Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches

Ahamed, Jasimuddin; Laurence, Jeffrey

doi:10.1172/jci161167

Cited by 93 publications

(98 citation statements)

References 147 publications

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“…In the meantime, changes in levels of D-dimer could serve as potential biomarkers of PCC to be used in routine practice, since D-dimers are a routine blood test, easy to perform and available in most settings. As showed in a recent review, there is growing understanding of a possible role of the endothelium in the pathophysiology of PCC 47 and, although the interpretation of abnormal D-dimer in this context has still to be elucidated, this may suggest the importance of closer follow-up of this subgroup of children or their participation in pharmacological trials, when available in pediatric practice. Importantly, elucidating the biological mechanisms responsible for sustained D‐dimer increases may be of relevance in PCC pathogenesis and has implications for clinical management of these patients.…”

Section: Discussionmentioning

confidence: 99%

Extended coagulation profile of children with Long Covid: a prospective study

Gennaro

Valentini

Sorrentino

et al. 2022

Sci Rep

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Emerging data suggests that endotheliopathy changes can be associated with post covid condition (PCC) in adults. Research on the matter in children is lacking. We analyzed an extended coagulation profile including biomarkers of endothelial damage in children with PCC and compared it with a control group of children that fully recovered post- SARS-CoV-2 infection. A case-control study enrolling children below 18 years of age with previous microbiologically confirmed SARS-CoV-2 infection in a pediatric post-covid unit in Italy ≥ 8 weeks after the initial infection. Samples were taken at 8 and 12 weeks after the SARS-CoV-2 diagnosis and analyzed for coagulation profiling (fibrinogen, prothrombin time, international normalized ratio, activated partial thromboplastin time, d-dimers, factor VIII coagulant activity, plasma von Willebrand factor (VWF) antigen and VWF ristocetin cofactor (RC)). We compared coagulation profiles in samples from children identified with PCC (at least one, or three or more symptoms, which could not be explained by an alternative diagnosis, at the 8- and 12-week follow-up assessment using the pediatric Long Covid International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) survey. Seventy-five children were enrolled, 49.3% were females, the median age was 10.2 (IQR 4.9) years. Forty-six (61%) of the children had at least one persisting symptom at the eight weeks post-onset, (PCC8); 39/75 (52%) had persistent symptoms for more than 12 weeks (PCC12) and 15/75(32%) had at least three persisting symptoms (PCC ≥ 3) at 12 weeks. Children with PCC presented more frequently with abnormal D-Dimer levels above the reference range compared to children that had fully recovered at the 8–12 weeks (39.1% vs. 17.2%, p = 0.04), and 12 week follow up or more (41% vs. 17.2%, p = 0.05), and in children with three or more symptoms at 12 weeks follow up compared to those that had recovered (64.3% vs. 22.2%, p = 0.002). For the other coagulation profiles, there were abnormal values detected for VWF, FVIII, RC and Fibrinogen but no significant differences between children with PCC compared to controls. Although the majority of children in our cohort showed coagulation profile within or close to normal ranges, we found that a higher proportion of children with PCC, and specifically those with a more severe spectrum characterized with three or more persisting symptoms, had abnormal D-dimer levels compared to other children that fully recovered from an acute SARS-CoV-2 infection.

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Section: Discussionmentioning

confidence: 99%

Extended coagulation profile of children with Long Covid: a prospective study

Gennaro

Valentini

Sorrentino

et al. 2022

Sci Rep

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“…There is also evidence that viral S-proteins can be shed; are present in bodily fluids, microvessels, and tissues of SARS-CoV-2 infected patients; and can directly affect the vascular endothelium [ 12 , 21 , 22 , 23 , 24 ]. Evidence also suggests that long COVID-19 syndrome involves persistent microvascular endotheliopathy associated with increased SARS-CoV-2 virions and S-proteins in the blood and tissues as well as increased peripheral levels of pro-thrombotic factors [ 25 , 26 , 27 ]. In the present study, we investigate the direct and indirect effects of S-proteins’ exposure on expression and secretion of thrombogenic factors by primary human lung microvascular endothelial cells (HLMEC) and neutrophils.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Spike Proteins and Cell–Cell Communication Inhibits TFPI and Induces Thrombogenic Factors in Human Lung Microvascular Endothelial Cells and Neutrophils: Implications for COVID-19 Coagulopathy Pathogenesis

Bhargavan

Kanmogne

2022

IJMS

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In SARS-CoV-2-infected humans, disease progression is often associated with acute respiratory distress syndrome involving severe lung injury, coagulopathy, and thrombosis of the alveolar capillaries. The pathogenesis of these pulmonary complications in COVID-19 patients has not been elucidated. Autopsy study of these patients showed SARS-CoV-2 virions in pulmonary vessels and sequestrated leukocytes infiltrates associated with endotheliopathy and microvascular thrombosis. Since SARS-CoV-2 enters and infects target cells by binding its spike (S) protein to cellular angiotensin-converting enzyme 2 (ACE2), and there is evidence that vascular endothelial cells and neutrophils express ACE2, we investigated the effect of S-proteins and cell–cell communication on primary human lung microvascular endothelial cells (HLMEC) and neutrophils expression of thrombogenic factors and the potential mechanisms. Using S-proteins of two different SARS-CoV-2 variants (Wuhan and Delta), we demonstrate that exposure of HLMEC or neutrophils to S-proteins, co-culture of HLMEC exposed to S-proteins with non-exposed neutrophils, or co-culture of neutrophils exposed to S-proteins with non-exposed HLMEC induced transcriptional upregulation of tissue factor (TF), significantly increased the expression and secretion of factor (F)-V, thrombin, and fibrinogen and inhibited tissue factor pathway inhibitor (TFPI), the primary regulator of the extrinsic pathway of blood coagulation, in both cell types. Recombinant (r)TFPI and a thiol blocker (5,5′-dithio-bis-(2-nitrobenzoic acid)) prevented S-protein-induced expression and secretion of Factor-V, thrombin, and fibrinogen. Thrombomodulin blocked S-protein-induced expression and secretion of fibrinogen but had no effect on S-protein-induced expression of Factor-V or thrombin. These results suggests that following SARS-CoV-2 contact with the pulmonary endothelium or neutrophils and endothelial–neutrophil interactions, viral S-proteins induce coagulopathy via the TF pathway and mechanisms involving functional thiol groups. These findings suggest that using rTFPI and/or thiol-based drugs could be a viable therapeutic strategy against SARS-CoV-2-induced coagulopathy and thrombosis.

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“…Notably, the crucial role of endothelial dysfunction in the pathobiology of COVID-19, initially described by our research group [ 72 ] has been later confirmed by numerous investigators [ 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. Indeed, endothelial cells have been shown to express the key co-factors involved for the internalization of SARS-CoV-2 in host cells, including angiotensin converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), cathepsins B and D, TIM-1, neuropilin-1, and others, thereby representing a natural target of SARS-CoV-2 [ 83 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 ]. Furthermore, the systemic inflammatory viral reaction observed in patients affected by COVID-19 has been shown to be linked to endothelial dysfunction [ 93 , 94 , 95 , 96 , 97 ], leading to thromboembolic events [ 98 , 99 , 100 ], which represent a common feature of COVID-19 cases with a severe outcome [ 101 , 102 , 103 ].…”

Section: Discussionmentioning

confidence: 99%

miR-142 Targets TIM-1 in Human Endothelial Cells: Potential Implications for Stroke, COVID-19, Zika, Ebola, Dengue, and Other Viral Infections

Kansakar

Gambardella

Varzideh

et al. 2022

IJMS

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T-cell immunoglobulin and mucin domain 1 (TIM-1) has been recently identified as one of the factors involved in the internalization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human cells, in addition to angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), neuropilin-1, and others. We hypothesized that specific microRNAs could target TIM-1, with potential implications for the management of patients suffering from coronavirus disease 2019 (COVID-19). By combining bioinformatic analyses and functional assays, we identified miR-142 as a specific regulator of TIM-1 transcription. Since TIM-1 has been implicated in the regulation of endothelial function at the level of the blood-brain barrier (BBB) and its levels have been shown to be associated with stroke and cerebral ischemia-reperfusion injury, we validated miR-142 as a functional modulator of TIM-1 in human brain microvascular endothelial cells (hBMECs). Taken together, our results indicate that miR-142 targets TIM-1, representing a novel strategy against cerebrovascular disorders, as well as systemic complications of SARS-CoV-2 and other viral infections.

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Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches

Cited by 93 publications

References 147 publications

Extended coagulation profile of children with Long Covid: a prospective study

Extended coagulation profile of children with Long Covid: a prospective study

SARS-CoV-2 Spike Proteins and Cell–Cell Communication Inhibits TFPI and Induces Thrombogenic Factors in Human Lung Microvascular Endothelial Cells and Neutrophils: Implications for COVID-19 Coagulopathy Pathogenesis

miR-142 Targets TIM-1 in Human Endothelial Cells: Potential Implications for Stroke, COVID-19, Zika, Ebola, Dengue, and Other Viral Infections

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