Endotheliopathy appears to be widespread among hospitalized patients with coronavirus disease 2019 (COVID-19), especially in critically ill patients, and endothelial markers may have prognostic value in patients with the disease, according to the results of a study published in The Lancet Haematology.

The investigators sought to determine whether endotheliopathy is involved in COVID-19–associated coagulopathy pathogenesis. They assessed markers of endothelial cell and platelet activation in hospitalized adult patients with COVID-19 who were critically ill (ICU) and not critically ill (non-ICU). The single-center, cross-sectional study was conducted at Yale-New Haven Hospital in New Haven, Connecticut, between April 13 and April 24, 2020.

The markers of endothelial cell and platelet activation included von Willebrand Factor (VWF) antigen, soluble thrombomodulin, soluble P-selectin, soluble CD40 ligand, coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes. According to the authors, this was the first study to measure VWF and other previously unreported endothelial markers (soluble P-selectin and soluble thrombomodulin) in both critically ill and noncritically ill patients.

The study assessed correlations between marker values and clinical outcomes, including hospital discharge and mortality. The association between marker values and survival was tested using Kaplan–Meier analysis.

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In total, the study included 68 hospitalized patients with COVID-19 (48 ICU patients and 20 non-ICU patients) and 13 nonhospitalized asymptomatic controls to establish normal ranges for some biomarkers. The average age of hospitalized patients was 62 years (range, 20-93 years). Both ICU and non-ICU patients had comorbid conditions. The proportion of men to women between the ICU and non-ICU groups was the only statistically significant patient characteristic (P =.033).

ICU patients had significantly elevated levels of markers of endothelial cell and platelet activation compared with non-ICU patients (VWF antigen mean, 565% vs 278%, respectively; P <.0001; and soluble P-selectin mean, 15.9 ng/mL vs 11.2 ng/mL, respectively; P =.0014). VWF antigen concentrations were above the normal range in a majority of non-ICU patients (80%, 16/20).

Among all patients, mortality was correlated with both VWF antigen (r=0.38; P =.0022) and soluble thrombomodulin (r=0.38; P =.0078). Higher soluble thrombomodulin concentrations (>3.26 ng/mL) were associated with lower rates of hospital discharge (52% of patients with higher concentrations [13/25] vs 88% patients with lower concentrations [22/25]; P =.0050) as well as lower likelihood of survival (hazard ratio, 5.9; 95% CI, 1.9-18.4; P =.0087).

The primary limitations of the study were its single-center design and small sample size. There was also heterogeneity among the groups and other uncontrolled factors, such as length of hospitalization and use of tocilizumab among patients, especially those with critical illness.

“To the best of our knowledge, our study is the first to provide biochemical evidence that endotheliopathy is an important feature in the coagulopathy of COVID-19,” wrote the authors. “We therefore propose that COVID-19-associated coagulopathy is an endotheliopathy that results in augmented VWF release, platelet activation, and hypercoagulability, leading to the clinical prothrombotic manifestations of COVID-19-associated coagulopathy, which can include venous, arterial, and microvascular thrombosis.”

The authors suggested that, in addition to traditional anticoagulation, antiplatelet therapy or endothelial cell modification may be potential therapeutic targets and additional studies on endotheliopathy in critical illness are needed.

Disclosures: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Goshua G, Pine AB, Meizlish ML, et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol. 2020;7(8):e575-e582. doi:10.1016/S2352-3026(20)30216-7