Figure 2.

Schematic illustration of how NETs might contribute to vaso-occlusion and endothelial damage. NETs are able to promote vaso-occlusion, initiated by von Willebrand production in platelets, which induces the upregulation of intercellular adhesion molecule-1 (ICAM-1), further strengthening neutrophil–endothelium interactions. Platelet-dependent NET formation requires the heterodimerized CXCL4 and CCL5, as well as the simultaneous stimulation of GPCRs and integrins. NET-derived NE cleaves the coagulation-inhibiting tissue factor pathway inhibitor (TFPI) and, in parallel, activates platelet receptors to increase platelet accumulation. NET-decorated proteins further contribute to tissue damage. Histones especially exhibit cytotoxic effects, disturbing the endothelial integrity.