Hypoxia modulates platelet purinergic signalling pathways

Gordon G Paterson, Jason M. Young, Joseph A Willson, Christopher J. Graham, Rebecca C. Dru, Eleanor W Lee, Greig S. Torpey, Sarah Walmsley, Melissa V. Chan, Timothy D. Warner, Kenneth Baillie, A.A. Roger Thompson

Research output: Contribution to journalArticlepeer-review

Abstract

Abstract
Background: Hypoxia resulting from ascent to high-altitude or pathological states at sea-level is known to increase platelet reactivity. Previous work from our group has suggested that this may be adenosine diphosphate (ADP)-specific. Given the clinical importance of drugs targeting ADP-pathways, research into the impact of hypoxia on platelet ADP pathways is highly important.
Methods: Optimul aggregometry was performed on plasma from 29 lowland residents ascending to 4,700m, allowing systematic assessment of platelet reactivity in response to several platelet agonists. Aggregometry was also performed in response to ADP in the presence of inhibitors of the two main ADP receptors, P2Y1 and P2Y12 (MRS2500 and cangrelor respectively). Phosphorylation of vasodilator-stimulated phosphoprotein (VASP), a key determinant of platelet aggregation, was analysed using the VASPFix assay.
Results: Hypobaric hypoxia significantly reduced the ability of a fixed-concentration of cangrelor to inhibit ADP-induced aggregation and increased basal VASP-phosphorylation.
However, in the absence of P2Y receptor inhibitors, we did not find evidence of increased platelet sensitivity to any of the agonists tested and found reduced sensitivity to thrombin receptor-activating peptide (TRAP)-6 amide.
Conclusions: Our results provide evidence of increased P2Y1 receptor activity at high-altitude and suggest down regulation of the P2Y12 pathway through increased VASP phosphorylation.
These changes in ADP pathway activity are of potential therapeutic significance to high-altitude sojourners and hypoxic sea-level patients prescribed platelet inhibitors and warrant further investigation
Original languageEnglish
JournalThrombosis and Haemostasis
Early online date13 Dec 2019
DOIs
Publication statusE-pub ahead of print - 13 Dec 2019

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