Higher anticoagulation targets and risk of thrombotic events in severe COVID-19 patients: bi-center cohort study

Boisramé-Helms, Julie; Séverac, François; Merdji, Hamid; Schenck, Maleka; Clère-Jehl, Raphaël; Baldacini, Mathieu; Ohana, Mickaël; Grunebaum, Lélia; Castelain, Vincent; Anglès-Cano, Eduardo; Sattler, Laurent; Meziani, Ferhat

doi:10.1186/s13613-021-00809-5

Cited by 40 publications

(44 citation statements)

References 24 publications

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“…These findings suggest vascular micro-thrombotic disease as a primary factor for mortality in critically ill COVID-19 [ 6 , 14 ]. Therefore, some authors supported the systematic use of curative anticoagulation upon admission to intensive care unit (ICU) [ 15 ], a strategy that has been reported to decrease mortality in severe COVID-19 [ 8 , 16 – 18 ].…”

Section: Introductionmentioning

confidence: 99%

Platelet activation in critically ill COVID-19 patients

Yatim

Boussier

Chocron

et al. 2021

Ann. Intensive Care

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Background Microvascular, arterial and venous thrombotic events have been largely described during severe coronavirus disease 19 (COVID-19). However, mechanisms underlying hemostasis dysregulation remain unclear. Methods We explored two independent cross-sectional cohorts to identify soluble markers and gene-expression signatures that discriminated COVID-19 severity and outcomes. Results We found that elevated soluble (s)P-selectin at admission was associated with disease severity. Elevated sP-selectin was predictive of intubation and death (ROC AUC = 0.67, p = 0.028 and AUC = 0.74, p = 0.0047, respectively). An optimal cutoff value was predictive of intubation with 66% negative predictive value (NPV) and 61% positive predictive value (PPV), and of death with 90% NPV and 55% PPV. An unbiased gene set enrichment analysis revealed that critically ill patients had increased expression of genes related to platelet activation. Hierarchical clustering identified ITG2AB, GP1BB, PPBP and SELPLG to be upregulated in a grade-dependent manner. ROC curve analysis for the prediction of intubation was significant for SELPLG and PPBP (AUC = 0.8, p = 0.046 for both). An optimal cutoff value for PBPP was predictive of intubation with 100% NPV and 45% PPV, and for SELPLG with 100% NPV and 50% PPV. Conclusion We provide evidence that platelets contribute to COVID-19 severity. Plasma sP-selectin level was associated with severity and in-hospital mortality. Transcriptional analysis identified PPBP/CXCL7 and SELPLG as biomarkers for intubation. These findings provide additional evidence for platelet activation in driving critical COVID-19. Specific studies evaluating the performance of these biomarkers are required.

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Section: Introductionmentioning

confidence: 99%

Platelet activation in critically ill COVID-19 patients

Yatim

Boussier

Chocron

et al. 2021

Ann. Intensive Care

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“…Even though AC has been shown to prevent macrothrombotic complications (23,24), intermediate doses did not worsen or modify the mortality outcome in these studies likely because treatment was introduced too late into the course of the disease. Indeed, it is clear that microthrombosis/lung obstruction is pathognomonic of COVID-19 worsening and hypoxemia, in contrast to most other respiratory viral infections.…”

Section: Discussionmentioning

confidence: 86%

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

et al. 2021

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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.

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“…Higher anticoagulation targets were considered to protect from thrombotic events in the most severely affected patients [ 62 , 37 ]. Helms et al demonstrated that anticoagulation was not associated with increased bleeding, differences in ICU mortality or length of stay compared with patients in regular prophylaxis [ 64 , 65 ]. In an observational retrospective study, Paranjpe et al [ 66 ] assessed the association between administration of in-hospital anticoagulation and survival in a large cohort of hospitalized patients with COVID-19 and showed that therapeutic anticoagulation may be associated with improved outcomes among patients hospitalized with COVID-19 (reduced risk of mortality: adjusted HR of 0.86 per day, 95% confidence interval 0.82–0.89, p < 0.001).…”

Section: Covid-19-associated Coagulopathymentioning

confidence: 99%

COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects

et al. 2021

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Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 β [IL-1β] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy.

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Higher anticoagulation targets and risk of thrombotic events in severe COVID-19 patients: bi-center cohort study

Cited by 40 publications

References 24 publications

Platelet activation in critically ill COVID-19 patients

Platelet activation in critically ill COVID-19 patients

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

COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects

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