Blood clots in COVID-19 patients: Simplifying the curious mystery

Biswas, Sourav; Thakur, Vikram; Kaur, Parneet; Khan, Azhar U.; Kulshrestha, Saurabh; Kumar, Pradeep

doi:10.1016/j.mehy.2020.110371

Cited by 67 publications

(53 citation statements)

References 16 publications

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“…Damaging the endothelium causes the release of the von Willebrand factor (vWF), which activates blood platelets and neutrophils. Activated platelets additionally stimulate neutrophils to produce NETs, which become a structure upon which blood platelets, erythrocytes, and fibrines aggregate aiding the development of clots [ 38 , 41 , 42 , 43 , 44 ].…”

Section: Neutrophil Extracellular Trapsmentioning

confidence: 99%

Significance of NETs Formation in COVID-19

Janiuk

Jabłońska

Garley

2021

Cells

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Severe contagious respiratory disease—COVID-19—caused by the SARS-CoV-2 coronavirus, can lead to fatal respiratory failure associated with an excessive inflammatory response. Infiltration and spread of SARS-CoV-2 are based on the interaction between the virus’ structural protein S and the cell’s receptor–angiotensin-converting enzyme 2 (ACE2), with the simultaneous involvement of human trans-membrane protease, serine 2 (TMPRSS2). Many scientific reports stress the importance of elevated recruitment and activity of neutrophils, which can form extracellular neutrophil traps (NETs) playing a significant role in the mechanism of combating pathogens, in the pathogenesis of COVID-19. Excessive generation of NETs during prolonged periods of inflammation predisposes for the occurrence of undesirable reactions including thromboembolic complications and damage to surrounding tissues and organs. Within the present manuscript, we draw attention to the impact of NET generation on the severe course of COVID-19 in patients with concurrent cardiovascular and metabolic diseases. Additionally, we indicate the necessity to explore not only the cellular but also the molecular bases of COVID-19 pathogenesis, which may aid the development of dedicated therapies meant to improve chances for the successful treatment of patients. We also present new directions of research into medications that display NETs formation regulatory properties as potential significant therapeutic strategies in the progress of COVID-19.

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Section: Neutrophil Extracellular Trapsmentioning

confidence: 99%

Significance of NETs Formation in COVID-19

Janiuk

Jabłońska

Garley

2021

Cells

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“…Blood clotting abnormalities in lungs and other organs in COVID-19 patients have been reported by several studies 92 . In autopsies of COVID-19 patients, thrombosis was found to be a prominent finding across multiple organs, even in spite of extensive anticoagulation treatment and regardless of timing of clinical progression, indicating that thrombosis might be at play in the early stages of disease 92 . One hypothesis to explain this observation is that the dysfunction of endothelial cells may play an important role in increased risk of thrombosis 93 .…”

Section: Discussionmentioning

confidence: 82%

Impact of natural selection on global patterns of genetic variation, and association with clinical phenotypes, at genes involved in SARS-CoV-2 infection

Zhang

Verma

Feng

et al. 2021

Preprint

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The COVID-19 pandemic caused by SARS-COV-2 has had a devastating impact on population health. We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (ACE2, TMPRSS2, DPP4, and LY6E). We analyzed novel data from 2,012 ethnically diverse Africans, 15,997 individuals of European (7,061) and African (8,916) ancestry recruited by the Penn Medicine BioBank (PMBB), and comparative data from 2,504 individuals from the 1000 Genomes project. At ACE2 we identified 41 non-synonymous variants, found to be at low frequency in most populations. However, three non-synonymous variants were frequent among Central African hunter-gatherers (CAHG) from Cameroon, and signatures of positive selection could be detected on haplotypes encompassing those variants. We also detected signatures of positive selection for variants at regulatory regions upstream of ACE2 in diverse African populations. At TMPRSS2, we identified 48 non-synonymous variants, several of which are common in global populations, and 13 amino acid changes that are fixed in the human lineage after divergence from Chimpanzee. At DPP4 and LY6E most variants were rare in global populations indicating that purifying selection is acting at these loci. At all four loci, we identified common non-coding variants associated with gene expression that vary in frequency across global populations. By analyzing electronic health records from the PMBB we discovered genetic associations with clinical phenotypes, such as respiratory failure with ACE2 and upper respiratory tract infection with DPP4. Our study provides new insights into global variation at genes potentially affecting susceptibility to SARS-CoV-2 infection.

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“…Lusutrombopag is another antithrombocytopenic agent that binds to ACE2 in the PD region where the spike protein interacts. SARS-CoV-2-associated injury may initiate activation of coagulation and clotting cascades leading to the formation of internal blood clots [ 52 ]. Two anticoagulants eptifibatide and betrixaban dock onto the spike protein binding sites in ACE1 and ACE2, respectively.…”

Section: Discussionmentioning

confidence: 99%

Repurposing of approved drugs with potential to interact with SARS-CoV-2 receptor

Ahsan

Sajib

2021

Biochemistry and Biophysics Reports

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Respiratory transmission is the primary route of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Angiotensin I converting enzyme 2 (ACE2) is the known receptor of SARS-CoV-2 surface spike glycoprotein for entry into human cells. A recent study reported absent to low expression of ACE2 in a variety of human lung epithelial cell samples. Three bioprojects ( PRJEB4337 , PRJNA270632 and PRJNA280600 ) invariably found abundant expression of ACE1 (a homolog of ACE2 and also known as ACE) in human lungs compared to very low expression of ACE2. In fact, ACE1 has a wider and more abundant tissue distribution compared to ACE2. Although it is not obvious from the primary sequence alignment of ACE1 and ACE2, comparison of X-ray crystallographic structures show striking similarities in the regions of the peptidase domains (PD) of these proteins, which is known (for ACE2) to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Critical amino acids in ACE2 that mediate interaction with the viral spike protein are present and organized in the same order in the PD of ACE1. In silico analysis predicts comparable interaction of SARS-CoV-2 spike protein with ACE1 and ACE2. In addition, this study predicts from a list of 1263 already approved drugs that may interact with ACE2 and/or ACE1 and potentially interfere with the entry of SARS-CoV-2 inside the host cells.

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Blood clots in COVID-19 patients: Simplifying the curious mystery

Cited by 67 publications

References 16 publications

Significance of NETs Formation in COVID-19

Significance of NETs Formation in COVID-19

Impact of natural selection on global patterns of genetic variation, and association with clinical phenotypes, at genes involved in SARS-CoV-2 infection

Repurposing of approved drugs with potential to interact with SARS-CoV-2 receptor

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