Biomarkers of coagulation, endothelial function, and fibrinolysis in critically ill patients with COVID‐19: A single‐center prospective longitudinal study

Abstract

Background: Immunothrombosis and coagulopathy in the lung microvasculature may lead to lung injury and disease progression in coronavirus disease 2019 .We aim to identify biomarkers of coagulation, endothelial function, and fibrinolysis that are associated with disease severity and may have prognostic potential. Methods:We performed a single-center prospective study of 14 adult COVID-19(+) intensive care unit patients who were age-and sex-matched to 14 COVID-19(−) intensive care unit patients, and healthy controls. Daily blood draws, clinical data, and patient characteristics were collected. Baseline values for 10 biomarkers of interest were compared between the three groups, and visualized using Fisher's linear discriminant function. Linear repeated-measures mixed models were used to screen biomarkers for associations with mortality. Selected biomarkers were further explored and entered into an unsupervised longitudinal clustering machine learning algorithm to identify trends and targets that may be used for future predictive modelling efforts.Results: Elevated D-dimer was the strongest contributor in distinguishing COVID-19 status; however, D-dimer was not associated with survival. Variable selection identified clot lysis time, and antigen levels of soluble thrombomodulin (sTM), plasminogen activator inhibitor-1 (PAI-1), and plasminogen as biomarkers associated with death.Longitudinal multivariate k-means clustering on these biomarkers alone identified two clusters of COVID-19(+) patients: low (30%) and high (100%) mortality groups. Biomarker trajectories that characterized the high mortality cluster were higher clot lysis times (inhibited fibrinolysis), higher sTM and PAI-1 levels, and lower plasminogen levels. Conclusions: Longitudinal trajectories of clot lysis time, sTM, PAI-1, and plasminogen may have predictive ability for mortality in COVID-19.| 1547 JUNEJA Et Al.

Immunothrombosis Biomarkers for Distinguishing Coronavirus Disease 2019 Patients From Noncoronavirus Disease Septic Patients With Pneumonia and for Predicting ICU Mortality

“…In this study, we found that plasma levels of sTM are higher in COVID-19 patients who died, suggesting that endothelial dysfunction contributes to poor outcome. These findings are consistent with a single-center study of hospitalized COVID-19 patients that showed that elevated levels of sTM predicts inhospital mortality ( 42 , 45 ). We also found that the predictive power of sTM is greater when using the most recent ICU plasma samples compared with the day 1 samples (Supplemental Table 3, http://links.lww.com/CCX/A861 ).…”

Endothelial, Immunothrombotic, and Inflammatory Biomarkers in the Risk of Mortality in Critically Ill COVID-19 Patients: The Role of Dexamethasone

“…COVID-19 patients had similar levels as non-COVID-19 sick controls, and ICU-admitted patients had lower values compared to ward patients [10]. ICU COVID-19 patients had lower levels compared to ICU non-COVID-19 patients [11].…”

The zinc finger transcription factor, KLF2, protects against COVID-19 associated endothelial dysfunction

“…Since this discovery, 7 the importance of endothelial activation and dysfunction in COVID-19 has been intensively pursued. 8 , 18 , 23 , 26 More recently, increased markers of vascular inflammation, 27 oxidative stress, 28 EndoMT, 29 coagulation (D-dimer and plasminogen activator inhibitor-1), 15 , 30 immunothrombosis, 31 angiogenesis, 15 altered endothelial cell metabolism (glycolysis), 32 glycocalyx disruption 33 have been observed in patients with COVID-19 or SARS-CoV-2 spike protein treated endothelial cells (reviewed in ref. 9 ).…”