Figure 6.

The role of VWF in TBI-IC and its blockage by A2. TBI-IC can be considered as a 2-step process of initiation and dissemination. The first step occurred at the site of injury, and trauma promotes endothelial cells to release hyperadhesive VWF and disrupts the blood–brain barrier, and injures cerebral cells to release BDEVs. The hyperadhesive VWF binds BDEVs, likely through integrins on BDEVs and the RGD sequence in the C domain of VWF, to become VWF-bound BDEVs (VBDEVs). In the second step, VBDEVs released into circulation bind and activate endothelial cells at vascular beds remote from the injury, using VWF as the adhesive ligand. The activated endothelial cells release procoagulant EVs (eEVs) and more hyperadhesive VWF multimers that can be either EC-bound or a soluble form. The EC-bound VWF tethers platelets, leukocytes, and EVs to the endothelium to propagate endothelial injury and permeability. The soluble VWF binds and activates platelets to express PS and release platelet EVs (pEVs). Together, activated endothelial cells and platelets, and PS⁺EVs induce consumptive coagulopathy (black circle with a plus sign), which can be inhibited by A2 at key action points by blocking hyperadhesive VWF (red circle with a minus sign).