Endotheliopathy in CAR T-Cell Therapy: Mechanistic Insights into the VWF/ADAMTS13 Axis and the Angiopoietin-Tie2 Pathway.

Chimeric antigen receptor (CAR) T cell therapy has transformed the management of hematologic malignancies, yet its clinical success is tempered by severe immune-mediated toxicities, including cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), often accompanied by CAR T cell therapy-related coagulopathy (CARAC). Converging evidence identifies therapy-related endotheliopathy as a central pathophysiological link between cytokine excess, hemostatic dysregulation, capillary leak, and organ injury. Parallel efforts aim to identify circulating biomarkers that can signal emerging toxicity before clinical deterioration. This review summarizes the biological basis of endotheliopathy during CAR T cell therapy, with particular emphasis on two interconnected regulatory systems: the von Willebrand factor (VWF)/ADAMTS13 axis, which governs platelet adhesion and microvascular thrombosis, and the angiopoietin (Ang)-tyrosine kinase receptor Tie2 signaling pathway, which regulates endothelial stability and vascular permeability. Dysregulation of these pathways drives the shift from adaptive immunothrombosis to pathological endothelial injury, characterized by loss of anticoagulant control, barrier disruption, and microvascular instability. Clinical studies show that alterations in the VWF/ADAMTS13 balance and increases in the Ang-2/Ang-1 ratio correlate with CRS and ICANS severity and may precede overt toxicity, highlighting their potential as markers of endothelial vulnerability. Defining actionable biomarker thresholds and evaluating endothelial-targeted interventions are key priorities for improving the safety and precision of CAR T cell therapy.