Potential Role of Platelets in COVID‐19: Implications for Thrombosis

For the past 150 years, platelets have been recognized as the major blood component that mediates hemostasis and thrombosis. In more recent years, however, we have come to appreciate that platelets also perform profound immune functions during infection with various pathogens. We now recognize that platelets can also mediate a response to various RNA viruses such as influenza and that many viral infections, including the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), can affect platelet count. Thrombocytopenia and increased coagulation have been independently associated with increased mortality. This article provides a perspective on the potential roles of platelets during COVID‐19

Diverse human extracellular RNAs are widely detected in human plasma

There is growing appreciation for the importance of non-protein-coding genes in development and disease. Although much is known about microRNAs, limitations in bioinformatic analyses of RNA sequencing have precluded broad assessment of other forms of small-RNAs in humans. By analysing sequencing data from plasma-derived RNA from 40 individuals, here we identified over a thousand human extracellular RNAs including microRNAs, piwi-interacting RNA (piRNA), and small nucleolar RNAs. Using a targeted quantitative PCR with reverse transcription approach in an additional 2,763 individuals, we characterized almost 500 of the most abundant extracellular transcripts including microRNAs, piRNAs and small nucleolar RNAs. The presence in plasma of many non-microRNA small-RNAs was confirmed in an independent cohort. We present comprehensive data to demonstrate the broad and consistent detection of diverse classes of circulating non-cellular small-RNAs from a large population

Micro RNAs from DNA Viruses are Found Widely in Plasma in a Large Observational Human Population

Viral infections associate with disease risk and select families of viruses encode miRNAs that control an efficient viral cycle. The association of viral miRNA expression with disease in a large human population has not been previously explored. We sequenced plasma RNA from 40 participants of the Framingham Heart Study (FHS, Offspring Cohort, Visit 8) and identified 3 viral miRNAs from 3 different human Herpesviridae. These miRNAs were mostly related to viral latency and have not been previously detected in human plasma. Viral miRNA expression was then screened in the plasma of 2763 participants of the remaining cohort utilizing high-throughput RT-qPCR. All 3 viral miRNAs associated with combinations of inflammatory or prothrombotic circulating biomarkers (sTNFRII, IL-6, sICAM1, OPG, P-selectin) but did not associate with hypertension, coronary heart disease or cancer. Using a large observational population, we demonstrate that the presence of select viral miRNAs in the human circulation associate with inflammatory biomarkers and possibly immune response, but fail to associate with overt disease. This study greatly extends smaller singular observations of viral miRNAs in the human circulation and suggests that select viral miRNAs, such as those for latency, may not impact disease manifestation

Biology of Platelet Purinergic Receptors and Implications for Platelet Heterogeneity

Platelets are small anucleated cells present only in mammals. Platelets mediate intravascular hemostatic balance, prevent interstitial bleeding, and have a major role in thrombosis. Activation of platelet purinergic receptors is instrumental in initiation of hemostasis and formation of the hemostatic plug, although this activation process becomes problematic in pathological settings of thrombosis. This review briefly outlines the roles and function of currently known platelet purinergic receptors (P1 and P2) in the setting of hemostasis and thrombosis. Additionally, we discuss recent novel studies on purinergic receptor distribution according to heterogeneous platelet size, and the possible implication of this distribution on hemostatic function

SARS-CoV-2 Receptors are Expressed on Human Platelets and the Effect of Aspirin on Clinical Outcomes in COVID-19 Patients [preprint]

Coronavirus disease-2019 (COVID-19) caused by SARS-CoV-2 is an ongoing viral pandemic marked by increased risk of thrombotic events. However, the role of platelets in the elevated observed thrombotic risk in COVID-19 and utility of anti-platelet agents in attenuating thrombosis is unknown. We aimed to determine if human platelets express the known SARS-CoV-2 receptor-protease axis on their cell surface and assess whether the anti-platelet effect of aspirin may mitigate risk of myocardial infarction (MI), cerebrovascular accident (CVA), and venous thromboembolism (VTE) in COVID-19. Expression of ACE2 and TMPRSS2 on human platelets were detected by immunoblotting and confirmed by confocal microscopy. We evaluated 22,072 symptomatic patients tested for COVID-19. Propensity-matched analyses were performed to determine if treatment with aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) affected thrombotic outcomes in COVID-19. Neither aspirin nor NSAIDs affected mortality in COVID-19. However, both aspirin and NSAID therapies were associated with increased risk of the combined thrombotic endpoint of (MI), (CVA), and (VTE). Thus, while platelets clearly express ACE2-TMPRSS2 receptor-protease axis for SARS-CoV-2 infection, aspirin does not prevent thrombosis and death in COVID-19. The mechanisms of thrombosis in COVID-19, therefore, appears distinct and the role of platelets as direct mediators of SARS-CoV-2-mediated thrombosis warrants further investigation

Platelets and COVID-19: Inflammation, Hyperactivation and Additional Questions

The mechanisms underlining thrombosis in COVID-19 patients are not known and likely due to multiple processes including inflammation, oxygen demand injury, and plaque rupture triggered by the infection. Platelets mediate thrombotic vascular occlusion but are also increasingly recognized to have immunomodulatory activity. Several of our recent studies have characterized the role of viral infections in cardiac disease. Although robust data on the scope of acute myocardial infarction in COVID-19 are not yet available, myocardial infarction contributed to in-hospital mortality during previous severe acute respiratory syndrome/coronavirus epidemics. A recent study has also demonstrated that influenza and other respiratory viruses increase the incidence of acute myocardial infarction particularly in the first 7 days post-infection, suggesting that platelets may be directly involved in mediating an immune response but, when dysregulated, can also lead to thrombotic vascular occlusion

Platelets and Immunity: Going Viral

Platelets are the major blood component bridging immunity and thrombosis. Abundant in the circulation, platelets encounter pathogens at a higher rate than any circulating leukocyte. Viral particles of various blood-borne pathogens such as HIV,1 dengue,2 or even respiratory viruses such as influenza3 are found inside human platelets. Viral infections with these viruses,4 as well as the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), can lead to thrombocytopenia5 along with thrombotic complications6–8 in patients. The presence of internalized viral particles, thrombocytopenia, and thrombosis implicates platelets as active participants in immunity during viral infections

Human Platelets and Influenza Virus: Internalization and Platelet Activation

Influenza infection has long been associated with prothrombotic outcomes in patients and platelets are the blood component predominantly responsible for thrombosis. In this review, we outline what is known about influenza interaction with human platelets, virion internalization, and viral RNA sensing, and the consequent impact on platelet function. We further discuss activation of platelets by IgG-influenza complexes and touch upon mechanisms of environmental platelet activation that relate to prothrombotic outcomes in patients during infection

ACEing COVID-19: A Role For Angiotensin Axis Inhibition in SARS-CoV-2 infection

Cardiometabolic disease, especially hypertension, is a common risk factor for mortality among individuals with SARS-CoV-2 disease (COVID-19). The role of hypertension and vascular disease in COVID-19 has raised considerable debate around how to best manage anti-hypertensive therapy to alter disease trajectory. Given the role of the ACE2 receptor in SARS-CoV-2 viral entry6, angiotensin system modulation by ACE inhibitors (ACE-I) or angiotensin-II receptor blockers (ARBs) in clinical management have taken center stage in this controversy

The macrophage A2B adenosine receptor regulates tissue insulin sensitivity.

High fat diet (HFD)-induced type 2 diabetes continues to be an epidemic with significant risk for various pathologies. Previously, we identified the A2b adenosine receptor (A2bAR), an established regulator of inflammation, as a regulator of HFD-induced insulin resistance. In particular, HFD was associated with vast upregulation of liver A2bAR in control mice, and while mice lacking this receptor showed augmented liver inflammation and tissue insulin resistance. As the A2bAR is expressed in different tissues, here, we provide the first lead to cellular mechanism by demonstrating that the receptor's influence on tissue insulin sensitivity is mediated via its expression in macrophages. This was shown using a newly generated transgenic mouse model expressing the A2bAR gene in the macrophage lineage on an otherwise A2bAR null background. Reinstatement of macrophage A2bAR expression in A2bAR null mice fed HFD restored insulin tolerance and tissue insulin signaling to the level of control mice. The molecular mechanism for this effect involves A2bAR-mediated changes in cyclic adenosine monophosphate in macrophages, reducing the expression and release of inflammatory cytokines, which downregulate insulin receptor-2. Thus, our results illustrate that macrophage A2bAR signaling is needed and sufficient for relaying the protective effect of the A2bAR against HFD-induced tissue inflammation and insulin resistance in mice