Wolfgang Miesbach: Uncovering the Role of Factor VIII in Endothelial Biology
Wolfgang Miesbach, Head of Hemostasis/Hemophilia Center at Medical Clinic 2 at University Hospital Frankfurt, shared a post on LinkedIn about a recent article by Cristina Olgasi et al., published in Blood Advances, adding:
“FVIII does more than stop bleeding: Endothelial cells grown from people with haemophilia A show a defective phenotype – reduced proliferation, migration and tubule formation, and a leaky barrier. Cells from haemophilia B behave like healthy controls, so this is FVIII, not haemophilia as such.
- What was tested: six rFVIII concentrates — simoctocog alfa and octocog alfa (unmodified, HEK and CHO), damoctocog alfa pegol and rurioctocog alfa pegol (PEGylated), efmoroctocog alfa (Fc fusion) and efanesoctocog alfa (Fc/D’D3/XTEN) — plus emicizumab.
- How: proliferation, migration, tubulogenesis and FITC-dextran permeability assays on patient-derived endothelial cells; ligand-based receptor capture to quantify binding to the cell surface; Evans blue extravasation and intradermal matrix plugs in FVIII-knockout mice.
- All rFVIII products improved endothelial function, but not equally. Simoctocog alfa performed best, the Fc-fusion molecule weakest, efanesoctocog alfa in between — and membrane binding followed the same order, pointing to a receptor-mediated effect independent of the coagulation cascade. Emicizumab showed no effect in vitro or in vivo, unsurprising for a molecule built to bridge FIXa and FX. The activity appears to come from free FVIII rather than the FVIII–VWF complex.
- Why the differences? The authors propose steric hindrance: Fc fusion may shield the domains needed for endothelial engagement, while the added D’D3 and XTEN elements of efanesoctocog alfa partly offset this. Pegylation impaired neither binding nor function, so this is not simply modified versus unmodified.
Preclinical, industry-funded, no clinical endpoints.
Still, a good argument for looking at vascular health, not only at bleeding rates, when we compare therapies”.
Title: Non-hemostatic effects of recombinant FVIII and emicizumab on endothelial cell function in hemophilia A
Authors: Cristina Olgasi, Giorgia Venturin, Chiara Borsotti, Alessia Cucci, Chiara Sgromo, Simone Assanelli, Jacopo Agnelli Giacchello, Roberto Mario Santi, Antonia Follenzi
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