Angiopoetin-2 and IGFBP-7 as novel biomarkers of abnormal angiogenesis in von Willebrand disease

Abstract von Willebrand factor (VWF) is recognized as an active regulator of angiogenesis, particularly through control of the endothelial storage and release of angiopoietin-2 (Ang-2). This offers a plausible explanation for the poorly understood association between von Willebrand disease (VWD) and gastrointestinal (GI) angiodysplasia. However, the circulating angiogenic biomarker profile of patients with VWD remains partially characterized. This study was designed to comprehensively explore angiogenic mediators across VWD types/subtypes and determine their relationship with the VWF multimeric profile and GI bleeding/angiodysplasia phenotype. Seventy-six genetically confirmed patients with VWD and 30 healthy controls were included. A large panel of over 12 angiogenic mediators was assessed by multiplexed immunoassay. Peripheral levels of Ang-2, IGFBP-7 and angiostatin were significantly higher in type 2A and 2B VWD compared to controls and type 1 VWD. IGFBP-7 was significantly higher in patients with an abnormal multimeric profile. These markers did not correlate with VWF antigen or activity. Soluble TIE-2 was significantly lower and PDGF-AB significantly higher in patients with angiodysplasia. TRAIL and soluble VEGF-R2 were lower in patients with angiodysplasia or GI bleeding. No differences were observed for VEGF-A, VEGF-C/D, BMP-10 or endoglin. The structural integrity of VWF, rather than its plasma concentration, was associated with a distinct proangiogenic signature combining elevated Ang-2 and IGFBP-7 and reduced soluble TIE-2, supporting a role for VWF in the regulation of angiogenesis independent from its hemostatic function. Ang-2 and IGFBP-7 emerge as promising biomarkers and candidate therapeutic targets for VWD-associated angiodysplasia and GI bleeding, warranting validation in larger cohorts.