Platelets in the NETworks interweaving inflammation and thrombosis

Abstract

Platelets are well characterized for their indispensable role in primary hemostasis to control hemorrhage. Research over the past years has provided a substantial body of evidence demonstrating that platelets also participate in host innate immunity. The surface expression of pattern recognition receptors, such as TLR2 and TLR4, provides platelets with the ability to sense bacterial products in their environment. Platelet α-granules contain microbicidal proteins, chemokines and growth factors, which upon release may directly engage pathogens and/or contribute to inflammatory signaling. Additionally, platelet interactions with neutrophils enhance neutrophil activation and are often crucial to induce a sufficient immune response. In particular, platelets can activate neutrophils to form neutrophil extracellular traps (NETs). This specific neutrophil effector function is characterized by neutrophils expelling chromatin fibres decorated with histones and antimicrobial proteins into the extracellular space where they serve to trap and kill pathogens. Until now, the mechanisms and signaling pathways between platelets and neutrophils inducing NET formation are still not fully characterized. NETs were also detected in thrombotic lesions in several disease backgrounds, pointing towards a role as an interface between neutrophils, platelets and thrombosis, also known as immunothrombosis. The negatively charged DNA within NETs provides a procoagulant surface, and in particular NET-derived proteins may directly activate platelets. In light of the current COVID-19 pandemic, the topic of immunothrombosis has become more relevant than ever, as a majority of COVID-19 patients display thrombi in the lung capillaries and other vascular beds. Furthermore, NETs can be found in the lung and other tissues and are associated with an increased mortality. Here, virus infiltration may lead to a cytokine storm that potently activates neutrophils and leads to massive neutrophil infiltration into the lung and NET formation. The resulting NETs presumably activate platelets and coagulation factors, further contributing to the subsequent emergence of microthrombi in pulmonary capillaries. In this review, we will discuss the interplay between platelets and NETs and the potential of this alliance to influence the course of inflammatory diseases. A better understanding of the underlying molecular mechanisms and the identification of treatment targets is of utmost importance to increase patients’ survival and improve the clinical outcome.

Pathophysiological mechanisms of thrombosis in acute and long COVID-19

“…TF expression is triggered by pyroptosis, which is a cell death process dependent on caspase-1, involving the formation of pores in the cell membrane and the release of inflammation mediators (IL-1β and IL-18). TF is the primary activator of the extrinsic coagulation pathway that functions by forming a complex with circulating FVIIa and enhancing the activation of FIX and FX, which goes on to initiate coagulation ( 10 , 69 ). Thus, TF exposure induces increased thrombin generation, which leads to the formation of fibrin clots.…”

“…The levels of platelet-derived EVs were higher in COVID-19 patients requiring hospitalization than in those not requiring hospitalization ( 73 ). Platelet-derived as well as endothelium-derived EVs are responsible for NET formation and endothelial cell death ( 10 , 74 ). Robust formation of NET induced by platelet-derived EVs further enhances immunothrombosis ( 59 ).…”

“…Immunothrombosis is described as the immune system triggering coagulation to form thrombosis that prevents pathogen transmission, with immune cells (neutrophils, etc. ), NETs, and platelets playing important roles in this process ( 9 , 10 ). Molecular interactions between inflammation and coagulation have been gradually confirmed.…”

Update on Innate Immunity in Acute Kidney Injury—Lessons Taken from COVID-19

“…Recent investigation has also provided evidence for platelet engagement in innate immunity [ 31 ]. Platelets expose TLRs and proinflammatory receptors CXCR4 and CXCR7 on their surface.…”

“…Platelet alpha-granules contain bactericidal proteins, chemokines and P-selectin. Moreover, platelets take part in neutrophil stimulation to excrete neutrophil extracellular traps (NETs) [ 31 ]. In detail, infection triggers the release of platelet factors (e.g., platelet factor 4) and extracellular vesicles, activating neutrophils to secrete NETs [ 32 ].…”