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CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(10): 1683-1692
DOI: 10.1055/s-0042-1749438
Cellular Haemostasis and Platelets

The Platelet Lipidome Is Altered in Patients with COVID-19 and Correlates with Platelet Reactivity

Alex R. Schuurman   *
1   Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, Amsterdam, The Netherlands
,
Valentine Léopold    *
1   Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, Amsterdam, The Netherlands
2   Department of Anesthesia and Intensive Care, Hôpital Lariboisière, INSERM U942S MASCOT, Université de Paris, Paris, France
,
Liza Pereverzeva
1   Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, Amsterdam, The Netherlands
,
Osoul Chouchane
1   Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, Amsterdam, The Netherlands
,
Tom D. Y. Reijnders
1   Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, Amsterdam, The Netherlands
,
Justin de Brabander
1   Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, Amsterdam, The Netherlands
,
Renée A. Douma
3   Department of Internal Medicine, Flevo Hospital, Almere, The Netherlands
,
Michel van Weeghel
4   Departments of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
6   Core Facility Metabolomics, Amsterdam UMC, Amsterdam, The Netherlands
,
Eric Wever
4   Departments of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
6   Core Facility Metabolomics, Amsterdam UMC, Amsterdam, The Netherlands
5   Department of Epidemiology & Data Science, Bioinformatics Laboratory, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
,
Bauke V. Schomaker
4   Departments of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
6   Core Facility Metabolomics, Amsterdam UMC, Amsterdam, The Netherlands
,
Frédéric M. Vaz
4   Departments of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
6   Core Facility Metabolomics, Amsterdam UMC, Amsterdam, The Netherlands
7   Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
,
Willem Joost Wiersinga
1   Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, Amsterdam, The Netherlands
8   Division of Infectious Diseases, Amsterdam University Medical Centers - Location AMC, University of Amsterdam, Amsterdam, The Netherlands
,
Cornelis van't Veer
1   Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, Amsterdam, The Netherlands
,
Tom van der Poll
1   Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, Amsterdam, The Netherlands
8   Division of Infectious Diseases, Amsterdam University Medical Centers - Location AMC, University of Amsterdam, Amsterdam, The Netherlands
› Author Affiliations Funding This work was supported by the Netherlands Organization for Health Research and Development (ZonMW grant #50-53000-98-139 to T.v.d.P.). V.L. is supported by Assistance Publique des Hôpitaux de Paris, Fondation Bettencourt-Schueller; L.P. is supported by JPI-AMR/ZonMW # 547001008; O.C. is supported by Landsteiner Foundation (LSBR # 1901). T.D.Y.R. is supported by NACTAR (# 16447) financed by the Dutch Research Council (NWO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Abstract

Background Activated platelets have been implicated in the proinflammatory and prothrombotic phenotype of coronavirus disease 2019 (COVID-19). While it is increasingly recognized that lipids have important structural and signaling roles in platelets, the lipidomic landscape of platelets during infection has remained unexplored.

Objective To investigate the platelet lipidome of patients hospitalized for COVID-19.

Methods We performed untargeted lipidomics in platelets of 25 patients hospitalized for COVID-19 and 23 noninfectious controls with similar age and sex characteristics, and with comparable comorbidities.

Results Twenty-five percent of the 1,650 annotated lipids were significantly different between the groups. The significantly altered part of the platelet lipidome mostly comprised lipids that were less abundant in patients with COVID-19 (20.4% down, 4.6% up, 75% unchanged). Platelets from COVID-19 patients showed decreased levels of membrane plasmalogens, and a distinct decrease of long-chain, unsaturated triacylglycerols. Conversely, platelets from patients with COVID-19 displayed class-wide higher abundances of bis(monoacylglycero)phosphate and its biosynthetic precursor lysophosphatidylglycerol. Levels of these classes positively correlated with ex vivo platelet reactivity—as measured by P-selectin expression after PAR1 activation—irrespective of disease state.

Conclusion Taken together, this investigation provides the first exploration of the profound impact of infection on the human platelet lipidome, and reveals associations between the lipid composition of platelets and their reactivity. These results warrant further lipidomic research in other infections and disease states involving platelet pathophysiology.

Keywords

platelets - platelet activation - lipidomics - COVID-19 - plasmalogens

Data Sharing Statement

The data that support the findings of this study are available from the corresponding author.


* A.R.S. and V.L. are co-first authors.


Supplementary Material



Publication History

Received: 09 December 2021

Accepted: 30 March 2022

Article published online:
18 July 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References

  • 1 Helms J, Tacquard C, Severac F. et al; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020; 46 (06) 1089-1098
    CrossrefPubMedGoogle Scholar
  • 2 Leentjens J, van Haaps TF, Wessels PF, Schutgens REG, Middeldorp S. COVID-19-associated coagulopathy and antithrombotic agents-lessons after 1 year. Lancet Haematol 2021; 8 (07) e524-e533
    CrossrefPubMedGoogle Scholar
  • 3 Middeldorp S, Coppens M, van Haaps TF. et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1995-2002
    CrossrefPubMedGoogle Scholar
  • 4 Manne BK, Denorme F, Middleton EA. et al. Platelet gene expression and function in patients with COVID-19. Blood 2020; 136 (11) 1317-1329
    CrossrefPubMedGoogle Scholar
  • 5 Zhang S, Liu Y, Wang X. et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J Hematol Oncol 2020; 13 (01) 120
    CrossrefPubMedGoogle Scholar
  • 6 Bury L, Camilloni B, Castronari R. et al. Search for SARS-CoV-2 RNA in platelets from COVID-19 patients. Platelets 2021; 32 (02) 284-287
    CrossrefPubMedGoogle Scholar
  • 7 Zaid Y, Puhm F, Allaeys I. et al. Platelets can associate with SARS-Cov-2 RNA and are hyperactivated in COVID-19. Circ Res 2020; 127: 1404-1418
    CrossrefPubMedGoogle Scholar
  • 8 Léopold V, Pereverzeva L, Schuurman AR. et al. Platelets are hyperactivated but show reduced glycoprotein VI reactivity in COVID-19 patients. Thromb Haemost 2021; 121 (09) 1258-1262
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Nicolai L, Leunig A, Brambs S. et al. Immunothrombotic dysregulation in COVID-19 pneumonia is associated with respiratory failure and coagulopathy. Circulation 2020; 142 (12) 1176-1189
    CrossrefPubMedGoogle Scholar
  • 10 Taus F, Salvagno G, Canè S. et al. Platelets promote thromboinflammation in SARS-CoV-2 pneumonia. Arterioscler Thromb Vasc Biol 2020; 40 (12) 2975-2989
    CrossrefPubMedGoogle Scholar
  • 11 O'Donnell VB, Murphy RC, Watson SP. Platelet lipidomics: modern day perspective on lipid discovery and characterization in platelets. Circ Res 2014; 114 (07) 1185-1203
    CrossrefPubMedGoogle Scholar
  • 12 McMahon HT, Boucrot E. Membrane curvature at a glance. J Cell Sci 2015; 128 (06) 1065-1070
    CrossrefPubMedGoogle Scholar
  • 13 Bodin S, Tronchère H, Payrastre B. Lipid rafts are critical membrane domains in blood platelet activation processes. Biochim Biophys Acta 2003; 1610 (02) 247-257
    CrossrefPubMedGoogle Scholar
  • 14 Peng B, Geue S, Coman C. et al. Identification of key lipids critical for platelet activation by comprehensive analysis of the platelet lipidome. Blood 2018; 132 (05) e1-e12
    CrossrefPubMedGoogle Scholar
  • 15 Harm T, Bild A, Dittrich K. et al. Acute coronary syndrome is associated with a substantial change in the platelet lipidome. Cardiovasc Res DOI: 10.1093/cvr/cvab238.
    CrossrefPubMedGoogle Scholar
  • 16 Haak BW, Brands X, Davids M. et al. Bacterial and viral respiratory tract microbiota and host characteristics in adults with lower respiratory tract infections: a case-control study. Clin Infect Dis 2022; 74 (05) 776-784
    CrossrefPubMedGoogle Scholar
  • 17 Molenaars M, Schomakers BV, Elfrink HL. et al. Metabolomics and lipidomics in Caenorhabditis elegans using a single-sample preparation. Dis Model Mech 2021; 14 (04) dmm047746
    CrossrefPubMedGoogle Scholar
  • 18 Jolliffe IT, Cadima J. Principal component analysis: a review and recent developments. Philos Trans- Royal Soc, Math Phys Eng Sci 2016; 374 (2065): 20150202
    PubMedGoogle Scholar
  • 19 Dean JM, Lodhi IJ. Structural and functional roles of ether lipids. Protein Cell 2018; 9 (02) 196-206
    CrossrefPubMedGoogle Scholar
  • 20 Grzelczyk A, Gendaszewska-Darmach E. Novel bioactive glycerol-based lysophospholipids: new data – new insight into their function. Biochimie 2013; 95 (04) 667-679
    CrossrefPubMedGoogle Scholar
  • 21 Bouvier J, Zemski Berry KA, Hullin-Matsuda F. et al. Selective decrease of bis(monoacylglycero)phosphate content in macrophages by high supplementation with docosahexaenoic acid. J Lipid Res 2009; 50 (02) 243-255
    CrossrefPubMedGoogle Scholar
  • 22 Showalter MR, Berg AL, Nagourney A, Heil H, Carraway III KL, Fiehn O. The emerging and diverse roles of bis(monoacylglycero) phosphate lipids in cellular physiology and disease. Int J Mol Sci 2020; 21 (21) 8067
    CrossrefPubMedGoogle Scholar
  • 23 Slatter DA, Aldrovandi M, O'Connor A. et al. Mapping the human platelet lipidome reveals cytosolic phospholipase A2 as a regulator of mitochondrial bioenergetics during activation. Cell Metab 2016; 23 (05) 930-944
    CrossrefPubMedGoogle Scholar
  • 24 Lepropre S, Kautbally S, Octave M. et al. AMPK-ACC signaling modulates platelet phospholipids and potentiates thrombus formation. Blood 2018; 132 (11) 1180-1192
    CrossrefPubMedGoogle Scholar
  • 25 Wood PL, Locke VA, Herling P. et al. Targeted lipidomics distinguishes patient subgroups in mild cognitive impairment (MCI) and late onset Alzheimer's disease (LOAD). BBA Clin 2015; 5: 25-28
    CrossrefPubMedGoogle Scholar
  • 26 Broniec A, Klosinski R, Pawlak A, Wrona-Krol M, Thompson D, Sarna T. Interactions of plasmalogens and their diacyl analogs with singlet oxygen in selected model systems. Free Radic Biol Med 2011; 50 (07) 892-898
    CrossrefPubMedGoogle Scholar
  • 27 Dalli J, Colas RA, Quintana C. et al. Human sepsis eicosanoid and proresolving lipid mediator temporal profiles: correlations with survival and clinical outcomes. Crit Care Med 2017; 45 (01) 58-68
    CrossrefPubMedGoogle Scholar
  • 28 Ambrosio AL, Di Pietro SM. Storage pool diseases illuminate platelet dense granule biogenesis. Platelets 2017; 28 (02) 138-146
    CrossrefPubMedGoogle Scholar
  • 29 Ravi S, Chacko B, Sawada H. et al. Metabolic plasticity in resting and thrombin activated platelets. PLoS One 2015; 10 (04) e0123597
    CrossrefPubMedGoogle Scholar
  • 30 Han X. Lipidomics for studying metabolism. Nat Rev Endocrinol 2016; 12 (11) 668-679
    CrossrefPubMedGoogle Scholar
  • 31 Chatterjee M, Rath D, Schlotterbeck J. et al. Regulation of oxidized platelet lipidome: implications for coronary artery disease. Eur Heart J 2017; 38 (25) 1993-2005
    CrossrefPubMedGoogle Scholar