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CC BY 4.0 · Thromb Haemost 2020; 120(02): 253-261
DOI: 10.1055/s-0039-3400305
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

Hypoxia Modulates Platelet Purinergic Signalling Pathways

Gordon G. Paterson
1   APEX (Altitude Physiology Expeditions), Edinburgh, United Kingdom
2   Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
,
Jason M. Young
1   APEX (Altitude Physiology Expeditions), Edinburgh, United Kingdom
2   Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
,
Joseph A. Willson
3   University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
,
Christopher J. Graham 
1   APEX (Altitude Physiology Expeditions), Edinburgh, United Kingdom
2   Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
,
Rebecca C. Dru
1   APEX (Altitude Physiology Expeditions), Edinburgh, United Kingdom
2   Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
,
Eleanor W. Lee
1   APEX (Altitude Physiology Expeditions), Edinburgh, United Kingdom
2   Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
,
Greig S. Torpey
1   APEX (Altitude Physiology Expeditions), Edinburgh, United Kingdom
2   Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
,
Sarah R. Walmsley
3   University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
,
Melissa V. Chan
4   Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
,
Timothy D. Warner 
4   Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
,
John Kenneth Baillie
1   APEX (Altitude Physiology Expeditions), Edinburgh, United Kingdom
5   Division of Genetics and Genomics, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
6   Department of Anaesthesia, Critical Care and Pain Medicine, Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, United Kingdom
,
Alfred Arthur Roger Thompson 
1   APEX (Altitude Physiology Expeditions), Edinburgh, United Kingdom
7   Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
› Author Affiliations Funding This study received funding from the Wilderness Medical Society Charles S. Houston Grant, supported by the Academy of Wilderness Medicine. It also received funding from British Heart Foundation, (Grant/Award Number: ‘FS/18/13/3328’,‘PG/15/47/31591’), Wilderness Medicine Society (Grant/Award Number: ‘Charles S. Houston grant’) and Wellcome Trust, (Grant/Award Number: ‘103258/Z/13/Z,A’).
Further Information

Publication History

24 April 2019

29 September 2019

Publication Date:
13 December 2019 (online)

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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 4,700 m, 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-6 amide.

Conclusion 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.

Keywords

hypoxia - platelet physiology - anti-platelet agents - ADP receptors - high altitude

Authors' Contributions

G.G.P., M.V.C., T.D.W. and A.A.R.T. conceived the study and designed the experiments; G.G.P., J.M.Y., J.A.W., C.J.G., R.C.D., E.W.L., G.S.T., M.V.C. and S.R.W. performed experiments and assisted with logistics; G.G.P., M.V.C., T.D.W., J.K.B. and A.A.R.T. analysed and interpreted the data; G.G.P. and A.A.R.T. drafted the manuscript with contributions from all authors.


Supplementary Material

 

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