Abstract Number: PB1844
Meeting: ISTH 2020 Congress
Background: The ubiquitously expressed small GTPases RalA and RalB are involved in cell proliferation and tumour metastasis. We reported that RalA/B conditional double knockout (RalAB DKO) in mouse platelets resulted in near complete defect in P-selectin externalisation on platelets upon activation, with no other significant secretion defect.
Aims: To address whether platelet-expressed Ral GTPases, through regulation of platelet surface expression of P selectin, control venous thrombosis in vivo in mice.
Methods: We used an in vivo inferior vena cava ligation model of venous thrombosis in mice, and analyses of neutrophil NET formation.
Results: RalAB DKO led to ablation of venous thrombosis in mice (thrombus weight in DKO: 0.4±0.2 mg vs 15.35±3.20 mg in Wt control, n=8 in DKO and n=10 in WT, p< 0.001). Immunohistochemical staining of thrombus sections demonstrated that in DKO mice there was no NET formation, and less neutrophil infiltration than in WT mice, where strong NETosis was detected. Platelet-specific conditional knockout of SNAP23 however did form (diminished) venous thrombi, even though absence of SNAP23 resulted in complete ablation of secretion. Histological examination of SNAP23-/- thrombi showed similar structures to WT, although diminished in size, and NETosis formation was normal, suggesting that secretion defects, particularly P-selectin externalisation, are only partially responsible for the ablated venous thrombosis in RalAB DKO mice. In addition to the defect in NETosis, we also found that P-selectin and HMGB1 did not colocalize in thrombus sections of RalAB DKO as they did in WT control mice.
Conclusions: Platelets play a critical role in venous thrombosis in a ligation model in mouse. Platelet-derived P-selectin and HMGB1 recruit and activate neutrophils and NET formation, coordinated by platelet-expressed RalA and RalB. As Rals are targets for drug development, future work is required to determine whether platelet Rals represent good novel targets in venous thrombosis management.
To cite this abstract in AMA style:Li Y, Williams C, Amulic B, Poole A. Critical Role for Platelet Ral GTPases in the Regulation of Venous Thrombosis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/critical-role-for-platelet-ral-gtpases-in-the-regulation-of-venous-thrombosis/. Accessed May 6, 2021.
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