BREAKING! SARS-CoV-2 Induced Platelets’s Genes S1000A8 & S1000A9 Produces More MRP-8 /14 That Increases Inflammation, Clotting & Severity!
Source: COVID-19 Research Sep 11, 2021 2 years, 7 months, 1 week, 6 days, 25 minutes ago
COVID-19 Research: A new breakthrough study by scientist from New York University Grossman School of Medicine has found SARS-CoV-2 induced hyperactive platelets’ unique genes S1000A8 and S1000A9 causes the platelets to produce more myeloid-related proteins (MRP) 8 and 14 that contribute to increased inflammation, clotting, disease severity and longer hospital stays. The study also showed that drugs known to block platelet activation via the platelet surface protein P2Y12 (clopidogrel or ticagrelor) reduced COVID-19-related inflammation in vessels.
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This is another breakthrough
COVID-19 Research that provides a better insight into the role of platelets in the COVID-19 disease and also new therapeutic approaches to managing the disease.
Considering the evidence for a hyperactive platelet phenotype in COVID-19, the study team investigated effector cell properties of COVID-19 platelets on endothelial cells (ECs). Integration of EC and platelet RNA sequencing revealed that platelet-released factors in COVID-19 promote an inflammatory hypercoagulable endotheliopathy.
The study team identified S100A8 and S100A9 as transcripts enriched in COVID-19 platelets and were induced by megakaryocyte infection with SARS-CoV-2. Consistent with increased gene expression, the heterodimer protein product of S100A8/A9, myeloid-related protein (MRP) 8/14, was released to a greater extent by platelets from COVID-19 patients relative to controls.
The study team demonstrated that platelet-derived MRP8/14 activates ECs, promotes an inflammatory hypercoagulable phenotype, and is a significant contributor to poor clinical outcomes in COVID-19 patients.
The study findings also present evidence that targeting platelet P2Y12 represents a promising candidate to reduce proinflammatory platelet-endothelial interactions. Together, these findings demonstrate a previously unappreciated role for platelets and their activation-induced endotheliopathy in COVID-19.
The study findings were published in the peer reviewed journal: Science Advances.
https://www.science.org/doi/10.1126/sciadv.abh2434
This new study findings reveal a new role for platelets in COVID-19 blood vessel damage and COVID-19 disease severity.
The study findings show that abnormal crosstalk between blood platelets and cells lining blood vessels are one cause of deadly organ damage in patients with severe COVID-19.
The study findings revealed the protein signals given off by platelets ie cell fragments that contribute to blood clotting, create inflammation, abnormal clotting, and damage to vessels when exposed to the pandemic virus.
The study identified two related genes, S1000A8 and S1000A9, that are turned up in the platelets of patients with COVID-19, causing them to make more of myeloid-related proteins (MRP) 8 and 14. Higher levels of the two proteins, known to operate as a pair and be present in large amounts in immune cells, were linked in the study to higher levels of clotting and inflammation in vessels, greater disease severity, and longer hospital stays.
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The study team also in support of the theory that platelets are at the core of blood vessel damage in COVID-19, presented evidence that approved medications known to block platelet activation via the platelet surface protein P2Y12 (clopidogrel or ticagrelor) reduced COVID-19-related inflammation in vessels. The study also found that COVID-19-exposed platelets change cells lining blood vessels (endothelial cells) largely through a protein called P-selectin, which makes platelets stickier and more likely to form clots.
Dr Tessa J. Barrett, PhD, corresponding author, research assistant professor, Department of Medicine, NYU Langone Health told Thailand Medical News, “The study findings reveal a new role for platelets in COVID-19 blood vessel damage and may explain in large part what makes the COVID-19 virus so much more deadly than its relatives that cause the common cold."
It must be noted that abnormal, body-wide inflammation and blood clotting were identified early in the pandemic as central features of severe COVID-19, with the two thought to be interrelated, say the study authors.
As blood components that react to injuries in vessels by triggering inflammation, and by becoming sticky to clump together in clots, platelets have been suggested as a culprit for the observed damage.
Further, evidence is mounting that the interplay between platelets and endothelial cells may be important to these disease mechanisms.
In the case of the current research, endothelial cells from small blood vessels were exposed to fluid released from the platelets of either patients with COVID-19 or healthy, similar patients (controls).
The genetic material (RNA) was then sequenced to read the order of the molecular "letters" making up codes of active genes (transcripts) in each case. In the presence of COVID-19-activated platelets, changes were observed in the activity of the endothelial cells exposed to them, with 485 transcripts made less active and 803 turned up.
Genes expressed differently in COVID-19 were linked to clotting, inflammation, and the weakening of junctions between endothelial cells, which lets blood serum seep into tissue to cause the pulmonary edema seen in severe cases, where patients' lungs fill with fluid.
Importantly, from the initial large list of potential culprits, cross-referencing with databases reduced the candidate list to two related snippets of genetic material: S100A8 and S100A9, which coded for the building of MRP8 and 14.
Interestingly the presence of COVID-19 in patients was found to increase the amount of MRP8/14 produced by platelets and other cells by 166 percent when compared to patients without the infection. Higher levels of MRP8/14 were linked to abnormal clotting (thrombosis), inflammation, and critical illness among hospitalized patients with COVID-19. Intriguingly, upregulation of S100A8/A9 did not occur after exposure of platelets to a relative of the pandemic virus, CoV-OC43, which causes the common cold.
Furthermore the study team found that platelet-driven endothelial damage and abnormal clotting may occur through the action of P-selectin in platelet components called alpha-granules.
Typically located inside alpha-granules, P-selectin "flips" to the outside as platelets are activated, where it promotes the clumping of platelets and signals that turn up the local immune response.
The study team also found that the anti-clotting P2Y12 inhibitors reduced the expression of S100A8 and S100A9 in platelets by 18 percent over 4 weeks, and in lab tests prevented COVID-19 platelets from inducing blood vessel damage.
Senior study author Dr Jeffrey S. Berger, MD, director of the Center for the Prevention of Cardiovascular Disease at NYU Langone and associate professor of medicine and surgery added, "The current study supports the theory that platelets are activating endothelial cells through P-selectin, and that both P-selectin and MRP8/14 contribute to vessel damage and an increased risk of dying."
Dr Berger further added, "As our team also leads ACTIV-4a, a large, ongoing NIH-funded, anti-clotting trial in COVID-19, we are currently testing in patients whether P2Y12 inhibitors can better prevent severe disease, with the results to be presented at the American Heart Association annual meeting in November."
ACTIV-4a will also soon begin testing the effect of a P-selectin inhibitor called crizanlizumab in patients hospitalized with COVID-19. Targeting P-selectin may block both platelet and endothelial cell activation, and their interactions, whereas P2Y12 inhibitors address only platelets.”
The study added, “The study findings describe how platelets isolated from hospitalized COVID-19 patients release significant quantities of MRP8/14 that can act in a paracrine fashion on nearby ECs promoting endotheliopathy. However, several limitations exist with our current study: (i) the relatively small sample size used for sequencing; (ii) the cellular source of plasma MRP8/14 cannot definitively be attributed to platelets and may originate from other cells, including neutrophils; (iii) it is unknown whether the observed MRP8/14 induced endotheliopathy occurs in other viral settings; (iv) a clinical diagnosis of thrombosis during hospitalization may be underestimated because imaging studies were limited due to concerns of transmitting infection or competing risk of death; and (v) the effect of antiplatelet therapies on the COVID-19 platelet–induced EC activation was not explored. “
The study team further added, “Future studies will aim to address these limitations to further our understanding of the interaction of platelets with SARS-CoV-2 and other viral illnesses and the endothelium. An ongoing multinational trial is underway exploring the effect of P2Y12 inhibition on clinical outcomes of hospitalized COVID-19 patients (NCT04505774).”
The study team concluded, “In conclusion, we define a novel role for platelet-induced endotheliopathy in COVID-19. The activated platelet phenotype observed in COVID-19 consistently induces a proinflammatory and dysfunctional endothelium. Platelet-derived MRP8/14 is increased in COVID-19 and induces endothelial injury. Circulating MRP8/14 has the potential to serve as a useful biomarker of thrombosis and severity of disease in patients infected with SARS-CoV-2. Platelet-directed therapy, specifically P2Y12 inhibitors, may represent a particularly attractive therapy because of its effect on platelet S100A8/A9 and platelet-induced endotheliopathy”
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