Abstract Number: OC 73.4
Meeting: ISTH 2022 Congress
Background: Glycoprotein VI (GPVI) is the major collagen receptor on platelets, it has been proposed as a promising anti-platelet target as its blockade prevents experimental thrombosis without impairing hemostasis.
Aims: This study aimed to use a humanized GP6 mouse line (hGP6KI) to investigate the effect of a novel function blocking anti-GPVI antibody (EMF-1) in thrombus formation and hemostasis.
Methods: Flow-cytometry, aggregometry and flow-adhesion assay were used to investigate the in vitro and ex vivo effect of EMF-1 on platelet function. Tail bleeding assay was performed to assess the effect on hemostasis and arterial thrombosis was studied in a model of mechanical aorta injury.
Results: A panel of anti-human GPVI (huGPVI) monoclonal antibodies (mAbs) was generated and characterized. Several mAbs displayed GPVI inhibitory activity, among them EMF-1 which completely inhibited collagen-related peptide (CRP) and collagen-induced platelet activation, aggregation and thrombus formation. Treatment of hGP6KI mice with EMF-1 (5 µg/g body weight) induced transient thrombocytopenia and long-lasting GPVI depletion from the platelet surface. In contrast, the Fab fragment of EMF-1 did neither affect platelet counts nor GPVI surface expression but reduced GPVI-dependent activation up to 72 hours after injection. GPVI-depleted hGP6KI mice did not show any significant increase in tail-bleeding times, but were protected from thrombosis after mechanical injury of abdominal aorta. Finally, EMF-1 Fab treatment only slightly increased tail-bleeding time, but prevented stable arterial thrombus formation after injury.
Conclusion(s): Our study presents a new antibody-based candidate compound to target human GPVI in vivo to prevent or limit arterial thrombosis without significantly altering hemostasis.
To cite this abstract in AMA style:Navarro S, Starke A, Brown H, Beck S, Orth V, Heemskerk J, Kuijpers M, Stegner D, Nieswandt B. Characterization of a novel anti-GPVI antibody in a humanized GP6 (hGP6KI) mouse model [abstract]. https://abstracts.isth.org/abstract/characterization-of-a-novel-anti-gpvi-antibody-in-a-humanized-gp6-hgp6ki-mouse-model/. Accessed February 28, 2024.
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