Platelet Versus Megakaryocyte: Who Is the Real Bandleader of Thromboinflammation in Sepsis?

Abstract

Platelets are mainly known for their key role in hemostasis and thrombosis. However, studies over the last two decades have shown their strong implication in mechanisms associated with inflammation, thrombosis, and the immune system in various neoplastic, inflammatory, autoimmune, and infectious diseases. During sepsis, platelets amplify the recruitment and activation of innate immune cells at the site of infection and contribute to the elimination of pathogens. In certain conditions, these mechanisms can lead to thromboinflammation resulting in severe organ dysfunction. Here, we discuss the interactions of platelets with leukocytes, neutrophil extracellular traps (NETs), and endothelial cells during sepsis. The intrinsic properties of platelets that generate an inflammatory signal through the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome are discussed. As an example of immunothrombosis, the implication of platelets in vaccine-induced immune thrombotic thrombocytopenia is documented. Finally, we discuss the role of megakaryocytes (MKs) in thromboinflammation and their adaptive responses.

Keywords: megakaryocytes; platelets; thromboinflammation.

Figure 1

A trio of leukocyte–platelet–endothelium interactions lead to thromboinflammation associated with sepsis. Patterns of interactions between ECs, leukocytes, and platelets in the basal, activation, and adhesion steps of sepsis.

Figure 2

Megakaryocytes and their great orchestra in the septic scene. Platelets interact with components of the circulating blood, as well as with the endothelial cells, and are also able to guide monocytes/macrophages to subendothelial infection sites. To do this, they engage in a wide repertoire of interactions, ranging from direct cell interactions to indirect interactions via the secretion of alpha and dense granule contents and the production of eicosanoids. In this ensemble, MKs, medullary or circulating, are also able to sense and respond to certain sepsis-specific signals, such as PAMPs, DAMPs, and cytokines/chemokines. This response can be a quantitative one but also functional, i.e., a dedicated production of platelets with immune functions.