{"id":4102,"date":"2022-04-05T21:35:39","date_gmt":"2022-04-05T21:35:39","guid":{"rendered":"http:\/\/wp.cov19longhaulfoundation.org\/?p=4102"},"modified":"2022-04-05T21:35:39","modified_gmt":"2022-04-05T21:35:39","slug":"the-ongoing-enigma-of-sars%e2%80%90cov%e2%80%902-and-platelet-interaction","status":"publish","type":"post","link":"https:\/\/cov19longhaulfoundation.org\/?p=4102","title":{"rendered":"The ongoing enigma of SARS\u2010CoV\u20102 and platelet interaction"},"content":{"rendered":"\n

Authors: Younes Zaid<\/a>, PhD 1 , 2 <\/sup>and Fadila Guessous<\/a>, PhD 3 , 4<\/sup> Res Pract Thromb Haemost.<\/a> 2022 Jan; 6(1): e12642.Published online 2022 Jan 25. doi: 10.1002\/rth2.12642<\/a> PMCID:  PMC8787413PMID :  35106430<\/a><\/p>\n\n\n\n

\"Logo<\/figure>\n\n\n\n

Abstract<\/h2>\n\n\n\n

Since the onset of the global pandemic of coronavirus disease 2019 (COVID\u201019), there is an urgent need to understand the pathogenesis of the common inflammatory and thrombotic complications associated with this illness leading to multiorgan failure and mortality. It is well established that platelets are hyperactivated during COVID\u201019. Data from independent studies reported an angiotensin\u2010converting enzyme (ACE2)\u2010dependent severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102) platelet interaction, raising the concern whether ACE2 receptor is the \u201ckey receptor\u201d in this process, while other platelet research groups demonstrated that thrombotic events occur via ACE2\u2010independent mechanisms, where the virus probably uses alternative pathways. In this study, we discuss the conflicting results and highlight the ongoing controversy related to SARS\u2010CoV\u20102\u2010platelet interaction.<\/p>\n\n\n\n

1.\u2003INTRODUCTION<\/h2>\n\n\n\n

Severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102) is a highly transmissible and pathogenic coronavirus that caused an outbreak of uncommon viral pneumonia called coronavirus disease 2019 (COVID\u201019), which originally emerged in Wuhan, China, in December 2019 (https:\/\/covid19.who.int\/<\/a>).<\/p>\n\n\n\n

With the pandemic already in its second year, the disease\u2019s impact on the respiratory tract is becoming increasingly obvious. Indeed, it is currently well established that, in addition to the staggering cytokine storm and lung inflammation associated with the infection, thrombotic complications, including microvascular, venous, or arterial thrombosis, and cardiovascular manifestations significantly contribute to the disease severity, leading to morbidity, multiorgan failure, and mortality. 1<\/a><\/sup><\/p>\n\n\n\n

Platelets, the small anucleated cellular fragments derived from their megakaryocytes precursors and traditionally linked to thrombosis and hemostasis, are also key players that mediate inflammation, infectious diseases, and immune response. 2<\/a><\/sup><\/p>\n\n\n\n

Upon exposure to invading pathogens, platelets contribute to the immunity either directly by cytokine production and anti\u2010microbial peptides release; or indirectly by amplifying the immune response through interaction with neutrophils, monocytes, and lymphocytes. 3 <\/a><\/sup>, <\/sup>4 <\/a><\/sup>However, the immunothrombosis triggered during infections may adversely impact immunological and hemostatic processes; thus leading to adverse clinical outcomes. 5<\/a><\/sup><\/p>\n\n\n\n

Several recent reports highlighted the association of coagulopathy events and COVID\u201019 severity; revealed by elevated levels of D\u2010dimers and fibrin\u2010degradation products and hyperactivated platelets in critically ill patients with COVID\u201019. 6 <\/a><\/sup>, <\/sup>7 <\/a><\/sup>However, how platelets interact with the SARS\u2010CoV\u20102 remains controversial. Such controversy is undoubtedly triggering an exciting debate among researchers in the SARS\u2010CoV\u20102\u2013related coagulopathy field during this pandemic.<\/p>\n\n\n\n

The recently published conflicting results of this interaction as well as its implication for better management of COVID\u201019\u2013related thrombotic complications will be debated here.Go to:<\/a><\/p>\n\n\n\n

2.\u2003PLATELETS ARE HYPERACTIVATED IN COVID\u201019<\/h2>\n\n\n\n

While the pandemic is progressing worldwide, numerous studies have reported that patients with COVID\u201019 demonstrated platelet activation, aggregation, and platelet\u2010leukocyte aggregate formation, thus highlighting the essential role of platelets during SARS\u2010CoV\u20102 infection and immunopathology. 8 <\/a><\/sup>, <\/sup>9 <\/a><\/sup>, <\/sup>10<\/a><\/sup><\/p>\n\n\n\n

Compared to donors not infected with SARS\u2010CoV\u20102, platelets isolated from patients with COVID\u201019 were hyperactivated when exposed to platelet agonists, such as thrombin, ADP, and collagen. 9 <\/a><\/sup>, <\/sup>11 <\/a><\/sup>Such hypersensitivity could be partially due to increased mitogen\u2010activated protein kinase signaling pathway activation and thromboxane synthesis. 9 <\/a><\/sup>, <\/sup>11<\/a><\/sup><\/p>\n\n\n\n

Additionally, platelet\u2010derived microvesicles can be involved in thrombosis, by providing anionic phospholipids, and support coagulation cascade. 12 <\/a><\/sup>Similarly, the release of neutrophil extracellular traps (NET), called NETosis, requires platelets and may participate to thrombosis during SARS\u2010CoV\u20102 infection. 13 <\/a><\/sup>NETs are networks of extracellular fibers of decondensed chromatin carrying histones and antimicrobial peptides. 14 <\/a><\/sup>They also bind blood cells and generate a procoagulant and prothrombotic scaffold. 15 <\/a><\/sup>, <\/sup>16 <\/a><\/sup>In fact, several studies have identified NETs as important components of micro\u2010 and macrovascular thrombi 17 <\/a><\/sup>, <\/sup>18 <\/a><\/sup>, <\/sup>19 <\/a><\/sup>and bronchoalveolar lavage fluid 20 <\/a><\/sup>in patients with COVID\u201019, even after virus clearance from the lungs.<\/p>\n\n\n\n

Moreover, upon SARS\u2010CoV\u20102 infection, activated platelets release immune and inflammatory molecules including platelet\u2010derived growth factor, platelet factor 4 (PF4), RANTES, serotonin, soluble P\u2010selectin (sP\u2010selectin), and soluble glycoprotein VI (sGPVI) 8 <\/a><\/sup>, <\/sup>9 <\/a><\/sup>, <\/sup>11 <\/a><\/sup>, <\/sup>21 <\/a><\/sup>, <\/sup>22 <\/a><\/sup>; and express a plethora of immune receptors, including CD40L, Toll\u2010like receptor, and the Fc receptor for the IgG (Fc\u03b3RIIA). 23 <\/a><\/sup>, <\/sup>24<\/a><\/sup><\/p>\n\n\n\n

A platelet transcriptome study conducted by Manne et al. 9 <\/a><\/sup>has revealed transcriptional changes in patients with COVID\u201019 distinct from those reported in other viral infections.<\/p>\n\n\n\n

Cytokine storm<\/em> is an umbrella term encompassing several disorders of immune dysregulation characterized by constitutional symptoms, systemic inflammation, and multiorgan dysfunction that can lead to multiorgan failure if inadequately treated. 25 <\/a><\/sup>This phenomenon, also known as hypercytokinemia<\/em>, is a hallmark of COVID\u201019, leading to the accumulation of chemokines, cytokines, and several soluble factors, which may activate platelets and other inflammatory cross\u2010talk pathways. 11 <\/a><\/sup>, <\/sup>26 <\/a><\/sup>Such activation triggers platelet adhesion to the subendothelium and results in thrombus formation, subsequently inducing ischemia and pulmonary embolism. 27<\/a><\/sup><\/p>\n\n\n\n

Other viruses can also trigger cytokine storm, including herpesviruses, such as herpes simplex virus, and other influenza viruses, such as H5N1. 25<\/a><\/sup><\/p>\n\n\n\n

Platelets are also known to be directly activated by certain viruses. Indeed, in response to direct infection by dengue and influenza viruses, megakaryocytes upregulate interferon\u2010\u03b1 genes. 28 <\/a><\/sup>, <\/sup>29 <\/a><\/sup>Similarly, simplex virus\u20101 can activate platelet aggregate formation and thrombosis using the previously generated opsonizing antibodies and their interaction with the Fc\u03b3RIIA. 30 <\/a><\/sup>Recently, a key role of platelet\u2010mediated immunothrombosis in COVID\u201019 that signals through Fc\u03b3RIIA and the C5a\u2013C5a receptor pathway has been identified, revealing the role of platelet hyperactivation in complications associated with SARS\u2010CoV\u20102 infection. 31<\/a><\/sup><\/p>\n\n\n\n

However, unlike for other viruses, mechanisms underlying the direct interaction of SARS\u2010CoV\u20102 and platelets and\/or megakaryocytes remain a true controversy. Indeed, two recent independent studies conducted in China resulted in conflicting findings. Zhang et al. 21 <\/a><\/sup>reported a possible activation of platelets and megakaryocytes directly by SARS\u2010CoV\u20102 as evidenced by the presence of the virus mRNA in platelets of some patients with COVID\u201019, while a most recent study revealed that platelet activation occurs through an angiotensin\u2010converting enzyme (ACE2)\u2010independent mechanism. 22<\/a><\/sup>Go to:<\/a><\/p>\n\n\n\n

3.\u2003DOES SARS\u2010COV\u20102 INTERACT DIRECTLY WITH PLATELETS?<\/h2>\n\n\n\n

SARS\u2010CoV\u20102 is a positive\u2010sense single\u2010stranded RNA virus related to a number of naturally occurring betacoronaviruses. 32<\/a><\/sup><\/p>\n\n\n\n

ACE2, the negative regulator of the renin\u2010angiotensin system, has been recognized as the entry receptor for the SARS\u2010CoV\u20102 infected host cells. 33<\/a><\/sup><\/p>\n\n\n\n

There is a little to no expression of ACE2 on most immune cells, including CD4+<\/sup>T cells, CD8+<\/sup>T cells, natural killer T cells, B cells, regulatory T cells, T helper 17 cells, monocytes, dendritic cells, and granulocytes. 34 <\/a><\/sup>On the contrary, this receptor is strongly expressed by alveolar epithelial cells, nasopharyngeal airway epithelial cells, and vascular endothelial cells, as well as lung macrophages. 35 <\/a><\/sup>Such virus tropism certainly explains the prevailing respiratory symptoms associated with the disease.<\/p>\n\n\n\n

Another potential cellular entry process has been proposed for the viral invasion, using the transmembrane serine protease\u20102 (TMPRSS2), which is essential for the cleavage of the SARS\u2010CoV\u20102 S protein, thus allowing the fusion of viral and cell membrane and the virus internalization by the cell. 36<\/a><\/sup><\/p>\n\n\n\n

Following the onset of the COVID\u201019 pandemic and considering its staggering proinflammatory feature, most studies have focused their interest on the expression of ACE2 on immune cells, but a little attention was given to platelets and their megakaryocytes precursors until a few research groups explored such expression on these cells.<\/p>\n\n\n\n

Using RNA sequencing (RNA\u2010seq), reverse transcriptase polymerase chain reaction, and western blot analyses, Manne et al. 9 <\/a><\/sup>did not reveal any ACE2 or TMPRSS2 in CD45\u2010depleted platelets collected from either patients with COVID\u201019 or healthy subjects. Using similar approaches, concomitant work by Zaid et al. 11 <\/a><\/sup>also reported that there is no detection of ACE2 on platelets derived from patients with COVID\u201019 nor from healthy volunteers.<\/p>\n\n\n\n

Consistent with these reports, a more recent retrospective survey of plasma samples from a cohort of 62 patients with severe and nonsevere COVID\u201019 revealed an increased thrombosis and high levels of sP\u2010selectin and sGPVI as well as RANTES and PF4 release during platelet activation. However, the characteristics and mechanisms of the direct SARS\u2010CoV\u20102\u2013platelet interaction are yet to be elucidated. 22<\/a><\/sup><\/p>\n\n\n\n

In contrast, an independent study carried out by Zhang et al. 21 <\/a><\/sup>has shown a strong expression of ACE2 and TMPRSS2 mRNA and protein on platelets from healthy individuals and mice. Moreover, using in vitro assays and in vivo ACE2 transgenic mice, the same group ascertained their findings and reported that the SARS\u2010CoV\u20102 virus and its spike protein induce direct platelet activation.<\/p>\n\n\n\n

Another aspect of platelet\u2013SARS\u2010CoV\u20102 interaction was recently reported by Koupenova et al., which reported that SARS\u2010CoV\u20102 initiates programmed cell death in platelets. Indeed, based on platelet RNA analysis by ARTIC v3 sequencing for SARS\u2010CoV\u20102, transmission electron microscopy and immunofluorescence, this group showed that SARS\u2010CoV\u20102 virions became internalized when they were attached to microparticles, bypassing the need for ACE2. Such internalization leads to rapid digestion, apoptosis, necroptosis, and extracellular vesicle release, thus contributing to dysregulated immunity and thrombosis. 37<\/a><\/sup>Go to:<\/a><\/p>\n\n\n\n

4.\u2003TAKING TOGETHER THESE DISCORDANT FINDINGS ON WHETHER PLATELETS EXPRESS ACE2 AND\/OR TMPRSS2, HOW COULD WE ARGUE IN FAVOR OF ONE OR THE OTHER STATEMENT?<\/h2>\n\n\n\n

Considering that investigations related to this topic were conducted in different parts of the world, the first possible explanation to such discrepancy would be ethnicity. Indeed, studies carried out by Zaid et al. 11 <\/a><\/sup>and Manne et al. 9 <\/a><\/sup>included individuals from North Africa and North America, while the cohort studied by Zhang et al. 21 <\/a><\/sup>was from Asia. However, in our opinion, this argument would not be valid given that Shen et al. 22 <\/a><\/sup>recently investigated patients from Asia as well. This group investigated in vitro<\/em> SARS\u2010CoV\u20102 infection in human platelets and their megakaryocyte cell line progenitor MEG\u201001.<\/p>\n\n\n\n

According to this study, the presence of SARS\u2010CoV\u20102 RNA in both MEG\u201001 cells and supernatant suggested that the virus may infect and reproduce in megakaryocytes despite insufficient efficiency; nevertheless, no viral particles were localized in MEG\u201001 cells as revealed by electron microscopy and immunofluorescence assay (IFA). The authors speculated that platelets may not support SARS\u2010CoV\u20102 duplication; a fact that was echoed by Zaid et al., 11 <\/a><\/sup>and Bury et al. 38 <\/a><\/sup>Additionally, the lack of ACE2 expression on platelets and megakaryocytes was also shown by western blot and IFA in the study of Shen et al. 22 <\/a><\/sup>Similarly, ACE2 and TMPRSS2 RNA were not detectable in a previous microarray\u2010based integrated plateletomics study that mainly included healthy Black subjects. 39<\/a><\/sup><\/p>\n\n\n\n

Besides the ethnicity argument, conflicting findings may be attributed to different technical approaches used to isolate RNA platelets in different investigations. Both studies conducted by Manne et al. 9 <\/a><\/sup>and Zaid et al. 11 <\/a><\/sup>used CD45+<\/sup>\u2010depleted washed platelets, a step that eliminated any remaining leukocytes from platelet preparation.<\/p>\n\n\n\n

On the contrary, using gel\u2010purified platelets, Zhang et al. 21 <\/a><\/sup>confirmed the absence of white cells by using CD14 marker in their platelet preparation, a step that would probably leave a residual contamination by CD14\u2010nonexpressing white cells, such as lymphocytes and natural killer cells, thus explaining ACE2 detection in their preparation. Moreover, on the animal level, the same group demonstrated that the administration of SARS\u2010CoV\u20102 spike protein in K18 hACE2 transgenic mice induces platelet hyperactivation and aggregation; however, the expression of this receptor either on platelets or megakaryocytes of these mice remains to be solved and needs to be further investigated, with still the main focus on how these findings in mice could be translated into humans. 39 <\/a><\/sup>It is also worth highlighting that a previous RNA\u2010seq analysis documented the lack of expression of ACE2 and TMPRSS2 by platelets and megakaryocytes in mice. 40<\/a><\/sup><\/p>\n\n\n\n

Despite the reported differences regarding the direct SARS\u2010CoV\u20102\u2010platelet interaction, it is worth noticing that all studies converge toward the same finding that platelets are activated during COVID\u201019; and some of them further ascertain that the virus RNA can be found within platelets. 38 <\/a><\/sup>All these data advocate in favor of a potential ACE2\u2010independent mechanism that SARS\u2010CoV\u20102 might use for possible binding and\/or entry into platelets.<\/p>\n\n\n\n

Using RNA\u2010seq analysis, Shen et al. 22 <\/a><\/sup>showed unchanged levels of glucose\u2010regulated protein (GRP 78), ADAM1, cathepsin L, GRP1, and asialoglycoprotein 1 in platelets between intensive care unit (ICU) and non\u2010ICU patients with COVID\u201019 and healthy individuals; and reported increased CD147 and kringle\u2010containing transmembrane protein 1 and reduced neuropilin 1 levels in patients as well as in MEG\u201001 cells upon SARS\u2010CoV\u20102 incubation. These data suggest a marked alteration of megakaryocyte and platelet transcriptomic profile, reflecting a similar finding to dengue virus infection. 28<\/a><\/sup><\/p>\n\n\n\n

Emerging evidence suggested CD147 as a potential receptor for SARS\u2010CoV\u20102 and its overexpression is associated with certain diseases, such as chronic obstructive pulmonary disease, asthma, that represent risk factors associated with complications during the COVID\u201019 pandemic. 28 <\/a><\/sup>Nonetheless, the binding of SARS\u2010CoV\u20102 to CD147 is to be uncovered and the role of this receptor in SARS\u2010CoV\u20102 infection remains disputable. 41<\/a><\/sup><\/p>\n\n\n\n

In contrast, in their report related to SARS\u2010COV\u20102 directly interacting with platelets via ACE2, Zhang et al. 21 <\/a><\/sup>also supported a direct interaction of CD147, SARS\u2010CoV\u20102, and the spike protein.<\/p>\n\n\n\n

Based on recent structural studies, CD26 was suggested to be another SARS\u2010CoV\u20102 receptor. 9 <\/a><\/sup>Such statement needs to be further investigated since the expression of this receptor on platelets is still debatable. Indeed, previous platelet RNA\u2010seq and proteomic analysis suggest that neither platelets nor megakaryocytes express CD26, under physiological or infectious conditions. 9 <\/a><\/sup>In contrast, the RNA abundance of 14 receptors and cofactors, including CD26, in human platelets and megakaryocytes was explored based on the RNA\u2010seq data reported in earlier studies and revealed the expression of CD26 on these cells, though at very low levels. 22 <\/a><\/sup>Together, these findings could be a hint of a possible CD26\u2010SARS\u2010CoV\u20102 direct interaction but does not provide tangible data to support a binding solely through this receptor.<\/p>\n\n\n\n

In addition to all discrepancy arguments cited above, it is worth mentioning that during this pandemic, there was a rapid and large volume of new COVID\u201019 data published in a very short time in the quest to disseminate this new information and insights, thus helping containing the virus spread worldwide.<\/p>\n\n\n\n

Therefore, considering that the technical barrier for COVID\u201019\u2013related studies was lowered and the well\u2010intended change of the publication process, the field is more likely to be inconsistent and needs to be revisited experimentally to clarify (Figure 1<\/a>).<\/a>FIGURE 1<\/a><\/p>\n\n\n\n

Proposed model for the SARS\u2010CoV\u20102 and platelet interaction. ACE2, angiotensin\u2010converting enzyme; CXCR, C\u2010X\u2010C chemokine receptor type 4; Fc\u03b3RIIA, Fc receptor for the IgG; MHC\u20101, major histocompatibility complex class 1; SARS\u2010CoV\u20102, severe acute respiratory syndrome coronavirus 2; TLR, Toll\u2010like receptor; TMPRSS2, transmembrane serine protease\u20102; TNFR, tumor necrosis factor receptorGo to:<\/a><\/p>\n\n\n\n

5.\u2003CONCLUSIONS AND RECOMMENDATIONS<\/h2>\n\n\n\n

As the pandemic is still wreaking havoc across the globe, more studies are carried out and the understanding of the COVID\u201019 pathophysiology is continuously evolving, shedding more light on still enigmatic mechanisms underlying platelet hyperactivation during SARS\u2010CoV2 infection. Following the cytokine storm triggered by the virus infection, platelets\u2019 reactivity may be a critical step in the inflammatory and prothrombotic response, named immunothrombosis.<\/p>\n\n\n\n

How the SARS\u2010CoV\u20102\u2013platelet interaction takes place is still obscure, and therefore more studies are warranted to uncover such mechanisms, taking into consideration ethnicity and gearing toward the expression of potential alternative SARS\u2010CoV\u20102 entry receptors or pathways other than the previously established ACE2 receptor and the spike priming serine protease TMPRSS2.<\/p>\n\n\n\n

Besides the uneven health care system efficiency in different countries, compiling clinical data worldwide demonstrated an unequal burden of this disease among certain populations, therefore urging the research community to explore a probable population\u2010based differential expression of SARS\u2010CoV\u20102 key receptors on the surface of platelets and\/or other immune cells.<\/p>\n\n\n\n

Moreover, as the megakaryocytes are the platelet precursors and considered the cargo carrying all the molecules and factors necessary to platelets\u2019 function before their release into circulation, all future studies should explore the SARS\u2010CoV\u20102 and platelet interaction without losing sight of behavior differences between these two interdependent entities.<\/p>\n\n\n\n

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Authors: Younes Zaid, PhD 1 , 2 and Fadila Guessous, PhD 3 , 4 Res Pract Thromb Haemost. 2022 Jan; 6(1): e12642.Published online 2022 Jan 25. doi: 10.1002\/rth2.12642 PMCID:  PMC8787413PMID :  35106430 Abstract Since the onset of the global […]<\/p>\n","protected":false},"author":2,"featured_media":4105,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[661,439],"tags":[],"class_list":["post-4102","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-ace2-receptors","category-platelets"],"_links":{"self":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts\/4102","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=4102"}],"version-history":[{"count":0,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts\/4102\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/media\/4105"}],"wp:attachment":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=4102"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=4102"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=4102"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}