Summary of the key findings by Puy et al and the connections to vascular thromboinflammation. FXIa is at the center of coagulation amplification and thromboinflammatory circuits, leading to vascular endothelial dysfunction. In the context of local coagulation activation by TF leading to thrombin (IIa) generation, FXI is activated on the platelet surface dependent on GPIba. In addition to the resulting amplification of thrombin generation through intrinsic FIX activation, FXIa also inactivates TFPI to amplify coagulation locally. PAI1 is a major inhibitor of FXIa on the endothelial cell surface and dampens coagulation. In contrast, engagement of VLDLR by the FXIa-PAI1 complex triggers a barrier-disruptive pathway through intracellular recruitment of Dab1, src kinase (SRC), and PLCγ1-dependent MAP kinase activation, leading to ADAM10-mediated proteolytic shedding of VE-cadherin and barrier disruption. Therapeutic targeting of FXIa may therefore have vascular protective effects in addition to dampening coagulation and thrombin-mediated barrier-disruptive PAR signaling. ADAM10, disintegrin and metalloproteinase 10; EC, endothelial cell; F, factor; GPIba, thrombin receptor glycoprotein Ibα; PAR, protease-activated receptor; PLCγ1; phospholipase Cγ1; TF, tissue factor; TFPI, TF pathway inhibitor; PAI1, plasminogen activator inhibitor 1; VE-cadherin, vascular endothelial cadherin; VLDLR, very-low-density lipoprotein receptor. Professional illustration by Somersault18:24.