Endotheliopathy and VWF-ADAMTS13 axis dysfunction in VEXAS thrombogenicity

Markedly increased risk of thrombosis has been described as a key clinical feature of the recently described VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic) syndrome. Critically however, the pathological mechanisms underlying VEXAS-associated hypercoagulability remain poorly understood. We addressed this question in a cohort of 40 VEXAS patients referred to the National Institutes of Health with defined pathological UBA1 sequence variants. In keeping with previous reports, twenty-one (52.5%) VEXAS patients in our cohort experienced thrombotic events. Plasma VWF and FVIII activity levels were both increased in VEXAS compared to age-matched controls. Consistent with endothelial cell (EC) activation and Weibel Palade body exocytosis, plasma VWF propeptide and angiopoietin II levels were also significantly elevated in VEXAS subjects. Furthermore, an accumulation of high molecular weight VWF multimers was seen in VEXAS patients. In keeping with ongoing endotheliopathy, plasma levels of soluble Vascular Cell adhesion Molecule-1 (VCAM-1) and soluble thrombomodulin (sTM) were significantly higher in VEXAS patients compared to controls. Finally, significantly increased thrombin generation and activated protein C resistance (APCR) were also observed in plasma from VEXAS patients. In conclusion, our novel findings demonstrate that VEXAS syndrome is associated with significant EC activation and endotheliopathy. This results in both quantitative and qualitative alterations in plasma VWF levels, increased FVIII levels, enhanced thrombin generation and an APCR phenotype. Further studies will be required to determine whether therapeutic interventions targeted at EC and/or the VWF-ADAMTS13 axis may be useful in VEXAS management.