Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies

Xu, Suowen; Ilyas, Iqra; Weng, Jianping

doi:10.1038/s41401-022-00998-0

Cited by 228 publications

(188 citation statements)

References 179 publications

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“… 10 , 11 Second, disease pathophysiology could influence the individual patient's pharmacokinetic (PK) parameters, such as clearance (CL) and volume of distribution (Vd): Changes in renal function, microvascular failure (by coagulopathy and endothelial dysfunction) and organ dysfunction have been reported in critically ill COVID‐19 patients, which are known to influence PK parameters in other infectious diseases. 1 , 11 , 12 , 13 Moreover, vasopressor use has been associated with lower levels of anti‐Xa. 14 In addition, the phenomenon of augmented renal clearance also has been suggested in COVID‐19 patients with high inflammation.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of nadroparin for thromboprophylaxis in COVID‐19 intensive care unit patients

Romano

Hunfeld

Kruip

et al. 2022

Brit J Clinical Pharma

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Aims Nadroparin is administered to COVID‐19 intensive care unit (ICU) patients as thromboprophylaxis. Despite existing population pharmacokinetic (PK) models for nadroparin in literature, the population PK of nadroparin in COVID‐19 ICU patients is unknown. Moreover, optimal dosing regimens achieving anti‐Xa target levels (0.3–0.7 IU/mL) are unknown. Therefore, a population PK analysis was conducted to investigate different dosing regimens of nadroparin in COVID‐19 ICU patients. Methods Anti‐Xa levels ( n = 280) from COVID‐19 ICU patients ( n = 65) receiving twice daily (BID) 5700 IU of subcutaneous nadroparin were collected to perform a population PK analysis with NONMEM v7.4.1. Using Monte Carlo simulations ( n = 1000), predefined dosing regimens were evaluated. Results A 1‐compartment model with an absorption compartment adequately described the measured anti‐Xa levels with interindividual variability estimated for clearance (CL). Inflammation parameters C‐reactive protein, D‐dimer and estimated glomerular filtration rate based on the Chronic Kidney Disease Epidemiology Collaboration equation allowed to explain the interindividual variability of CL. Moreover, CL was decreased in patients receiving corticosteroids (22.5%) and vasopressors (25.1%). Monte Carlo simulations demonstrated that 5700 IU BID was the most optimal dosing regimen of the simulated regimens for achieving prespecified steady‐state t = 4 h anti‐Xa levels with 56.7% on target (0.3–0.7 IU/mL). Conclusion In our study, clearance of nadroparin is associated with an increase in inflammation parameters, use of corticosteroids, vasopression and renal clearance in critically ill patients. Furthermore, of the simulated regimens, targeted anti‐Xa levels were most adequately achieved with a dosing regimen of 5700 IU BID. Future studies are needed to elucidate the underlying mechanisms of found covariate relationships.

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Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of nadroparin for thromboprophylaxis in COVID‐19 intensive care unit patients

Romano

Hunfeld

Kruip

et al. 2022

Brit J Clinical Pharma

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“…Endothelial dysfunction is a hallmark of systemic disease resulting from SARS-CoV-2 infection [ 1 ]. Endothelium is a dynamic cell layer involved in a multitude of physiologic functions, including control of vasomotor tone, trafficking of cells and nutrients, maintenance of blood fluidity, and growth of new blood vessels [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Longitudinal Assessment of Plasma Syndecan-1 Predicts 60-Day Mortality in Patients with COVID-19

Zhang

Bignotti

et al. 2023

JCM

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Background: Endotheliopathy is a common pathologic finding in patients with acute and long COVID-19. It may be associated with disease severity and predispose patients to long-term complications. Plasma levels of a proteoglycan, syndecan-1, are found to be significantly elevated in patients with COVID-19, but its roles in assessing disease severity and predicting long-term outcome are not fully understood. Methods: A total of 124 consecutive hospitalized patients with SARS-CoV-2 infection were prospectively enrolled and blood samples were collected on admission (T1), 3–4 days following treatment (T2), and 1–2 days prior to discharge or death (T3). Plasma levels of syndecan-1 were determined using an immunosorbent assay; various statistical analyses were performed to determine the association between plasma syndecan-1 levels and disease severity or the 60-day mortality rate. Results: Compared with those in the healthy controls, plasma levels of syndecan-1 in patients with critical COVID-19 were significantly higher (p < 0.0001). However, there was no statistically significant difference among patients with different disease severity (p > 0.05), resulting from large individual variability. Longitudinal analysis demonstrated that while the levels fluctuated during hospitalization in all patients, plasma syndecan-1 levels were persistently elevated from baseline in critical COVID-19 patients. Cox proportional hazard regression analyses revealed that elevated plasma levels of syndecan-1 (>260 ng/mL at T1, >1018 ng/mL at T2, and >461 ng/mL at T3) were significantly associated with the 60-day mortality rate. Conclusions: Endotheliopathy, marked by glycocalyx degradation and elevated plasma syndecan-1, occurs in nearly all hospitalized patients with SARS-CoV-2 infection; elevated plasma syndecan-1 is associated with increased mortality in COVID-19 patients.

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“…Endothelial dysfunction is a hall marker of systemic disease resulting from SARS-CoV2 infection 1 . Endothelium is a dynamic cell layer involved in multitude of physiologic functions, including control of vasomotor tone, trafficking of cells and nutrients, maintenance of blood fluidity, and growth of new blood vessels 2 .…”

Section: Introductionmentioning

confidence: 99%

Longitudinal Assessment of Plasma Syndecan-1 Predicts 60-Day Mortality in Patients with COVID-19

Zhang¹,

Ye²,

Bignotti³

et al. 2023

Preprint

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Background: Endotheliopathy is common pathologic findings in patients with acute and long COVID-19. It may be associated with disease severity and predispose to long-term complications. Plasma levels of a proteoglycan syndecan-1 are found to be significantly elevated in patients with COVID-19, but its roles in assessing the disease severity and predicting long-term outcome are not fully understood. Methods: 124 consecutive hospitalized patients with SARS-CoV2 infection were prospectively enrolled and blood samples were collected on admission (T1), 3-4 days following treatment (T2), and 1-2 days prior to discharge or death (T3). Plasma levels of syndecan-1 were determined using an immunosorbent assay; various statistical analyses were performed to determine the association between plasma syndecan-1 levels and disease severity or the 60-day mortality rate. Results: Compared with those in the healthy controls, plasma levels of syndecan-1 in patients with critical COVID-19 were significantly higher (p<0.0001). However, there was no statistically significant difference among patients with different disease severity (p>0.05), resulting from large individual variability. Longitudinal analysis demonstrated that while the levels fluctuated during hospitalization in all patients, plasma syndecan-1 levels were persistently elevated from baseline in critical COVID19 patients. Cox proportional hazard regression analyses revealed that elevated plasma levels of syndecan-1 (>260 ng/mL at T1, >1018 ng/mL at T2, and >461 ng/mL at T3) were significantly associated with the 60-day mortality rate. Conclusions: Endotheliopathy, marked by glycocalyx degradation and elevated plasma syndecan-1, occurs in nearly all hospitalized patients with SARS-CoV2 infection; the elevated plasma syndecan-1 is associated with increased mortality in COVID-19 patients.

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Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies

Cited by 228 publications

References 179 publications

Population pharmacokinetics of nadroparin for thromboprophylaxis in COVID‐19 intensive care unit patients

Population pharmacokinetics of nadroparin for thromboprophylaxis in COVID‐19 intensive care unit patients

Longitudinal Assessment of Plasma Syndecan-1 Predicts 60-Day Mortality in Patients with COVID-19

Longitudinal Assessment of Plasma Syndecan-1 Predicts 60-Day Mortality in Patients with COVID-19

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