Effect of stimulated platelets in COVID-19 thrombosis: Role of alpha7 nicotinic acetylcholine receptor

Since early 2020, SARS-CoV-2-induced infection resulted in global pandemics with high morbidity, especially in the adult population. COVID-19 is a highly prothrombotic condition associated with subsequent multiorgan failure and lethal outcomes. The exact mechanism of the prothrombotic state is not well understood and might be multifactorial. Nevertheless, platelets are attributed to play a crucial role in COVID-19-associated thrombosis. To date, platelets' role was defined primarily in thrombosis and homeostasis. Currently, more focus has been set on their part in inflammation and immunity. Moreover, their ability to release various soluble factors under activation as well as internalize and degrade specific pathogens has been highly addressed in viral research. This review article will discuss platelet role in COVID-19-associated thrombosis and their role in the cholinergic anti-inflammatory pathway. Multiple studies confirmed that platelets display a hyperactivated phenotype in COVID-19 patients. Critically ill patients demonstrate increased platelet activation markers such as P-selectin, PF4, or serotonin. In addition, platelets contain acetylcholine and express alpha 7 nicotinic acetylcholine receptors (alpha 7nAchR). Thus, acetylcholine can be released under activation, and alpha 7nAchR can be stimulated in an autocrine manner and support platelet function. alpha 7 receptor is one of the most important mediators of the anti-inflammatory properties as it is associated with humoral and intrinsic immunity and was demonstrated to contribute to better outcomes in COVID-19 patients when under stimulation. Hematopoietic alpha 7nAchR deficiency increases platelet activation and, in experimental studies, alpha 7nAchR stimulation can diminish the pro-inflammatory state and modulate platelet reactiveness via increased levels of NO. NO has been described to inhibit platelet adhesion, activation, and aggregation. In addition, acetylcholine has been demonstrated to decrease platelet aggregation possibly by blocking the e p-38 pathway. SARS-CoV-2 proteins have been found to be similar to neurotoxins which can bind to nAChR and prevent the action of acetylcholine. Concluding, the platelet role in COVID-19 thrombotic events could be explained by their active function in the cholinergic anti-inflammatory pathway.

Automated summary

Since early 2020, SARS-CoV-2-induced infection has caused global pandemics with high morbidity, especially in adults. COVID-19 is associated with a highly prothrombotic condition and platelets are believed to play a crucial role in COVID-19-associated thrombosis. Platelets' role in inflammation and immunity, as well as their ability to release soluble factors and degrade pathogens, have been widely studied. This review focuses on the role of platelets in COVID-19-associated thrombosis and their involvement in the cholinergic anti-inflammatory pathway. Hyperactivated platelets have been observed in COVID-19 patients, and the presence of acetylcholine and α7nAchR on platelets suggests their involvement in platelet function. The stimulation of α7nAchR has anti-inflammatory effects and has been associated with better outcomes in COVID-19 patients. The inhibition of platelet activation and aggregation through the release of NO and blocking of the e p-38 pathway by acetylcholine may contribute to the platelet's role in COVID-19 thrombotic events. The similarity between SARS-CoV-2 proteins and neurotoxins suggests a potential mechanism for the interference with acetylcholine action.