Platelets of COVID-19 patients display mitochondrial dysfunction, oxidative stress, and energy metabolism failure compatible with cell death
Valentine Léopold, Osoul Chouchane, Joe M. Butler, Alex R. Schuurman, Erik H.A. Michels, Justin de Brabander, Bauke V. Schomakers, Michel van Weeghel, Daisy I. Picavet-Havik, Anita E. Grootemaat, Renée A. Douma, Tom D. Y. Reijnders, Augustijn M. Klarenbeek, Brent Appelman, Michiel A. van Agtmael, Anna Geke Algera, Brent Appelman, Floor van Baarle, Martijn Beudel, Harm Jan Bogaard, Marije K. Bomers, Peter I. Bonta, Lieuwe D. J. Bos, Michela Botta, Justin de Brabander, Godelieve de Bree, Sanne de Bruin, Marianna Bugiani, Esther Bulle, David T. P. Buis, Osoul Chouchane, Alex Clohert, Mirjam Dijkstra, Dave A. Dongelmans, Romein W. G. Dujardin, Paul Elbers, Lucas M. Fleuren, Suzanne E. Geerlings, Theo Geijtenbeek, Armand R. J. Girbes, Bram Goorhuis, Martin P. Grobusch, Laura A. Hagens, Jörg Hamann, Vanessa Harris, Robert Hemke, Sabine Hermans, Leo Heunks, Markus W. Hollmann, Janneke Horn, Joppe W. Hovius, Menno D. de Jong, Rutger Koning, Endry H. T. Lim, Niels van Mourik, Jeaninne Nellen, Esther J. Nossent, Sabine E. Olie, Frederique Paulus, Edgar Peters, Dan Piña‐Fuentes, Tom van der Poll, Bennedikt Preckel, Jorinde Raasveld, Tom D. Y. Reijnders, Maurits C. F. J. de Rotte, Michiel Schinkel, Marcus J. Schultz, Femke A. P. Schrauwen, Alex R. Schuurman, Jaap Schuurmans, Kim Sigaloff, Marleen A. Slim, Patrick Smeele, Marry R. Smit, Cornelis Stijnis, Willemke Stilma, Charlotte E. Teunissen, Patrick Thoral, Anissa M. Tsonas, Pieter R. Tuinman, Marc van der Valk, Denise P. Veelo, Carolien Volleman, Heder de Vries, Lonneke A. van Vught, Michèle van Vugt, Dorien Wouters, Aeilko H. Zwinderman, Matthijs C. Brouwer, W. Joost Wiersinga, Alexander P. J. Vlaar, Diederik van de Beek, W. Joost Wiersinga, Nicole N. van der Wel, Jeroen den Dunnen, Riekelt H. Houtkooper, Cornelis van’t Veer, Tom van der Poll
Abstract
BackgroundAlterations in platelet function have been implicated in the pathophysiology of COVID-19 since the beginning of the pandemic. While early reports linked hyperactivated platelets to thromboembolic events in COVID-19, subsequent investigations demonstrated hyporeactive platelets with a procoagulant phenotype. Mitochondria are important for energy metabolism and function of platelets.ObjectiveHere we sought to map the energy metabolism of platelets in a cohort of non-critically ill COVID-19 patients and assess platelet mitochondrial function, activation status and responsiveness to external stimuli.ResultsPlatelets from COVID-19 patients showed increased phosphatidylserine externalization indicating a procoagulant phenotype and hyporeactivity to ex-vivo stimuli, associated with profound mitochondrial dysfunction characterized by mitochondrial depolarization, lower mitochondrial DNA-encoded transcript levels, an altered mitochondrial morphology consistent with increased mitochondrial fission, and increased pyruvate/lactate ratios in platelet supernatants. Metabolic profiling by untargeted metabolomics revealed NADH, NAD+ and ATP amongst the top decreased metabolites in patients’ platelets, suggestive of energy metabolism failure. Consistently, platelet fluxomics analyses showed a strongly reduced utilization of 13C-glucose in all major energy pathways together with a rerouting of glucose to de novo generation of purine metabolites. Patients’ platelets further showed evidence of oxidative stress, together with increased glutathione oxidation and synthesis. Addition of plasma from COVID-19 patients to normal platelets partially reproduced the phenotype of patients’ platelets and disclosed a temporal relationship between mitochondrial decay and (subsequent) phosphatidylserine exposure and hyporeactivity.ConclusionThese data link energy metabolism failure in platelets from COVID-19 patients with a prothrombotic platelet phenotype with features matching cell death.