Association of the angiopoietin/TIE2 and VEGF-a pathways with clinical and laboratory markers of disease severity incovid-19

ABSTRACT

Background: Endothelial barrier (EB) disruption is an important part of immunothrombosis, allowing the access of leukocytes to inflamed tissues. Pathways involving angiopoietin (Ang) 1 and 2 and their receptor Tie2, and VEGF-A/VE-cadherin (VEC) are key regulators of EB integrity. While the association of these mediators with sepsis severity have been known for more than 15 years, it was only recently that their role in coagulation activation was described. Moreover, these proteins also mediate angiogenesis, which has been shown to be upregulated in COVID-19. Aims: To measure circulating levels of key mediators of Ang/Tie2 and VEGF-A pathways in COVID-19 patients, and to explore their association with disease severity and hemostatic activation. Methods: Samples were obtained from patients admitted to a COVID-19 ward, within 24 h from COVID-19 confirmation. EB mediator levels were measured by immunological methods (Elisa or multiplex assays). The study was approved by the IRB and all participants provided written informed consent. Results: Data were obtained from 30 patients and 30 age and sexmatched healthy individuals. Mean length of hospital stay (LOS) was 12.9 ± 9.8 days respectively, twelve patients (40%) required intensive care (ICU), and 28/30 patients survived. Mean D-dimer was 3,609 ± 14,440 ng/mL. Levels of EB mediators are shown in Table 1. Associations between these parameters with relevant clinical and laboratory markers of disease severity are shown in Table 2. Conclusions: All mediators of EB disruption were significantly elevated in COVID-19 patients. In addition, these mediators were consistently associated with proteins involved in immunothrombosis, in particular with fibrinogen, VWFAg, uPAR, PAI-1 and P-selectin. Clinically significant associations were observed between Ang-2 and VEGF-A and extension of lung disease (for both) and ICU stay (for VEGF-A). Additional studies are warranted to explore the crosstalk between Ang/Tie2 and VEGF-A pathways with hemostasis in COVID-19.