience is now extended to a national level (all French regions).
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http://dx.doi.org/10.1177/1078155214560639DOI Listing
February 2016