In:
Neonatology, S. Karger AG, Vol. 117, No. 1 ( 2020), p. 15-23
Abstract:
〈 b 〉 〈 i 〉 Background: 〈 /i 〉 〈 /b 〉 The mechanisms underlying neonatal platelets hyporesponsiveness are not fully understood. While previous studies have demonstrated developmental impairment of agonist-induced platelet activation, differences in inhibitory signaling pathways have been scarcely investigated. 〈 b 〉 〈 i 〉 Objective: 〈 /i 〉 〈 /b 〉 To compare neonatal and adult platelets with regard to inhibition of platelet reactivity by prostaglandin E1 (PGE 〈 sub 〉 1 〈 /sub 〉 ). 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 Platelet-rich plasma from umbilical cord (CB) or adult blood was incubated with PGE 〈 sub 〉 1 〈 /sub 〉 (0–1 μM). We assessed aggregation in response to adenosine diphosphate (ADP), collagen, and thrombin receptor activating peptide as well as cyclic adenosine 3′5′-monophosphate (cAMP) levels (ELISA). G 〈 sub 〉 αs 〈 /sub 〉 , G 〈 sub 〉 αi2 〈 /sub 〉 , and total- and phospho-protein kinase A (PKA) were evaluated in adult and CB ultrapure and washed platelets, respectively, by immunoblotting. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 Neonatal (vs. adult) platelets display hypersensitivity to inhibition by PGE 〈 sub 〉 1 〈 /sub 〉 of platelet aggregation induced by ADP and collagen (PGE 〈 sub 〉 1 〈 /sub 〉 IC 〈 sub 〉 50 〈 /sub 〉 : 14 and 117 nM for ADP and collagen, respectively, vs. 149 and 491 nM in adults). They also show increased basal and PGE 〈 sub 〉 1 〈 /sub 〉 -induced cAMP levels. Mechanistically, PGE 〈 sub 〉 1 〈 /sub 〉 acts by binding to the prostanoid receptor IP (prostacyclin receptor), which couples to the G 〈 sub 〉 αs 〈 /sub 〉 protein-adenylate cyclase axis and increases intracellular levels of cAMP. cAMP activates PKA, which phosphorylates different target inhibitor proteins. Neonatal platelets showed higher basal and PGE 〈 sub 〉 1 〈 /sub 〉 -induced cAMP levels, higher G 〈 sub 〉 αs 〈 /sub 〉 protein expression, and a trend to increased PKA-dependent protein phosphorylation compared to adult platelets. 〈 b 〉 〈 i 〉 Conclusion: 〈 /i 〉 〈 /b 〉 Neonatal platelets have a functionally increased PGE 〈 sub 〉 1 〈 /sub 〉 -cAMP-PKA axis. This finding supports a downregulation of inhibitory when going from neonate to adult contributing to neonatal platelet hyporesponsiveness.
Type of Medium:
Online Resource
ISSN:
1661-7800
,
1661-7819
Language:
English
Publisher:
S. Karger AG
Publication Date:
2020
detail.hit.zdb_id:
2403535-X
SSG:
12
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