Publications by authors named "Bernard Tardy"

47 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

PHILEOS () Study: protocol of a multicentre prospective case-control study.

BMJ Open 2021 01 13;11(1):e042283. Epub 2021 Jan 13.

Inserm CIC 1408, Saint-Etienne University Hospital Center, Saint-Etienne, Rhône-Alpes, France.

Introduction: Two meta-analyses showed lower bone mineral density (BMD) in patients with haemophilia (haemophilia type and severity were often not specified) compared with healthy controls. This finding could be related to reduced mobility and sedentary lifestyle, and/or hepatitis C or HIV infection. The aim of this study is to determine osteoporosis prevalence in patients with haemophilia classified in function of the disease type (A or B) and severity, and to evaluate the potential role of regular prophylactic factor replacement (early vs delayed initiation) in preserving or restoring BMD.

Methods And Analysis: The haemoPHILia and ostEoporOSis Study is a prospective, controlled, multicentre study that will include patients in France (13 haemophilia treatment centres), Belgium (1 centre) and Romania (1 centre). In total, 240 patients with haemophilia and 240 matched healthy controls will be recruited (1:1). The primary objective is to determine osteoporosis prevalence in patients with severe haemophilia A and B (HA and HB) without prophylaxis, compared with healthy controls. Secondary outcomes include: prevalence of osteoporosis and osteopenia in patients with mild, moderate and severe HA or HB with prophylaxis (grouped in function of their age at prophylaxis initiation), compared with healthy subjects; BMD in patients with HA and HB of comparable severity; correlation between BMD and basal factor VIII/IX levels and thrombin potential; and quantification of plasmatic markers of bone remodelling (formation and resorption) in patients with haemophilia.

Ethics And Dissemination: The protocol was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2019-A03358-49). The results of this study will be actively disseminated through scientific publications and conference presentations.

Trial Registration Number: NCT04384341.
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http://dx.doi.org/10.1136/bmjopen-2020-042283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812091PMC
January 2021

Intention to participate in a COVID-19 vaccine clinical trial and to get vaccinated against COVID-19 in France during the pandemic.

Vaccine 2020 10 17;38(45):7002-7006. Epub 2020 Sep 17.

Centre d'investigation clinique-INSERM 1408, University Hospital of Saint-Etienne, France; Groupe Immunité des Muqueuses et Agents Pathogènes, Université Jean Monnet, Université de Lyon, Saint-Etienne, France; PRESAGE Insitute, Université de Lyon, Saint-Etienne, France. Electronic address:

Introduction: The world is facing the COVID-19 pandemic. The development of a vaccine is challenging. We aimed to determine the proportion of people who intend to get vaccinated against COVID-19 in France or to participate in a vaccine clinical trial.

Methods: We conducted an anonymous on-line survey from the 26th of March to the 20th of April 2020. Primary endpoints were the intention to get vaccinated against COVID-19 if a vaccine was available or participate in a vaccine clinical trial.

Results: Three thousand two hundred and fifty nine individuals answered the survey; women accounted for 67.4% of the respondents. According to their statements, 2.512 participants (77.6%, 95% CI 76.2-79%) will certainly or probably agree to get vaccinated against COVID-19. Older age, male gender, fear about COVID-19, being a healthcare worker and individual perceived risk were associated with COVID-19 vaccine acceptance. Vaccine hesitancy was associated with a decrease in COVID-19 vaccine acceptance. One thousand and five hundred and fifty respondents (47.6% 95% CI 45.9-49.3%) will certainly or probably agree to participate in a COVID-19 vaccine clinical trial. Older age, male gender, being a healthcare worker and individual perceived risk were associated with potential acceptance to participate in a COVID-19 vaccine clinical trial. Vaccine hesitancy was associated with refusal for participation in a COVID-19 vaccine clinical trial.

Conclusions: Nearly 75% and 48% of the survey respondents were respectively likely to accept vaccination or participation in a clinical trial against COVID-19. Vaccine hesitancy will be the major barrier to COVID-19 vaccine uptake.
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http://dx.doi.org/10.1016/j.vaccine.2020.09.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498238PMC
October 2020

[Use and management of proton pump inhibitors: An observational study].

Therapie 2020 Nov - Dec;75(6):649-662. Epub 2020 Jun 4.

Service de médecine interne, CHU de Saint-Étienne, 42055 Saint-Étienne cedex 2, France.

Introduction: Proton pump inhibitors (PPIs) have improved the management and prevention of digestive diseases, leading to a heavy prescription of this therapy. In 2015, nearly one quarter of the French population had consumed a PPI and half of them were long-term users. The main objective of this study was to analyze, in patients hospitalized in several medical departments, the adequacy of long-term PPI prescriptions to recommendations.

Method: The Use and management of proton pump inhibitors: an observational study project (UTOPPIA) is a longitudinal observational study conducted at the University Hospital of Saint-Étienne in the departments of hepato-gastroenterology, infectious and tropical diseases, internal medicine, vascular medicine and nephrology. All patients with PPI treatment on their usual outpatient prescription were interviewed.

Results: Over a 3-month period, 334 of hospitalized patients (30.7%) had received a long-term PPI prescription and 181 patients (54.2%) could be included in the study for a total of 274 indications. Ninety-nine patients (54.7%) had a long-term PPI prescription in accordance with the recommendations. The most frequent indication (70 prescriptions) was the prescription of an antiplatelet drug or anticoagulant for subjects at high risk of bleeding in 70 prescriptions. Fifty-three PPI treatments were amended during the hospital stay, including 9 discontinuations. The justification for the change was documented in the patients' chart in only 17% of cases. Individual interviews of patients revealed that 75.1% of them were in favour of discontinuing their PPI treatment.

Conclusions: About one-third of hospitalized patients in medical wards in France have long-term PPI treatment and half of these prescriptions do not comply with good practice recommendations. A majority of patients report being willing to try to stop PPI therapy.
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http://dx.doi.org/10.1016/j.therap.2020.03.002DOI Listing
June 2020

Comparative Analysis of a French Prospective Series of 144 Patients with Heparin-Induced Thrombocytopenia (FRIGTIH) and the Literature.

Thromb Haemost 2020 Jul 22;120(7):1096-1107. Epub 2020 Jun 22.

EA 7501, GICC, Université de Tours, Tours, France.

Background:  Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatments, and only a few large patient cohorts have been reported. In this study, biological and clinical data from 144 French patients with HIT were analyzed in comparison with the literature.

Methods:  The diagnosis of HIT was confirmed in all patients by an immunoassay combined with serotonin release assay. In the literature, only cohorts of at least 20 HIT patients published from 1992 were selected for a comparative analysis.

Results:  Two-thirds of patients were hospitalized in surgery and most were treated with unfractionated heparin (83.2% vs. 16.8% with low molecular weight heparin only). Thrombotic events in 54 patients (39.7%) were mainly venous (41/54). However, arterial thrombosis was more frequent after cardiac surgery (13.2% vs. 2.4% in other surgeries,  = 0.042) with a shorter recovery time (median = 3 vs. 5 days,  < 0.001). The mortality rate was lower in our series than in the 22 selected published studies (median = 6.3% vs. 15.9%). Three genetic polymorphisms were also studied and homozygous subjects FcγRIIA RR were more frequent in patients with thrombosis (37.8 vs. 18.2% in those without thrombosis,  = 0.03).

Conclusion:  This study shows that the mortality rate due to HIT has recently decreased in France, possibly due to earlier diagnosis and improved medical care. It also confirms the strong association between polymorphism FcγRIIA H131R and thrombosis in HIT.
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http://dx.doi.org/10.1055/s-0040-1712957DOI Listing
July 2020

Impact of take-home messages written into slide presentations delivered during lectures on the retention of messages and the residents' knowledge: a randomized controlled study.

BMC Med Educ 2020 Jun 3;20(1):180. Epub 2020 Jun 3.

Biostatistics unit, Delegation à la Recherche Clinique (DRCI), University Hospital of Clermont-Ferrand, Clermont-Ferrand, France.

Background: Lectures with slide presentations are widely used to teach evidence-based medicine to large groups. Take-home messages (THMs) are poorly identified and recollected by students. We investigated whether an instruction to list THMs in written form on slides would improve the retention thereof by residents, and the residents' level of knowledge, 1 month after lectures.

Methods: Prospective blinded randomized controlled study was conducted. Twelve lectures (6 control and 6 intervention lectures) were delivered to 73 residents. For the intervention lectures, the lecturers were instructed to incorporate clear written THMs into their slide presentations. The outcomes were ability of resident to recollect THMs delivered during a lecture (as assessed by accordance rate between the lecturers' and residents' THMs) and knowledge (as assessed by multiple choice questions (MCQs)).

Results: Data for 3738 residents' THMs and 3410 MCQs were analyzed. The intervention did not significantly increase the number of THMs written on slides (77% (n = 20/26), 95% CI 56-91 vs 64% (n = 18/28), 95% CI 44-81, p = 0.31) nor THMs retention (13% (n = 238/1791), 95% CI 12-15 vs 17% (n = 326/1947), 95% 15-18, p = 0.40) nor knowledge (63.8 ± 26.2 vs 61.1 ± 31.4 /100 points, p = 0.75). In multivariable analyses performed with all THMs written on slides from the two groups, a superior knowledge was associated with notetaking during lectures (OR 1.88, 95% CI 1.41-2.51) and THMs retention (OR 2.17, 95% CI 1.54-3.04); and THMs retention was associated with written THMs (OR 2.94, 95% CI 2.20-3.93).

Conclusions: In lectures delivered to residents, a third of the THMs were not in written form. An intervention based on an explicit instruction to lecturers to provide THMs in written form in their slide presentations did not result in increased use of written THMs into the slide presentation or improvement of the THMs retention or level of knowledge. However, we showed that there was a strong positive association between writing THMs on a slide, retention of THMs and residents' knowledge. Further researches are needed to assess interventions to increase written THMs in lectures by faculty.

Trial Registration: ClinicalTrials.gov NCT01795651 (Fev 21, 2013).
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http://dx.doi.org/10.1186/s12909-020-02092-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271544PMC
June 2020

Graduated compression stockings in prevention of venous thromboembolism among acutely ill medical patients aged over 75 years: a French national survey.

Clin Interv Aging 2019 25;14:1153-1157. Epub 2019 Jun 25.

Centre d'Investigation Clinique, Inserm CIC-EC 1408, Saint Etienne, France.

The thromboprophylactic efficacy of graduated compression stockings (GCS) has not yet been demonstrated in acutely ill medical patients, and guidelines vary considerably. Older acutely ill medical patients appear to constitute a distinctive population presenting high risks of both thrombosis and bleeding. To evaluate the practices and beliefs of a panel of French geriatricians regarding GCS management in acutely ill medical patients aged over 75 years. A survey was designed to study French geriatric practice concerning GCS use for thromboprophylaxis. A total of 111 geriatricians answered the questionnaire. Among the responders, 46% declared frequent or very frequent prescription of GCS for preventing venous thromboembolism (VTE) in acutely ill, hospitalized medical patients, 54% declaring that they frequently re-evaluated GCS prescription during the patient's hospitalization. The main reason reported for discontinuing GCS use was patient request. Regarding complications of GCS, 87% of responders declared having already noted adverse effects with the use of GCS, although 80% estimated the risk of complications to be low or very low. In the context considered, the efficacy of wearing GCS was believed to be high or very high for 73% of responders. GCS prescription was judged to be in accordance with evidence-based medicine for 69%. There is a gap between the frequent use of GCS to prevent VTE in older patients presenting an acute medical illness and the availability of data concerning their efficacy, safety, and management by nurses. Prospective trials including clinical and cost effectiveness are needed.
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http://dx.doi.org/10.2147/CIA.S197603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601338PMC
December 2019

Thromboprophylaxis in pregnant women: For whom and which LMWH dosage?

J Thromb Haemost 2019 08;17(8):1401-1403

Department of Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1111/jth.14547DOI Listing
August 2019

Drug Management in End-of-Life Hospitalized Palliative Care Cancer Patients: The RHESO Cohort Study.

Oncology 2019 20;97(4):217-227. Epub 2019 Jun 20.

Centre Hygée, Public Health Department, Lucien Neuwirth Cancer Institute, Saint-Priest en Jarez, France.

Objective: Little data about the management of drugs in terminally ill palliative care cancer patients is available. The present study aimed at describing the evolution of anticancer and non-anticancer treatments (NACTs) in cancer patients in palliative care units. The second objective was to identify factors leading to the medical decision to withdraw or not NACTs.

Methods: Data from 1,091 cancer patients hospitalized in palliative care units were prospectively collected in 2010-2011, through a multicenter, observational French cohort.

Results: The median overall survival after admittance in palliative care units was 15 days. Specific anticancer treatments were systematically stopped in the first 24 h in palliative care units, but for 4.5% of patients. Regarding NACTs, patients were heavily treated with strong opioids (74%), corticosteroids (51%), and antidepressants (21.8%) until death. Antiulcer agents (63.4%), antibiotics (25.7%), thrombosis prevention (21.8%), antidiabetics (7.6%), and transfusions (4%) were often also continuously prescribed. In multivariate analysis, ECOG PS 4 was an independent predictor of continuous prescription of morphine and an independent predictor of discontinuation of corticosteroids, proton-pump inhibitors, antidiabetics, and preventive anticoagulant therapy. Infection symptoms independently predicted continuous prescription of paracetamol. Paralysis and cancer palpable mass independently predicted corticosteroid withdrawal. Brain metastases independently predicted antiulcer withdrawal. Hemorrhage independently predicted preventive anticoagulant withdrawal. Availability to a venous access independently predicted paracetamol and antiulcer continuous prescriptions. Co-prescriptions independently predicted continuous prescriptions (antibiotics with antiulcer, antifungals with antibiotics) or withdrawal (preventive anticoagulant with antiplatelets and antifungals).

Conclusions: NACT prescription remained commonplace in terminally ill palliative cancer patients, although their benefit is questionable.
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http://dx.doi.org/10.1159/000500783DOI Listing
October 2019

Effect of heparin thromboprophylaxis on thrombin generation in multiple myeloma patients.

Br J Haematol 2019 07 21;186(2):337-339. Epub 2019 Feb 21.

Centre d'Investigation Clinique Inserm CIC 1408, CHU Saint Etienne, Saint Etienne, France.

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http://dx.doi.org/10.1111/bjh.15815DOI Listing
July 2019

Thrombin generation in newly diagnosed multiple myeloma during the first three cycles of treatment: An observational cohort study.

Res Pract Thromb Haemost 2019 Jan 13;3(1):89-98. Epub 2018 Dec 13.

Centre d'Investigation Clinique Inserm CIC 1408 CHU de Saint-Etienne Saint-Etienne France.

Background: Multiple myeloma (MM) is associated with a high risk of thrombosis, particularly during the first months of treatment including immunomodulatory drugs (IMiDs). There is no consensus on prevention of thromboembolic risk in patients with de novo MM, and identification of patients requiring anticoagulant thromboprophylaxis remains challenging. Evaluating coagulability by an in vitro thrombin generation (TG) test might be a way of identifying such patients.

Objective: To determine whether TG assessment could reveal an increase in coagulability during the first three chemotherapy cycles.

Methods: This prospective and longitudinal observational study included patients newly diagnosed with MM. TG was determined in platelet-rich and platelet-poor plasma using calibrated automated thrombography with a low tissue factor (TF) concentration.

Results: Seventy-one patients were enrolled, allowing TG analysis during 213 chemotherapy cycles. TG remained unchanged throughout follow-up irrespective of treatment regimen, but values determined before cycles 2 and 3 were significantly higher in patients receiving iMiDs-containing regimens. No association was found between TG and its changes and thrombosis occurrence during follow-up: venous thrombosis in eight patients; no cardiovascular event. A significantly (87%) lower risk of venous thrombosis was observed in patients receiving prophylaxis with a low-molecular-weight heparin (LMWH; OR: 0.13 (95% CI: 0.02-0.76). Neither bortezomib- nor dexamethasone-containing regimens were associated with thrombotic risk. Changes in TG, as studied, were not associated with thrombotic events.

Conclusions: The only factor associated with a reduction in early thrombotic risk was prophylaxis with LMWH. The issue of how to identify patients requiring prophylactic anticoagulation remains unresolved.
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http://dx.doi.org/10.1002/rth2.12161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332829PMC
January 2019

Platelet toll-like receptors are crucial sensors of infectious danger moieties.

Platelets 2018 Sep 13;29(6):533-540. Epub 2018 Mar 13.

a EA3064-GIMAP , University of Lyon-UJM , Saint-Etienne , France.

In addition to their haemostatic role and function in the repair of damaged vascular epithelium, platelets play a defensive role in innate immunity, having the capacity to produce and secrete various anti-infectious factors, as well as cytokines, chemokines and related products, to interact with other immune cells to modulate immune responses to pathogens. Thus, it is now widely acknowledged that platelets participate in inflammatory processes and infection resolution, most notably by expressing and using receptors to bind infectious pathogen moieties and contributing to pathogen clearance. The ability of platelets to sense external danger signals relates to the expression of certain innate immunity receptors, such as toll-like receptors (TLRs), and the activation of efficient cell signalling machinery. TLR engagement triggers platelet response, which results in adapted degranulation according to: the type of TLR engaged, the nature of the ligand and the milieu; together, the TLR-mediated event and other signalling events may be followed by aggregation. Platelets thus use complex tools to mediate a whole range of functions upon sensing danger. By linking the inflammatory and haemostatic platelet response to infection, TLRs play a central role. The extent of the inflammatory response to pathogen clearance is still a debatable issue and is discussed in this short review.
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http://dx.doi.org/10.1080/09537104.2018.1445842DOI Listing
September 2018

Antithrombotic therapy and platelet transfusions in hematologic malignancy patients presenting chemotherapy-induced thrombocytopenia: a French survey.

Transfusion 2017 07 25;57(7):1717-1723. Epub 2017 Apr 25.

Centre d'Investigation Clinique-CIC 1408.

Background: Patients with hematologic malignancies are at high risk for both thrombosis and bleeding. During the prolonged periods of thrombocytopenia experienced by patients who are receiving intensive chemotherapy, clinicians often hesitate to prescribe any protection against thrombosis. In case of anticoagulant prescription, it is the prescribers' responsibility to weigh risks and benefits for each patient. Current guidelines exist but do not take into account types of thrombosis, patients' comorbidities, or previous bleeding events.

Study Design And Methods: We proposed to gain insight into hematologists' beliefs about antithrombotic prescription in hematologic malignancy patients, to design future clinical trials. Therefore, we conducted a survey in France to evaluate the practices among a panel of hematologists.

Results: We found that more than 92% of the respondents prescribed therapeutic anticoagulation in case of pulmonary embolism or deep venous thrombosis. In the case of therapeutic anticoagulation, only 64% of the physicians reconsidered treatment under a platelet threshold of 50 × 10 /L. None of the respondents decided to renounce treatment, nor to discontinue it because of thrombocytopenia, except in distal venous thrombosis or superficial vein thrombosis. One-fifth of clinicians proposed the insertion of a vena cava filter.

Conclusion: As observed in the United States and Canada, we noticed discrepancies between recommendations and current practices in France. This highlights the urgent need to conduct studies to evaluate both efficacy and safety of antithrombotics in patients with hematologic cancer and thrombocytopenia.
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http://dx.doi.org/10.1111/trf.14120DOI Listing
July 2017

When Hypereosinophilia Leads to Stroke.

Eur J Case Rep Intern Med 2017 3;4(6):000614. Epub 2017 Apr 3.

Intensive care unit, CHU Saint Etienne, Hopital Nord, 42055 Saint Etienne, France.

AFIP1L1-PDGFRA fusion can only be confirmed through molecular and cytogenetic investigations causing a delay in the diagnosis. However, patients with this mutation need urgent treatment because they present hypereosinophilia which may be associated with short-term tissue damage. Thromboembolism is a known cause of death in hypereosinophilic syndrome. A case of Loeffler endocarditis due to FIP1L1-PDGFRA-associated chronic eosinophilic leukemia presenting hemiparesis with fever, which also mislead the initial diagnosis, is reported.

Learning Points: FIP1L1-PDGFRA fusion occurs in 10% of patients with idiopathic hypereosinophilia.Thromboembolism is a known cause of death in hypereosinophilia.The prognosis of FIP1L1-PDGFRA-associated chronic eosinophilic leukemia has been profoundly changed by imatinib treatment.
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http://dx.doi.org/10.12890/2017_000614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346789PMC
April 2017

Cost-effectiveness analysis of low-molecular-weight heparin versus aspirin thromboprophylaxis in patients newly diagnosed with multiple myeloma.

Thromb Res 2016 Sep 10;145:119-25. Epub 2016 Aug 10.

Inserm, CIC1408, F-42055 Saint-Etienne, France. Electronic address:

Introduction: The aim of this study was to assess the cost-effectiveness of low molecular weight heparin versus aspirin as primary thromboprophylaxis throughout chemotherapy for newly diagnosed multiple myeloma patients treated with protocols including thalidomide from the perspective of French health care providers.

Methods: We used a modeling approach combining data from the only randomized trial evaluating the efficacy of the two treatments and secondary sources for costs, and utility values. We performed a decision-tree analysis and our base case was a hypothetical cohort of 10,000 patients. A bootstrap resampling technique was used. The incremental cost-effectiveness ratio was calculated using estimated quality-adjusted life years as the efficacy outcome. Incremental costs and effectiveness were estimated for each strategy and the incremental cost-effectiveness ratio was calculated. One-way sensitivity analyses were performed.

Results: The number of quality-adjusted life years was estimated to be 0.300 with aspirin and 0.299 with heparin. The estimated gain with aspirin was therefore approximately one day. Over 6months, the mean total cost was € 1518 (SD=601) per patient in the heparin arm and € 273 (SD=1019) in the aspirin arm. This resulted in an incremental cost of € 1245 per patient treated with heparin. The incremental cost-effectiveness ratio for the aspirin versus heparin strategy was calculated to be - 687,398 € (95% CI, -13,457,369 to -225,385).

Conclusions: Aspirin rather than heparin thromboprophylaxis, during the first six months of chemotherapy for myeloma, is associated with significant cost savings per patient and also with an unexpected slight increase in quality of life.
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http://dx.doi.org/10.1016/j.thromres.2016.08.008DOI Listing
September 2016

Usual risk factors do not predict venous thromboembolism in newly diagnosed myeloma treated with immunomodulatory drugs.

Am J Hematol 2016 10 14;91(10):E455-6. Epub 2016 Jul 14.

Centre d'investigation Clinique CIC 1408, CHU Saint Etienne, France.

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http://dx.doi.org/10.1002/ajh.24454DOI Listing
October 2016

Limited screening with versus without (18)F-fluorodeoxyglucose PET/CT for occult malignancy in unprovoked venous thromboembolism: an open-label randomised controlled trial.

Lancet Oncol 2016 Feb 8;17(2):193-199. Epub 2015 Dec 8.

Service de Médecine Nucléaire, EA 3878 (GETBO) IFR 148, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, Brest, France. Electronic address:

Background: Clear guidelines for the investigation of occult malignancy after unprovoked venous thromboembolism are not yet available. (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT could serve as a comprehensive screening strategy for occult malignancy in this context. We aimed to compare a screening strategy based on (18)F-FDG PET/CT with a limited screening strategy for detection of malignant disease in patients with unprovoked venous thromboembolism.

Methods: In an open-label, multicentre, randomised study we enrolled patients from four French university hospitals. Patients aged 18 years or older, diagnosed with unprovoked venous thromboembolism (not provoked by a major inherited or acquired risk factor) were invited to participate. Patients were randomly assigned in a 1:1 ratio to a limited screening strategy (physical examination, usual laboratory tests, and basic radiographs) or a screening strategy consisting of the limited strategy plus an (18)F-FDG PET/CT scan. Randomisation was done with a dedicated central web-based randomisation system, in block sizes of six, stratified by centre, and concealed from the investigators. Patients and investigators were not masked to study group assignment. Patients were followed up for 2 years. The primary outcome was the proportion of patients with a cancer diagnosis in each group after the initial screening assessment. Analyses were conducted in modified intention-to-test and per-protocol populations. This trial is completed and registered with ClinicalTrials.gov, number NCT00964275.

Findings: Between March 3, 2009, and Aug 18, 2012, we enrolled and randomly assigned 399 patients; five withdrew consent, leaving 197 in each group for the modified intention-to-test analysis. After initial screening assessment, cancer was diagnosed in 11 (5·6%) patients in the (18)F-FDG PET/CT group and four (2·0%) patients in the limited screening group (absolute risk difference 3·6%, 95% CI -0·4 to 7·9; p=0·07). At the initial screening assessment, seven (64%) of the 11 cancers diagnosed in the (18)F-FDG PET/CT group were early-stage compared with two of four cancers diagnosed in the limited screening group (p=1·00). One (0·5%) occult malignancy was detected in 186 patients who had negative initial screening in the (18)F-FDG PET/CT group, compared with nine (4·7%) in 193 patients in the limited screening group (absolute risk difference 4·1%, 95% CI 0·8 to 8·4, p=0·01). Overall, five (42%) of the 12 cancers diagnosed in the (18)F-FDG PET/CT group were advanced stage, compared with seven (54%) of the 13 cancers diagnosed in the limited screening group (p=0·70). 16 patients died during follow-up, eight (4·1%) in each group. Two (1·0%) patients in the (18)F-FDG PET/CT group and five (2·5%) in the limited screening group had cancer-related deaths.

Interpretation: A strategy including limited screening and a (18)F-FDG PET/CT was not associated with a significantly higher rate of cancer diagnosis after unprovoked venous thromboembolism. The risk of subsequent cancer diagnosis was, however, lower in patients who had negative initial screening that included (18)F-FDG PET/CT than in patients who had negative initial limited screening. Whether or not (18)F-FDG PET/CT might be useful in a more selected population of patients with a high risk of cancer remains to be determined.

Funding: Programme Hospitalier de Recherche Clinique (French Department of Health).
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http://dx.doi.org/10.1016/S1470-2045(15)00480-5DOI Listing
February 2016

Seasonal variation in the superficial vein thrombosis frequency.

Thromb Res 2015 Dec 8;136(6):1116-9. Epub 2015 Oct 8.

CIC-EC Inserm, CIE3, CHU Hôpital Nord, Saint-Etienne, France; EA3065, Université Jean Monnet, PRES de Lyon, Saint-Etienne, France; Service de Médecine Vasculaire et Thérapeutique, CHU de Saint-Etienne, Saint-Etienne, France.

Introduction: A seasonal variation of venous thromboembolic disease frequency is subject to discussion, and has been recently suggested for superficial vein thrombosis (SVT) in a small retrospective study. Our aim was to search for a seasonal variation of SVT frequency according to the data of larger studies.

Materials And Methods: We analyzed the data of three French prospective multicenter studies with different designs which have included patients with SVT (STENOX, POST, and STEPH studies). Seasonal variation of SVT frequency was evaluated by comparing the observed seasonal frequency of SVT to a theoretical frequency of 25% for each season.

Results: The analysis included 1395 patients and 4.75 seasonal cycles. The difference to a theoretical frequency of 25% was statistically significant in one study (POST, p = 0.044). The higher risk difference was -6.1% (95% CI -11.7–−0.5) in summer in STENOX, +7.1% (95% CI +2.7-+11.5) in winter in POST and 4.2% (95% CI -5.2-+13.7) in spring in STEPH, corresponding to a relative risk of 0.80, 1.40 and 1.20, respectively.

Conclusions: A seasonal variation was found in only one study which has the weakest methodology to warrant completeness. Variation pattern was
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http://dx.doi.org/10.1016/j.thromres.2015.10.007DOI Listing
December 2015

Delayed-onset heparin-induced thrombocytopenia without thrombosis in a patient receiving postoperative thromboprophylaxis with rivaroxaban.

Thromb Haemost 2015 Aug 11;114(3):652-4. Epub 2015 Jun 11.

Bernard Tardy, CHU - Intensive care, InsermCIE3, CHU Saint Etienne, Saint Etienne, Loire 42055, France, Tel.: +33 4 77 12 07 97, Fax: +33 4 77 12 78 20, E-mail:

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http://dx.doi.org/10.1160/TH14-07-0593DOI Listing
August 2015

Transient and Persistent Acute Kidney Injury and the Risk of Hospital Mortality in Critically Ill Patients: Results of a Multicenter Cohort Study.

Crit Care Med 2015 Aug;43(8):e269-75

1Medical-Surgical Intensive Care Unit, Saint-Etienne University Hospital, Jean Monnet University, Saint-Etienne, France. 2Medical-Surgical Intensive Care Unit, Le Raincy-Montfermeil Hospital, Montfermeil, France. 3Medical ICU, Clermont-Ferrand University Hospital, Clermont-Ferrand, France. 4UFR de Médecine, Clermont-Ferrand University, Clermont-Ferrand, France. 5Medical Intensive Care Unit, Archet University Hospital, Nice, France. 6UFR de Médecine, Nice University, Nice, France. 7Nephrology, Dialysis and Renal Transplantation, Saint-Etienne University Hospital, Jean Monnet University, Saint-Etienne, France. 8Thrombosis Research Group, EA 3065, Saint-Etienne University Hospital and Saint-Etienne Medical School, Saint-Etienne, France. 9Department of Emergency Medicine, Saint-Etienne University Hospital, Jean Monnet University, Saint-Etienne, France.

Objective: To assess the prognostic impact of transient and persistent acute kidney injury in critically ill patients.

Design: Retrospective analysis of prospectively collected patient data

Setting: : Six hospital ICUs.

Patients: Critically-ill patients with ICU stay longer than three days.

Intervention: None.

Measurements And Main Results: Assessment of hospital survival with respect to acute kidney injury duration. A total of 447 patients were included in this study, including 283 patients (63.3%) with an acute kidney injury at admission (175 and 108 patients with persistent and transient acute kidney injury, respectively). Patients with persistent acute kidney injury more frequently had stage 3 acute kidney injury (42.9% vs 30.6%; p = 0.04). Hospital survival was 76.2% (n = 125) in patients without acute kidney injury, 70.4% (n = 76) in patients with transient acute kidney injury, and 61.1% (n = 107) in patients with persistent acute kidney injury. After adjustment for confounding factors, the factors associated with lower hospital survival were the need for vasopressors (odds ratio, 0.65; 95% CI, 0.43-0.98) and the presence of persistent acute kidney injury (odds ratio, 0.58; 95% CI, 0.36-0.95). When included in the final model, stage 3 acute kidney injury was independently associated with a lower hospital survival (odds ratio, 0.83; 95% CI, 0.70-0.98), and persistent acute kidney injury was no longer associated with outcome.

Conclusion: Two thirds of the critically ill patients with acute kidney injury have persistent acute kidney injury. Although mortality increased progressively with the duration of acute kidney injury, we found no independent association between this duration and patient outcome when the acute kidney injury severity is taken into account. Our results suggest that the classical "prerenal acute kidney injury" and "acute tubular necrosis" paradigm might be of limited interest from a pathophysiological or prognostic point of view.
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http://dx.doi.org/10.1097/CCM.0000000000001077DOI Listing
August 2015

Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial.

JAMA 2015 Apr;313(16):1627-35

Université Nantes Angers Le Mans, France.

Importance: Although retrievable inferior vena cava filters are frequently used in addition to anticoagulation in patients with acute venous thromboembolism, their benefit-risk ratio is unclear.

Objective: To evaluate the efficacy and safety of retrievable vena cava filters plus anticoagulation vs anticoagulation alone for preventing pulmonary embolism recurrence in patients presenting with acute pulmonary embolism and a high risk of recurrence.

Design, Setting, And Participants: Randomized, open-label, blinded end point trial (PREPIC2) with 6-month follow-up conducted from August 2006 to January 2013. Hospitalized patients with acute, symptomatic pulmonary embolism associated with lower-limb vein thrombosis and at least 1 criterion for severity were assigned to retrievable inferior vena cava filter implantation plus anticoagulation (filter group; n = 200) or anticoagulation alone with no filter implantation (control group; n = 199). Initial hospitalization with ambulatory follow-up occurred in 17 French centers.

Interventions: Full-dose anticoagulation for at least 6 months in all patients. Insertion of a retrievable inferior vena cava filter in patients randomized to the filter group. Filter retrieval was planned at 3 months from placement.

Main Outcomes And Measures: Primary efficacy outcome was symptomatic recurrent pulmonary embolism at 3 months. Secondary outcomes were recurrent pulmonary embolism at 6 months, symptomatic deep vein thrombosis, major bleeding, death at 3 and 6 months, and filter complications.

Results: In the filter group, the filter was successfully inserted in 193 patients and was retrieved as planned in 153 of the 164 patients in whom retrieval was attempted. By 3 months, recurrent pulmonary embolism had occurred in 6 patients (3.0%; all fatal) in the filter group and in 3 patients (1.5%; 2 fatal) in the control group (relative risk with filter, 2.00 [95% CI, 0.51-7.89]; P = .50). Results were similar at 6 months. No difference was observed between the 2 groups regarding the other outcomes. Filter thrombosis occurred in 3 patients.

Conclusions And Relevance: Among hospitalized patients with severe acute pulmonary embolism, the use of a retrievable inferior vena cava filter plus anticoagulation compared with anticoagulation alone did not reduce the risk of symptomatic recurrent pulmonary embolism at 3 months. These findings do not support the use of this type of filter in patients who can be treated with anticoagulation.

Trial Registration: clinicaltrials.gov Identifier: NCT00457158.
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http://dx.doi.org/10.1001/jama.2015.3780DOI Listing
April 2015

A diagnosis of haemolytic-uraemic syndrome blurred by alcohol abuse.

BMJ Case Rep 2014 Dec 24;2014. Epub 2014 Dec 24.

Intensive Care Unit, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Priest-en-Jarez, France.

A 60-year-old man with a history of alcohol abuse was admitted to the intensive care unit (ICU) for status epilepticus. At first, laboratory and imagery findings were almost normal, and the symptoms were attributed to severe alcohol withdrawal due to a history of gastroenteritis reported by his family. But, during the following days, haemolytic anaemia, thrombocytopenia, acute renal failure, and ischaemic and haemorrhagic lesions seen on a cerebral CT scan led to the diagnosis of haemolytic-uraemic syndrome (HUS). Despite these severe complications, the patient made a good recovery following ICU and plasma exchange with fresh frozen plasma (FFP), but cognitive deficit still existed after 1 month. It is important to know that neurological manifestations can precede typical biological and radiological signs in HUS, and to not be misled in the diagnosis process, especially when a more common differential diagnosis is possible.
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http://dx.doi.org/10.1136/bcr-2014-205940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281547PMC
December 2014

Performance of 18F fluoro-2-désoxy-D-glucose positron emission tomography/computed tomography for the diagnosis of venous thromboembolism.

Thromb Res 2015 Jan 20;135(1):31-5. Epub 2014 Oct 20.

Université Européenne de Bretagne, Brest, France; Université de Brest, EA3878 (GETBO) IFR 148, Brest, France; CHRU de la Cavale Blanche, Service de médecine nucléaire, Boulevard Tanguy Prigent, 29609 Brest cedex, France.

Introduction: Thrombosis and inflammation are intimately linked. Inflammatory component of venous thromboembolism (VTE) may allow the use of FDG positron emission tomography / computed tomography (FDG PET/CT) in the detection of thrombotic process. Published studies remain limited and contradictory. We aimed at evaluating the performance of FDG PET/CT in the detection of VTE in a population of patients enrolled in a prospective study evaluating FDG PET/CT for cancer screening in etiological assessment of idiopathic VTE.

Materials And Methods: The first consecutive 100 patients who underwent FDG PET/CT were included. Visual and quantitative analyses of vascular axes was performed and compared with lower limb veins compression ultrasonography, lung scintigraphy and/or computed tomography pulmonary angiography.

Results: Out of the 100 patients, 63 presented lobar pulmonary embolism for a total of 217 embolic sites and 62 had a deep vein thrombosis for a total of 143 thrombotic sites. Regarding pulmonary embolism, sensitivity and specificity of FDG PET/CT were 3% (95%CI: 1-6%) and 99% (95%CI: 98-100%). SUV max ratio between pulmonary embolism location and non-pathological contralateral vessel was 1.04±0.18 (p=0.7). Regarding deep vein thrombosis, sensitivity and specificity were 31% (95%CI: 24-39%) and 88% (95%CI: 81-92%). The metabolic activity was significantly higher than in contralateral vessels (p<0.001), with a SUV max ratio of 1.25±0.53, but without any significant SUVmax threshold applicable in routine practice for deep vein thrombosis diagnosis.

Conclusions: FDG PET/CT is not accurate enough for the diagnosis of VTE.
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http://dx.doi.org/10.1016/j.thromres.2014.10.008DOI Listing
January 2015

Restarting anticoagulation after major gastrointestinal bleeding.

Am J Cardiol 2014 May 19;113(10):1776. Epub 2014 Mar 19.

Saint Etienne, France.

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http://dx.doi.org/10.1016/j.amjcard.2014.03.003DOI Listing
May 2014

[Venous thromboembolism medical thromboprophylaxis in patients admitted to palliative units].

Presse Med 2013 Sep 22;42(9 Pt 1):1246-50. Epub 2013 Jul 22.

CHU de Saint-Étienne, fédération de soins palliatifs, 42055 Saint-Étienne cedex 2, France; CHU de Saint-Étienne, Inserm CIE3, 42055 Saint-Étienne cedex 2, France. Electronic address:

Venous thromboembolism incidence as identification of bleeding risk factors is not well defined in patients admitted to palliative units. There is no randomized controlled trial evaluating medical thromboprophylaxis in patients admitted to palliative units. Medical thromboprophylaxis seems to be inappropriate in patients admitted to palliative units. Medical thromboprophylaxis prescription should be discussed individually in patients admitted to palliative units. Conversely, cancer patients admitted for an acute medical disease should receive medical thromboprophylaxis, if their prognosis exceeds several months.
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http://dx.doi.org/10.1016/j.lpm.2013.06.006DOI Listing
September 2013

Diagnostic accuracy of early urinary index changes in differentiating transient from persistent acute kidney injury in critically ill patients: multicenter cohort study.

Crit Care 2013 Mar 26;17(2):R56. Epub 2013 Mar 26.

Introduction: Urinary indices have limited effectiveness in separating transient acute kidney injury (AKI) from persistent AKI in ICU patients. Their time-course may vary with the mechanism of AKI. The primary objective of this study was to evaluate the diagnostic value of changes over time of the usual urinary indices in separating transient AKI from persistent AKI.

Methods: An observational prospective multicenter study was performed in six ICUs involving 244 consecutive patients, including 97 without AKI, 54 with transient AKI, and 93 with persistent AKI. Urinary sodium, urea and creatinine were measured at ICU admission (H0) and on 6-hour urine samples during the first 24 ICU hours (H6, H12, H18, and H24). Transient AKI was defined as AKI with a cause for renal hypoperfusion and reversal within 3 days.

Results: Significant increases from H0 to H24 were noted in fractional excretion of urea (median, 31% (22 to 41%) and 39% (29 to 48%) at H24, P<0.0001), urinary urea/plasma urea ratio (15 (7 to 28) and 20 (9 to 40), P<0.0001), and urinary creatinine/plasma creatinine ratio (50 (24 to 101) and 57 (29 to 104), P=0.01). Fractional excretion of sodium did not change significantly during the first 24 hours in the ICU (P=0.13). Neither urinary index values at ICU admission nor changes in urinary indices between H0 and H24 performed sufficiently well to recommend their use in clinical setting (area under the receiver-operating characteristic curve≤0.65).

Conclusion: Although urinary indices at H24 performed slightly better than those at H0 in differentiating transient AKI from persistent AKI, they remain insufficiently reliable to be clinically relevant.
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http://dx.doi.org/10.1186/cc12582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733426PMC
March 2013

Effects of argatroban, danaparoid, and fondaparinux on trombin generation in heparin-induced thrombocytopenia.

Thromb Haemost 2013 Mar 17;109(3):504-9. Epub 2013 Jan 17.

Laboratoire d'Hématologie, Groupe de Recherche sur la Thrombose, EA 3065, Université J Monet, Inserm CIE 3, CHU Saint Etienne, 42055 Saint Etienne cedex 2, France.

There is no in vitro data on the comparison of the effects of danaparoid, argatroban and fondaparinux on thrombin generation in patients with heparin-induced thrombocytopenia. It was the study objective to compare the in vitro anticoagulant potential of argatroban, danaparoid and fondaparinux using a thrombin generation assay TGA on a mixture of control platelet-rich plasma (PRP) and HIT patient platelet-poor plasma (PPP). The plasma of seven patients with a clear HIT diagnosed at our institution was selected. Mixtures of donor PRP and patient PPP were incubated with unfractionated heparin 0.2 U.mL⁻¹, argatroban at 600 ng.mL⁻¹, argatroban at 400 ng.mL⁻¹, danaparoid at 0.65 IU.mL⁻¹ and fondaparinux at 1 μg.mL⁻¹. Thrombin generation was assessed by calibrated thrombinography. The percentage of inhibition of the endogenous thrombin potential observed with argatroban at 600 ng.mL⁻¹ was statistically significantly higher compared with those observed with fondaparinux (median: 53.6% vs. 3.9%; p=0.031) but not compared with argatroban at 400 ng.mL⁻¹ and danaparoid. The percentage of inhibition of the thrombin peak observed with argatroban at 600 ng.mL⁻¹ was statistically significantly higher compared with those observed with danaparoid (median: 71.2 vs. 56.8; p=0.031) and fondaparinux (mean: 71.2 vs. 30; p=0.031) but not with argatroban at 400 ng.mL⁻¹. In conclusion, the in vitro effect of argatroban and danaparoid on thrombin generation seems to corroborate the results of clinical studies of these drugs in the treatment of HIT in term of efficiency. Fondaparinux showed a very small effect on thrombin generation evaluated by calibrated thrombinography.
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http://dx.doi.org/10.1160/TH12-05-0321DOI Listing
March 2013