OC 36.5 - Factor VIII is a regulator of angiogenesis and a promoter of endothelial barrier stability

Monday, June 24, 2024

10:30 – 10:45 ICT

Room: 111 A-C

Co-Author(s)

Cristina Olgasi

Tenure-track Assistant Professor
University of Piemonte Orientale, Department Translational Medicine
Novara, Piemonte, Italy
Alessia Cucci, PhD

Post Doc
University of Piemonte Orientale, Department of Health Sciences
Novara, Piemonte, Italy
SA

Simone Assanelli

PhD student
Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
Novara, Piemonte, Italy
CS

Chiara Sgromo

PhD student
Department of Health Sciences, University of Piemonte Orientale
Novara, Piemonte, Italy
GV

Giorgia Venturin

PhD Student
University of Piemonte Orientale, Department of Health Sciences
Novara, Piemonte, Italy
CB

Chiara Borsotti

Tenure-track Assistant Professor
Department of Health Sciences, University of Piemonte Orientale
Novara, Piemonte, Italy
RS

Roberto Santi

Haematologist
Dipartimento Attività Integrate Ricerca Innovazione, Azienda Ospedaliera Universitaria SS. Antonio e Biagio e C. Arrigo
Alessandria, Piemonte, Italy

Presenting Author(s)

Antonia Follenzi, MD, PhD

Full Professor
University of Piemonte Orientale, Department of Health Sciences
Novara, Piemonte, Italy

Background: Haemophilia A (HA) is a rare bleeding disorder caused by the absence or dysfunction of factor VIII (FVIII). The main clinical manifestation is spontaneous bleeding, but an attenuated microvascular endothelial functionality was also observed in HA patients, suggesting an altered homeostasis of endothelial cells (ECs).

Aims: To elucidate the effect of several rFVIII concentrates on the maintenance of EC functionality and stability.

Methods: Blood outgrowth endothelial cells (BOECs) were isolated from HA patients and healthy donors. HA BOECs were treated in vitro with simoctocog alfa, efmoroctocog alfa, rurioctocog alfa pegol, damoctocog alfa pegol, or octocog alfa. EC functionality was evaluated in vitro by tubulogenic, migration, permeability and proliferation assays. The binding of rFVIII to BOEC membranes was assessed by TriCEPS technology. In vivo, the impact of the different rFVIII concentrates was evaluated in NOD/SCID γ–Null HA (NSG-HA) mice with a permeability assay by Evans Blue dye injection.

Results: Impaired tubulogenesis, migration and permeability of HA ECs vs healthy ECs were observed. A significant enhancement of EC functionality was demonstrated by treating HA BOECs with rFVIII products, with a higher positive effect for simoctocog alfa. Moreover, in NSG-HA mice treated with different rFVIII concentrates, and subsequently injected with Evans Blue dye, we showed a significant reduction of dye extravasation with a complete correction in mice treated with simoctocog alfa compared with other rFVIII products. Interestingly, we demonstrated that simoctocog alfa can bind to ECs surface triggering the effect on ECs functionality.

Conclusion(s): Information about the possible extra-coagulative role of FVIII may be crucial to understand the key molecular targets responsible for the impaired EC functionality observed in HA patients. Knowledge of the possible effects of different rFVIII products on EC function may contribute to optimisation of therapeutic approaches for HA patients.