Publications by authors named "Benjamin Planquette"

78 Publications

[Treatment of cancer associated thrombosis].

Bull Cancer 2022 Jan 18. Epub 2022 Jan 18.

Université de Paris, Paris, France; Hôpital Européen Georges-Pompidou, service de pneumologie et de soins intensifs, Assistance Publique des hôpitaux de Paris, 20 rue Leblanc, 75015 Paris, France; INSERM UMRS-1140 Innovations thérapeutiques en hémostase Paris, France; Réseau F-CRIN INNOVTE, 42000 Saint Etienne, France.

In active cancers, venous thromboembolism is a poor prognosis factor and one of the main causes of death. Venous thromboembolism is 4 to 7 times more common in patients with active cancer compared with the general population. The risk of thrombosis depends on characteristics related to the patient, cancer, and current treatments. The management of these patients is essentially based on therapeutic anticoagulation, which prevents the progression of the thrombus and reduces the risk of recurrence. Risks of thromboembolism recurrence and bleeding are increased in oncologic context, despite therapeutic anticoagulation, which complicates the management of these patients. Low molecular weight heparins have been the treatment of choice in recent decades, because more effective than vitamin K antagonists with a similar tolerance profile. More recently, several studies have evaluated direct oral anticoagulants, which are easier to use, in cancer-associated thrombosis. Compared with low molecular weight heparins, direct oral anticoagulants have similar efficacity concerning thromboembolism recurrence, but an increased risk of bleeding observed mainly in gastrointestinal and urogenital cancers. This overview summarizes the epidemiology, pathophysiology, and therapeutic management of cancer-associated thrombosis.
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http://dx.doi.org/10.1016/j.bulcan.2021.11.015DOI Listing
January 2022

Intermediate- vs. Standard-Dose Prophylactic Anticoagulation in Patients With COVID-19 Admitted in Medical Ward: A Propensity Score-Matched Cohort Study.

Front Med (Lausanne) 2021 15;8:747527. Epub 2021 Oct 15.

Paris Cardiovascular Research Center (PARCC), INSERM, Université de Paris, Paris, France.

Microthrombosis and large-vessel thrombosis are the main triggers of COVID-19 worsening. The optimal anticoagulant regimen in COVID-19 patients hospitalized in medical wards remains unknown. To evaluate the effects of intermediate-dose vs. standard-dose prophylactic anticoagulation (AC) among patients with COVID-19 hospitalized in medical wards. We used a large French multicentric retrospective study enrolling 2,878 COVID-19 patients hospitalized in medical wards. After exclusion of patients who had an AC treatment before hospitalization, we generated a propensity-score-matched cohort of patients who were treated with intermediate-dose or standard-dose prophylactic AC between February 26 and April 20, 2020 (intermediate-dose, = 261; standard-dose prophylactic anticoagulation, = 763). The primary outcome of the study was in-hospital mortality; this occurred in 23 of 261 (8.8%) patients in the intermediate-dose group and 74 of 783 (9.4%) patients in the standard-dose prophylactic AC group ( = 0.85); while time to death was also the same in both the treatment groups (11.5 and 11.6 days, respectively, = 0.17). We did not observe any difference regarding venous and arterial thrombotic events between the intermediate dose and standard dose, respectively (venous thrombotic events: 2.3 vs. 2.4%, p=0.99; arterial thrombotic events: 2.7 vs. 1.2%, = 0.25). The 30-day Kaplan-Meier curves for in-hospital mortality demonstrate no statistically significant difference in in-hospital mortality (HR: 0.99 (0.63-1.60); = 0.99). Moreover, we found that no particular subgroup was associated with a significant reduction in in-hospital mortality. Among COVID-19 patients hospitalized in medical wards, intermediate-dose prophylactic AC compared with standard-dose prophylactic AC did not result in a significant difference in in-hospital mortality.
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http://dx.doi.org/10.3389/fmed.2021.747527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553987PMC
October 2021

Cardiometabolic Disorders and the Risk of Critical COVID-19 as Compared to Influenza Pneumonia.

J Clin Med 2021 Oct 8;10(19). Epub 2021 Oct 8.

Université de Paris, F-75006 Paris, France.

We aimed to compare the influence of cardiometabolic disorders on the incidence of severe COVID-19 vs. non-COVID pneumonia. We included all consecutive patients admitted with SARS-CoV-2-positive pneumonia between 12 March 2020 and 1 April 2020 and compared them to patients with influenza pneumonia hospitalized between December 2017 and December 2019 at the same tertiary hospital in Paris. Patients with COVID-19 were significantly younger and more frequently male. In the analysis adjusted for age and sex, patients with COVID-19 were more likely to be obese (adjOR: 2.25; 95% CI 1.24-4.09; = 0.0076) and receive diuretics (adjOR: 2.13; 95% CI 1.12-4.03; = 0.021) but were less likely to be smokers (adjOR: 0.40; 95% CI 0.24-0.64; = 0.0002), have COPD (adjOR: 0.25; 95% CI 0.11-0.56; = 0.0008), or have a previous or active cancer diagnosis (adjOR: 0.54, 95% CI 0.32-0.91; = 0.020). The rate of ICU admission was significantly higher in patients with COVID-19 (32.4% vs. 5.2% < 0.0001). Obesity was significantly associated with the risk of direct ICU admission in patients with COVID-19 but not in patients with influenza pneumonia. Likewise, pre-existing hypertension was significantly associated with mortality in patients with COVID-19 but not in patients with influenza pneumonia. Cardiometabolic disorders differentially influenced the risk of presenting with severe COVID-19 or influenza pneumonia.
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http://dx.doi.org/10.3390/jcm10194618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509116PMC
October 2021

Rivaroxaban vs Dalteparin in Cancer-Associated Thromboembolism: A Randomized Trial.

Chest 2021 Oct 8. Epub 2021 Oct 8.

F-CRIN INNOVTE Network, Saint-Etienne, France; Service de Médecine Vasculaire et Thérapeutique, CHU Saint-Etienne, Hôpital Nord, Saint-Etienne, France.

Background: Direct oral anticoagulants (DOACs) are an alternative to low-molecular-weight heparin for treating cancer-associated VTE.

Research Question: Is rivaroxaban as efficient and safe as dalteparin to treat patients with cancer-associated VTE?

Study Design And Methods: In a randomized open-label noninferiority trial, patients with active cancer who had proximal DVT, pulmonary embolism (PE), or both were assigned randomly to therapeutic doses of rivaroxaban or dalteparin for 3 months. The primary outcome was the cumulative incidence of recurrent VTE, a composite of symptomatic or incidental DVT or PE, and worsening of pulmonary vascular or venous obstruction at 3 months.

Results: Of 158 randomized patients, 74 and 84 patients were assigned to receive rivaroxaban and dalteparin, respectively. Mean age was 69.4 years, and 115 patients (76.2%) had metastatic disease. The primary outcome occurred in 4 and 6 patients in the rivaroxaban and dalteparin groups, respectively (both the intention-to-treat and per-protocol populations: cumulative incidence, 6.4% vs 10.1%; subdistribution hazard ratio [SHR], 0.75; 95% CI, 0.21-2.66). Major bleeding occurred in 1 and 3 patients in the rivaroxaban and dalteparin groups, respectively (cumulative incidence, 1.4% vs 3.7%; SHR, 0.36; 95% CI, 0.04-3.43). Major or clinically relevant nonmajor bleeding occurred in 9 and 8 patients in the rivaroxaban and dalteparin groups, respectively (cumulative incidence, 12.2% vs 9.8%; SHR, 1.27; 95% CI, 0.49-3.26). Overall, 19 patients (25.7%) and 20 patients (23.8%) died in the rivaroxaban and dalteparin groups, respectively (hazard ratio, 1.05; 95% CI, 0.56-1.97).

Interpretation: In this trial comparing rivaroxaban and dalteparin in the treatment of cancer-associated VTE, the number of patients was insufficient to reach the predefined criteria for noninferiority, but efficacy and safety results were consistent with those previously reported with DOACs. An updated meta-analysis of randomized trials comparing DOACs with low-molecular-weight heparin in patients with cancer-associated VTE is provided.

Trial Registry: ClinicalTrials.gov; No.: NCT02746185; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.09.037DOI Listing
October 2021

Direct Oral Anticoagulants as Successful Treatment of Heparin-Induced Thrombocytopenia: A Parisian Retrospective Case Series.

Front Med (Lausanne) 2021 5;8:713649. Epub 2021 Aug 5.

Hematology-Immunology-Transfusion Department, Hôpitaux Universitaires Paris Ile De France Ouest, Université Versailles Saint Quentin, Boulogne, France.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic life-threatening disorder caused by an adverse reaction to heparin exposure. In this context, it is imperative to stop heparin immediately and to replace it by a non-heparin anticoagulant therapy. Despite their advantages, the use of direct oral anticoagulants (DOACs) is only emerging for HIT treatment, and their use remains rare. To improve our knowledge on the emerging role of DOACs as treatment of HIT and give an overview of our local practices in this context. This is a multi-centric retrospective case series of HIT patients referred to our Parisian pharmacovigilance network and treated with DOACs. We report the cases of seven patients from four healthcare centers, diagnosed with HIT (4T score ≥ 4, positive anti-PF4/heparin immunoassay and positive serotonin-release assay) and treated with DOACs. After a few days on substitutive parenteral treatment ( = 6) or directly at HIT diagnosis ( = 1), these patients were treated with either rivaroxaban ( = 6) or apixaban ( = 1) during acute HIT phase. Mean time to platelet count recovery after heparin discontinuation was 3.3 days (range 3-5). No patient experienced major or clinically relevant non-major bleeding or thrombosis that could be related to DOAC treatment during follow-up. Our cases studies are consistent with recent guidelines credit to the potential and safe use of DOAC during acute HIT in clinically stable patients.
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http://dx.doi.org/10.3389/fmed.2021.713649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374891PMC
August 2021

Triaging acute pulmonary embolism for home treatment by Hestia or simplified PESI criteria: the HOME-PE randomized trial.

Eur Heart J 2021 08;42(33):3146-3157

F-CRIN, INNOVTE, Saint-Etienne, France.

Aims: The aim of this study is to compare the Hestia rule vs. the simplified Pulmonary Embolism Severity Index (sPESI) for triaging patients with acute pulmonary embolism (PE) for home treatment.

Methods And Results: Normotensive patients with PE of 26 hospitals from France, Belgium, the Netherlands, and Switzerland were randomized to either triaging with Hestia or sPESI. They were designated for home treatment if the triaging tool was negative and if the physician-in-charge, taking into account the patient's opinion, did not consider that hospitalization was required. The main outcomes were the 30-day composite of recurrent venous thrombo-embolism, major bleeding or all-cause death (non-inferiority analysis with 2.5% absolute risk difference as margin), and the rate of patients discharged home within 24 h after randomization (NCT02811237). From January 2017 through July 2019, 1975 patients were included. In the per-protocol population, the primary outcome occurred in 3.82% (34/891) in the Hestia arm and 3.57% (32/896) in the sPESI arm (P = 0.004 for non-inferiority). In the intention-to-treat population, 38.4% of the Hestia patients (378/984) were treated at home vs. 36.6% (361/986) of the sPESI patients (P = 0.41 for superiority), with a 30-day composite outcome rate of 1.33% (5/375) and 1.11% (4/359), respectively. No recurrent or fatal PE occurred in either home treatment arm.

Conclusions: For triaging PE patients, the strategy based on the Hestia rule and the strategy based on sPESI had similar safety and effectiveness. With either tool complemented by the overruling of the physician-in-charge, more than a third of patients were treated at home with a low incidence of complications.
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http://dx.doi.org/10.1093/eurheartj/ehab373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408662PMC
August 2021

Seasonal burden of severe influenza virus infection in the critically ill patients, using the Assistance Publique-Hôpitaux de Paris clinical data warehouse: a pilot study.

Ann Intensive Care 2021 Jul 29;11(1):117. Epub 2021 Jul 29.

Unité de Santé Publique, INSERM, Institut Pierre Louis d'Epidemiologie et de Sante Publique, Hopital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, 75012, Paris, France.

Purpose: At the critical care level, the flu surveillance system is limited in France, with heterogeneous regional modalities of implementation.

Materials, Patients And Methods: We aimed at assessing the relevance of the Assistance Publique-Hôpitaux de Paris (AP-HP) clinical data warehouse for estimating the burden of the influenza epidemic on medical adult critical care units of the AP-HP, and outcome of patients during the flu season 2017-2018. This exploratory multi-site epidemiological study comprised all consecutive adult stays (n = 320) in 18 medical intensive care units (ICU) or intermediate care wards (ICW) for probable or confirmed Influenza virus infection during the 2017-2018 flu season.

Results: Patients admitted to ICU/ICW had low vaccination coverage (21%), required life support in 60% of cases, stayed in the ICU for a median of 8 days, and had high 28-day mortality rate (19.7%; 95% confidence interval 15.5-24.5). Early prognostic factors included age, core temperature, the acute organ failures score, and the early administration of antiviral therapy.

Conclusions: Data directly extracted from the electronic medical records stored in the data warehouse provide detailed clinical, care pathway and prognosis information. The real-time availability should enable to detect and assess the burden of the most severe cases. By a firmer and more acute monitoring and adjustment of care and patient management, hospitals could generate more ICU/ICW capacities, sensitize their emergency department and contribute to the recommendations from health authorities. This pilot study is of particular relevance in the context of emerging epidemics of severe acute respiratory diseases.
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http://dx.doi.org/10.1186/s13613-021-00884-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319596PMC
July 2021

Intramuscular Vaccination in Adults with Therapeutic Anticoagulation in the Era of COVID-19 Vaccines Outbreak: A Practical Review.

TH Open 2021 Apr 25;5(2):e166-e170. Epub 2021 May 25.

Hematology department and Biosurgical Research Lab (Carpentier Foundation), Assistance Publique Hôpitaux de Paris.Centre-Université de Paris (APHP-CUP), Université de Paris, Innovative Therapies in Haemostasis, INSERM, Paris, France.

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http://dx.doi.org/10.1055/s-0041-1729627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149207PMC
April 2021

Von Willebrand factor collagen-binding capacity predicts in-hospital mortality in COVID-19 patients: insight from VWF/ADAMTS13 ratio imbalance.

Angiogenesis 2021 08 11;24(3):407-411. Epub 2021 May 11.

Université de Paris, Innovative Therapies in Haemostasis, INSERM, 75006, Paris, France.

Background: Microthrombosis is a hallmark of COVID-19. We previously described von willebrand factor (VWF) and their high molecular weight multimers (HMWMs) as potential trigger of microthrombosis.

Objectives: Investigate VWF activity with collagen-binding assay and ADAMTS13 in COVID-19.

Methods And Results: Our study enrolled 77 hospitalized COVID-19 patients including 37 suffering from a non-critical form and 40 with critical form. Plasma levels of VWF collagen-binding ability (VWF:CB) and ADAMTS13 activity (ADAMTS13:Act) were measured in the first 48 hours following admission. VWF:CB was increased in critical (631% IQR [460-704]) patients compared to non-critical patients (259% [235-330], p < 0.005). VWF:CB was significantly associated (r = 0.564, p < 0.001) with HMWMs. Moreover, median ADAMTS13:Act was lower in critical (64.8 IU/dL IQR 50.0-77.7) than non-critical patients (85.0 IU/dL IQR 75.8-94.7, p < 0.001), even if no patients displayed majors deficits. VWF:Ag-to-ADAMTS13:Act ratio was highly associated with VWF:CB (r = 0.916, p < 0.001). Moreover, VWF:CB level was highly predictive of COVID-19 in-hospital mortality as shown by the ROC curve analysis (AUC = 0.92, p < 0.0001) in which we identified a VWF:CB cut-off of 446% as providing the best predictor sensitivity-specificity balance. We confirmed this cut-off thanks to a Kaplan-Meier estimator analysis (log-rank p < 0.001) and a Cox-proportional Hazard model (HR = 49.1, 95% CI 1.81-1328.2, p = 0.021) adjusted on, BMI, C-reactive protein, and D-dimer levels.

Conclusion: VWF:CB levels could summarize both VWF increased levels and hyper-reactivity subsequent to ADAMTS13 overflow and, therefore, be a valuable and easy to perform clinical biomarker of microthrombosis and COVID-19 severity.
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http://dx.doi.org/10.1007/s10456-021-09789-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111656PMC
August 2021

Lupus Anticoagulant Single Positivity During the Acute Phase of COVID-19 Is Not Associated With Venous Thromboembolism or In-Hospital Mortality.

Arthritis Rheumatol 2021 11 22;73(11):1976-1985. Epub 2021 Sep 22.

Université de Paris, Innovative Therapies in Haemostasis, INSERM, F-75006, and Respiratory Medicine Department and Biosurgical Research Lab (Carpentier Foundation), APHP-CUP, F-75015 Paris, France and F-CRIN INNOVTE, Saint-Étienne, France.

Objective: The clinical relevance of antiphospholipid antibodies (aPLs) in COVID-19 is controversial. This study was undertaken to investigate the prevalence and prognostic value of conventional and nonconventional aPLs in patients with COVID-19.

Methods: This was a multicenter, prospective observational study in a French cohort of patients hospitalized with suspected COVID-19.

Results: Two hundred forty-nine patients were hospitalized with suspected COVID-19, in whom COVID-19 was confirmed in 154 and not confirmed in 95. We found a significant increase in lupus anticoagulant (LAC) positivity among patients with COVID-19 compared to patients without COVID-19 (60.9% versus 23.7%; P < 0.001), while prevalence of conventional aPLs (IgG and IgM anti-β -glycoprotein I and IgG and IgM anticardiolipin isotypes) and nonconventional aPLs (IgA isotype of anticardiolipin, IgA isotype of anti-β -glycoprotein I, IgG and IgM isotypes of anti-phosphatidylserine/prothrombin, and IgG and IgM isotypes of antiprothrombin) was low in both groups. Patients with COVID-19 who were positive for LAC, as compared to patients with COVID-19 who were negative for LAC, had higher levels of fibrinogen (median 6.0 gm/liter [interquartile range 5.0-7.0] versus 5.3 gm/liter [interquartile range 4.3-6.4]; P = 0.028) and C-reactive protein (CRP) (median 115.5 mg/liter [interquartile range 66.0-204.8] versus 91.8 mg/liter [interquartile range 27.0-155.1]; P = 0.019). Univariate analysis did not show any association between LAC positivity and higher risks of venous thromboembolism (VTE) (odds ratio 1.02 [95% confidence interval 0.44-2.43], P = 0.95) or in-hospital mortality (odds ratio 1.80 [95% confidence interval 0.70-5.05], P = 0.24). With and without adjustment for CRP level, age, and sex, Kaplan-Meier survival curves according to LAC positivity confirmed the absence of an association with VTE or in-hospital mortality (unadjusted P = 0.64 and P = 0.26, respectively; adjusted hazard ratio 1.13 [95% confidence interval 0.48-2.60] and 1.80 [95% confidence interval 0.67-5.01], respectively).

Conclusion: Patients with COVID-19 have an increased prevalence of LAC positivity associated with biologic markers of inflammation. However, LAC positivity at the time of hospital admission is not associated with VTE risk and/or in-hospital mortality.
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http://dx.doi.org/10.1002/art.41777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250965PMC
November 2021

D-dimer at hospital admission for COVID-19 are associated with in-hospital mortality, independent of venous thromboembolism: Insights from a French multicenter cohort study.

Arch Cardiovasc Dis 2021 May 9;114(5):381-393. Epub 2021 Mar 9.

Université de Paris, PARCC, INSERM, 75015 Paris, France.

Background: Coronavirus disease 2019 (COVID-19) has been associated with coagulation disorders, in particular high concentrations of D-dimer, and increased frequency of venous thromboembolism.

Aim: To explore the association between D-dimer at admission and in-hospital mortality in patients hospitalised for COVID-19, with or without symptomatic venous thromboembolism.

Methods: From 26 February to 20 April 2020, D-dimer concentration at admission and outcomes (in-hospital mortality and venous thromboembolism) of patients hospitalised for COVID-19 in medical wards were retrospectively analysed in a multicenter study in 24 French hospitals.

Results: Among 2878 patients enrolled in the study, 1154 (40.1%) patients had D-dimer measurement at admission. Receiver operating characteristic curve analysis identified a D-dimer concentration>1128ng/mL as the best cut-off value for in-hospital mortality (area under the curve 64.9%, 95% confidence interval [CI] 60-69), with a sensitivity of 71.1% (95% CI 62-78) and a specificity of 55.6% (95% CI 52-58), which did not differ in the subgroup of patients with venous thromboembolism during hospitalisation. Among 545 (47.2%) patients with D-dimer concentration>1128ng/mL at admission, 86 (15.8%) deaths occurred during hospitalisation. After adjustment, in Cox proportional hazards and logistic regression models, D-dimer concentration>1128ng/mL at admission was also associated with a worse prognosis, with an odds ratio of 3.07 (95% CI 2.05-4.69; P<0.001) and an adjusted hazard ratio of 2.11 (95% CI 1.31-3.4; P<0.01).

Conclusions: D-dimer concentration>1128ng/mL is a relevant predictive factor for in-hospital mortality in patients hospitalised for COVID-19 in a medical ward, regardless of the occurrence of venous thromboembolism during hospitalisation.
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http://dx.doi.org/10.1016/j.acvd.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942155PMC
May 2021

Placental growth factor level in plasma predicts COVID-19 severity and in-hospital mortality.

J Thromb Haemost 2021 07 17;19(7):1823-1830. Epub 2021 May 17.

Université de Paris, PARCC, INSERM U970, Paris, France.

Background: Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with vascular inflammation and endothelial injury.

Objectives: To correlate circulating angiogenic markers vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF), and fibroblast growth factor 2 (FGF-2) to in-hospital mortality in COVID-19 adult patients.

Methods: Consecutive ambulatory and hospitalized patients with COVID-19 infection were enrolled. VEGF-A, PlGF, and FGF-2 were measured in each patient ≤48 h following admission.

Results: The study enrolled 237 patients with suspected COVID-19: 208 patients had a positive diagnostic for COVID-19, of whom 23 were mild outpatients and 185 patients hospitalized after admission. Levels of VEGF-A, PlGF, and FGF-2 significantly increase with the severity of the disease (P < .001). Using a logistic regression model, we found a significant association between the increase of FGF-2 or PlGF and mortality (odds ratio [OR] 1.11, 95% confidence interval [CI; 1.07-1.16], P < .001 for FGF-2 and OR 1.07 95% CI [1.04-1.10], P < .001 for PlGF) while no association were found for VEGF-A levels. Receiver operating characteristic curve analysis was performed and we identified PlGF above 30 pg/ml as the best predictor of in-hospital mortality in COVID-19 patients. Survival analysis for PlGF confirmed its interest for in-hospital mortality prediction, by using a Kaplan-Meier survival curve (P = .001) and a Cox proportional hazard model adjusted to age, body mass index, D-dimer, and C-reactive protein (3.23 95% CI [1.29-8.11], P = .001).

Conclusion: Angiogenic factor PlGF is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that PlGF blocking strategies could be a new interesting therapeutic approach in COVID-19.
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http://dx.doi.org/10.1111/jth.15339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250221PMC
July 2021

Anticoagulation Before Hospitalization Is a Potential Protective Factor for COVID-19: Insight From a French Multicenter Cohort Study.

J Am Heart Assoc 2021 04 8;10(8):e018624. Epub 2021 Feb 8.

PARCC INSERM Université de Paris France.

Background Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with thrombotic outcomes with coagulation and endothelial disorders. Based on that, several anticoagulation guidelines have been proposed. We aimed to determine whether anticoagulation therapy modifies the risk of developing severe COVID-19. Methods and Results Patients with COVID-19 initially admitted in medical wards of 24 French hospitals were included prospectively from February 26 to April 20, 2020. We used a Poisson regression model, Cox proportional hazard model, and matched propensity score to assess the effect of anticoagulation on outcomes (intensive care unit admission or in-hospital mortality). The study enrolled 2878 patients with COVID-19, among whom 382 (13.2%) were treated with oral anticoagulation therapy before hospitalization. After adjustment, anticoagulation therapy before hospitalization was associated with a better prognosis with an adjusted hazard ratio of 0.70 (95% CI, 0.55-0.88). Analyses performed using propensity score matching confirmed that anticoagulation therapy before hospitalization was associated with a better prognosis, with an adjusted hazard ratio of 0.43 (95% CI, 0.29-0.63) for intensive care unit admission and adjusted hazard ratio of 0.76 (95% CI, 0.61-0.98) for composite criteria intensive care unit admission or death. In contrast, therapeutic or prophylactic low- or high-dose anticoagulation started during hospitalization were not associated with any of the outcomes. Conclusions Anticoagulation therapy used before hospitalization in medical wards was associated with a better prognosis in contrast with anticoagulation initiated during hospitalization. Anticoagulation therapy introduced in early disease could better prevent COVID-19-associated coagulopathy and endotheliopathy, and lead to a better prognosis.
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http://dx.doi.org/10.1161/JAHA.120.018624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174166PMC
April 2021

Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality.

Angiogenesis 2021 08 15;24(3):505-517. Epub 2021 Jan 15.

Université de Paris, Institut Cochin, INSERM, 75014 Paris, France, Hematology Department Assistance Publique Hôpitaux de Paris. Centre-Université de Paris (APHP-CUP), Cochin Hospital, 75014, Paris, France.

Background: Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with endotheliitis and microthrombosis.

Objectives: To correlate endothelial dysfunction to in-hospital mortality in a bi-centric cohort of COVID-19 adult patients.

Methods: Consecutive ambulatory and hospitalized patients with laboratory-confirmed COVID-19 were enrolled. A panel of endothelial biomarkers and von Willebrand factor (VWF) multimers were measured in each patient ≤ 48 h following admission.

Results: Study enrolled 208 COVID-19 patients of whom 23 were mild outpatients and 189 patients hospitalized after admission. Most of endothelial biomarkers tested were found increased in the 89 critical patients transferred to intensive care unit. However, only von Willebrand factor antigen (VWF:Ag) scaled according to clinical severity, with levels significantly higher in critical patients (median 507%, IQR 428-596) compared to non-critical patients (288%, 230-350, p < 0.0001) or COVID-19 outpatients (144%, 133-198, p = 0.007). Moreover, VWF high molecular weight multimers (HMWM) were significantly higher in critical patients (median ratio 1.18, IQR 0.86-1.09) compared to non-critical patients (0.96, 1.04-1.39, p < 0.001). Among all endothelial biomarkers measured, ROC curve analysis identified a VWF:Ag cut-off of 423% as the best predictor for in-hospital mortality. The accuracy of VWF:Ag was further confirmed in a Kaplan-Meier estimator analysis and a Cox proportional Hazard model adjusted on age, BMI, C-reactive protein and D-dimer levels.

Conclusion: VWF:Ag is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that VWF, including excess of HMWM forms, drives microthrombosis in COVID-19.
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http://dx.doi.org/10.1007/s10456-020-09762-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809553PMC
August 2021

Impact of integrating objective structured clinical examination into academic student assessment: Large-scale experience in a French medical school.

PLoS One 2021 14;16(1):e0245439. Epub 2021 Jan 14.

Université de Paris, Faculté de Médecine, Paris, France.

Purpose: Objective structured clinical examinations (OSCE) evaluate clinical reasoning, communication skills, and interpersonal behavior during medical education. In France, clinical training has long relied on bedside clinical practice in academic hospitals. The need for a simulated teaching environment has recently emerged, due to the increasing number of students admitted to medical schools, and the necessity of objectively evaluating practical skills. This study aimed at investigating the relationships between OSCE grades and current evaluation modalities.

Methods: Three-hundred seventy-nine 4th-year students of University-of-Paris Medical School participated to the first large-scale OSCE at this institution, consisting in three OSCE stations (OSCE#1-3). OSCE#1 and #2 focused on cardiovascular clinical skills and competence, whereas OSCE#3 focused on relational skills while providing explanations before planned cholecystectomy. We investigated correlations of OSCE grades with multiple choice (MCQ)-based written examinations and evaluations of clinical skills and behavior (during hospital traineeships); OSCE grade distribution; and the impact of integrating OSCE grades into the current evaluation in terms of student ranking.

Results: The competence-oriented OSCE#1 and OSCE#2 grades correlated only with MCQ grades (r = 0.19, P<0.001) or traineeship skill grades (r = 0.17, P = 0.001), respectively, and not with traineeship behavior grades (P>0.75). Conversely, the behavior-oriented OSCE#3 grades correlated with traineeship skill and behavior grades (r = 0.19, P<0.001, and r = 0.12, P = 0.032), but not with MCQ grades (P = 0.09). The dispersion of OSCE grades was wider than for MCQ examinations (P<0.001). When OSCE grades were integrated to the final fourth-year grade with an incremental 10%, 20% or 40% coefficient, an increasing proportion of the 379 students had a ranking variation by ±50 ranks (P<0.001). This ranking change mainly affected students among the mid-50% of ranking.

Conclusion: This large-scale French experience showed that OSCE designed to assess a combination of clinical competence and behavioral skills, increases the discriminatory capacity of current evaluations modalities in French medical schools.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245439PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808634PMC
June 2021

Predictive Factor for COVID-19 Worsening: Insights for High-Sensitivity Troponin and D-Dimer and Correlation With Right Ventricular Afterload.

Front Med (Lausanne) 2020 12;7:586307. Epub 2020 Nov 12.

Innovative Therapies in Haemostasis, INSERM, Université de Paris, Paris, France.

Coronavirus disease 2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders. To explore clinical and biological parameters of COVID-19 patients with hospitalization criteria that could predict referral to intensive care unit (ICU). Analyzing the clinical and biological profiles of COVID-19 patients at admission. Among 99 consecutive patients that fulfilled criteria for hospitalization, 48 were hospitalized in the medicine department, 21 were first admitted to the medicine ward department and referred later to ICU, and 30 were directly admitted to ICU from the emergency department. At admission, patients requiring ICU were more likely to have lymphopenia, decreased SpO, a D-dimer level above 1,000 ng/mL, and a higher high-sensitivity cardiac troponin (Hs-cTnI) level. A receiver operating characteristic curve analysis identified Hs-cTnI above 9.75 pg/mL as the best predictive criteria for ICU referral [area under the curve (AUC), 86.4; 95% CI, 76.6-96.2]. This cutoff for Hs-cTnI was confirmed in univariate [odds ratio (OR), 22.8; 95% CI, 6.0-116.2] and multivariate analysis after adjustment for D-dimer level (adjusted OR, 20.85; 95% CI, 4.76-128.4). Transthoracic echocardiography parameters subsequently measured in 72 patients showed an increased right ventricular (RV) afterload correlated with Hs-cTnI ( = 0.42, = 0.010) and D-dimer ( = 0.18, = 0.047). Hs-cTnI appears to be the best relevant predictive factor for referring COVID-19 patients to ICU. This result associated with the correlation of D-dimer with RV dilatation probably reflects a myocardial injury due to an increased RV wall tension. This reinforces the hypothesis of a COVID-19-associated microvascular thrombosis inducing a higher RV afterload.
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http://dx.doi.org/10.3389/fmed.2020.586307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689153PMC
November 2020

Multidimensional Proteomic Approach of Endothelial Progenitors Demonstrate Expression of KDR Restricted to CD19 Cells.

Stem Cell Rev Rep 2021 04 17;17(2):639-651. Epub 2020 Nov 17.

Innovative Therapies in Haemostasis, INSERM, Université de Paris, F-75006, Paris, France.

Endothelial progenitor cells (EPCs) are involved in vasculogenesis and cardiovascular diseases. However, the phenotype of circulating EPCs remains elusive but they are more often described as CD34KDR. The aim of the study was to extensively characterize circulating potential vasculogenic stem cell candidates in two populations of patients with cardiovascular disease by powerful multidimensional single cell complementary cytometric approaches (mass, imaging and flow). We identified cellular candidates in one patient before and after bioprosthetic total artificial heart implantation and results were confirmed in healthy peripheral and cord blood by mass cytometry. We also quantified cellular candidates in 10 patients with different COVID-19 severity. Both C-TAH implantation and COVID-19 at critical stage induce a redistribution of circulating CD34 and CD19 sub-populations in peripheral blood. After C-TAH implantation, circulating CD34 progenitor cells expressed c-Kit stem marker while specific subsets CD34CD133CD45c-KitKDR were mobilized. KDR was only expressed by CD19 B-lymphocytes and CD14 monocytes subpopulations in circulation. We confirmed by mass cytometry this KDR expression on CD19 in healthy peripheral and cord blood, also with a VE-cadherin expression, confirming absence of endothelial lineage marker on CD34 subtypes. In COVID-19, a significant mobilization of CD34c-KitKDR cells was observed between moderate and critical COVID-19 patients regardless CD133 or CD45 expression. In order to better evaluate EPC phenotype, we performed imaging flow cytometry measurements of immature CD34KDR cells in cord blood and showed that, after elimination of non-circular events, those cells were all CD19. During COVID-19, a significant mobilization of CD19KDR per million of CD45 cells was observed between moderate and critical COVID-19 patients regardless of CD34 expression. CD34c-Kit cells are mobilized in both cardiovascular disease described here. KDR cells in peripheral blood are CD19 positive cells and are not classic vasculogenic stem and/or progenitor cells. A better evaluation of c-Kit and KDR expressing cells will lead to the redefinition of circulating endothelial progenitors.Graphical abstract Central illustration figure. Multidimensional proteomic approach of endothelial progenitors demonstrate expression of KDR restricted to CD19 cells. Endothelial progenitor cells (EPCs) are involved in cardiovascular diseases, however their phenotype remains elusive. We elucidated here EPCs phenotype by a deep characterization by multidimensional single cell complementary cytometric approaches after Bioprosthetic total artificial heart implantation and during COVID-19. We showed a redistribution of circulating CD34 and CD19 sub-populations in both situations. None of the immature cell population expresses KDR. Mobilized CD34 expressed c-Kit. Imaging flow cytometry demonstrated that CD34KDR cells, after elimination of non-circular events, are all CD19. Our results suggest a new definition of circulating EPCs and emphasize involvement of CD19 cells in cardiovascular disease.
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http://dx.doi.org/10.1007/s12015-020-10062-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670993PMC
April 2021

Prevalence and characteristics of pulmonary embolism in 1042 COVID-19 patients with respiratory symptoms: A nested case-control study.

Thromb Res 2021 01 7;197:94-99. Epub 2020 Nov 7.

Université de Paris, France; Groupe Hospitalier Paris Saint-Joseph, F-75014 Paris, France; Department of Vascular Medicine, France; INSERM CRESS UMR 1153, F-75005 Paris, France.

Introduction: Coronavirus disease 2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders. Previous studies reported pulmonary embolism (PE) in severe COVID-19 patients. Aim of the study was to estimate the prevalence of symptomatic PE in COVID-19 patients and to identify the clinical, radiological or biological characteristics associated with PE.

Patients/methods: We conducted a retrospective nested case-control study in 2 French hospitals. Controls were matched in a 1:2 ratio on the basis of age, sex and center. PE patients with COVID-19 were compared to patients in whom PE was ruled out (CTPA controls) and in whom PE has not been investigated (CT controls).

Results: PE was suspected in 269 patients among 1042 COVID-19 patients, and confirmed in 59 patients (5.6%). Half of PE was diagnosed at COVID-19 diagnosis. PE patients did not differ from CT and CTPA controls for thrombosis risk factors. PE patients more often required invasive ventilation compared to CTPA controls (odds ratio (OR) 2.79; 95% confidence interval (CI) 1.33-5.84) and to CT controls (OR 8.07; 95% CI 2.70-23.82). PE patients exhibited more extensive parenchymal lesions (>50%) than CT controls (OR 3.90; 95% CI 1.54-9.94). D-dimer levels were 5.1 (95% CI 1.90-13.76) times higher in PE patients than CTPA controls.

Conclusions: Our results suggest a PE prevalence in COVID-19 patients close to 5% in the whole population and to 20% of the clinically suspected population. PE seems to be associated with more extensive lung damage and to require more frequently invasive ventilation.
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http://dx.doi.org/10.1016/j.thromres.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648521PMC
January 2021

Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19.

Blood 2020 11;136(20):2290-2295

Paris University, Institut Necker-Enfants Malades, CNRS UMR 8253 and INSERM UMR1151, Hôpital Necker-Enfants Malades, Paris, France.

Anti-CD20 monoclonal antibodies are widely used for the treatment of hematological malignancies or autoimmune disease but may be responsible for a secondary humoral deficiency. In the context of COVID-19 infection, this may prevent the elicitation of a specific SARS-CoV-2 antibody response. We report a series of 17 consecutive patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms, negative immunoglobulin G (IgG)-IgM SARS-CoV-2 serology, and positive RNAemia measured by digital polymerase chain reaction who were treated with 4 units of COVID-19 convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Only 1 patient who needed mechanical ventilation for severe COVID-19 disease died of bacterial pneumonia. SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. In 3 patients, virus-specific T-cell responses were analyzed using T-cell enzyme-linked immunospot assay before convalescent plasma transfusion. All showed a maintained SARS-CoV-2 T-cell response and poor cross-response to other coronaviruses. No adverse event was reported. Convalescent plasma with anti-SARS-CoV-2 antibodies appears to be a very promising approach in the context of protracted COVID-19 symptoms in patients unable to mount a specific humoral response to SARS-CoV-2.
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http://dx.doi.org/10.1182/blood.2020008423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702482PMC
November 2020

Long-Term Treatment of Cancer-Associated Thrombosis (CAT) Beyond 6 Months in the Medical Practice: USCAT, a 432-Patient Retrospective Non-Interventional Study.

Cancers (Basel) 2020 Aug 12;12(8). Epub 2020 Aug 12.

F-CRIN INNOVTE network, F-42055 Saint-Etienne, France.

Background: extended anticoagulant therapy beyond the initial 6 months is suggested in patients with cancer-associated thrombosis (CAT) and active cancer. Few data are available on patient management and outcomes on the period between 6 and 12 months after the venous thromboembolism (VTE) event.

Objectives: our objective was to document patient management and outcomes beyond 6 months and up to 12 months in CAT patients initially treated for 6 months with tinzaparin.

Methods: adult CAT patients with a cancer still alive at the end of an initial 6-month treatment period were eligible to participate in this retrospective non-interventional French multicenter study.

Results: a total of 432 patients aged 66.5 ± 12.7 years were available to participate in this study. Out of the patients included in the study, the anticoagulant treatment was maintained in 348 of 422 documented patients (82.5%) while it was discontinued in 74 (17.5%) patients (before the end or at the end of the initial 6-month treatment period). Between 6 and 12 months, 24 patients (5.7%) experienced VTE recurrence, while 21 (5.1%) patients had clinically relevant bleeding, 11 patients (2.7%) had major bleeding and 96 patients (22.3%) died, mostly from cancer. VTE recurrence was more frequent in patients with lung (14.3%) and colorectal cancer (6.0%) while major bleeding was more frequent in patients with colorectal cancer (6.0%).

Conclusion: clinical outcomes were consistent with previous observations and variable according to the type of cancer. Further clinical research is required to orient the management of patients with CAT beyond 6 months based on cancer-specific treatment strategies.
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http://dx.doi.org/10.3390/cancers12082256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463918PMC
August 2020

[A step forward for thromboembolic disease treatment in patients with cancer].

Bull Cancer 2020 Jul - Aug;107(7-8):723-725. Epub 2020 Jul 24.

AH-HP, hôpital Cochin, Department of Respiratory Medicine, 75014 Paris, France; Université Paris Descartes, équipe « cancer, immune control and escape », centre de recherches des Cordeliers, Inserm U1138, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.bulcan.2020.06.001DOI Listing
September 2020

Curative anticoagulation prevents endothelial lesion in COVID-19 patients.

J Thromb Haemost 2020 09 30;18(9):2391-2399. Epub 2020 Jul 30.

Innovative Therapies in Haemostasis, INSERM, Université de Paris, Paris, France.

Background: Coronavirus disease-2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders.

Objectives: To explore the coagulopathy and endothelial dysfunction in COVID-19 patients.

Methods: The study analyzed clinical and biological profiles of patients with suspected COVID-19 infection at admission, including hemostasis tests and quantification of circulating endothelial cells (CECs).

Results: Among 96 consecutive COVID-19-suspected patients fulfilling criteria for hospitalization, 66 were tested positive for SARS-CoV-2. COVID-19-positive patients were more likely to present with fever (P = .02), cough (P = .03), and pneumonia at computed tomography (CT) scan (P = .002) at admission. Prevalence of D-dimer >500 ng/mL was higher in COVID-19-positive patients (74.2% versus 43.3%; P = .007). No sign of disseminated intravascular coagulation were identified. Adding D-dimers >500 ng/mL to gender and pneumonia at CT scan in receiver operating characteristic curve analysis significantly increased area under the curve for COVID-19 diagnosis. COVID-19-positive patients had significantly more CECs at admission (P = .008) than COVID-19-negative ones. COVID-19-positive patients treated with curative anticoagulant prior to admission had fewer CECs (P = .02) than those without. Interestingly, patients treated with curative anticoagulation and angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers had even fewer CECs (P = .007).

Conclusion: Curative anticoagulation could prevent COVID-19-associated coagulopathy and endothelial lesion.
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http://dx.doi.org/10.1111/jth.14968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323356PMC
September 2020

Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of COVID-19 patients.

Angiogenesis 2020 11 27;23(4):611-620. Epub 2020 May 27.

Université de Paris, Innovative Therapies in Haemostasis, INSERM, 75006, Paris, France.

Background: Coronavirus disease-2019 (COVID-19), a respiratory disease has been associated with ischemic complications, coagulation disorders, and an endotheliitis.

Objectives: To explore endothelial damage and activation-related biomarkers in COVID-19 patients with criteria of hospitalization for referral to intensive care unit (ICU) and/or respiratory worsening.

Methods: Analysis of endothelial and angiogenic soluble markers in plasma from patients at admission.

Results: Study enrolled 40 consecutive COVID-19 patients admitted to emergency department that fulfilled criteria for hospitalization. Half of them were admitted in conventional wards without any ICU transfer during hospitalization; whereas the 20 others were directly transferred to ICU. Patients transferred in ICU were more likely to have lymphopenia, decreased SpO2 and increased D-dimer, CRP and creatinine levels. In those patients, soluble E-selectin and angiopoietin-2 were significantly increased (p value at 0.009 and 0.003, respectively). Increase in SELE gene expression (gene coding for E-selectin protein) was confirmed in an independent cohort of 32 patients using a whole blood gene expression profile analysis. In plasma, we found a strong association between angiopoetin-2 and CRP, creatinine and D-dimers (with p value at 0.001, 0.001 and 0.003, respectively). ROC curve analysis identified an Angiopoietin-2 cut-off of 5000 pg/mL as the best predictor for ICU outcome (Se = 80.1%, Sp = 70%, PPV = 72.7%, NPV = 77%), further confirmed in multivariate analysis after adjustment for creatinine, CRP or D-dimers.

Conclusion: Angiopoietin-2 is a relevant predictive factor for ICU direct admission in COVID-19 patients. This result showing an endothelial activation reinforces the hypothesis of a COVID-19-associated microvascular dysfunction.
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http://dx.doi.org/10.1007/s10456-020-09730-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250589PMC
November 2020

Evaluation of Venous Thromboembolism Recurrence Scores in an Unprovoked Pulmonary Embolism Population: A Post-hoc Analysis of the PADIS-PE trial.

Am J Med 2020 08 22;133(8):e406-e421. Epub 2020 Apr 22.

Département de Médecine Interne et Pneumologie, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, and EA 3878, CIC INSERM 1412, Brest, France.

Background: We aimed to validate the Men Continue and HERDOO2 (HERDOO2), D-dimer, age, sex, hormonal therapy (DASH), and updated Vienna recurrent venous thromboembolism prediction models in a population composed entirely of first unprovoked pulmonary embolism, and to analyze the impact of the addition of the pulmonary vascular obstruction index (PVOI) on score accuracy.

Methods: Analyses were based on the double-blind, randomized PADIS-PE trial, which included 371 unprovoked pulmonary embolism patients initially treated for 6 months, successively randomized to receive an additional 18 months of warfarin or placebo, and subsequently followed-up for 2 years.

Results: The HERDOO2, DASH, and updated Vienna scores displayed C-statistics of 0.61 (95% CI 0.54-0.68), 0.60 (95% CI 0.53-0.66), and 0.58 (95% CI 0.51-0.66), respectively. Only the HERDOO2 score identified low recurrence risk patients (<3%/year) after anticoagulation was stopped. When added to either of the prediction models, PVOI measured at pulmonary embolism diagnosis, after 6 months of anticoagulation, or both, improved scores' C-statistics between +0.06 and +0.11 points and consistently led to identifying at least 50% of patients who experienced recurrence but in whom the scores would have indicated against extended anticoagulation.

Conclusions: In patients with a first unprovoked pulmonary embolism, the HERDOO2 score is able to identify patients with a low recurrence risk after treatment discontinuation. Addition of PVOI improves accuracy of all scores.

Clinical Trials Registration: URL: http://www.controlled-trials.com. Unique identifier: NCT00740883.
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http://dx.doi.org/10.1016/j.amjmed.2020.03.040DOI Listing
August 2020

Incidental venous thromboembolism, detected by chance, but still venous thromboembolism.

Eur Respir J 2020 02 6;55(2). Epub 2020 Feb 6.

Division of Respiratory Disease, APHP Centre, Université Paris Descartes, Université de Paris, Paris, France.

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http://dx.doi.org/10.1183/13993003.00028-2020DOI Listing
February 2020

Predictors for Residual Pulmonary Vascular Obstruction after Unprovoked Pulmonary Embolism: Implications for Clinical Practice-The PADIS-PE Trial.

Thromb Haemost 2019 Sep 23;119(9):1489-1497. Epub 2019 Jun 23.

Département de Médecine Interne et Pneumologie, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, and EA 3878, CIC INSERM 1412, Brest, France.

Background:  We aimed to identify risk factors for residual pulmonary vascular obstruction after a first unprovoked pulmonary embolism (PE).

Methods:  Analyses were based on data from the double-blind randomized "PADIS-PE" trial that included 371 patients with a first unprovoked PE initially treated during 6 uninterrupted months; all patients underwent baseline ventilation-perfusion lung scanning at inclusion (i.e., after 6 months of anticoagulation). Each patient's pulmonary vascular obstruction indexes (PVOIs) at PE diagnosis and at inclusion were centrally assessed.

Results:  Among the 371 included patients, residual PVOI was available in 356 patients, and 150 (42.1%) patients had PVOI ≥ 5%. At multivariable analysis, age > 65 years (odds ratio [OR], 2.81, 95% confidence interval [CI], 1.58-5.00), PVOI ≥ 25% at PE diagnosis (OR, 3.53, 95% CI, 1.94-6.41), elevated factor VIII (OR, 3.89, 95% CI, 1.41-10.8), and chronic respiratory disease (OR, 2.18, 95% CI, 1.11-4.26) were independent predictors for residual PVOI ≥ 5%. Patients with ≥ 1 of these factors represented 94.5% (123 patients) of all patients with residual PVOI ≥ 5%.

Conclusion:  Six months after a first unprovoked PE, age > 65 years, PVOI ≥ 25% at PE diagnosis, elevated factor VIII, or chronic respiratory disease were found to be independent predictors for residual pulmonary vascular obstruction.

Clinical Trials Registration:  URL: http://www.controlled-trials.com. Unique identifier: NCT00740883.
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http://dx.doi.org/10.1055/s-0039-1692424DOI Listing
September 2019

Prognostic value of right ventricular dysfunction or elevated cardiac biomarkers in patients with low-risk pulmonary embolism: a systematic review and meta-analysis.

Eur Heart J 2019 03;40(11):902-910

F-CRIN INNOVTE, Hôpital Nord, CHU Saint Etienne, Avenue Albert Raimond, Saint Priest en Jarez (Saint Etienne), France.

Aims: Patients with acute pulmonary embolism (PE) classified as low risk by the Pulmonary Embolism Severity Index (PESI), its simplified version (sPESI), or the Hestia criteria may be considered for early discharge. We investigated whether the presence of right ventricular (RV) dysfunction may aggravate the early prognosis of these patients.

Methods And Results: We did a systematic review and meta-analysis of studies including low-risk patients with acute PE to investigate the prognostic value of RV dysfunction. Diagnosis of RV dysfunction was based on echocardiography or computed tomography pulmonary angiography. In addition, we investigated the prognostic value of elevated troponin or natriuretic peptide levels. The primary outcome was all-cause mortality at 30 days or during hospitalization. We included 22 studies (N = 3295 low-risk patients) in the systematic review: 21 were selected for quantitative analysis. Early all-cause mortality rates in patients with vs. without RV dysfunction on imaging were 1.8% [95% confidence interval (CI) 0.9-3.5%] vs. 0.2% (95% CI 0.03-1.7%), respectively, [odds ratio (OR) 4.19, 95% CI 1.39-12.58]. For troponins, rates were 3.8% (95% CI 2.1-6.8%) vs. 0.5% (95% CI 0.2-1.3%), (OR 6.25, 95% CI 1.95-20.05). For natriuretic peptides, only data on early PE-related mortality were available: rates were 1.7% (95% CI 0.4-6.9%) vs. 0.4% (95% CI 0.1-1.1%), (OR 3.71, 95% CI 0.81-17.02).

Conclusions: In low-risk patients with acute PE, the presence of RV dysfunction on admission was associated with early mortality. Our results may have implications for the management of patients who appear at low risk based on clinical criteria alone, but present with RV dysfunction as indicated by imaging findings or laboratory markers.
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http://dx.doi.org/10.1093/eurheartj/ehy873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416533PMC
March 2019

Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism: protocol for a systematic review and meta-analysis of individual participant data.

BMJ Open 2018 11 28;8(11):e023939. Epub 2018 Nov 28.

EA3878 (GETBO), Université de Brest, Brest, France.

Background: In patients with a first, unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulant therapy (AT) is controversial due to tightly balanced risks and benefits of indefinite anticoagulation. The objective of this study is to assess among patients with a first acute pulmonary embolism (PE) who received ≥3 months of AT and thereafter had a planar lung scan, whether residual pulmonary vascular obstruction (RPVO) is associated with VTE recurrence after discontinuation of AT.

Methods And Analysis: We will conduct a systematic review with a meta-analysis of individual participant data of contemporary studies evaluating the prognostic significance of RPVO in patients with a first acute PE. We will search from inception to 24 January 2018, PubMed, Medline, Embase and Cochrane's Central Registry for Randomized Controlled Trials, CENTRAL for randomized controlled trials and prospective cohort studies. Two reviewers will conduct all screening and data collection independently. The methodological quality and risk of bias of eligible studies will be carefully and rigorously assessed using the Risk Of Bias In Non-randomised Studies of Interventions tool. The primary objective will be to assess the relationship between RPVO on ventilation-perfusion scan after completion of at least 3 months of AT after an acute PE event, and the risk of an objectively confirmed symptomatic recurrent VTE (including deep vein thrombosis or PE) or death due to PE. The secondary objectives will include the assessment of the optimal RPVO cut-off and the risk of recurrent VTE, as well as the relationship between the relative change in RPVO between PE diagnosis and at discontinuation of AT (≥3 months) and risk of recurrent VTE.

Ethics And Dissemination: This study of secondary data does not require ethics approval. It will be presented internationally and published in the peer-reviewed literature.

Prospero Registration Number: CRD42017081080.
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http://dx.doi.org/10.1136/bmjopen-2018-023939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278780PMC
November 2018
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