Abstract Number: OC 41.2
Meeting: ISTH 2022 Congress
Theme: Platelets and Megakaryocytes » Platelet Function and Interactions
Background: The VWF-GPIbα axis is not only important for platelet capture at sites of vessel injury but also in thromboinflammatory conditions, such as venous thrombosis. We recently demonstrated that human VWF-bound platelets are ‘primed’ under flow, recruiting neutrophils and inducing NETosis via activated αIIbβ3. We also identified SLC44A2 as the neutrophil counter-receptor for activated αIIbβ3. The SLC44A2 locus has been linked to venous thromboembolism risk in several genome-wide association studies. To analyse the role of VWF-priming in vivo, we generated a novel GpIbαδsig/δsig mouse with a 24 amino acid deletion of the GPIbα intracellular tail and showed that these mice exhibited normal haemostasis but impaired VWF-GPIbα signalling.
Aims: To evaluate the (patho)physiological importance of VWF/flow-dependent signalling through GPIbα.
Methods: GpIbαδsig/δsig mice have been previously generated. VWF-mediated platelet priming was assessed on VWF surfaces under static and flow conditions in a microfluidic platform.
Results: As previously shown, although VWF-mediated platelet capture under flow was unchanged in GpIbαδsig/δsig platelets compared to GpIbα+/+ platelets, they exhibited a significant decrease (50%) in αIIbβ3 activation. Defect in VWF-GPIbα-mediated signalling in GpIbαδsig/δsig platelets was further characterized by diminished calcium spike responses when stimulated with botrocetin. Consistent with a diminished expression of activated αIIbβ3, GpIbαδsig/δsig platelets exhibited a significantly reduced ability to recruit neutrophils compared to GpIbα+/+ platelets. Similar to VWF-primed human platelets, GpIbα+/+ primed platelets recruited neutrophils under low shear and these interactions could be inhibited by αIIbβ3 or SLC44A2 blockade, but not by β2-integrin inhibition. Neutrophil recruitment to VWF-primed platelets was also significantly increased in the absence of plasma.
Conclusion(s): Our data suggest an important role for the GPIbα intracellular tail in transducing signals downstream of the VWF A1- GPIbα interaction and to mediate subsequent platelet-neutrophil interactions. Additional thrombosis models and platelet signalling assays are underway to fully appreciate the pathophysiological role of the GPIbα A1 signalling.
To cite this abstract in AMA style:
Constantinescu-Bercu A, Lee J, Petri A, Mangin P, Vanhoorelbeke K, Crawley J, Salles-Crawley I. The GPIbα intracellular tail is important for VWF-mediated platelet signaling events that promote platelet/neutrophil interactions under flow [abstract]. https://abstracts.isth.org/abstract/the-gpib%ce%b1-intracellular-tail-is-important-for-vwf-mediated-platelet-signaling-events-that-promote-platelet-neutrophil-interactions-under-flow/. Accessed September 22, 2023.« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/the-gpib%ce%b1-intracellular-tail-is-important-for-vwf-mediated-platelet-signaling-events-that-promote-platelet-neutrophil-interactions-under-flow/