Abstract Number: PB1762
Meeting: ISTH 2020 Congress
Background: The exocyst is an octameric complex comprising eight distinct protein subunits, exocyst complex components (EXOC) 1-8, and has an established role in regulating the tethering of secretory vesicles to the plasma membrane.
Aims: Proteomic studies demonstrate the expression of the exocyst in platelets, but its relevance to platelet granule secretion and function remains to be determined.
Methods: EXOC3 conditional knockout mice in the megakaryocyte/platelet lineage were generated to assess exocyst function in platelets.
Results: Significant defects in GPVI-induced platelet aggregation, integrin activation, α- (P-selectin and platelet factor 4), dense and lysosomal granule secretion were detected in EXOC3-/- platelets following treatment with collagen related peptide (CRP). With the exception of P-selectin exposure, these defects were completely recovered by maximal concentrations of CRP. Notably, FACS analysis revealed a significant reduction in resting GPVI surface levels in EXOC3-/- platelets. Analysis of the GPVI pathway revealed significant defects in activation of proximal signalling molecules, Syk and LAT, while calcium responses were also reduced, implying an indirect mechanism for the majority of these defects in platelet activation due to a decrease in surface GPVI levels. In contrast to GPVI driven platelet responses, platelet dense granule secretion, integrin activation and changes in surface expression of CD41 were significantly increased in EXOC3-/- platelets in response to PAR4-AP- and thrombin treatment. These elevated integrin activation responses were completely suppressed with a P2Y12 receptor antagonist suggesting enhanced secretion of ADP was a critical mediator of these responses in EXOC3-/- platelets. However, calcium responses to PAR4-AP or thrombin were unaltered suggesting that the respective receptor signalling events were normal in EXOC3-/- platelets. Finally, an in vivo injury model of arterial thrombosis revealed a significantly accelerated rate of thrombosis in EXOC3-/- mice.
Conclusions: Overall, the exocyst complex appears to negatively regulate platelet dense granule secretion which constrains arterial thrombosis.
To cite this abstract in AMA style:
Walsh T, Li Y, Poole A. Loss of the Exocyst Complex Component, EXOC3, Accelerates Arterial Thrombosis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/loss-of-the-exocyst-complex-component-exoc3-accelerates-arterial-thrombosis/. Accessed March 21, 2024.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/loss-of-the-exocyst-complex-component-exoc3-accelerates-arterial-thrombosis/