Fig. 2

Incomplete NET degradation leads to hypercoagulation. (1) Incomplete NET degradation causes macrophage and dendritic cells (DCs) to present NET components to CD4 + T cells. (2) The T cells release IL-21 inducing differentiation of B cells into plasma cells to induce autoantibody production. (3) Anti-neutrophil cytoplasmic antibodies (ANCAs) can form circulating immune complex (CIC). (4) ANCAs and CIC activate neutrophils through FcɣR and complement receptor binding. Hyperactivation of neutrophils by autoantibodies produces Reactive Oxygen Species (ROS), cytokines storms, lytic enzymes, and NET. (5) NETosis releases decondensation of chromatin constructed from unwound neutrophil DNA and histones coated with neutrophil enzymes such as neutrophil elastase (NE), myeloperoxidase (MPO), and proteinase 3 (PR3). (6) Von Willebrand Factor (vWF) attracts platelets and histones activate them leading to the intrinsic pathway of coagulation. (7) NE cleaves anticoagulant which contributes to more coagulation. (8) CIC can trigger a fibrotic response from DCs and macrophages. (9) Macrophages carry inactive tissue factors which will be activated by pyroptosis, specifically by protein disulfide isomerase. Pyroptosis results in microvesicles that contain active tissue factors that lead to the extrinsic pathway of coagulation. (10) The vicious cycle of uncontrolled neutrophils activation and incomplete net degradation causes hypercoagulation through intrinsic and extrinsic pathways. Created with BioRender.com and adapted from Bautista-Becerril et al. (2021) and Jayarangaiah et al. 2020)