Hepatic Surgical Stress Promotes Systemic Immunothrombosis That Results in Distant Organ Injury

• Published in: Frontiers in immunology 2020-05, Vol.11, p.987-987
• Main Authors: Zhang, Hongji, Goswami, Julie, Varley, Patrick, van der Windt, Dirk J, Ren, Jinghua, Loughran, Patricia, Yazdani, Hamza, Neal, Matthew D, Simmons, Richard L, Zhang, Jinxiang, Tsung, Allan, Huang, Hai
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Blood Coagulation; Blood Platelets - immunology; Blood Platelets - metabolism; Case-Control Studies; Child; Child, Preschool; Disease Models, Animal; Extracellular Traps - immunology; Extracellular Traps - metabolism; Female; Hepatectomy - adverse effects; Humans; Immunology; immunothrombosis; liver sterile inflammation; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; neutrophil extracellular traps; Neutrophils - immunology; Neutrophils - metabolism; Platelet Activation; platelets; Protein-Arginine Deiminase Type 4 - deficiency; Protein-Arginine Deiminase Type 4 - genetics; Reperfusion Injury - blood; Reperfusion Injury - immunology; Signal Transduction; Stress, Physiological; surgical stress; Thrombosis - blood; Thrombosis - immunology; Toll-Like Receptor 4 - deficiency; Toll-Like Receptor 4 - genetics; Young Adult
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.00987

Innate immunity can initiate platelet activation during the development of thrombosis through a process, termed immunothrombosis. Neutrophils form neutrophil extracellular traps (NETs) that have been shown to interact directly with platelets and play pro-coagulant roles in a variety of infectious and sterile inflammatory settings. Hepatic surgical stress initiated by ischemia/reperfusion (I/R) injury has wide systemic consequences on distant organs. However, the mechanisms of this remote injury phenomenon are not well-understood. Here, we sought to determine the role of NETs in causing systemic immunothrombosis and distant organ injury following a local inflammatory insult with liver I/R. Postoperative thromboelastographic revealed that the speed of clot formation (alpha-angle) was significantly increased whereas time to clot formation (R-time) were decreased by in patients undergoing liver resection, indicating a hypercoagulable state after surgery. In mice subjected to liver I/R, circulating platelet activation and platelet-neutrophil aggregates were significantly increased. Injured distant organs such as the lung and kidney displayed NETs and platelet-rich micro-thrombi in the microvasculature following liver I/R. The immune-thrombi and organ damage were dramatically decreased when NETs were inhibited by DNase treatment. Depletion of on platelets limited NET-induced activation of platelets but had no effect on NET formation. Furthermore, platelet-specific TLR4 KO mice had significantly reduced distant organ injury with decreased circulating platelet activation, platelet-neutrophil aggregates following liver I/R in comparison to their control counterparts. These data establish that after an acute local inflammatory process, NET-activated platelets can lead to a systemic pro-coagulant state with resultant remote organ injury by immunothrombosis.