Platelet Signalling Implicated in COVID Organ Damage
New research finds that one cause of organ damage in COVID patients is abnormal crosstalk between blood platelets and cells lining blood vessels.
The study published in Science Advances, revealed the protein signals released by platelets cause inflammation, abnormal clotting, and damage to vessels when exposed to SARS-CoV-2.
The work identified two related genes, S1000A8 and S1000A9, which are turned up in the platelets of COVID patients, causing them to make more of myeloid-related proteins (MRP) 8 and 14. Higher levels of the dual proteins were linked in the study to higher levels of clotting and inflammation in vessels and worse outcomes.
In support of the theory that platelets are at the core of blood vessel damage in COVID, the research team also presented evidence that approved medications known to block platelet activation via the platelet surface protein P2Y12 (clopidogrel or ticagrelor) reduced COVID-related inflammation in vessels. The study also found that COVID-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.
“Our findings reveal a new role for platelets in COVID blood vessel damage, and may explain in large part what makes the COVID virus so much more deadly than its relatives that cause the common cold,” said corresponding author Tessa Barrett, PhD,.
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 are a possible culprit. Increasing evidence shows that interplay between platelets and endothelial cells may be important to these disease mechanisms.
For the current study, endothelial cells from small blood vessels were exposed to fluid released from the platelets of either COVID patients or healthy controls. RNA was then sequenced, In the presence of COVID-activated platelets, changes were observed in the activity of the exposed endothelial cells. 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 oedema seen in severe cases, where patients’ lungs fill with fluid.
The large list was narrowed down to S100A8 and S100A9, which coded for the building of MRP 8 and 14. COVID in patients was found to increase the amount of MRP8/14 produced by platelets and other cells by 166 percent compared to controls. Higher levels of these proteins were linked to abnormal thrombosis, inflammation, and critical illness among hospitalised COVID patients. Curiously S100A8/A9 were not upregulated after exposure of platelets to a coronavirus relative, CoV-OC43, which causes the common cold.
Additionally, damage and abnormal clotting could arise from p-selectin, which promotes platelet clumping and immune-boosting signals. The researchers also found that the anti-clotting P2Y12 inhibitors reduced the expression of S100A8 and S100A9 in platelets by 18 percent over four weeks, and in lab tests prevented COVID platelets from inducing blood vessel damage.
“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,” said senior study author Jeffrey S. Berger, MD. “As our team also leads ACTIV4a, a large, ongoing NIH-funded, anti-clotting trial in COVID, 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.”
Source: NYU Langone Health
