Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications

Ma, Zhangjing; Yang, Kevin Yi; Huang, Yü; Lui, Kathy O.

doi:10.1016/j.yjmcc.2021.11.010

Cited by 48 publications

(42 citation statements)

References 198 publications

(313 reference statements)

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“…[32] This may progress to a distinct syndrome, termed Covid-19-associated coagulopathy, characterised by markedly elevated D-dimer and fibrinogen concentrations and pulmonary microvascular thrombosis, which has been linked with worse outcome. [5,[7][8][9][10][11]33,34] VTE is common even with use of standard dose thromboprophylaxis, possibly occurring at higher rates than other respiratory conditions. [1] Given the prominence of thrombo-inflammation in the pathogenesis of Covid-19 and the likelihood that pulmonary thrombotic complications contribute to progressive hypoxic respiratory failure, one might expect that by preventing VTE, intensified dosing of anticoagulation should reduce disease severity and related mortality.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19: a systematic review and meta-analysis

Wills

Nair

Patel

et al. 2022

Preprint

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Background Randomised controlled trials (RCTs) have reported inconsistent effects from intensified anticoagulation on clinical outcomes in Covid-19. We performed an aggregate data meta-analysis from available trials to quantify effect on non-fatal and fatal outcomes and identify subgroups who may benefit. Methods We searched multiple databases for RCTs comparing intensified (intermediate or therapeutic dose) versus standard prophylactic dose anticoagulation in adults with laboratory-confirmed Covid-19 through 19 January 2022. The primary efficacy outcome was all-cause mortality at end of follow-up or discharge. We used random effects meta-analysis to estimate pooled risk ratios for mortality, thrombotic, and bleeding events, and performed subgroup analysis for clinical setting and dose of intensified anticoagulation. Results Eleven RCTs were included (n = 5873). Intensified anticoagulation was not associated with a reduction in mortality for up to 45 days compared with prophylactic anticoagulation: 17.5% (501/2861) died in the intensified anticoagulation group and 18.8% (513/2734) died in the prophylactic anticoagulation group, relative risk (RR) 0.93; 95%CI, 0.79 – 1.10. On subgroup analysis, there was a possible signal of mortality reduction for inpatients admitted to general wards, although with low precision and high heterogeneity (5 studies; RR 0.84; 95% CI, 0.49 – 1.44; I2 = 75%) and not significantly different to studies performed in the ICU (interaction P = 0.51). Risk of venous thromboembolism was reduced with intensified anticoagulation compared with prophylaxis (8 studies; RR 0.53, 95%CI 0.41 – 0.69; I2 = 0%). This effect was driven by therapeutic rather than intermediate dosing on subgroup analysis (interaction P = 0.04). Major bleeding was increased with use of intensified anticoagulation (RR 1.73, 95% CI 1.17 – 2.56) with no interaction for dosing and clinical setting. Conclusion Intensified anticoagulation has no effect on short term mortality among hospitalised adults with Covid-19 and is associated with increased risk of bleeding. The observed reduction in venous thromboembolism risk and trend towards reduced mortality in non-ICU hospitalised patients requires exploration in additional RCTs.

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Section: Discussionmentioning

confidence: 99%

Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19: a systematic review and meta-analysis

Wills

Nair

Patel

et al. 2022

Preprint

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“…Several mechanisms have been proposed to cause thrombosis in COVID-19 patients, including platelet activation and turnover; leukocyte activation; and the formation of neutrophil extracellular traps, complement system activation, coagulation defects, and endothelial dysfunction [ 6 , 105 , 106 ]. However, endothelial injury and malfunction evolve as a central pathological feature in COVID-19 [ 106 , 107 , 108 , 109 ]. Clinical signs of endothelial inflammation are widespread and seen in multiple organs, such as the lungs, heart, liver, kidney, intestine, and skin [ 101 , 110 , 111 , 112 , 113 ].…”

Section: Vascular Complications In Covid-19mentioning

confidence: 99%

Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy

Durante

2022

Metabolites

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Coronavirus disease 2019 (COVID-19) represents a major public health crisis that has caused the death of nearly six million people worldwide. Emerging data have identified a deficiency of circulating arginine in patients with COVID-19. Arginine is a semi-essential amino acid that serves as key regulator of immune and vascular cell function. Arginine is metabolized by nitric oxide (NO) synthase to NO which plays a pivotal role in host defense and vascular health, whereas the catabolism of arginine by arginase to ornithine contributes to immune suppression and vascular disease. Notably, arginase activity is upregulated in COVID-19 patients in a disease-dependent fashion, favoring the production of ornithine and its metabolites from arginine over the synthesis of NO. This rewiring of arginine metabolism in COVID-19 promotes immune and endothelial cell dysfunction, vascular smooth muscle cell proliferation and migration, inflammation, vasoconstriction, thrombosis, and arterial thickening, fibrosis, and stiffening, which can lead to vascular occlusion, muti-organ failure, and death. Strategies that restore the plasma concentration of arginine, inhibit arginase activity, and/or enhance the bioavailability and potency of NO represent promising therapeutic approaches that may preserve immune function and prevent the development of severe vascular disease in patients with COVID-19.

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“…This could have resulted from direct infection of endothelial cells by SARS-CoV-2 or as a result of the inflammatory reaction derived by the infection. Many mechanisms for viral cell invasion are being studied such as the role of angiotensin-converting enzyme 2 (ACE2) receptors and scavenger receptor B type 1 (SR-B1) and other cellular wall receptors that facilitate the entry of the virus to the endothelial cells causing vascular dysfunction and vasculitis [ 6 ]. COVID-19 infections were linked to overactive immune responses including the increased levels of inflammatory mediators such as TNF- α which in turn induces the production of reactive oxygen species which are known to damage the endothelial cells and cause endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…COVID-19 infections were linked to overactive immune responses including the increased levels of inflammatory mediators such as TNF- α which in turn induces the production of reactive oxygen species which are known to damage the endothelial cells and cause endothelial dysfunction. It was demonstrated that cytokines level differ according to the stage of the disease and they could represent the basis for the prediction for morbidity duration and mortality in infected patients [ 6 ]. Moreover, the evidence suggests that the multiorgan failure reported in the severe cases of COVID-19 infection is caused mainly by the inflammatory response from the body as a result of the invasion of viral particles to the endothelial cells and that is the basis for the recommendations of the guidelines to the use of antiplatelet agents and anticoagulants in severe cases of infection which might reduce the vascular compromise and the risk of microthrombi occluding small vessels in the lungs and other body organs [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

New-Onset Henoch–Schonlein Purpura after COVID-19 Infection: A Case Report and Review of the Literature

Asiri

Alzahrani

Al-Shehri

et al. 2022

Case Reports in Pediatrics

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Extrapulmonary manifestations of COVID-19 infection include a wide spectrum of cutaneous, endocrine, and cardiovascular complications. We report three cases of new-onset Henoch–Schonlein purpura (HSP) in COVID-19 infected children that were diagnosed and treated in Abha Maternity and Children Hospital, Saudi Arabia, between 28th July 2020 and 10th August 2020. All three cases were males younger than 5 years of age that presented with Henoch–Schonlein purpura characteristic rash and arthralgia without a recent history of any infection, especially respiratory infections. They all tested positive for COVID-19. At the time of the admission, pediatric COVID-19 cases were managed conservatively and we ruled out any other diagnosis before establishing the diagnosis of Henoch–Schonlein purpura according to the clinical picture. The three boys responded significantly to prednisolone and achieved a rapid recovery. We present the clinical scenario and laboratory tests of these children along with pictures of the lesions detected in each case.

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Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications

Cited by 48 publications

References 198 publications

Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19: a systematic review and meta-analysis

Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19: a systematic review and meta-analysis

Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy

New-Onset Henoch–Schonlein Purpura after COVID-19 Infection: A Case Report and Review of the Literature

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