Endothelial dysfunction and immunothrombosis in sepsis

Abstract

Sepsis is a life-threatening clinical syndrome characterized by multiorgan dysfunction caused by a dysregulated or over-reactive host response to infection. During sepsis, the coagulation cascade is triggered by activated cells of the innate immune system, such as neutrophils and monocytes, resulting in clot formation mainly in the microcirculation, a process known as immunothrombosis. Although this process aims to protect the host through inhibition of the pathogen’s dissemination and survival, endothelial dysfunction and microthrombotic complications can rapidly lead to multiple organ dysfunction. The development of treatments targeting endothelial innate immune responses and immunothrombosis could be of great significance for reducing morbidity and mortality in patients with sepsis. Medications modifying cell-specific immune responses or inhibiting platelet–endothelial interaction or platelet activation have been proposed. Herein, we discuss the underlying mechanisms of organ-specific endothelial dysfunction and immunothrombosis in sepsis and its complications, while highlighting the recent advances in the development of new therapeutic approaches aiming at improving the short- or long-term prognosis in sepsis.

Incidence of Thrombosis in COVID-19 Patients Compared to Non-COVID-19 Sepsis Patients in the Intensive Care Unit

“…This rate appears to be similar to a meta-analysis conducted by Porfidia et al, which showed a VTE rate of approximately 26% in patients with COVID-19 [19]. Thrombosis in sepsis is thought to result from a complex interplay of numerous factors, from systemic inflammation, endothelial injury, altered blood flow, and hypercoagulability to fibrinolytic dysregulation [20][21][22]. Sepsis results in endothelial damage, eventually leading to the activation of platelets that then recruit leukocytes, leading to the formation of platelet-leukocyte aggregates that promotes thrombus formation [21].…”

“…Sepsis also triggers the systemic release of procoagulant molecules such as tissue factor, leading to widespread activation of the extrinsic coagulation cascade. This in turn results in the rapid conversion of prothrombin to thrombin, which drives fibrin clot formation [20,21]. Finally, sepsis impairs the regulation of fibrinolysis, allowing for excessive fibrin accumulation and thrombus formation [22].…”

Deciphering the triad of endothelial glycocalyx, von Willebrand Factor, and P-selectin in inflammation-induced coagulation

“…In the vascular system, perturbed endothelial cells and mononuclear cells produce proinflammatory cytokines that promotes coagulation ( Levi et al, 1997 ; Okamoto et al, 2016 ; Song et al, 2017 ). Proteins expressed on these cells such as thrombin elicits the production of monocytes chemoattractant proteins one and interlukein-6, and interleukin-8 ( Esmon, 2000 ; Maneta et al, 2023 ), leading to intravascular fibrin deposition ( Souza et al, 2015 ).…”

The role and therapeutic potential of SIRTs in sepsis

“…This metabolic disarray not only weakens the cellular response to infection but can also result in damage or even death of cells and tissue organs, releasing damage-associated molecular patterns (DAMPs) ( 12 , 13 ). Concurrently, platelet and neutrophil activation, endothelial cell injury, and coagulation pathway perturbations foster the formation of microcirculatory immune thrombi ( 14 – 16 ), resulting in maldistribution of blood flow, dysoxia, and exacerbation of organ injury ( 17 ), culminating in multiple organ dysfunction syndrome (MODS). The excessive production of reactive oxygen species (ROS) induces oxidative stress, damaging cell membranes, proteins, and DNA, leading to cellular dysfunction and even death.…”