Abstract Number: PB0885
Meeting: ISTH 2022 Congress
Background: Pregnancy-specific glycoproteins (PSGs) are immunoglobulin superfamily members secreted by the syncytiotrophoblast layer of the placenta into the maternal circulation during pregnancy. PSGs exert immunoregulatory functions by triggering anti-inflammatory responses in circulating leukocytes. However, the effect of PSGs on platelet functional responses remains largely unknown.
Aims: To determine whether PSGs regulate human platelet function ex vivo.
Methods: Recombinant PSGs were produced in HEK293 and CHO cells. Platelets were isolated from healthy volunteers and incubated with PSGs in the presence or absence of classical platelet agonists such as collagen-related peptide (CRP-XL). Platelet function was analyzed by Western Blot, static adhesion assays, flow cytometry, aggregation, and secretion assays.
Results: PSG1, PSG4, PSG7 and PSG9 did not induce platelet granule secretion or integrin activation ex vivo. However, PSG9 concentration-dependently potentiated granule secretion and integrin activation induced by suboptimal concentrations of the glycoprotein (GP)VI agonist CRP-XL. PSG9 also potentiated platelet aggregation following stimulation with CRP-XL. Conversely, incubation with PSG9 completely abrogated platelet function induced by the Toll-like receptor (TLR)2 ligands Pam2CSK4 and Pam3CSK4 and had no effects on thrombin-induced responses. Studies using Western Blot demonstrated that PSG9 primed CRP-XL-mediated tyrosine phosphorylation as well as phosphorylation of substrates downstream of the protein kinase C (PKC) and protein kinase B (Akt) pathways. Mechanistic studies with select pharmacologic inhibitors showed that PSG9-mediated platelet priming is dependent on Akt and on nuclear factor (NF)-κB and Bruton’s-tyrosine kinase (BTK) pathways. Finally, stimulation of whole blood with PSG9 also potentiated granule secretion and integrin activation upon incubation with CRP-XL, but not with thrombin receptor activator peptide 6 (TRAP6).
Conclusion(s): Our results suggest that PSG9 modulates platelet function in an agonist-specific manner and therefore it may play an important role in regulating hemostasis during pregnancy.
To cite this abstract in AMA style:Parra-Izquierdo I, Melrose A, Pang J, Lo J, Hinds M, Maloyan A, Dveskler G, McCarty O, Aslan J. Pregnancy-specific glycoprotein 9 potentiates platelet function mediated by immunoreceptor tyrosine-based activation motif pathways [abstract]. https://abstracts.isth.org/abstract/pregnancy-specific-glycoprotein-9-potentiates-platelet-function-mediated-by-immunoreceptor-tyrosine-based-activation-motif-pathways/. Accessed September 29, 2023.
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