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Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study
George Goshua1, Alexander B Pine1, Matthew L Meizlish2
1Section of Hematology, New Haven, CT, USA.
Insights
Endotheliopathy, or endothelial cell dysfunction, is present in COVID-19 patients and linked to severe illness and mortality. Identifying and treating this condition early may improve patient outcomes.
Area of Science:
- Cardiovascular Biology
- Infectious Diseases
- Hematology
Background:
- COVID-19 pathogenesis involves coagulopathy, characterized by thrombotic and microvascular complications.
- Endothelial cell injury is a suspected contributor to COVID-19-associated coagulopathy.
- This study investigates endotheliopathy by assessing endothelial and platelet activation markers in hospitalized COVID-19 patients.
Purpose of the Study:
- To determine the role of endotheliopathy in COVID-19-associated coagulopathy.
- To assess markers of endothelial cell and platelet activation in critically and non-critically ill COVID-19 patients.
- To correlate these markers with clinical outcomes, including mortality.
Main Methods:
- A single-center, cross-sectional study of hospitalized adult COVID-19 patients (ICU and non-ICU) and non-hospitalized controls.
- Assessed markers of endothelial and platelet activation: von Willebrand Factor (VWF) antigen, soluble thrombomodulin, soluble P-selectin, and soluble CD40 ligand.
- Compared marker levels between patient groups and controls, and correlated laboratory results with clinical outcomes using Kaplan-Meier analysis.
Main Results:
- Endothelial and platelet activation markers were significantly elevated in ICU patients compared to non-ICU patients (e.g., VWF antigen, soluble P-selectin).
- Elevated VWF antigen was observed in 80% of non-ICU patients.
- Mortality correlated with elevated VWF antigen and soluble thrombomodulin. High soluble thrombomodulin levels were associated with lower hospital discharge rates and survival.
Conclusions:
- Endotheliopathy is present in COVID-19 patients and associated with critical illness and mortality.
- Early identification of endotheliopathy is crucial.
- Strategies to mitigate endotheliopathy progression may improve COVID-19 outcomes.
Background:
An important feature of severe acute respiratory syndrome coronavirus 2 pathogenesis is COVID-19-associated coagulopathy, characterised by increased thrombotic and microvascular complications. Previous studies have suggested a role for endothelial cell injury in COVID-19-associated coagulopathy. To determine whether endotheliopathy is involved in COVID-19-associated coagulopathy pathogenesis, we assessed markers of endothelial cell and platelet activation in critically and non-critically ill patients admitted to the hospital with COVID-19.
Methods:
In this single-centre cross-sectional study, hospitalised adult (≥18 years) patients with laboratory-confirmed COVID-19 were identified in the medical intensive care unit (ICU) or a specialised non-ICU COVID-19 floor in our hospital. Asymptomatic, non-hospitalised controls were recruited as a comparator group for biomarkers that did not have a reference range. We assessed markers of endothelial cell and platelet activation, including von Willebrand Factor (VWF) antigen, soluble thrombomodulin, soluble P-selectin, and soluble CD40 ligand, as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes. We compared the level of each marker in ICU patients, non-ICU patients, and controls, where applicable. We assessed correlations between these laboratory results with clinical outcomes, including hospital discharge and mortality. Kaplan-Meier analysis was used to further explore the association between biochemical markers and survival.
Findings:
68 patients with COVID-19 were included in the study from April 13 to April 24, 2020, including 48 ICU and 20 non-ICU patients, as well as 13 non-hospitalised, asymptomatic controls. Markers of endothelial cell and platelet activation were significantly elevated in ICU patients compared with non-ICU patients, including VWF antigen (mean 565% [SD 199] in ICU patients vs 278% [133] in non-ICU patients; p<0·0001) and soluble P-selectin (15·9 ng/mL [4·8] vs 11·2 ng/mL [3·1]; p=0·0014). VWF antigen concentrations were also elevated above the normal range in 16 (80%) of 20 non-ICU patients. We found mortality to be significantly correlated with VWF antigen (r = 0·38; p=0·0022) and soluble thrombomodulin (r = 0·38; p=0·0078) among all patients. In all patients, soluble thrombomodulin concentrations greater than 3·26 ng/mL were associated with lower rates of hospital discharge (22 [88%] of 25 patients with low concentrations vs 13 [52%] of 25 patients with high concentrations; p=0·0050) and lower likelihood of survival on Kaplan-Meier analysis (hazard ratio 5·9, 95% CI 1·9-18·4; p=0·0087).
Interpretation:
Our findings show that endotheliopathy is present in COVID-19 and is likely to be associated with critical illness and death. Early identification of endotheliopathy and strategies to mitigate its progression might improve outcomes in COVID-19.
Funding:
This work was supported by a gift donation from Jack Levin to the Benign Hematology programme at Yale, and the National Institutes of Health.
