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

Hongji Zhang,Allan Tsung,Jinxiang Zhang,Hamza Yazdani,Richard L Simmons,Jinghua Ren,Julie Goswami,Dirk J Van Der Windt,Patricia Loughran,Patrick Varley,Matthew D Neal,Hai Huang

doi:10.3389/fimmu.2020.00987

Abstract

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 Tlr4 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.

Highlights

Multiple molecular and cellular pathways are involved in the normal coagulation of blood, including fibrin producing coagulation cascade and platelet activation [1, 2]
Hepatic Surgical Stress Leads to a Systemic Pro-coagulant State Mediated by Platelet Activation
To investigate if a local hepatic injury could lead to systemic disruptions in coagulation, whole blood samples from 49 human patients between the years 2015–2016, undergoing liver resection and 12 healthy age/gender-matched subjects were collected on postoperatively day 1 for thromboelastography (TEG) analysis (Supplementary Figure 1A)

Summary

Introduction

Multiple molecular and cellular pathways are involved in the normal coagulation of blood, including fibrin producing coagulation cascade and platelet activation [1, 2]. Dysregulation of the normal hemostatic process can contribute to a vast array of common regional thromboembolic events, such as myocardial infarction, stroke, deep vein thrombosis and pulmonary embolism [3, 4]. One of the links between innate immunity and coagulation was discovered after the identification of neutrophil extracellular traps (NETs), which form when neutrophils extrude both their cytoplasmic/granular and nuclear contents into the extracellular space [10]. During this process, decondensed chromatin filaments decorated with pro-inflammatory proteins provide host defense by capturing microbial pathogens. NETs have been found to be generated by sterile injury and in turn, orchestrate intense inflammatory responses [11]

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