Involvement of GPVI in FVIII-platelet interactions and PS exposure

Introduction Platelets play a pivotal role in clot formation by adopting distinct phenotypes that drive clot formation. While proaggregatory platelets stabilize the fibrin network through adhesion and contraction, sustained activation induced the formation of procoagulant platelets that expose phosphatidylserine (PS), providing a catalytic surface for factor VIII (FVIII) to drive thrombin generation and fibrin polymerization [ 1 ] [ 2 ] [ 3 ]. While FVIII’s role in coagulation is well established, its direct impact on platelet function, particularly via glycoprotein VI (GPVI) mediated signaling [ 4 ], remains poorly understood. This study aimed to elucidate the influence of activated rFVIII (rFVIIIa, simoctocog alfa) on platelet dynamics and to determine the role of GPVI signaling in regulating FVIII–platelet interactions [ 5 ]. Method Platelets were isolated from healthy and patients with hemophilia A (HA) and activated in the presence or absence of rFVIIIa. Phenotypic platelet distributions were quantified over time using flow cytometry. GPVI activity was selectively inhibited by varying concentrations of Glenzocimab (Acticor Biotech) to assess its contribution to FVIIIa-mediated platelet responses. Results Incubation with rFVIIIa enhanced PS exposure per platelet in both healthy donors and HA samples ([ Fig. 1 ]). Partial inhibition of GPVI reduced the relative binding of rFVIIIa to platelets and decreased the frequency the proportion of procoagulant platelets. Interestingly, PS exposure per procoagulant platelet increased with GPVI inhibition ([ Fig. 2 ]), mirroring the effect observed upon rFVIIIa addition. Fig. 1 Impact of rFVIIIa on procoagulant platelet function. rFVIIIa enhances the procoagulant potential of activated platelets from both healthy donors and hemophilia A patients Fig. 2 Involvement of GPVI in rFVIII-platelets interactions and PS exposure. Partial inhibition of GPVI reduced the relative binding of rFVIIIa to platelets, while PS exposure per procoagulant platelet increased with GPVI inhibition. Conclusion rFVIIIa binding promotes a procoagulant platelet phenotype and enhances haemostatic potential. Paradoxically, inhibition of GPVI signaling increases PS exposure per platelet, suggesting that rFVIIIa may modulate or bypass GPVI-dependent pathways. These findings reveal an unrecognized role for FVIII in platelet activation and support the development of refined FVIII-based therapeutic strategies for HA. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany