Abstract Number: OC 52.1
Meeting: ISTH 2021 Congress
Background: The role of the VWF A1 domain interaction with platelet GPIbα has classically been limited to platelet capture at sites of vessel injury. We recently demonstrated that human VWF-bound platelets are ‘primed’ under flow, recruiting neutrophils and inducing NETosis via activated αIIbβ3. We also identified the receptor on the surface of neutrophils as SLC44A2, a 10x membrane spanning protein for which the locus has been linked to venous thromboembolism risk in several genome wide association studies.
Aims: To evaluate the (patho)physiological importance of VWF/flow-dependent signaling through GPIbα.
Methods: GpIbαΔsig/Δsig mice were generated via the CRISPR-Cas9 technology, by deleting the last 24 amino acids from the intracellular tail of GPIbα. GpIbαΔsig/Δsig mice were subjected to tail bleeding assays and laser-induced thrombosis models. VWF-GPIbα platelet function was assessed on VWF surfaces under static and flow conditions in a microfluidic platform.
Results: GpIbαΔsig/Δsig mice exhibited normal tail-bleeding responses, and unchanged platelet/fibrin accumulation in the laser-induced thrombosis model. GpIbαΔsig/Δsig platelets bound normally to VWF under flow but had a reduced ability to form filopodia on VWF, in the presence of Botrocetin and GR144053, confirming that VWF-dependent signaling is impaired in these mice. GpIbα+/+ primed platelets recruited neutrophils under low shear, in a manner that could be inhibited by αIIbβ3 or SLC44A2 blockade, but not by β2-integrin inhibition. Neutrophil recruitment to VWF-primed platelets was significantly increased in the absence of plasma. GpIbαΔsig/Δsig platelets exhibited a significantly reduced ability to recruit neutrophils compared to GpIbα+/+ platelets, confirming the importance of the intracellular tail of GPIbα in mediating interactions between VWF-primed platelets and neutrophils under flow.
Conclusions: Our data suggest an important role for the GPIbα intracellular tail to transduce signals downstream of the VWF A1-GPIbα interaction and mediate subsequent platelet-neutrophil interactions. Additional thrombosis models and platelet signaling assays are underway to fully appreciate the pathophysiological role of the GPIbα-A1 signaling.
To cite this abstract in AMA style:Adela Constantinescu-Bercu A, A Wang Y, J Woollard K, Mangin P, Vanhoorelbeke K, Crawley JT, I Salles-Crawley I. The Importance of the GPIbα Intracellular Tail in VWF-mediated Platelet Signaling Events and Platelet/Neutrophil Interactions [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/the-importance-of-the-gpib%ce%b1-intracellular-tail-in-vwf-mediated-platelet-signaling-events-and-platelet-neutrophil-interactions/. Accessed November 28, 2023.
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