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. 2022 Aug 1;13:953129. doi: 10.3389/fimmu.2022.953129

Figure 3.

Figure 3

NETs activate platelets and drive coagulation. Cathepsin G and histones, especially H3 and H4, but also tissue factor directly activate platelets. PtdSer+ve microparticles in NETs provide a negatively charged surface, ideal for accumulation of coagulation factors. NETs with histones activate FXII and FXI, which results in thrombin generation. FXII and FXI also bind PtdSer exposed on platelets. Activated platelets increase P-selectin and GPIIb/IIIa activity, resulting in increased aggregation as well as signaling events leading to release of polyP and dense granule secretion. Ultimately, subsequent thrombin generation leads to clot formation in the vasculature. PAD4 was shown to inhibit ADAMTS13 activity, which hampers cleavage and removal of VWF strings. NET cathepsin G triggers tissue factor production in endothelial cells, further driving coagulation. ADAMTS13, a disintegrin and metalloproteinase with thrombospondin type-1 motif-1, member 13; FXII, factor XII; FXI, factor XI; GP, glycoprotein; MPs, microparticles; PAD4, peptidylarginine deiminase 4; PtdSer, phosphatidylserine; P-sel, P-selectin; polyP, inorganic polyphosphate; VWF, von Willebrand factor.