Recent Advances in Pathogenesis and Anticoagulation Treatment of Sepsis-Induced Coagulopathy

Abstract

Coagulopathy in sepsis is common and is associated with high mortality. Although immunothrombosis is necessary for infection control, excessive thrombus formation can trigger a systemic thrombo-inflammatory response. Immunothrombosis plays a core role in sepsis-induced coagulopathy, and research has revealed a complex interplay between inflammation and coagulation. Different mechanisms underlying sepsis-related coagulopathy are discussed, including factors contributing to the imbalance of pro- and anticoagulation relevant to endothelial cells. The potential therapeutic implications of anticoagulants on these mechanisms are discussed. This review contributes to our understanding of the pathogenesis of coagulopathy in patients with sepsis. Recent studies suggest that endothelial cells play an important role in immunoregulation and hemostasis. Meanwhile, the non-anticoagulation effects of anticoagulants, especially heparin, which act in the pathogenesis of coagulopathy in septic patients, have been partially revealed. We believe that further insights into the pathogenesis of sepsis-induced coagulopathy will help physicians evaluate patient conditions effectively, leading to advanced early recognition and better decision-making in the treatment of sepsis.

Keywords: anticoagulant; coagulopathy; endotheliopathy; immunothrombosis; sepsis; thromboinflammation.

Figure 1

Pathogenesis of Sepsis-induced Coagulation. (a) External pathogen invasion induces intravascular hypercytokinemia through PAMP-PRR recognition. (b) Pathogen clearance is initiated by pan-cellular activation, involving neutrophils, monocytes-macrophages, megakaryocytes-platelets, and endothelial cells. Immune and non-immune cells synergistically regulate immunomodulation and coagulation. (c) Activated immune cells release a series of pro-coagulant factors that further initiate the coagulation cascade while causing endothelial cell damage. (d) Neutrophils play a crucial role in innate immune defense. NETosis, aimed at pathogen elimination, ultimately leads to intravascular coagulation due to increased circulatory and cytotoxic components. (e) Oxidative stress generated during pan-cellular activation is closely associated with immunomodulation, endotheliopathy, and mitochondrial dysfunction. (f and g) Intact endothelium with a well-preserved endothelial glycocalyx is essential for the expression of endothelial antithrombotic and anticoagulant factors. Under systemic inflammatory conditions, the endothelial glycocalyx is degraded by heparinase, and ULVWF formation occurs due to secondary ADAMTS13 deficiency. (h) Increased shear stress exacerbates endothelial damage. (i) The regulation of immunothrombosis and thromboinflammation by endothelial cells along the coagulation cascade is highly complex. By Figdraw.