Circulating markers of angiogenesis and endotheliopathy in COVID‐19

Pine, Alexander B; Meizlish, Matthew L; Goshua, George; Chang, C‐Hong; Zhang, Hanming; Bishai, Jason; Bahel, Parveen; Patel, Amisha; Gbyli, Rana; Kwan, Jennifer M.; Won, Christine; Price, Christina; Cruz, Charles S. Dela; Halene, Stephanie; Dijk, David van; Hwa, John; Lee, Alfred Ian; Chun, Hyung J.

doi:10.1177/2045894020966547

Cited by 103 publications

(96 citation statements)

References 6 publications

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“…Our data add to the findings on various markers of endothelial cell and platelet activation, including vWf, soluble thrombomodulin, soluble CD40 ligand, and plasminogen activator inhibitor (PAI)-1, studied in COVID-19 [ 5 , 25 , 38 ]. Results from these reports have shown that these biomarkers were elevated in patients with critical COVID-19 infection.…”

Section: Discussionsupporting

confidence: 63%

“…Elevated ICU admission levels of Ang-2 have been associated with higher ICU sepsis-associated mortality [ 23 , 24 ]; Ang-2 was shown to be a relevant predictive factor for ICU direct admission in hospitalized COVID-19 patients, indicating that endothelial activation reinforces the hypothesis of a COVID-19-associated microvascular dysfunction [ 12 ]. Very recently, it was also demonstrated that Ang-2 was elevated in critically ill COVID-19 patients compared to controls and, moreover, it was strongly predictive of in-hospital mortality [ 25 ]. Our results agree with these findings; we also found elevated levels of Ang-2 in patients who will be admitted to the ICU as opposed to the ward, but most importantly, amongst the ICU patients, those who will eventually die in the ICU have even higher admission Ang-2 levels.…”

Section: Discussionmentioning

confidence: 99%

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ICU Admission Levels of Endothelial Biomarkers as Predictors of Mortality in Critically Ill COVID-19 Patients

Vassiliou

Keskinidou

Jahaj

et al. 2021

Cells

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Endotheliopathy is suggested to be an important feature of COVID-19 in hospitalized patients. To determine whether endotheliopathy is involved in COVID-19-associated mortality, markers of endothelial damage were assessed in critically ill COVID-19 patients upon intensive care unit (ICU) admission. Thirty-eight critically ill COVID-19 patients were included in this observational study, 10 of whom died in the ICU. Endothelial biomarkers, including soluble (s)E-selectin, sP-selectin, angiopoietin 1 and 2 (Ang-1 and Ang-2, respectively), soluble intercellular adhesion molecule 1 (sICAM-1), vascular endothelial growth factor (VEGF), soluble vascular endothelial (VE)-cadherin, and von Willebrand factor (vWf), were measured upon ICU admission. The ICU cohort was subsequently divided into survivors and non-survivors; Kaplan–Meier analysis was used to explore associations between biomarkers and survival, while receiver operating characteristic (ROC) curves were generated to determine their potential prognostic value. sE-selectin, sP-selectin, Ang-2, and sICAM-1 were significantly elevated in ICU non-survivors compared to survivors, and also associated with a higher mortality probability in the Kaplan–Meier analysis. The prognostic values of sE-selectin, Ang-2, and sICAM-1 from the generated ROC curves were greater than 0.85. Hence, we conclude that in our cohort, ICU non-survivors had higher levels of specific endothelial markers compared to survivors. Elevated levels of these markers upon ICU admission could possibly predict mortality in COVID-19.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

ICU Admission Levels of Endothelial Biomarkers as Predictors of Mortality in Critically Ill COVID-19 Patients

Vassiliou

Keskinidou

Jahaj

et al. 2021

Cells

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“…We did find, however, that the dynamic 3-day angiopoietin-2 course, blunting the heterogeneity of the stage of disease at admission, was an early, strong, and independent risk factor for COVID-19 mortality. Interestingly, Pine et al 9 provided further evidence that angiopoietin-2 levels at intensive care unit admission were elevated in patients with critical COVID-19, strongly predicting in-hospital mortality. All these data may prove useful to guide novel therapeutic strategies, including those that protect the endothelium.…”

Section: Discussionmentioning

confidence: 99%

Dynamic angiopoietin-2 assessment predicts survival and chronic course in hospitalized patients with COVID-19

et al. 2021

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This study examined the association between dynamic angiopoietin-2 assessment and COVID-19 short- and long-term clinical course. We included consecutive hospitalized patients from 1 February to 31 May 2020 with laboratory-confirmed COVID-19 from 2 Italian tertiary referral centers (derivation cohort, n = 187 patients; validation cohort, n = 62 patients). Serum biomarker levels were measured by sandwich enzyme-linked immunosorbent assay. Lung tissue from 9 patients was stained for angiopoietin-2, Tie2, CD68, and CD34. Cox model was used to identify risk factors for mortality and nonresolving pulmonary condition. Area under the receiver operating characteristic curve (AUROC) was used to assess the accuracy of 3- and 10-day angiopoietin-2 for in-hospital mortality and nonresolving pulmonary condition, respectively. Three-day angiopoietin-2 increase of at least twofold from baseline was significantly associated with in-hospital mortality by multivariate analysis (hazard ratio [HR], 6.69; 95% confidence interval [CI], 1.85-24.19; P = .004) with AUROC = 0.845 (95% CI, 0.725-0.940). Ten-day angiopoietin-2 of at least twofold from baseline was instead significantly associated with nonresolving pulmonary condition by multivariate analysis (HR, 5.33; 95% CI, 1.34-11.77; P ≤ .0001) with AUROC = 0.969 (95% CI, 0.919-1.000). Patients with persistent elevation of 10-day angiopoietin-2 levels showed severe reticular interstitial thickening and fibrous changes on follow-up computed tomography scans. Angiopoietin-2 and Tie2 were diffusely colocalized in small-vessel endothelia and alveolar new vessels and macrophages. Angiopoietin-2 course is strongly associated with COVID-19 in-hospital mortality and nonresolving pulmonary condition. Angiopoietin-2 may be an early and useful predictor of COVID-19 clinical course, and it could be a relevant part of disease pathogenesis. Angiopoietin-2 blockade may be a COVID-19 treatment option.

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“…At Yale School of Medicine, plasma samples from 23 patients with COVID-19 were collected between April 13, 2020 to April 24, 2020 (‘Yale cross-sectional cohort’) (Goshua et al ., 2020; Pine et al ., 2020). A second Yale cohort (‘Yale longitudinal cohort’) was also analyzed, which included blood samples obtained longitudinally on day 1 (within 24 hours), day 4, and day 7 of hospitalization from 49 consecutive adult patients who were admitted for treatment of laboratory-confirmed COVID-19 between May 23, 2020 and May 28, 2020 and remained hospitalized until at least day 4.…”

Section: Methodsmentioning

confidence: 99%

“…The resulting plasma supernatant was used for further testing. Further details on processing the samples have been reported in prior publications (Goshua et al ., 2020; Pine et al ., 2020).…”

Section: Methodsmentioning

confidence: 99%

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

Sahu

Cano

et al. 2021

Preprint

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Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and, if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers. We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza, and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV). We demonstrate that circulating markers of complement activation (i.e., sC5b-9) are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., Ang2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials.

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Circulating markers of angiogenesis and endotheliopathy in COVID‐19

Cited by 103 publications

References 6 publications

ICU Admission Levels of Endothelial Biomarkers as Predictors of Mortality in Critically Ill COVID-19 Patients

ICU Admission Levels of Endothelial Biomarkers as Predictors of Mortality in Critically Ill COVID-19 Patients

Dynamic angiopoietin-2 assessment predicts survival and chronic course in hospitalized patients with COVID-19

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

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