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1.
Res Pract Thromb Haemost ; 6(4): e12730, 2022 May.
Article in English | MEDLINE | ID: covidwho-1866565

ABSTRACT

D-dimer is a fragment of crosslinked fibrin resulting from plasmin cleavage of fibrin clots and hence an indirect biomarker of the hemostatic system activation. Early in the coronavirus disease 2019 (COVID-19) pandemic, several studies described coagulation disorders in affected patients, including high D-dimer levels. Consequently, D-dimer has been widely used in not-yet-approved indications. Ruling out pulmonary embolism and deep vein thrombosis in patients with low or intermediate clinical suspicion is the main application of D-dimer. D-dimer is also used to estimate the risk of venous thromboembolism recurrence and is included in the ISTH algorithm for the diagnosis of disseminated intravascular coagulation. Finally, numerous studies identified high D-dimer levels as a biomarker of poor prognosis in hospitalized patients with COVID-19. This report focuses on validated applications of D-dimer testing in patients with and without COVID-19.

3.
Vieillard-Baron, Antoine, Flicoteaux, Rémi, Salmona, Maud, Annane, Djillali, Ayed, Soufia, Azoulay, Elie, Bellaiche, Raphael, Beloucif, Sadek, Berti, Enora, Bertier, Astrid, Besset, Sébastien, Bret, Marlène, Cariou, Alain, Carpentier, Christophe, Chaouch, Oussama, Chariot, Appoline, Charron, Cyril, Charpentier, Julien, Cheurfa, Cherifa, Cholley, Bernard, Clerc, Sébastien, Combes, Alain, Chousterman, Benjamin, Cohen, Yves, Constantin, Jean-Michel, Damoisel, Charles, Darmon, Michael, Degos, Vincent, D’Ableiges, Bertrand De Maupeou, Demeret, Sophie, Montmollin, Etienne De, Demoule, Alexandre, Depret, Francois, Diehl, Jean-Luc, Djibré, Michel, Do, Chung-Hi, Dudoignon, Emmanuel, Duranteau, Jacques, Fartoukh, Muriel, Fieux, Fabienne, Gayat, Etienne, Gennequin, Mael, Guidet, Bertrand, Gutton, Christophe, Hamada, Sophie, Heming, Nicholas, Jouffroy, Romain, Keita-Meyer, Hawa, Langeron, Olivier, Lortat-Jacob, Brice, Marey, Jonathan, Mebazaa, Alexandre, Megarbane, Bruno, Mekontso-Dessap, Armand, Mira, Jean-Paul, Molle, Julie, Mongardon, Nicolas, Montravers, Philippe, Morelot-Panzini, Capucine, Nemlaghi, Safaa, Nguyen, Bao-long, Parrot, Antoine, Pasqualotto, Romain, Peron, Nicolas, Picard, Lucile, de Chambrun, Marc Pineton, Planquette, Benjamin, Plaud, Benoit, Pons, Stéphanie, Quesnel, Christophe, Raphalen, Jean-Herlé, Razazi, Keyvan, Ricard, Jean-Damien, Roche, Anne, Rohaut, Benjamin, Roux, Damien, Savale, Laurent, Sobotka, Jennifer, Teboul, Jean-Louis, Timsit, Jean-François, Voiriot, Guillaume, Weiss, Emmanuel, Wildenberg, Lucille, Zogheib, Elie, Riou, Bruno, Batteux, Frédéric.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327150

ABSTRACT

Importance Information about the severity of Omicron is scarce. Objective To report the respective risk of ICU admission in patients hospitalized with Delta and Omicron variants and to compare the characteristics and disease severity of critically ill patients infected with both variants according to vaccination status. Design Analysis from the APHP database, called Reality, prospectively recording the following information in consecutive patients admitted in the ICU for COVID-19: age, sex, immunosuppression, vaccination, pneumonia, need for invasive mechanical ventilation, time between symptom onset and ICU admission, and in-ICU mortality. Retrospective analysis on an administrative database, “Système d’Information pour le Suivi des Victimes” (SI-VIC), which lists hospitalized COVID-19 patients. Setting 39 hospitals in the Paris area from APHP group. Participants Patients hospitalized from December 1, 2021 to January 18, 2022 for COVID-19. Main outcomes and measures Risk of ICU admission was evaluated in 3761 patients and Omicron cases were compared to Delta cases in the ICU in 888 consecutive patients. Results On January 18, 45% of patients in the ICU and 63.8% of patients in conventional hospital units were infected with the Omicron variant (p < 0.001). The risk of ICU admission with Omicron was reduced by 64% than with Delta (9.3% versus 25.8% of cases, respectively, p < 0.001). In critically ill patients, 400 had the Delta variant, 229 the Omicron variant, 98 had an uninformative variant screening test and 161 did not have information on variant screening test. 747 patients (84.1%) were admitted for pneumonia. Compared to patients infected with Delta, Omicron patients were more vaccinated (p<0.001), even with 3 doses, more immunocompromised (p<0.001), less admitted for pneumonia (p<0.001), especially when vaccinated (62.1% in vaccinated versus 80.7% in unvaccinated, p<0.001), and less invasively ventilated (p=0.02). Similar results were found in the subgroup of pneumonia but Omicron cases were older. Unadjusted in-ICU mortality did not differ between Omicron and Delta cases, neither in the overall population (20.0% versus 27.9%, p = 0.08), nor in patients with pneumonia (31.6% versus 29.7%, respectively) where adjusted in-ICU mortality did not differ according to the variant (HR 1.43 95%CI [0.89;2.29], p=0.14). Conclusion and relevance Compared to the Delta variant, the Omicron variant is less likely to result in ICU admission and less likely to be associated with pneumonia. However, when patients with the Omicron variant are admitted for pneumonia, the severity seems similar to that of patients with the Delta variant, with more immunocompromised and vaccinated patients and no difference in adjusted in-ICU mortality. Further studies are needed to confirm our results.

4.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-308437

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) has been associated with coagulation disorders, in particular high levels of D-dimers, and increased frequency of venous thromboembolism (VTE). We explore the association between D-dimers at admission and in-hospital mortality in hospitalized COVID-19 patients with or without symptomatic VTE. Methods: : From February 26 to April 20, 2020, D-dimer level at admission and outcomes of patients hospitalized for COVID-19 in medical wards (in-hospital mortality or VTE) were retrospectively analyzed in a multicenter study in 24 French hospitals. Results: : Among 2878 patients enrolled in the study, 1154 (40.9%) patients had D-dimer measurement at admission. A receiver operating characteristic (ROC) curve analysis identified D-dimer level above 1128 ng/mL as the optimum cutoff value to predict in-hospital mortality (Area Under the Curve of 64.9% (95% CI 0.60–0.69) with a sensitivity of 71.1% (95% CI 0.62–0.78) and a specificity of 55.6% (95% CI 0.52–0.58) that not differ in the subgroup of patients with VTE during hospitalization. Among 609 (52.8%) patients with D-dimers level < 1128 ng/mL at admission, only 35 (5.7%) deaths occurred during hospitalization. After adjustment, in a cox proportional hazard and logistic regression models, D-dimers above 1128 ng/mL at admission were also associated to a worth prognosis with a OR of 3.07 (95% CI 2.05–4.69, p < 0.001) and an unadjusted hazard ratio of 2.11 (95%CI 1.31–3.4, p < 0.01). Conclusions: : D-dimer level over 1128 ng/mL is a relevant predictive factor for in-hospital mortality in COVID-19 hospitalized patients in medical ward, regardless the occurrence of VTE during hospitalization.

5.
Thromb Haemost ; 2022 Feb 10.
Article in English | MEDLINE | ID: covidwho-1684157

ABSTRACT

INTRODUCTION: D-dimer measurement is a safe tool to exclude pulmonary embolism (PE) but its specificity decreases in COVID-19. Our aim was to derive a new algorithm with specific D-dimer threshold in COVID-19 patients. METHODS: We conducted a French multicenter, retrospective cohort study among 774 COVID-19 patients with suspected PE. D-dimer threshold adjusted to computed tomography (CT) extent of lung damage was derived in a patient set (n=337), and its safety assessed in an independent validation set (n=337). RESULTS: According to ROC curves, in the derivation set D-dimer safely excluded PE, with one false negative when using a 900 ng/mL threshold when lung damage extent was <50% and 1700 ng/mL when lung damage extent was ≥50%. In the derivation set, the algorithm sensitivity was 98.2% (95% CI: 94.7-100.0) and its specificity 28.4% (95% CI: 24.1-32.3). The negative likelihood ratio (NLR) was 0.06 (95% CI: 0.01-0.44) and the area under the curve (AUC) was 0.63 (95% CI: 0.60-0.67). In the validation set, sensitivity and specificity were 96.7% (95% CI: 88.7-99.6) and 39.2% (95% CI: 32.2-46.1), respectively. The NLR was 0.08 (95% CI; 0.02-0.33) and the AUC did not differed from that of the derivation set (0.68 ,95% CI: 0.64-0.72, P = 0.097). Using the Co-LEAD algorithm, 76/250 (30.4%) COVID-19 patients with suspected PE could have been managed without CT pulmonary angiography (CTPA). CONCLUSION: The Co-LEAD algorithm safely excludes PE, and allows reducing the use of CTPA among COVID-19 patients. Further prospective studies are necessary to validate this strategy.

6.
Front Med (Lausanne) ; 8: 747527, 2021.
Article in English | MEDLINE | ID: covidwho-1497093

ABSTRACT

Background: 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. Objectives: To evaluate the effects of intermediate-dose vs. standard-dose prophylactic anticoagulation (AC) among patients with COVID-19 hospitalized in medical wards. Methods and results: 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, n = 261; standard-dose prophylactic anticoagulation, n = 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 (p = 0.85); while time to death was also the same in both the treatment groups (11.5 and 11.6 days, respectively, p = 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%, p = 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); p = 0.99). Moreover, we found that no particular subgroup was associated with a significant reduction in in-hospital mortality. Conclusion: 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.

7.
J Clin Med ; 10(19)2021 Oct 08.
Article in English | MEDLINE | ID: covidwho-1463727

ABSTRACT

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; p = 0.0076) and receive diuretics (adjOR: 2.13; 95% CI 1.12-4.03; p = 0.021) but were less likely to be smokers (adjOR: 0.40; 95% CI 0.24-0.64; p = 0.0002), have COPD (adjOR: 0.25; 95% CI 0.11-0.56; p = 0.0008), or have a previous or active cancer diagnosis (adjOR: 0.54, 95% CI 0.32-0.91; p = 0.020). The rate of ICU admission was significantly higher in patients with COVID-19 (32.4% vs. 5.2% p < 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.

8.
Arthritis Rheumatol ; 73(11): 1976-1985, 2021 11.
Article in English | MEDLINE | ID: covidwho-1432359

ABSTRACT

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-ß2 -glycoprotein I and IgG and IgM anticardiolipin isotypes) and nonconventional aPLs (IgA isotype of anticardiolipin, IgA isotype of anti-ß2 -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.


Subject(s)
COVID-19/complications , Lupus Coagulation Inhibitor/blood , Venous Thromboembolism/etiology , Aged , Aged, 80 and over , COVID-19/blood , COVID-19/mortality , Female , Hospital Mortality , Humans , Male , Middle Aged , Prognosis , Prospective Studies , Risk Factors , Survival Rate , Venous Thromboembolism/blood
9.
Angiogenesis ; 24(3): 407-411, 2021 08.
Article in English | MEDLINE | ID: covidwho-1222775

ABSTRACT

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.


Subject(s)
ADAMTS13 Protein/blood , COVID-19/blood , COVID-19/mortality , Pandemics , SARS-CoV-2 , von Willebrand Factor/metabolism , Aged , Biomarkers/blood , Collagen/metabolism , Cross-Sectional Studies , Female , Hospital Mortality , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Paris/epidemiology , Proportional Hazards Models , Protein Binding , Severity of Illness Index
10.
J Am Heart Assoc ; 10(8): e018624, 2021 04 20.
Article in English | MEDLINE | ID: covidwho-1189969

ABSTRACT

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.


Subject(s)
Anticoagulants/therapeutic use , COVID-19 , Intensive Care Units/statistics & numerical data , Thromboembolism/prevention & control , Blood Coagulation/drug effects , COVID-19/blood , COVID-19/mortality , COVID-19/therapy , Early Medical Intervention/methods , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiopathology , Female , France/epidemiology , Hospital Mortality , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Prognosis , Protective Factors , SARS-CoV-2/isolation & purification , Severity of Illness Index , Thromboembolism/epidemiology
11.
Arch Cardiovasc Dis ; 114(5): 381-393, 2021 May.
Article in English | MEDLINE | ID: covidwho-1179190

ABSTRACT

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.


Subject(s)
COVID-19/blood , Fibrin Fibrinogen Degradation Products/analysis , Thrombophilia/blood , Adolescent , Adult , Aged , Aged, 80 and over , Anticoagulants/therapeutic use , Area Under Curve , COVID-19/complications , COVID-19/mortality , COVID-19 Nucleic Acid Testing , Child , Child, Preschool , Electronic Health Records , France/epidemiology , Hospital Mortality , Humans , Infant , Infant, Newborn , Kaplan-Meier Estimate , Male , Middle Aged , Patient Admission , Patients' Rooms , Prognosis , Proportional Hazards Models , ROC Curve , Retrospective Studies , Thrombophilia/drug therapy , Thrombophilia/etiology , Venous Thromboembolism/epidemiology , Young Adult
12.
J Thromb Haemost ; 19(7): 1823-1830, 2021 07.
Article in English | MEDLINE | ID: covidwho-1172713

ABSTRACT

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.


Subject(s)
COVID-19 , Vascular Endothelial Growth Factor A , Adult , Biomarkers , Female , Hospital Mortality , Humans , Placenta Growth Factor , SARS-CoV-2
14.
Angiogenesis ; 24(3): 505-517, 2021 08.
Article in English | MEDLINE | ID: covidwho-1032491

ABSTRACT

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.


Subject(s)
COVID-19/blood , COVID-19/mortality , Pandemics , SARS-CoV-2 , von Willebrand Factor/metabolism , Adult , Aged , Biomarkers/blood , Biomarkers/chemistry , COVID-19/physiopathology , Cross-Sectional Studies , Endothelium, Vascular/physiopathology , Female , Hospital Mortality , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Molecular Weight , Paris/epidemiology , Proportional Hazards Models , Protein Multimerization , Severity of Illness Index , Thrombosis/blood , Thrombosis/etiology , von Willebrand Factor/chemistry
15.
Front Med (Lausanne) ; 7: 586307, 2020.
Article in English | MEDLINE | ID: covidwho-954333

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders. Objectives: To explore clinical and biological parameters of COVID-19 patients with hospitalization criteria that could predict referral to intensive care unit (ICU). Methods: Analyzing the clinical and biological profiles of COVID-19 patients at admission. Results: 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 SpO2, 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 (r = 0.42, p = 0.010) and D-dimer (r = 0.18, p = 0.047). Conclusion: 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.

16.
Blood ; 136(20): 2290-2295, 2020 11 12.
Article in English | MEDLINE | ID: covidwho-950941

ABSTRACT

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.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/pathology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Immune Sera/administration & dosage , Lymphopenia/therapy , Pneumonia, Viral/immunology , Adult , Aged , B-Lymphocytes/immunology , Blood Component Transfusion , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/therapy , Coronavirus Infections/virology , Female , France , Hematologic Neoplasms/complications , Humans , Immunization, Passive , Lymphopenia/etiology , Lymphopenia/pathology , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/therapy , Pneumonia, Viral/virology , SARS-CoV-2
17.
Stem Cell Rev Rep ; 17(2): 639-651, 2021 04.
Article in English | MEDLINE | ID: covidwho-932630

ABSTRACT

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 CD34+KDR+. 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 CD34+CD133-/+CD45-/dimc-Kit+KDR- 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 CD34+c-Kit+KDR- 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 CD34+KDR+ 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 CD19+KDR+ per million of CD45+ cells was observed between moderate and critical COVID-19 patients regardless of CD34 expression. CD34+c-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 CD34+KDR+ 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.


Subject(s)
Antigens, CD19/metabolism , COVID-19/metabolism , Endothelial Progenitor Cells/metabolism , Gene Expression Regulation , Heart, Artificial , SARS-CoV-2/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Endothelial Progenitor Cells/pathology , Female , Humans , Male , Middle Aged , Proteomics
18.
Thromb Res ; 197: 94-99, 2021 01.
Article in English | MEDLINE | ID: covidwho-912640

ABSTRACT

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.


Subject(s)
COVID-19/complications , Pulmonary Embolism/etiology , Aged , COVID-19/blood , COVID-19/drug therapy , COVID-19/therapy , Case-Control Studies , Chest Pain/etiology , Combined Modality Therapy , Computed Tomography Angiography , Female , Fibrin Fibrinogen Degradation Products/analysis , France/epidemiology , Humans , Male , Middle Aged , Prevalence , Pulmonary Embolism/blood , Pulmonary Embolism/diagnostic imaging , Pulmonary Embolism/epidemiology , Respiration, Artificial/statistics & numerical data , Retrospective Studies , Symptom Assessment , Tachycardia/etiology , Thrombophilia/blood , Thrombophilia/etiology , Tomography, X-Ray Computed
19.
J Thromb Haemost ; 18(9): 2391-2399, 2020 09.
Article in English | MEDLINE | ID: covidwho-607342

ABSTRACT

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.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/complications , COVID-19/therapy , Aged , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Blood Coagulation , Blood Coagulation Disorders/complications , Blood Coagulation Disorders/drug therapy , Cardiovascular Diseases/complications , Endothelial Cells/metabolism , Female , Fibrin Fibrinogen Degradation Products/analysis , Hemostasis , Hospitalization , Humans , Male , Middle Aged , Patient Admission , Pneumonia, Viral/diagnostic imaging , Prevalence , Prospective Studies , ROC Curve , Tomography, X-Ray Computed
20.
Angiogenesis ; 23(4): 611-620, 2020 11.
Article in English | MEDLINE | ID: covidwho-377964

ABSTRACT

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.


Subject(s)
Angiopoietin-2/blood , Coronavirus Infections/blood , Coronavirus Infections/therapy , Endothelium, Vascular/metabolism , Intensive Care Units , Pneumonia, Viral/blood , Pneumonia, Viral/therapy , Aged , Betacoronavirus , Biomarkers/blood , COVID-19 , Critical Care/methods , E-Selectin/blood , Female , Gene Expression Profiling , Hospitalization , Humans , Male , Middle Aged , Pandemics , Patient Admission , Prospective Studies , Respiration, Artificial , SARS-CoV-2
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