Endotheliopathy in COVID-19 linked to severe illness, mortality
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Endotheliopathy among patients with COVID-19 appeared associated with severe illness and death, according to study results published in The Lancet Haematology.
“Early on in the pandemic, I was very interested in trying to understand why patients with COVID-19 appeared at high risk for thrombosis, both large-vessel thrombosis in the form of pulmonary embolism and, to a lesser extent, deep venous thrombosis,” Alfred I. Lee, MD, PhD, associate professor of medicine at Yale Cancer Center, told Healio.
More pressingly, small-vessel or microvascular thrombosis appeared to underlie a significant amount of respiratory decompensation, he added.
“Many experts in the field had discussions about [patients with COVID-19] having disseminated intravascular coagulation [DIC], particularly in advanced stages of the disease,” Lee said. “Yet, at my institution, we were not seeing evidence of overt DIC in our patients, which led us to wonder if the pathophysiology of this COVID-19-associated coagulopathy might be distinct. Our hope was to better understand the mechanisms of thrombosis in COVID-19 and whether such patients really had DIC or some other type of pathophysiology altogether. Our findings shed light on the pathophysiology of COVID-19 and provide a framework for understanding how thrombosis may occur.”
Between April 13 and April 24, Lee and colleagues examined incidence of endotheliopathy in COVID-19-associated coagulopathy pathogenesis among 48 critically ill patients (mean age, 64 years; 69%, men) in an ICU compared with 20 noncritically ill patients (mean age, 58 years; 60% women) receiving treatment for COVID-19 in a non-ICU hospital unit. Thirteen disease-free volunteers (mean age, 48 years; 61.5% women) served as controls.
Researchers assessed markers of endothelial cell and platelet activation — including von Willebrand factor antigen, soluble thrombomodulin, soluble P-selectin and soluble CD40 ligand — in addition to coagulation factors, endogenous anticoagulants and fibrinolytic enzymes.
Overall, 37% of patients had obesity, 56% had hypertension, 26% had hyperlipidemia and 29% had diabetes. Among patients in the ICU cohort, three had active malignancy, three had cirrhosis and one had a history of cirrhosis that resolved after liver transplantation.
According to study results, patients in the ICU had significantly elevated markers of endothelial cell and platelet activation compared with patients not admitted to the ICU. Specifically, mean von Willebrand factor antigen was 565% among ICU patients compared with 278% among non-ICU patients (P < .0001), and soluble P-selectin was 15.9 ng/mL vs. 11.2 ng/mL (P = .0014).
Researchers observed significant associations between mortality and von Willebrand factor antigen (r = 0.38; P = .0022) and soluble thrombomodulin (r = 0.38; P = .0078) among all patients.
In addition, soluble thrombomodulin concentration higher than 3.26 ng/mL appeared associated with lower hospital discharge rates compared with low soluble thrombomodulin concentration rates (52% vs. 88%; P = .005). Results of a Kaplan-Meier survival analysis showed significantly lower in-hospital mortality among patients with low vs. high soluble thrombomodulin in the entire cohort (HR = 5.9; 95% CI, 1.9-18.4) and among ICU patients (HR = 4.5; 95% CI, 1.5-14).
“At the time that we started our study, there was a scant amount of evidence from autopsy reports that the COVID-19 virus could infect endothelial cells and that some deceased patients had inflammation of the vascular channels, known as endothelialitis,” Lee said. “Hence, many of us were suspecting that endothelial injury or activation might play a role in the pathogenesis of COVID-19, but definitive demonstrations of this were lacking. Our study became the first to measure specific biochemical markers of endothelial cell function in the blood and demonstrate that endotheliopathy is common in COVID-19, particularly when patients are critically ill.”
The findings also highlight opportunities for therapeutic intervention directed toward preserving endothelial function, Lee added.
“These agents include dipyridamole, eculizumab [Soliris, Alexion Pharmaceuticals] and even aspirin — all of which we are now using at our institution as a result of our findings,” he said.
Lee and colleagues are involved in various collaborative studies looking at different aspects of COVID-19 infection — including basic science and the biology of endothelial cells, complement and inflammatory cells — and clinical studies of different therapeutic interventions — including anticoagulation and targeted therapies.
“This entire experience has been an amazing story of collaboration across our institution and beyond,” Lee said. “We have also gained some valuable insights into thrombotic diseases affecting the microvasculature and are thinking about how these findings might apply to other disease models.”
Lee and colleagues provided novel mechanistic insights into COVID-19-associated endotheliopathy, Jamie M. O’Sullivan, BsC, PhD, researcher at the Irish Center for Vascular Biology at Royal College of Surgeons in Ireland, and colleagues wrote in a commentary accompanying the study.
“In keeping with previous studies, they show that coagulation activation is common in hospitalized patients with COVID-19,” they wrote. “Additionally, they report elevated plasma von Willebrand factor concentrations in these patients, increasing with disease severity.
“Further studies will be required to define the different mechanisms through which SARS-CoV-2 infection causes marked endothelial cell effects, particularly within the pulmonary microvasculature,” O’Sullivan and colleagues added. “Given the diffuse nature of COVID-19 pneumonia, the large volume of alveolar cavity and proximity with the pulmonary microvasculature, local inflammation and dysregulated pro-inflammatory cytokine generation are undoubtedly important in this context.”
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For more information:
Alfred I. Lee, MD, PhD, can be reached at Yale School of Medicine, 333 Cedar St., New Haven, CT 06510; email: alfred.lee@yale.edu.
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