Proinflammatory and prothrombotic function of inflamed endothelial cells. (A) Perturbation of the endothelium by oxidative stress (reactive oxygen species [ROS]), pathogen infection, or proinflammatory molecules (eg, lipids and cytokines) leads to increased expression of adhesion molecules, such as von Willebrand factor (VWF) and P-selectins, α_vβ₃ and ICAM-1, leading to the recruitment of platelets and leukocytes. Activated endothelial cells also express TF, leading to activation of FVII, FXa, and, ultimately, thrombin generation. Thrombin cleaves fibrinogen to generate fibrin, as well as multiple protease-activated receptors on the surface of endothelial cells, platelets, and leukocytes, thereby propagating the thromboinflammatory process. (B) Recruitment of platelets and leukocytes to sites of inflamed endothelium: the expression of VWF and P-selectin on the damaged endothelial cell surface supports platelet tethering and rolling. Subsequently, stable platelet adhesion occurs through fibrinogen–integrin α_IIbβ₃ complexes binding to α_vβ₃ or ICAM-1 on endothelial cells. Adherent platelets secrete numerous bioactive substances that alter the chemotactic and adhesive properties of endothelial cells. Platelet-derived interleukin-1 (IL-1) induces active TF expression on the endothelium. The expression of P-selectin on adherent activated platelets induces leukocyte tethering followed by their adhesion, mainly through the interaction of macrophage-1 antigen (Mac-1) with GPIb–GPV–GPIX and fibrinogen–α_IIbβ₃ complexes. PAMPs, pathogen-associated molecular patterns; TNFα, tumor necrosis factor-1.