Damage to endothelial barriers and its contribution to long COVID

Wu, Xiaoming; Xiang, Mengqi; Jing, Haijiao; Wang, Chengyue; Novakovic, Valerie A.; Shi, Jialan

doi:10.1007/s10456-023-09878-5

Cited by 32 publications

(33 citation statements)

References 133 publications

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“…Endothelial cells have a vital role in vascular homeostasis and haemostasis, including regulating vascular tone, blood flow, fibrinolysis, and platelet aggregation [32][33][34][35]. Acute COVID-19 appears to be primarily a disease of the vascular endothelium resulting in a microcirculatory thrombotic vasculitis [33,34,[36][37][38][39][40][41][42][43]. SARS-CoV-2 spike proteins allow viral attachment to target cells via to angiotensin converting enzyme 2 (ACE2) protein binding, followed by intracellular viral replication [42,44,45].…”

Section: Acute Covid-19: the Foundations Underpinning Long Covidmentioning

confidence: 99%

“…Endothelial injury can result from direct infection by SARS-CoV-2 causing endothelial cell apoptosis and endotheliitis as well as subsequent systemic inflammatory responses [33,34,37,39,49,51,52]. The spike protein alone can induce neuronal injury [53], destabilise microvascular haemostasis [54], induce thrombosis [55], (irreversibly) activate platelets [56][57][58] and impair endothelial function [43,59], with some effects independent of ACE2 [60] or possibly from anti-spike antibodies [61]. With endothelial dysfunction comes impaired vascular tone and a prothrombotic state [32,34,35,37,43,49].…”

Section: Acute Covid-19: the Foundations Underpinning Long Covidmentioning

confidence: 99%

“…The spike protein alone can induce neuronal injury [53], destabilise microvascular haemostasis [54], induce thrombosis [55], (irreversibly) activate platelets [56][57][58] and impair endothelial function [43,59], with some effects independent of ACE2 [60] or possibly from anti-spike antibodies [61]. With endothelial dysfunction comes impaired vascular tone and a prothrombotic state [32,34,35,37,43,49].…”

Section: Acute Covid-19: the Foundations Underpinning Long Covidmentioning

confidence: 99%

“…COVID-19 is a highly inflammatory disease, with potential to cause cytokine storms [64]. Indeed, COVID-19 activates platelets and complement, causing endothelial dysfunction [43,65]. The resultant proinflammatory milieu can cause immunothrombosis, particularly affecting the microvasculature [65].…”

Section: Microclotsmentioning

confidence: 99%

“…Current ideas include mast cell activation syndrome (MCAS), neuroinflammation, viral reactivation, SARS-CoV-2 and/or spike protein persistence, autoimmunity, and gut dysbiosis [9,79]. An increasingly recognised pathology is related to microclots, platelet hyperactivation, and endothelial dysfunction [36,40,43,[80][81][82]. Herein we describe our perspective that Long COVID is primarily (though not necessarily exclusively) a thrombotic vasculitis.…”

Section: Long Covid As a Coagulopathymentioning

confidence: 99%

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Long COVID is primarily a Spike protein Induced Thrombotic Vasculitis

Carroll

2023

Preprint

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Long COVID describes an array of often debilitating symptoms in the aftermath of SARS-CoV-2 infection, with similar symptomatology affecting some people post-vaccination. With an estimated > 200 million Long COVID patients worldwide and cases still rising, the effects on quality of life and the economy are significant, thus warranting urgent attention to understand the pathophysiology. Herein we describe our perspective that Long COVID is a continuation of acute COVID-19 pathology, whereby coagulopathy is the main driver of disease and can cause or exacerbate other pathologies common in Long COVID, such as mast cell activation syndrome and dysautonomia. Considering the SARS-CoV-2 spike protein can independently induce fibrinaloid microclots, platelet activation, and endotheliitis, we predict that persistent spike protein will be a key mechanism driving the continued coagulopathy in Long COVID. We discuss several treatment targets to address the coagulopathy, and predict that (particularly early) treatment with combination anticoagulant and antiplatelet drugs will bring significant relief to many patients, supported by a case study. To help focus attention on such treatment targets, we propose Long COVID should be referred to as Spike protein Induced Thrombotic Vasculitis (SITV). These ideas require urgent testing, especially as the world tries to co-exist with COVID-19.

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Section: Acute Covid-19: the Foundations Underpinning Long Covidmentioning

confidence: 99%

Section: Acute Covid-19: the Foundations Underpinning Long Covidmentioning

confidence: 99%

Section: Acute Covid-19: the Foundations Underpinning Long Covidmentioning

confidence: 99%

Section: Microclotsmentioning

confidence: 99%

Section: Long Covid As a Coagulopathymentioning

confidence: 99%

See 3 more Smart Citations

Long COVID is primarily a Spike protein Induced Thrombotic Vasculitis

Carroll

2023

Preprint

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Long COVID across SARS‐CoV‐2 variants: Clinical features, pathogenesis, and future directions

Lok,

Sarkar,

Lam

et al. 2024

MedComm – Future Medicine

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Long coronavirus disease (COVID) is characterized by persistent symptoms following severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and has emerged as a significant health concern. As SARS‐CoV‐2 evolved from the wild‐type strain to the Alpha, Beta, Delta, and Omicron variants, there may be a variant‐specific influence on long COVID akin to the acute disease. This review aims to summarize our current knowledge of variant‐specific influences in long COVID incidence, symptom profile as well as mechanisms of pathogenesis. We highlight that long COVID incidence may be lower with the Omicron variants. The symptom profile of long COVID may also show some dependence on the different variants, with a reduction in cardiopulmonary symptoms with more recent SARS‐CoV‐2 variants. This heterogeneity of long COVID may also be related to the variant‐specific differences in affecting the immune system, viral persistence, and autoimmunity. However, emerging data also suggest that vaccinations may play a big role in shaping the presentation of long COVID. We also highlight ongoing work on long COVID incidence and symptom profiles in populations infected only by the Omicron variants. This will be beneficial toward more useful disease definitions and the development of effective diagnostic and therapeutic strategies.

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Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation

Kuchler,

Günthner,

Ribeiro

et al. 2023

Angiogenesis

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Background Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians. Methods In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort (n = 41, matched out of n = 204). Measurements and main results PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular flicker-induced dilation (vFID; 3.42% ± 1.77% vs. 4.64% ± 2.59%; p = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5–190.2] vs. 189.1 [179.4–197.2], p = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8–0.9] vs. 0.88 [0.8–0.9], p = 0.007). When combining AVR and vFID, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR (R = − 0.37 p = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of inflammatory parameters. Conclusion Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management. Trial registration This study was previously registered at ClinicalTrials (“All Eyes on PCS—Analysis of the Retinal Microvasculature in Patients with Post-COVID-19 Syndrome”. NCT05635552. https://clinicaltrials.gov/ct2/show/NCT05635552). Graphical abstract Persistent endothelial dysfunction in post-COVID-19 syndrome. Acute SARS-CoV-2 infection indirectly or directly causes endotheliitis in patients. N = 41 PCS patients were recruited and retinal vessel analysis was performed to assess microvascular endothelial function. Images of SVA and DVA are illustrative for RVA data analysis. For each PCS patient and healthy cohort, venular vessel diameter of the three measurement cycles was calculated and plotted on a diameter-time curve. Patients exhibited reduced flicker-induced dilation in veins (vFID) measured by dynamic vessel analysis (DVA) and lower central retinal arteriolar equivalent (CRAE) and arteriolar-venular ratio (AVR) and a tendency towards higher central retinal venular equivalent (CRVE) when compared to SARS-CoV-2 infection naïve participants. Created with BioRender.com

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Damage to endothelial barriers and its contribution to long COVID

Cited by 32 publications

References 133 publications

Long COVID is primarily a Spike protein Induced Thrombotic Vasculitis

Long COVID is primarily a Spike protein Induced Thrombotic Vasculitis

Long COVID across SARS‐CoV‐2 variants: Clinical features, pathogenesis, and future directions

Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation

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